Bewertung der Expertengruppe Off-Label Fachbereich

Transcription

30.04.2013
Bewertung der Expertengruppe Off-Label Fachbereich Onkologie
nach § 35 c Abs. 1 SGB V
zur Anwendung von
„Liposomalem Doxorubicin bei kutanen T-Zell-Lymphomen
(nach Versagen von PUVA und INF α, Chlorambucil)“
1. a. Wirkstoff (INN)
Doxorubicin-Hydrochlorid, das in Liposomen eingeschlossen und an deren Oberfläche
Methoxypolyethylenglykol (MPEG) gebunden ist (Caelyx® 2mg/ml)
Liposomenverkapselter Doxorubicin-Citrat-Komplex, entsprechend 50mg Doxorubicinhydrochlorid (HCl) (Myocet®)
b. Im Geltungsbereich des AMG/zentral zugelassene Fertigarzneimittel
(gemäß Recherche in der Datenbank AMIS aktualisiert am 03.05.2013)
Caelyx® 2mg/ml
Janssen-Cilag International NV, Belgien
Parallelimporte: Haemato Pharm AG,
Medicopharm AG, Aaston Healthcare
GmbH, Inopha GmbH, Pharma Westen
GmbH, Eurim-Pharm Arzneimittel GmbH,
CC-Pharma GmbH, EMRA-MED Arzneimittel GmbH, Maxi Pharma GmbH, MZGPharma Vertriebs-GmbH, kohlpharma
GmbH, MTK-Pharma-Vertriebs-GmbH,
Pharma Gerke Arzneimittelvertriebs
GmbH
Myocet®
TEVA Pharma B. V., Niederlande
Parallelimporte: Pharma Gerke Arzneimittelvertriebs GmbH, kohlpharma GmbH,
EMRA-MED Arzneimittel GmbH, CCPharma GmbH, Haemato Pharm AG, Inopha GmbH
2.
Zugelassene Indikationen gemäß Zentralisiertem Zulassungsverfahren
(http://www.ema.europa.eu/ema/)
Für Caelyx®
Caelyx ist indiziert:
– Als Monotherapie bei Patientinnen mit metastasierendem Mammakarzinom mit
erhöhtem kardialen Risiko.
– Zur Behandlung von Patientinnen mit fortgeschrittenem Ovarialkarzinom nach
Versagen einer platinhaltigen First-Line-Chemotherapie.
Seite: 1
– In Kombination mit Bortezomib zur Behandlung des progressiven multiplen
Myeloms bei Patienten, die zumindest eine vorangegangene Therapie erhalten
haben, und die sich bereits einer Knochenmarkstransplantation unterzogen
haben bzw. dafür ungeeignet sind.
– Zur Behandlung von Patienten mit AIDS assoziiertem Kaposi-Sarkom (KS) mit
niedrigen CD4-Werten (<200 CD4-Lymphozyten/mm3) und umfangreichem mukokutanem und viszeralem Befall.
Die Anwendung von Caelyx kann entweder als primäre systemische Chemotherapie
erfolgen oder als sekundäre Chemotherapie bei AIDS-KS-Patienten, bei denen die
Krankheit fortschreitet oder eine vorherige, systemische Kombinationschemotherapie mit
mindestens zwei der folgenden Wirkstoffe – ein Vinca-Alkaloid, Bleomycin und StandardDoxorubicin (oder sonstige Anthrazykline) – nicht toleriert wurde.
(Fachinformation für Caelyx® 2mg/ml Konzentrat zur Herstellung einer Infusionslösung, JanssenCilag International NV, Belgien, Stand: Juni 2012)
Für Myocet®
Myocet in Kombination mit Cyclophosphamid ist für die First-line-Behandlung von
metastasiertem Brustkrebs bei erwachsenen Frauen angezeigt.
(Fachinformation Für Myocet® 50 mg Pulver, Dispersion und Lösungsmittel für ein Konzentrat zur
Herstellung einer Infusionsdispersion, TEVA Pharma B.V., Niederlande, Stand: Januar 2013)
3. Epidemiologische Daten zur beurteilten Indikation
Nach den Lymphomen des Gastrointestinaltraktes sind die kutanen Lymphome die zweithäufigste Gruppe der primär extranodalen Non-Hodgkin Lymphome.
Die Inzidenz der kutanen T-Zell Lymphome wird auf 1 Neuerkrankung pro Jahr und 100 000
Einwohner geschätzt. Dabei sind ca. 2/3 der Fälle T-Zell-Lymphome und ca. 1/3 B-ZellLymphome. (Li JY, 2012)
Die Mycosis fungoides (MF) und das Sézary-Syndrom (SS) als häufigste Vertreter kutaner TZell-Lymphome zeigen anhand von Daten aus Krebsregistern in den USA eine Inzidenz von
0,3 Fällen pro Jahr und 100 000 Einwohner. Insgesamt bestehen eine Häufung der Erkrankung mit zunehmendem Alter sowie eine Geschlechterverteilung zwischen Mann und Frau
von 2:1.
Die Inzidenz der kutanen Lymphome scheint in den letzten Jahren zuzunehmen, die Ursache
hierfür ist unklar.
4. Zugelassene Wirkstoffe für die beurteilte Indikation
s. Anlage 0
5. Weitere Behandlungsstrategien/Outcome
Eine Standardtherapie in der Behandlung rezidivierter primär kutaner T-Zell-Lymphome ist
momentan nicht definitiv festgelegt. Dies spiegelt sich auch in den Leitlinien verschiedener
Fachgesellschaften (Willemze und Dreyling, Whittacker et al, Trautinger et al) und TherapieReviews (Prince et al) wider. Als arzneimittelrechtlich zugelassene Therapieoption im Rezidiv
stehen u. a. Interferon alpha-2a, 8-Methoxypsoralen und Bexaroten zur Verfügung.
Seite: 2
Zusatzinformationen:
Denileukin Diftitox, auch als DAB(389)IL-2 bezeichnet, ist der internationale Freiname für ein
in den Vereinigten Staaten zugelassenes Immuntoxin zur Behandlung von Patienten mit therapierefraktärem kutanem T-Zell-Lymphom.
Vorinostat der Firma Merck Sharp & Dohme Limited, United Kingdom ist ein HistonDeacetylase-Hemmer, der innerhalb der EU eine „Orphan Drug Designation“ für „die Behandlung multipler Myelome“ (EU/3/11/854) besitzt. Ein Zulassungsantrag bei der europäischen Arzneimittelbehörde EMA für die Behandlung kutaner T-Zell-Lymphome wurde aufgrund einer negativen Nutzen-Risiko-Bewertung durch das CHMP vom pharmazeutischen
Unternehmen zurückgezogen (EMEA/CHMP/559066/2008).
In den USA ist der Wirkstoff unter dem Namen ZolinzaTM für die Behandlung kutaner T-Zell
Lymphome zugelassen ∗
Pralatrexat (Folotyn) der Firma Allos Therapeutics ist ein Antimetabolit, der die Aktivität des
Enzyms Dihydrofolat-Reductase blockiert. Dieses Enzym ist notwendig für die Replikation
der Tumorzellen. Auch bei Pralatrexat hat die EMA aufgrund einer negativen Nutzen-RisikoBewertung durch das CHMP keine Zulassungsempfehlung ausgesprochen.
(EMA/CHMP/255106/2012)
Romidepsin ist ebenfalls ein Histon-Deactylase-Hemmer, dessen Zulassung für die Behandlung von T-Zell-Lymphomen vom CHMP der EMA ebenfalls nicht empfohlen wurde, da ein
Einfluss auf die Überlebenszeit im Vergleich zu Standardbehandlungen nicht gesichert wurde und ein Zertifikat über die Einhaltung der GMP-Bestimmungen bei der Produktion nicht
vorgelegt wurde (19 July 2012, EMA/475603/2012, EMA/H/C/002122)
Das zu prüfende Medikament (liposomales Doxorubicin) ist eine besondere Präparation des
Wirkstoffs Doxorubicin, welcher in konventioneller Präparation ebenfalls als zugelassenes
Arzneimittel verfügbar ist. Um den Stellenwert von liposomalem Doxorubicin bewerten zu
können, sind Daten klinischer Studien zum Einsatz von konventionellem Doxorubicin ebenfalls relevant. Dazu wurde eine orientierende Literaturrecherche in Medline durchgeführt.
Konventionelles Doxorubicin als Monotherapie zeigte in einer sehr kleinen Beobachtungsstudie bei Mykosis fungoides Anti-Tumor-Wirksamkeit. 1977 berichteten Levi et al über 13
Patienten, die wegen einer weit fortgeschrittenen, überwiegend vorbehandelten (n=11) Mykosis fungoides mit Doxorubicin 60 mg/m2 alle 3 Wochen behandelt worden waren (Levi JA
et al., 1977). 3 Patienten erreichten eine auch histologisch gesicherte komplette Remission
und 5 weitere Patienten eine partielle Remission.
In den Folgejahren wurde Doxorubicin bei Patienten mit fortgeschrittenen T-Zell-Lymphomen
– genau wie bei Patienten mit B-NHL - überwiegend im Rahmen des CHOP-Protokolls oder
ähnlicher Kombinationen eingesetzt. Meist wurden Patienten mit T-NHL in die gleichen Protokolle wie Patienten mit B-NHL eingeschlossen. Die Auswertung der Ergebnisse der Patienten mit T-NHL ergab, dass es Untergruppen mit sehr unterschiedlicher Prognose gibt. Eine
günstige Prognose unter CHOP-Therapie haben Patienten mit ALK-positiven anaplastischen
großzelligen NHL (ALCL), die vergleichbar günstig ist wie die von Patienten mit großzelligen
B-NHL, während die der anderen Unterformen (ALK-negative ALCL, unspezifizierte periphere T-NHL (PTCLU) und angioimmunoblastische T-NHL (AILT) ungünstiger ist. Bei Patienten
mit erhöhter LDH scheint die zusätzliche Gabe von Etoposid (CHOEP) zur Verbesserung der
Langzeitüberlebensraten zu führen (Schmitz N et al., 2010). CHOP oder CHOEP werden
somit – genau wie bei B-NHL – regelhaft in der Behandlung von Patienten mit fortgeschrittenen T-NHL eingesetzt. Dies gilt auch für Patienten mit primär kutanen T-NHL bei denen die
∗
“ZOLINZA is a histone deacetylase (HDAC) inhibitor indicated for: Treatment of cutaneous manifestations in
patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or
following two systemic therapies. “(US-amerikanissche Fachinformation für Zolinza, Merck & Ci Inc, Stand
11/2011)
Seite: 3
lokalen Therapieoptionen wie Bestrahlung, PUVA oder topische Anwendung von Medikamenten ausgeschöpft sind.
6. Sonstige Angaben
Unter http://clinicaltrials.gov wurde mit dem Suchalgorithmus “cutaneous t-cell lymphoma
and liposomal doxorubicin” 1 relevante Studie gefunden:
Liposomal Doxorubicin in Treating Patients With Stage IIB, Stage IVA, or Stage IVB Recurrent or Refractory Mycosis Fungoides
Study NCT00074087, EORTC-21012, EUDRACT-2004-001746-32
Investigator: Dummer, R.; University of ZuerichNach Abschluss des Gutachtens durch den
externen Gutachter wurde das Ergebnis dieser Studie als Epub veröffentlicht (Dummer R et
al., J Clin Oncol 2012 Oct 8). Eingeschlossen wurden 49 auswertbare Patienten mit refraktärer oder rezidivierter Mykosis fungoides Stadium IIB, IVA oder IVB nach mindestens 2 systemischen Vorbehandlungen. Im Median erhielten die Patienten 5 Zyklen Chemotherapie mit
pegyliertem, liposomalen Doxorubicin 20 mg/m2. 3 Patienten erreichten eine CR und 17 Patienten eine PR (Ansprechrate 41 %). Die mediane Zeit bis zum Progress betrug 7,4 Monate
und die mediane Remissionsdauer 6 Monate. Bei einer medianen Nachbeobachtung von
10,6 Monaten verstarben 14 Patienten, davon 7 am Tumorprogress. Es gab nur extrahämatologische Toxizität > Grad 3. Ein Patient verstarb an einem Myokardinfarkt innerhalb von 8
Wochen nach Therapieeinleitung und wurde als Frühtodesfall bewertet.
7. Literatur-Recherche
Die Recherche wurde in folgenden Datenbanken durchgeführt:
• Cochrane Datenbank (The Cochrane library; http://www.thecochranelibrary.com)
Datum: 20.02.2012
• PubMed; Literatursuche mit PubMed Advanced Search Builder
Datum: 20.02.2012; Wiederholung 27.02.2012 und 28.02.2012
Die Wiederholung der Recherche am 24.01.2013 lieferte keine neuen Treffer.
Die Suche in der Cochrane Datenbank (The Cochrane library;
http://www.thecochranelibrary.com) ergab 0 Treffer.
(Suchvorgang: “liposomal doxorubicin in Keywords and cutaneous t-cell lymphoma in
Keywords”)
Die Suche in PubMed ergab folgende Resultate:
Tab. 1: Darstellung der Suchstrategie und Suchwörter in PubMed:
insges. erfolgten 6 Suchvorgänge mit unterschiedlichen Suchbegriffen in PubMed mittels
PubMed Advanced Search Builder.
Seite: 4
Suchvorgang #5 (s. Anlage 1d):
Die Suche # 5 (((sezary syndrome[MeSH Terms]) AND mycosis fungoides[MeSH Terms])
AND liposomal doxorubicin) AND pegylated liposomal doxorubicin ergibt 1 Treffer.
Ein Abgleich der gefundenen ‚Publikation mit den Publikationen der Suche #2 und #4 ergab
eine Übereinstimmung, die Suche #5 ergibt somit keine neuen Ergebnisse.
Suchvorgang #6:
Die Suche #6 “(cutaneous t-cell lymphoma[MeSH Terms]) AND liposomal doxorubicin[Pharmacological Action]” ergibt 0 Treffer.
Auswahlkriterien der gefundenen Studien:
Einschlußkriterien:
Indikation: primär kutane T-Zell-Lymphome
Prüfintervention: Therapie mit liposomalem pegyliertem Doxorubicin
Fallserie mit n > 5
Phase II/Phase-III-Studien
Vollpublikation
Ausschlußkriterien:
Indikation: nicht primär kutane T-Zell-Lymphome
Prüfintervention: nicht liposomales bzw. nicht liposomales pegyliertes Doxorubicin
narrativer Review
Phase-I-Studien
Einzelfallkasuistik (n= 1)
8. Darstellung des Ergebnisses der Recherche
Tab. 2: Darstellung der Suchergebnisse aus Suchvorgang #2, die die Auswahlkriterien nicht
erfüllen:
Erstautor
Titel
Quelle
Ausschlußgrund
Bird BR
Uncommon hematologic
malignancies. Case 3.
Parotid swelling during
treatment for transformed
mycosis fungoides.
J Clin Oncol. 2003 Nov
15;21(22):4251-2.
2, 4
Levi JA
Adriamycin therapy in
advanced mycosis fungoides.
Cancer
May;39(5):1967-70.1977
3, 4
Lybaek D
Pegylated liposomal doxorubicin in the treatment
of mycosis fungoides
Acta Derm Venereol.
2006;86(6):545-7.
1
Seite: 6
Prince HM,
Pegylated liposomal doxorubicin in the treatment
of cutaneous T-cell lymphoma.
J Am Acad Dermatol.
2001 Jan;44(1):149-50.
1
Sterry W
Clinical research in cutaneous T-cell lymphoma
moving forward.
Arch Dermatol. 2008
Jun;144(6):786-7.
1
Tsatalas C
Long-term remission of
recalcitrant tumour-stage
mycosis fungoides following chemotherapy with
pegylated liposomal doxorubicin.
J Eur Acad Dermatol
Venereol. 2003
Jan;17(1):80-2.
4
Ausschlußgrund:
1: narrativer Review
2: andere Indikation
3: keine Intervention mit liposomalem oder liposomalem pegyliertem Adriamycin
4: Kasuistik mit n = 1
Tab. 3: Darstellung der Suchergebnisse aus Suchvorgang #4, die die Auswahlkriterien nicht
erfüllen:
Erstautor
Titel
Quelle
Ausschlußgrund
Apisarnthanarax N
Treatment of cutaneous
T cell lymphoma: current
status and future directions.
Am J Clin Dermatol.
2002; 3(3):193-215.
1
Dummer R.
Future perspectives in
the treatment of cutaneous T-cell lymphoma
(CTCL).
Semin Oncol. 2006
Feb;33(1 Suppl 3):S336.
1
Horwitz SM
Novel therapies for cutaneous T-cell lymphomas.
Lymphoma Service,
Memorial SloanKettering Cancer Center,
New York, NY 10021,
1
Huber MA
Management of refractory early-stage cutaneous
T-cell lymphoma
Am J Clin Dermatol.
2006;7(3):155-69.
1
Lybaek D
Pegylated liposomal
doxorubicin in the treatment of mycosis fungoides
Acta Derm Venereol.
2006;86(6):545-7.
1
Prince HM
Pegylated liposomal
doxorubicin in the treatment of cutaneous T-cell
lymphoma.
J Am Acad Dermatol.
2001 Jan;44(1):149-50.
1
Quéreux G
Sudden onset of an aggressive cutaneous lymphoma in a young patient
with
psoriasis: role of immunosuppressants
Acta Derm Venereol.
2010 Nov;90(6):616-20.
3, 4
Seite: 7
Sterry W
Clinical research in cutaneous T-cell lymphoma
moving forward.
Arch Dermatol. 2008
Jun;144(6):786-7.
1
Tsatalas C
Long-term remission of
recalcitrant tumour-stage
mycosis fungoides following chemotherapy
with pegylated liposomal
doxorubicin.
J Eur Acad Dermatol
Venereol. 2003
Jan;17(1):80-2.
4
Ausschlußgrund:
1: narrativer Review
2: andere Indikation
3: keine Intervention mit liposomalem oder liposomalem pegyliertem Adriamycin
4: Kasuistik mit n = 1
Tab. 4: Darstellung der Suchergebnisse aus Suchvorgang #2, die die Auswahlkriterien erfüllen:
Erstautor
Titel
Quelle
Di Lorenzo G
Pegylated liposomal doxorubicin in
stage IVB mycosis fungoides
Br J Dermatol. 2005
Jul;153(1):183-5.
Pulini S
the treatment of primary cutaneous
T-cell
lymphomas
Prospective multicenter study of
pegylated liposomal doxorubicin
treatment in
patients with advanced or refractory
mycosis fungoides or Sézary syndrome.
Haematologica. 2007
May;92(5):686-9.
Multicenter study of pegylated
liposomal doxorubicin in patients
with cutaneous
T-cell lymphoma
Pegylated doxorubicin for primary
cutaneous T cell lymphoma: a
report on ten
patients with follow-up.
Cancer. 2003 Sep 1;98(5):9931001.
Wollina U x
cutaneous T-cell lymphoma: a
report on ten
J Cancer Res Clin Oncol. 2001
Feb;127(2):128-34.
Wollina U
Treatment of relapsing or recalcitrant cutaneous T-cell lymphoma
with pegylated
liposomal doxorubicin.
J Am Acad Dermatol. 2000
Jan;42(1 Pt 1):40-6.
Quereux G
Wollina U
1
Wollina U x
1
Arch Dermatol. 2008
Jun;144(6):727-33.
Ann N Y Acad
Sep;941:214-6
Sci.
2001
x1: In beiden Publikationen wird über die 10 gleichen Patienten berichtet (Doppelpublikation).
Seite: 8
Tab. 5: Darstellung der Suchergebnisse aus Suchvorgang #4, die die Auswahlkriterien
erfüllen
Erstautor
Titel
Quelle
Di Lorenzo G
stage IVB mycosis fungoides.
Br J Dermatol. 2005
Jul;153(1):183-5.
Pulini S
the treatment of primary cutaneous
T-cell
lymphomas.
Haematologica 2007
Quereux G
Prospective multicenter study of
pegylated liposomal doxorubicin
treatment in
patients with advanced or refractory
mycosis fungoides or Sézary syndrome.
Arch Dermatol. 2008
Jun;144(6):727-33.
Wollina U
Multicenter study of pegylated
liposomal doxorubicin in patients
with cutaneous
T-cell lymphoma.
Cancer. 2003 Sep 1;98(5):993-
Wollina U
cutaneous T-cell lymphoma: a
report on ten
J Cancer Res Clin Oncol. 2001
Feb;127(2):128-34.
Wollina U
Treatment of relapsing or recalcitrant cutaneous T-cell lymphoma
with pegylated
J Am Acad Dermatol. 2000
Jan;42(1 Pt 1):40-6.
May;92(5):686-9.
1001.
Hinweis:
Alle berücksichtigten Publikationen aus Suchvorgang #4 finden sich auch in Suchvorgang
#2.
Somit verbleiben 7 zu berücksichtigende Publikationen. Die Publikation „Pegylated doxorubicin for primary cutaneous T cell lymphoma: a report on ten patients with follow-up” von Wollina-U wurde in 2 verschiedenen Zeitschriften publiziert, ist aber inhaltlich identisch (Doppelpublikation).
Ergebnis der Recherche:
Letztendlich verbleiben 6 Publikationen, die die Auswahlkriterien erfüllen und somit in der
Auswertung berücksichtigt werden (siehe Tab. 6).
Seite: 9
Tab. 6: Übersicht der Studien/Fallserien, die die Auswahlkriterien erfüllen
Publikation
Studiendesign
Fallzahl
Einschlusskriterien
Therapieschema
Med. Nachbeobachtung
Di Lorenzo G
2005
Retrospektiv,
unizentrisch
n = 10
histol. Bestätigte
Mycosis fungiodes (MF)
Stadium IV b
Pegyliertes liposomales Doxorubicin;
20 mg/qm alle
4 Wochen
Nicht angegeben
Pulini S
2007
Prospektiv,
Phase-II-Studie,
offen, einarmig
multizentrisch
n = 19
fortgeschrittene,
relabierte oder
refraktäre primär
kutane T-Zell
Lymphome
med. Follow-up:
22,6 Monate
Quereux G
2008
Prospektive,
Phase-II-Studie,
offen, einarmig,
multizentrisch
n = 25
Wollina U
2003
Retrospektiv,
offen, einarmig,
multizentrisch
n = 34
Wollina U
2001
x1
Fallserie,
monozentrisch
Wollina U
2000
Fallserie,
monozentrisch
20 mg/qm alle
4 Wochen bis zum
Progreß
Evidenzkriterien
Relevante
1
Zielkriterien
nach SIGN
Ansprechrate: 50%,
med. OS: 5 Mo.
2--
Gesamtansprechrate:
84,2%
med. OS: 34 Mo.
med. PFS: 22,6 Mo.
2+
Med. EFS: 18 Mo.
liposomales pegyliertes Doxorubicin
40 mg/qm i.v.
alle 4 Wochen;
max. 8 Zyklen
Nicht angegeben
Ansprechrate: 56%,
med. OS: 43,7 Mo.
2+
Rezidiv CTLC
i.v. 20 mg/qm
bis 40 mg/qm alle 2-4
Wochen
Nicht angegeben
Ansprechrate: 88,2%,
OS : 17,8 Mo. +/- 10,5
Mo. ,
DFS: 13,3 Mo.
2--
n = 10
Rezidiv CTCL
Stadium Ib bis IVa
i.v. 20 mg/qm
alle 4 Wochen
Nicht angegeben
OS: 19,8 Mo.
med. EFS 16,7 mo.
med. PFS: 18,2 Mo.
3
n=6
refraktäres oder
rezidiviertes CTLC
St. Ib, IIa und IIb
20 mg/qm i.v.
alle 4 Wochen;
max. 8 Zyklen
Therapiedauer
Ansprechrate: 83%
3
Kutane T-ZellLymphome (CTLC)
St. II-IV
mind. 2 Vortherapien
x1: Die Fallserie von Wollina wird in der Bewertung nicht berücksichtigt, da diese Patienten auch in der retrospektiven Studie von Wollina aus dem Jahre
2003 ausgewertet wurden.
1
OS = Gesamtüberleben, PFS=Progressionsfreies Überleben, DFS/EFS = Krankheitsfreies- bzw- ereignisfreies Überleben
Seite: 10
9. Studienextraktionsbögen
Die Darstellung erfolgt gesondert in den Anlagen 2a – 2f.
10. Bewertungsvorschlag
Zum Zeitpunkt der Literaturabfrage liegen nur 6 Publikationen zum Einsatz von pegyliertem, liposomalem Doxorubicin bei primär kutanen T-Zell-Lymphomen vor, die die Auswahlkriterien (s.o.) erfüllen.
Die zwei qualitativ hochwertigsten Studien (prospektive Studien ohne Vergleichsarm, Evidenzniveau
SIGN 2+) sind die von Quereux et al. und Pulini et al.. Die anderen 4 Publikationen sind retrospektive
Studien bzw. Fallserien (SIGN 2 bzw. 3). Die Fallserie von Wollina aus dem Jahr 2001 mit 10 Patienten wird nicht berücksichtigt, da diese Patienten auch in der retrospektiven Studie von Wollina aus
dem Jahre 2003 ausgewertet wurden.
In den beiden prospektiven Phase-II-Studien von Quereux und Pulini wurden zusammen 44 Patienten untersucht (25 bzw. 19 Patienten).
In der Studie von Quereux wurden 25 Patienten mit rezidiviertem kutanem T-Zell-Lymphom (CTLC)
und mindestens 2 Vortherapien sowie transformierte CTLC behandelt. Alle Patienten hatten mindestens 2 Vortherapien, 60% waren mit einer system. Chemotherapie vorbehandelt. 10 Patienten hatten
ein Sezary-Syndrom und weitere 10 Patienten ein transformiertes CTLC, die prognostisch ungünstiger sind. Primärer Endpunkt war die Ansprechrate, sekundäre Endpunkte Dauer des Therapieansprechens und Überleben. Die Nachbeobachtungsdauer wird nicht angegeben. Die verwendete Dosierung betrug 40 mg/qm KOF. Die Gesamtansprechrate lag bei 56% mit 5 kompletten und 9 partiellen Remissionen (CR 20% und PR 36%). Das mediane Gesamtüberleben betrug 43,7 Monate. Das
mediane PFS bei den 14 Patienten mit Therapieansprechen wird mit 5,02 Monaten angegeben, das
mediane Gesamtüberleben mit 45,8 Monate. Von den 5 Patienten mit CR rezidivierten 3 nach einer
Zeit von median 358 Tagen.
Die häufigsten Nebenwirkungen waren Anämie, Asthenie sowie Nausea und Emesis. 80% der Nebenwirkungen waren Grad 1 und 2, allerdings wurden auch 4 schwere Infektionen beobachtet. Dies
könnte lt. Autoren auf die höhere Dosis des liposomalen Doxorubicins zurückzuführen sein.
Die Studie von Pulini schloss 19 Patienten mit fortgeschrittenen, rezidivierten oder refraktären CTLC
ein. Primäre und sekundäre Studienendpunkte werden nicht expressis verbis genannt. Die verwendete Dosierung war mit 20mg/qm KOF niedriger als in der Studie von Quereux. Die Gesamtansprechrate betrug 84,2% mit einer Rate an kompletten Remissionen von 42,1% bei den vorbehandelten Patienten. Nach einem max. Follow-up von 46 Monaten betrug das mediane Gesamtüberleben
34 Monate und das PFS 19 Monate. Nebenwirkungen traten bei 26% der Patienten auf, bei 2 Patienten traten Grad 3/4-Toxizitäten auf.
Beide Studien sind nicht verblindet, nicht randomisiert und ohne Vergleichsarm. Die verwendeten
Dosierungen der Prüfsubstanz sind unterschiedlich. In der Studie von Quereux erfolgt ein Vergleich
mit historischen Kontrollen. Die Vergleichbarkeit ist jedoch aufgrund der Unterschiede in den betrachteten Patientenkollektiven und den unterschiedlichen Methoden der Remissionsbeurteilung nur sehr
eingeschränkt gegeben.
Die Aussagekraft beider Studien ist demnach aufgrund ihrer methodischen Limitationen, dem fehlenden Vergleichsarm und der geringen Patientenzahl (insges. 44 Patienten) als eingeschränkt zu bewerten. Da die Prüfmedikation mit keiner anderen Behandlung direkt verglichen wurde, kann die
Wirksamkeit nur indirekt bewertet werden.
Die Aussagekraft der retrospektiven Studien und Fallserien ist naturgemäß als noch geringer einzustufen.
Seite: 11
Studien, die die Wirksamkeit von konventionellem Doxorubicin bei primär kutanen T-Zell-Lymphomen
mit der von liposomalem, pegylierten Doxorubicin vergleichen, existieren nicht (s. Anlage 3 „Suchstrategie Doxorubicin“). Es gibt Evidenzen für eine Wirksamkeit beider Substanzen; eine Überlegenheit der liposomalen / pegylierten Substanz ist nicht belegt.
Die am 8. Oktober 2012 veröffentlichte Auswertung der EORTC-Studie 21012 (Dummer R et al.) zur
Gabe von liposomalem Doxorubicin bei Patienten mit refraktärer / rezidivierter Mycosis fungoides
weist im Vergleich mit den in Tabelle 6 dargestellten Phase 2-Studien bzw. Fallserien mit 41 % eine
eher niedrige Ansprechrate und mit 7,4 Monaten (Median) ein eher kurzes progressionsfreies Überleben auf. Dabei muss berücksichtigt werden, dass die Patienten umfangreich vorbehandelt waren.
Insgesamt begründet diese Studie keine andere Bewertung der Wirksamkeit oder Toxizität von liposomalem Doxorubicin bei Patienten mit kutanem T-Zell-Lymphom als die in Tabelle 6 aufgeführten
Publikationen.
Zusammenfassende Bewertung:
Alle drei Studien sind nicht verblindet, nicht randomisiert und ohne Vergleichsarm. Die verwendeten
Dosierungen der Prüfsubstanz sind unterschiedlich. In der Studie von Quereux erfolgt ein Vergleich
mit historischen Kontrollen. Die Vergleichbarkeit ist jedoch aufgrund der Unterschiede in den betrachteten Patientenkollektiven und den unterschiedlichen Methoden der Remissionsbeurteilung nur sehr
eingeschränkt gegeben.
Pegyliertes liposomales Doxorubicin zeigt symptomatisch-palliative Wirksamkeit. Ob die Substanz
diesbezüglich besser oder schlechter als die anderen Behandlungsverfahren ist, kann wegen des
Fehlens randomisierter Vergleiche nicht festgestellt werden.
Auch kann wegen der Nicht-Durchführbarkeit einer Studie mit Placebo-Arm nicht gesagt werden, ob
die Behandlung das Überleben oder die gesundheitsbezogene Lebensqualität verbessert.
Die Aussagekraft aller drei Studien ist demnach aufgrund ihrer methodischen Limitationen, dem fehlenden Vergleichsarm, der geringen Patientenzahl (insgesamt 93 Patienten) und unterschiedlicher
Dosierungen in den einzelnen Studien als eingeschränkt zu bewerten.
Die Aussagekraft der zusätzlich aufgefundenen Fallserien ist aufgrund der Methodik und der noch
geringeren Fallzahl noch eingeschränkter.
Aufgrund der dargestellten Datenlage mit Fehlen vergleichender Studien ist eine Bewertung des Stellenwertes von liposomalem Doxorubicin zur Behandlung von Patienten mit T-Zell-Lymphomen nicht
möglich. Dies gilt auch für die zu prüfende Indikation kutane T-Zell-Lymphome nach Versagen von
PUVA und INF α und Chlorambucil.
Bei der Beurteilung muss allerdings berücksichtigt werden, dass es sich bei kutanen T-ZellLymphomen (CTLC) um eine sehr seltene Erkrankung handelt, bei denen im Rezidiv bei fortgeschrittenem Tumorstadium nur wenige Optionen für die systemische Therapie zur Verfügung stehen. Besonders in der Zweitlinientherapie ist eine für eine Phase 3-Studie ausreichend große Studienpopulation innerhalb eines adäquaten Zeitraums selbst auf supranationaler Ebene nur schwer zu rekrutieren. Somit ist auch unwahrscheinlich, dass zukünftig zu dieser Fragestellung Daten aus randomisierten Studien zur Verfügung stehen werden.
11. Fazit (Bewertung durch die Expertengruppe)
Die vorgelegten Daten sind unzureichend, um eine zulassungsüberschreitende Anwendung von
liposomalem Doxorubicin für Patienten mit rezidiviertem T-Zell-Lymphom, auch bei überwiegend
kutaner Manifestation nach Ausschöpfen der lokalen Therapiemöglichkeiten wie Bestrahlung,
PUVA oder topische Medikamentenanwendung, als neue Therapieoption empfehlen zu können.
Seite: 12
Im Einzelfall kann nicht ausgeschlossen werden, dass die Gabe von liposomalem Doxorubicin bei
Patienten mit T-Zell-NHL in Betracht gezogen werden muss. Dies gilt insbesondere für Patienten
mit Indikation für eine Doxorubicin- bzw. CHOP-Therapie, bei denen eine Kontraindikation für
konventionelles Doxorubicin besteht, z. B. aufgrund einer kardialen Erkrankung.
12. Ergänzendes Fazit (Empfehlung an den Gemeinsamen Bundesausschuss)
Die Expertengruppe empfiehlt dem G-BA nicht, die zulassungsüberschreitende Anwendung von
liposomalem Doxorubicin bei Patienten mit T-Zell-Lymphom nach Versagen von PUVA, INF α
und Chlorambucil als neue Indikation positiv zu bewerten. Wenngleich es Hinweise auf eine klinisch relevante Wirksamkeit gibt, ist die Datenlage für eine grundlegende, ausreichend sichere
Bewertung unzureichend.
13. Bemerkungen
Es wird dringend empfohlen Patienten mit T-Zell-Lymphomen in klinischen Studien zu behandeln.
Aufgrund der Seltenheit der Erkrankung sind wichtige versorgungsrelevante Fragen zur optimalen Therapiestrategie noch unbeantwortet.
Seite: 13
14.
Literaturverzeichnis
Sortierung alphabetisch nach Erstautor
1. Akpek G, Koh HK, Bogen S, O'Hara C, Foss FM. Chemotherapy with etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone in patients with refractory cutaneous Tcell lymphoma. Cancer. 1999 Oct 1;86(7):1368-76.
2. Ali CM, Sikdar TK, Sultana N, Hoque MR, Ahmed N, Parvez Z, Kamal B, Rahman F.
Sezary syndrome. Mymensingh Med J. 2011 Jul;20(3):497-500.
3. Balaraman B, Conley JA, Sheinbein DM. Evaluation of cutaneous angioimmunoblastic T-cell
lymphoma. J Am Acad Dermatol. 2011 Oct;65(4):855-62. Epub 2011 May 6.
4. Ballanger F, Barbarot S, Le Gouill S, Gaillard F, Cassagnau E, Lodé L, Dréno B, Stalder JF.
Thoracic subcutaneous infiltration: an unusual presentation of subcutaneous panniculitis-like Tcell lymphoma. Acta Derm Venereol. 2009;89(4):427-9.
5. Benbouzid MA, Bencheikh R, Benhammou A, El Edghiri H, Boulaich M, Essakali L, Kzadri M.
[Cervicofacial cellulitis revealing cutaneous lymphomas]. Rev Stomatol Chir Maxillofac. 2007
Jun;108(3):228-30. Epub 2007 Mar 30.
6. Bindu B, Kurien A, Shenoi SD, Prabhu S. Role of slit skin smear examination in cutaneous T-cell
lymphomas and other chronic dermatoses. Dermatol Online J. 2006 Mar 30;12(3):2.
7. Bird BR, Daly PA. Uncommon hematologic malignancies. Case 3. Parotid swelling during treatment for transformed mycosis fungoides. J Clin Oncol. 2003 Nov 15;21(22):4251-2.
8. Bittencourt AL, Mota K, Oliveira RF, Farré L. A dyshidrosis-like variant of adult T-cell leukemia/lymphoma with clinicopathological aspects of mycosis fungoides. A case report.
Am J Dermatopathol. 2009 Dec;31(8):834-7.
9. Bohmeyer J, Stadler R, Kremer A, Nashan D, Muche M, Gellrich S, Luger T, Sterry W.
Bexarotene--an alternative therapy for progressive cutaneous T-cell lymphoma? First experiences. J Dtsch Dermatol Ges. 2003 Oct;1(10):785-9.
10. Braverman IM, Yager NB, Chen M, Cadman EC, Hait WN, Maynard T. Combined total body electron beam irradiation and chemotherapy for mycosis fungoides. J Am Acad Dermatol. 1987
Jan;16(1 Pt 1):45-60.
11. Castelo-Branco C, Torné A, Cararach V, Iglesias X. Mycosis fungoides and pregnancy. Oncol
Rep. 2001 Jan-Feb;8(1):197-9.
12. Caudron A, Bouaziz JD, Battistella M, Sibon D, Lok C, Leclech C, Ortonne N, Molinier-Frenkel V,
Bagot M. Two atypical cases of cutaneous gamma/delta T-cell lymphomas. Dermatology.
2011;222(4):297-303. Epub 2011 May 21.
13. Chattopadhyay A, Slater DN, Hancock BW. Cutaneous CD56 positive natural killer and cytotoxic
T-cell lymphomas. Int J Oncol. 2005 Jun;26(6):1559-62.
14. Csomor J, Bognár A, Benedek S, Sinkó J, Fekete S, Krenács L, Matolcsy A, Reiniger L.
Rare provisional entity: primary cutaneous aggressive epidermotropic CD8+cytotoxic T-cell lymphoma in a young woman. J Clin Pathol. 2008 Jun;61(6):770-2.
15. Dashkovsky I, Cozacov JC. Unusual presentation of angiocentric T-cell lymphoma mimicking
perianal abscess. J Cutan Med Surg. 2003 May-Jun;7(3):247-9.
Seite: 14
16. Dawn G, Morrison A, Morton R, Bilsland D, Jackson R. Co-existent primary cutaneous anaplastic
large cell lymphoma and lymphomatoid papulosis. Clin Exp Dermatol. 2003 Nov;28(6):620-4.
17. Dearden CE, Matutes E, Hoffbrand AV, Ganeshaguru K, Brozovic M, Williams HJ, Traub N, Mills
M, Linch DC, Catovsky D. Membrane phenotype and response to deoxycoformycin in mature T
cell malignancies. Br Med J (Clin Res Ed). 1987 Oct 10;295(6603):873-5.
18. Di Lorenzo G, Di Trolio R, Delfino M, De Placido S. Pegylated liposomal doxorubicin in stage IVB
mycosis fungoides. Br J Dermatol. 2005 Jul;153(1):183-5.
19. Di Mario A, Garzia M, d'Alò F, Rumi C, Massini G, Bellesi S, Zini G. Rapid leukaemic evolution in
a cutaneous blastic NK-cell lymphoma initially diagnosed as pseudolymphoma. Hematology.
2007 Apr;12(2):155-7.
20. Diamantidis MD, Papadopoulos A, Kaiafa G, Ntaios G, Karayannopoulou G,Kostopoulos I, Girtovitis F, Saouli Z, Kontoninas Z, Raptis ID, Savopoulos C, Hatzitolios A. Differential diagnosis
and treatment of primary, cutaneous, anaplastic large cell lymphoma: not always an easy task.
Int J Hematol. 2009 Sep;90(2):226-9. Epub 2009 Jun 23.
20a Dummer R et al.: Prospective International Multicenter Phase II Trial of Intravenous Pegylated
Liposomal Doxorubicin Monochemotherapy in Patients With Stage IIB, IVA, or IVB Advanced Mycosis Fungoides: Final Results From EORTC 21012. J Clin Oncol 2012 October 8, Epub
21. Du-Thanh A, Durand L, Costes V, Guillot B, Dereure O. [Aggressive T cytotoxic CD8+ epidermotropic cutaneous lymphoma: a case in a patient with Steinert's myotonic dystrophy].
Ann Dermatol Venereol. 2006 Dec;133(12):991-4.
22. Fierro MT, Quaglino P, Savoia P, Verrone A, Bernengo MG. Systemic polychemotherapy in the
treatment of primary cutaneous lymphomas: a clinical follow-up study of 81 patients treated with
COP or CHOP. Leuk Lymphoma. 1998 Nov;31(5-6):583-8.
23. Friedman A, Abadi M, Wu K, Fisher M, Abadi J. An unusual ulcer in an 8-year-old girl.
Dermatol Online J. 2010 Feb 15;16(2):6.
24. Fukuda N, Shinohara K, Ota I, Muraki K, Shimohakamada Y. Therapy-related myelodysplastic
syndrome in a case of cutaneous adult T-cell lymphoma. Int J Hematol. 2002 Jan;75(1):67-71.
25. Gottlieb K, Anders K, Kaya H. Obstructive jaundice in a patient with mycosis fungoides metastatic
to the pancreas. EUS findings. JOP. 2008 Nov 3;9(6):719-24.
26. Grozea PN, Jones SE, McKelvey EM, Coltman CA Jr, Fisher R, Haskins CL. Combination chemotherapy for mycosis fungoides: a Southwest Oncology Group study. Cancer Treat Rep. 1979
Apr;63(4):647-53.
27. Grubb B, Henderson DB, Pandya AG. Adult T-cell lymphoma/leukemia presenting as pagetoid
reticulosis of the palms and soles. J Am Acad Dermatol. 2011 Nov;65(5):1063-4.
28. Guizzardi M, Hendrickx IA, Mancini LL, Monti M. Cytotoxic gamma/delta subcutaneous panniculitis-like T-cell lymphoma: report of a case with pulmonary involvement unresponsive to therapy.
J Eur Acad Dermatol Venereol. 2003 Mar;17(2):219-22.
29. Gutierrez A, Rodriguez J, Ramos R, Gines J, Sampol A, Galmes B, Besalduch J. Treatment with
alemtuzumab in a case of refractory primary cutaneous CD30-negative CD8-positive cytotoxic
large T-cell lymphoma. Eur J Haematol. 2004 May;72(5):377-8.
30. Haycox CL, Back AL, Raugi GJ, Piepkorn M. Subcutaneous T-cell lymphoma treated with systemic chemotherapy, autologous stem cell support, and limb amputation. J Am Acad Dermatol.
1997 Nov;37(5 Pt 2):832-5.
Seite: 15
31. Hoppe RT. The role of radiation therapy in the management of the non-Hodgkin's lymphomas.
Cancer. 1985 May 1;55(9 Suppl):2176-83.
32. Hosler GA, Liégeois N, Anhalt GJ, Moresi JM. Transformation of cutaneous gamma/delta T-cell
lymphoma following 15 years of indolent behavior. J Cutan Pathol. 2008 Nov;35(11):1063-7.
Epub 2008 Jun 9.
33. Huang JJ, Cai MY, Ye S, Li ZM, Huang HQ, Lin TY. [Clinical analysis of 19 cases of subcutaneous panniculitis T-cell lymphoma with literature review]. Ai Zheng. 2009 Oct;28(10):1093-9.
34. Ingram RM, Williams ME, Fintel WA, Ross M. Testicular lymphoma: a literature review and report
of a case with a zoster-like cutaneous recurrence. Clin Lymphoma. 2002 Mar;2(4):238-41.
35. Inokuchi T, Shincho M, Moriwaki Y, Ka T, Takahashi S, Tsutsumi Z, Lin Y, Hirota S, Yamamoto
T. Coexistent B-cell lymphoma and cutaneous T-cell lymphoma. Intern Med. 2006;45(9):641-7.
Epub 2006 Jun 1.
36. Isogai R, Kawada A, Hashimoto K, Aragane Y, Tezuka T, Maeda Y, Kanamaru A. Nasal-type
NK/T-cell lymphoma successfully treated with ProMACE-CytaBOM therapy. Dermatology.
2004;209(3):243-5.
37. Ito T, Yamamoto T, Matsumoto Y, Wakamatsu J, Kato Y, Tsuboi R. Folliculotropic mycosis fungoides and a leonine clinical appearance of the face. Dermatol Online J. 2008 Sep 15;14(9):6.
38. Kahata K, Hashino S, Takahata M, Fujisawa F, Kondo T, Kobayashi S, Fujita Y, Shimizu H,
Imamura M, Asaka M. Durable remission of Sézary syndrome after unrelated bone marrow transplantation by reduced-intensity conditioning. Acta Haematol. 2008;120(1):14-8. Epub 2008 Aug
21.
39. Kaye FJ, Bunn PA Jr, Steinberg SM, Stocker JL, Ihde DC, Fischmann AB, Glatstein EJ, Schechter GP, Phelps RM, Foss FM, et al. A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides.
N Engl J Med. 1989 Dec 28;321(26):1784-90.
40. Keane AM, Kasten MJ. 39-year-old woman with fever and weight loss. Mayo Clin Proc. 2008
Mar;83(3):351-4.
41. Koeppel MC, Horschowski N, Terrier G, Andrac L, Stoppa AM, Signoret R, Sayag J. Lymphomatoid papulosis and Hodgkin's disease: report of a case. Dermatology. 1994;189(2):188-92.
42. Koizumi K, Sawada K, Nishio M, Katagiri E, Fukae J, Fukada Y, Tarumi T, Notoya A, Shimizu T,
Abe R, Kobayashi H, Koike T. Effective high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation in a patient with the aggressive form of cytophagic histiocytic
panniculitis. Bone Marrow Transplant. 1997 Jul;20(2):171-3.
43. Kost Al M, Kost Alová M, Belada D, Laco J. Cutaneous natural killer (NK) / T-cell lymphoma: nasal type with extensive facial destruction. Int J Dermatol. 2009 Dec;48(12):1338-42.
44. Kunisada M, Adachi A, Matsumoto S, Ogawa Y, Horikawa T, Iwatsuki K. Nasal-type natural killer
cell lymphoma preceded by benign panniculitis arising in an asymptomatic HTLV-1 carrier.
Int J Dermatol. 2003 Sep;42(9):710-4.
45. Lan MX, Zhen ZX, Ming WH. CD56-negative extranodal nasal type of natural killer/T-cell lymphoma with extranasal skin involvement. Leuk Lymphoma. 2009 Oct;50(10):1715-7.
46. Lee NH, Lee SW, Choi EH, Lee WS, Ahn SK. A case of pre-Sézary syndrome preceded by hand
lesions. J Dermatol. 1999 Jul;26(7):465-8.
Seite: 16
47. Levi JA, Diggs CH, Wiernik PH. Adriamycin therapy in advanced mycosis fungoides. Cancer.
1977 May;39(5):1967-70.
48. Li Y, Li Z, Lin HL, Chen XH, Li B. Primary cutaneous blastic plasmacytoid dendritic cell neoplasm
without extracutaneous manifestation: case report and review of the literature. Pathol Res Pract.
2011 Jan 15;207(1):55-9. Epub 2010 Jun 22.
48a: Li JY, Horwitz S, Moskowitz A, Myskowski PL, Pulitzer M, Querfeld C: Management of cutaneous T cell lymphoma: new and emerging targets and treatment options. Cancer Manag Res 2012,
4: 75-89. 2012, Epub 2012 Mar 12
49. Lomaga MA, Walsh S. A young man with fever and skin nodules. J Cutan Med Surg. 2008 NovDec;12(6):299-301.
50. Lybaek D, Iversen L. Pegylated liposomal doxorubicin in the treatment of mycosis fungoides.
Acta Derm Venereol. 2006;86(6):545-7.
51. Maalej M, Frikha H, Daoud J, Sellami D, Ben Romdhane K, Kamoun MR, Souissi R, Ben Osmen
A, Zahaf A, Nouira R, Bouaouina N, Ben Abdallah M. [Cutaneous lymphoma in Tunisia: clinical
profile and therapeutic results]. Cancer Radiother. 1998 Jul-Aug;2(4):404-7.
52. Magro CM, Seilstad KH, Porcu P, Morrison CD. Primary CD20+CD10+CD8+ T-cell lymphoma of
the skin with IgH and TCR beta gene rearrangement. Am J Clin Pathol. 2006 Jul;126(1):14-22.
53. Medhi K, Kumar R, Rishi A, Kumar L, Bakhshi S. Subcutaneous panniculitislike T-cell lymphoma
with hemophagocytosis: complete remission with BFM-90 protocol. J Pediatr Hematol Oncol.
2008 Jul;30(7):558-61.
54. Molin L, Thomsen K, Volden G, Groth O, Hellbe L, Holst R, Knudsen EA, Roupe G, Schmidt H.
Combination chemotherapy in the tumour stage of mycosis fungoides with cyclophosphamide,
vincristine, vp-16, adriamycin and prednisolone (cop, chop, cavop): a report from the Scandinavian mycosis fungoides study group. Acta Derm Venereol. 1980;60(6):542-4.
55. Nagatani T, Okazawa H, Mizuno H, Yanagi N, Miyazawa M, Baba N. [Primary cutaneous lymphoma--mycosis fungoides]. Gan To Kagaku Ryoho. 1997 Jan;24(1):23-9.
56. Nakahashi H, Tsukamoto N, Yamane A, Saitoh T, Uchiumi H, Handa H, Karasawa M, Murakami
H, Kojima M, Nojima Y. Autologous peripheral blood stem cell transplantation to treat CHOPrefractory aggressive subcutaneous panniculitis-like T cell lymphoma. Acta Haematol.
2009;121(4):239-42. Epub 2009 Jun 29.
57. Natsuga K, Shimizu T, Abe R, Kodama K, Shimizu H. Mycosis fungoides bullosa. Arch Dermatol.
2006 Jun;142(6):793-5.
58. Nguyen NQ. Subcutaneous T-cell lymphoma. Dermatol Online J. 2003 Oct;9(4):42.
59. O'Connor OA. At long last, it's finally 'T' time. Clin Lymphoma Myeloma. 2008 Dec;8 Suppl
5:S166-7.
60. Ohnishi K. [Recent progress in the management of malignant lymphoma]. Gan To Kagaku Ryoho. 1997 Jul;24(9):1074-8.
61. Onesti MG, Mazzocchi M, De Leo A, Scuderi N. T-cell lymphoma presenting as a rapidly enlarging tumor on the lower eyelid. Acta Chir Plast. 2005;47(3):65-6.
Seite: 17
62. Onizuka T, Satou S, Koike M, Ishiyama T, Tomoyasu S, Tsuruoka N, Ohta H, Fujisawa R, Yamaguchi A, Tashiro T. [Parapsoriasis en plaque suspected of progression to mycosis fungoides associated with extranodal malignant B cell lymphoma of the cheek]. Rinsho Ketsueki. 1993
Jun;34(6):723-7.
63. Pan CC, Lee WL. Vaginal obliteration in a woman with a history of cutaneous T-cell lymphoma:
the results of combined chemotherapy-induced gonadal toxicity and lymphoma relapse. Taiwan J
Obstet Gynecol. 2010 Mar;49(1):69-71.
64. Perna AG, Jones DM, Duvic M. Lymphomatoid papulosis from childhood with anaplastic largecell lymphoma of the small bowel. Clin Lymphoma. 2004 Dec;5(3):190-3.
65. Prince HM, Seymour JF, Ryan G, McCormack C. Pegylated liposomal doxorubicin in the treatment of cutaneous T-cell lymphoma. J Am Acad Dermatol. 2001 Jan;44(1):149-50.
66. Pulini S, Rupoli S, Goteri G, Pimpinelli N, Alterini R, Tassetti A, Scortechini AR, Offidani M, Mulattieri S, Stronati A, Brandozzi G, Giacchetti A, Mozzicafreddo G, Ricotti G, Filosa G, Bettacchi A,
Simonacci M, Novelli N, Leoni P. Pegylated liposomal doxorubicin in the treatment of primary cutaneous T-cell lymphomas. Haematologica. 2007 May;92(5):686-9.
67. Pérez-Barrio S, Izu R, García-Ruiz JC, Acebo E, Martínez de Lagrán Z, Díaz-Pérez JL.
[Autologous hematopoietic stem cell transplantation followed by oral bexarotene in a patient with
advanced mycosis fungoides]. Actas Dermosifiliogr. 2008 Sep;99(7):560-4.
67a Prince HM, Whittaker S, Hoppe RT: How I treat mycosis fungoides and Sezary syndrome. Blood
2009;114:4337-4353
68. Quereux G, Marques S, Nguyen JM, Bedane C, D'incan M, Dereure O, Puzenat E, Claudy A,
Martin L, Joly P, Delaunay M, Beylot-Barry M, Vabres P, Celerier P, Sasolas B, Grange F,
Khammari A, Dreno B. Prospective multicenter study of pegylated liposomal doxorubicin treatment in
patients with advanced or refractory mycosis fungoides or Sézary syndrome. Arch Dermatol.
2008 Jun;144(6):727-33.
69. Quéreux G, Renaut JJ, Peuvrel L, Knol AC, Brocard A, Dréno B. Sudden onset of an aggressive
cutaneous lymphoma in a young patient with psoriasis: role of immunosuppressants. Acta Derm
Venereol. 2010 Nov;90(6):616-20.
70. Rifkin S, Valderrama E, Lipton JM, Karayalcin G. Lymphomatoid papulosis and Ki-1+ anaplastic
large cell lymphoma occurring concurrently in a pediatric patient. J Pediatr Hematol Oncol. 2001
Jun-Jul;23(5):321-3.
71. Robey RW, Zhan Z, Piekarz RL, Kayastha GL, Fojo T, Bates SE. Increased MDR1 expression in
normal and malignant peripheral blood mononuclear cells obtained from patients receiving depsipeptide (FR901228, FK228, NSC630176). Clin Cancer Res. 2006 Mar 1;12(5):1547-55.
72. Rodis DG, Liatsos GD, Moulakakis A, Pirounaki M, Tasidou A. Paraneoplastic cerebellar degeneration: initial presentation in a patient with anaplastic T-cell lymphoma, associated with ichthyosiform cutaneous lesions. Leuk Lymphoma. 2009 Aug;50(8):1369-71.
73. Rojnuckarin P, Nakorn TN, Assanasen T, Wannakrairot P, Intragumtornchai T. Cyclosporin in
subcutaneous panniculitis-like T-cell lymphoma. Leuk Lymphoma. 2007 Mar;48(3):560-3.
74. Rubin DL, Blank N. Rapid pulmonary dissemination in mycosis fungoides simulating pneumonia.
A case report and review of the literature. Cancer. 1985 Aug 1;56(3):649-51.
75. Savage KJ. Prognosis and primary therapy in peripheral T-cell lymphomas. Hematology Am Soc
Hematol Educ Program. 2008:280-8.
Seite: 18
76. Schmidt CG. [Chemotherapy in non-Hodgkin's lymphomas (author's transl)]. Strahlentherapie.
1977 May;153(5):283-92.
76a. Schmitz N et al.: Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis
of patients with t-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin lymphoma Study Group. Blood 2010, 116: 3418-3425
77. Sheehy O, Catherwood M, Pettengell R, Morris TC. Sustained response of primary cutaneous
CD30 positive anaplastic large cell lymphoma to bexarotene and photopheresis. Leuk Lymphoma. 2009 Aug;50(8):1389-91.
78. Shiman M, Marchione R, Ricotti C, Romanelli P, Alonso-Llamazares J. CD4+/CD56+ Hematodermic neoplasm (plasmacytoid dendritic cell tumor). Dermatol Online J. 2008 Nov 15;14(11):5.
79. Sibbing D, Barthel P, Abbrederis K, Dennig K, Gaa J. Intracardiac right ventricular metastatic
tumor of malignant T-cell lymphoma. Int J Cardiol. 2007 Apr 25;117(2):e84-5. Epub 2007 Feb 27.
80. Silva MM, Morais JC, Spector N, Maceira J, Sousa MA, Filgueira AL. Lymphomatoid papulosis
followed by Hodgkin's disease. Int J Dermatol. 1998 Jul;37(7):541-3.
81. Simal E, Hörndler C, Porta N, Baldellou R. [Primary cutaneous CD30+ large T-Cell lymphoma
with lymph node and cerebral metastases]. Actas Dermosifiliogr. 2010 Nov;101(9):810-2.
82. Singh A, Kumar J, Kapur S, Ramesh V. Subcutaneous panniculitis-like T-cell cutaneous lymphoma. Indian J Dermatol Venereol Leprol. 2008 Mar-Apr;74(2):151-3.
83. Stadler R. Optimal combination with PUVA: rationale and clinical trial update. Oncology (Williston
Park). 2007 Feb;21(2 Suppl 1):29-32.
84. Sterry W, Heinzerling L. Clinical research in cutaneous T-cell lymphoma moving forward. Arch
Dermatol. 2008 Jun;144(6):786-7.
85. Stetsenko GY, McFarlane R, Kalus A, Olerud J, Cherian S, Fromm J, George E, Argenyi Z.
CD4+/CD56+ hematodermic neoplasm: report of a rare variant with a T-cell receptor gene rearrangement. J Cutan Pathol. 2008 Jun;35(6):579-84. Epub 2007 Nov 12.
86. Su O, Onsun N, Demirkesen C, Aydin Y, Pirmit S, Gereli M. A case of CD4+/CD56+ hematodermic neoplasm (plasmacytoid dendritic cell neoplasm). Dermatol Online J. 2010 Apr
15;16(4):8.
87. Sumner WT, Grichnik JM, Shea CR, Moore JO, Miller WS, Burton CS. Follicular mucinosis as a
presenting sign of acute myeloblastic leukemia. J Am Acad Dermatol. 1998 May;38(5 Pt 2):803-5.
87a Trautinger F, Knobler R, Willemze R et al. EORTC consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome. Eur J Cancer 2006; 42: 1014–1030.
89. Tsatalas C, Martinis G, Margaritis D, Spanoudakis E, Kotsianidis I, Karpouzis A, Bourikas G.
Long-term remission of recalcitrant tumour-stage mycosis fungoides following chemotherapy with
pegylated liposomal doxorubicin. J Eur Acad Dermatol Venereol. 2003 Jan;17(1):80-2.
89a Whittaker SJ, Marsden JR, Spittle M, Russell Jones R. Joint British Association of Dermatologists and U.K. Cutaneous Lymphoma Group guidelines for the management of primary cutaneous T-cell lymphomas. Br J Dermatol 2003; 149: 1095–1107
89b Willemze R, Dreyling M on behalf of the ESMO Guidelines Working Group: Primary cutaneous
lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of
Oncology 21 (Supplement 5): v177–v180, 2010
Seite: 19
90. Wilson LD, Licata AL, Braverman IM, Edelson RL, Heald PW, Feldman AM, Kacinski BM. Systemic chemotherapy and extracorporeal photochemotherapy for T3 and T4 cutaneous T-cell lymphoma patients who have achieved a complete response to total skin electron beam therapy.
Int J Radiat Oncol Biol Phys. 1995 Jul 15;32(4):987-95.
91. Wollina U, Dummer R, Brockmeyer NH, Konrad H, Busch JO, Kaatz M, Knopf B, Koch HJ,
Hauschild A. Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous
T-cell lymphoma. Cancer. 2003 Sep 1;98(5):993-1001.
92. Wollina U, Graefe T, Feldrappe S, André S, Wasano K, Kaltner H, Zick Y, Gabius HJ.
Galectin fingerprinting by immuno- and lectin histochemistry in cutaneous lymphoma.
J Cancer Res Clin Oncol. 2002 Feb;128(2):103-10. Epub 2001 Nov 16.
93. Wollina U, Graefe T, Kaatz M. Pegylated doxorubicin for primary cutaneous T cell lymphoma: a
report on ten patients with follow-up. Ann N Y Acad Sci. 2001 Sep;941:214-6.
94. Wollina U, Graefe T, Kaatz M. Pegylated doxorubicin for primary cutaneous T-cell lymphoma: a
report on ten patients with follow-up. J Cancer Res Clin Oncol. 2001 Feb;127(2):128-34.
95. Wollina U, Graefe T, Karte K. Treatment of relapsing or recalcitrant cutaneous T-cell lymphoma
with pegylated liposomal doxorubicin. J Am Acad Dermatol. 2000 Jan;42(1 Pt 1):40-6.
96. Xie JJ, Zhou ZQ, Wang Y, Li Y, Zhang RY, Ren YB, Chen B, Zhou GY. [Granulomatous slack
skin with anaplastic large cell lymphoma: report of a case]. Zhonghua Bing Li Xue Za Zhi. 2011
Apr;40(4):267-8.
97. Xu H, Qian J, Wei J, Zhao Y, Zhou C, Chen D, Zhang J. CD8-positive primary cutaneous anaplastic large cell lymphoma presenting as multiple scrotal nodules and plaques. Eur J Dermatol.
2011 Jul-Aug;21(4):609-10.
98. Yung A, Snow J, Jarrett P. Subcutaneous panniculitic T-cell lymphoma and cytophagic histiocytic
panniculitis. Australas J Dermatol. 2001 Aug;42(3):183-7.
99. Zakem MH, Davis BR, Adelstein DJ, Hines JD. Treatment of advanced stage mycosis fungoides
with bleomycin, doxorubicin, and methotrexate with topical nitrogen mustard (BAM-M).
Cancer. 1986 Dec 15;58(12):2611-6.
100. Zhang H, Gupta R, Wang JC, Lipton JF, Huang YW. Subcutaneous panniculitis-like T-cell lymphoma in a patient with long-term remission with standard chemotherapy. J Natl Med Assoc.
2007 Oct;99(10):1190-2.
Seite: 20
Anlage 0
a. folgende Wirkstoffe besitzen eine Zulassung für „kutanes T-Zell-Lymphom“
(Recherche in der Datenbank AMIS, aktualisiert am 19.03.2012, Suchkriterien:
„Anwendungsgebiet “kutanes T-Zell Lymphom” OR “CTCL” OR „Mycosis?”)
Interferon alfa-2a
……
Kutanes T-Zell-Lymphom. Interferon alfa-2a könnte in der Behandlung von Patienten
wirksam sein, die an einer fortschreitenden Erkrankung leiden und auf eine
konventionelle Behandlung nicht ansprechen oder für eine solche ungeeignet sind.
…….
(Fachinformation für Roferon®-A 18 Mio. I.E /0,6 ml, Roche Pharma AG, Stand der Information
August 2011)
Psoralen (Methoxsalen = 8-Methoxypsoralen)
Orale Anwendung
Schwere Formen der Psoriasis vulgaris. Mycosis fungoides und andere Formen des
kutanen T-Zell-Lymphoms (besonders frühe Stadien mit Plaques, weniger späte Stadien
mit tumorösen Veränderungen). Vitiligo bei entsprechendem Hauttyp (ab Typ III).
Art und Dauer der Anwendung :
……. Die Einnahme darf nur an den Tagen erfolgen, an denen auch eine Bestrahlung
vorgenommen wird. Meladinine (Methoxsalen) wird ausschließlich im Zusammenhang
mit UVA therapeutisch eingesetzt (PUVA-Therapie).
…….
(Fachinformation für Meladinine® 10 mg Tabletten, Galderma Laboratorium GmbH, Stand der
Information 05/2008)
Extrakorporale Anwendung
Methoxsalen wird in Verbindung mit entweder dem Therakos® Cellex® oder dem
UvarTM XTSTM Photopherese-System bei der palliativen Behandlung der
Hautmanifestationen (Patch-Plaque, ausgedehnte Plaque, Erythrodermie) der
fortgeschrittenen
Phase (T2 – T4) von kutanem T-Zell-Lymphom (CTCL) nur bei Patienten eingesetzt,
die auf andere Behandlungsformen nicht angesprochen haben (z.B. PUVA-Therapie,
Systemisches Corticosteroid,Caryolysin, Interferon Alpha).
TM
(Fachinformation für Uvadex 20 Mikrogramm/ml Lösung zur Modifikation einer Blutfraktion,
Therakos, UK, Stand der Information September 2009)
Bexaroten
Bexaroten dient zur Behandlung von Hautmanifestationen bei Patienten mit kutanem TZell-Lymphom (CTCL) im fortgeschrittenen Stadium, die auf mindestens eine
systemische Behandlung nicht angesprochen haben.
(Fachinformation für Targretin® 75 mg Weichkapseln®, Eisai Ltd., Stand der Information Juli
2012)
b. für die Indikation „Non-Hodgkin-Lymphome“ sind in Deutschland mehrere Wirkstoffe zugelassen z.B.
Chlorambucil
Chronisch lymphatische Leukämie (CLL), niedrig maligne Non-Hodgkin-Lymphome,
Waldenström Makroglobulinämie.
(Fachinformation für Leukeran® 2 mg Filmtabletten, Aspen Pharma Trading Limited, Irl., Stand der
Information September 2011)
Vincristinsulfat
Vincristinsulfat wird bei folgenden Indikationen in der Regel in der
Kombinationschemotherapie angewendet:
– Remissionseinleitung und Konsolidierung bei akuter lymphatischer Leukämie
− Hodgkin-Lymphome,
− Non-Hodgkin-Lymphome,
− Metastasiertes Mammakarzinom (Palliativtherapie bei ansonsten therapieresistenten
Fällen),
− Kleinzelliges Bronchialkarzinom,
− Sarkome (osteogenes Sarkom, Ewing-Sarkom, Rhabdomyosarkom),
− Wilms-Tumor
− Neuroblastome.
(Fachinformation für Vincristinsulfat-Gry 1 mg/ ml Injektionslösung , Gry-Pharma GmbH, Stand
der Information November 2006)
Etoposid/Etoposidphosphat
Etoposid ist in Kombination mit anderen antineoplastisch wirksamen Präparaten bei der
Behandlung folgender bösartiger Neubildungen angezeigt:
− Palliative Therapie des fortgeschrittenen, kleinzelligen Bronchialkarzinoms
− Palliative Therapie des fortgeschrittenen, nicht-kleinzelligen Bronchialkarzinoms
− Reinduktionstherapie bei Morbus Hodgkin nach Versagen (nicht vollständiges
Ansprechen auf die Therapie bzw. Wiederauftreten der Erkrankung) von
Standardtherapien
− Non-Hodgkin-Lymphome von intermediärem und hohem Malignitätsgrad nach
Versagen (nicht vollständiges Ansprechen auf die Therapie bzw.
Wiederauftreten der Erkrankung) von Standardtherapien
In der Mono- und Polychemotherapie ist Etoposid angezeigt zur Behandlung der akuten
myeloischen Leukämie bei Patienten, für die eine intensive, myeloablative Therapie nicht
geeignet ist.
In der Monotherapie ist Etoposid angezeigt
− zur Behandlung des rezidivierten oder therapierefraktären Hodenkarzinoms
− zur palliativen systemischen Behandlung fortgeschrittener Ovarialkarzinome nach
Versagen von platinhaltigen Standardtherapien..
(Fachinformation für Vepesid®, Bristol-Myers Squibb GmbH, Stand der Information August 2008)
Methotrexat
in der Onkologie:
Methotrexat in niedriger (Einzeldosis <100 mg/m2 Körperoberfläche [KOF]) und
mittelhoher Dosierung (Einzeldosis 100 – 1000 mg/m2 KOF) ist angezeigt bei folgenden
onkologischen Erkrankungen:
Maligne Trophoblasttumoren
– als Monochemotherapie bei Patientinnen mit guter Prognose („low risk“)
– in Kombination mit anderen zytostatischen Arzneimitteln bei Patientinnen mit schlechter
Prognose („high risk“)
Mammakarzinome
– in Kombination mit anderen zytostatischen Arzneimitteln zur adjuvanten Therapie nach
Resektion des Tumors oder Mastektomie sowie zur palliativen Therapie im
fortgeschrittenen Stadium
Karzinome im Kopf-Hals-Bereich
– zur palliativen Monotherapie im metastasierten Stadium oder bei Rezidiven
Non-Hodgkin-Lymphome
– im Erwachsenenalter:
Zur Behandlung von Non-Hodgkin-Lymphomen von intermediärem oder hohem
Malignitätsgrad in Kombination mit anderen zytostatischen Arzneimitteln
– im Kindesalter:
in Kombination mit anderen zytostatischen Arzneimitteln
Akute lymphatische Leukämien (ALL)
Methotrexat in niedriger Dosierung wird angewendet zur Behandlung akuter
lymphatischer Leukämien im Kindes- und Erwachsenenalter im Rahmen komplexer
Therapieprotokolle in Kombination mit anderen zytostatischen Arzneimitteln zur
remissionserhaltenden Therapie (bei systemischer Anwendung) und zur Prophylaxe und
Therapie der Meningeosis leucaemica bei intrathekaler Anwendung mit einer
Verdünnung auf
eine maximale Methotrexat-Konzentration von 5 mg/ml.
Bei der intrathekalen Anwendung von Methotrexat zur Prophylaxe und Therapie der
Meningeosis leucaemica darf nach Verdünnung des methotrexathaltigen Arzneimittels
eine maximale Methotrexat-Konzentration von 5 mg/ml nicht überschritten werden.
Methotrexat in hoher Dosierung (Einzeldosis> 1000 mg/m2 KOF) ist angezeigt bei
folgenden onkologischen Erkrankungen:
Osteosarkome
– in Kombination mit anderen zytostatischen Arzneimitteln zur adjuvanten und
neoadjuvanten Therapie
– im Erwachsenenalter:
Zur Behandlung von Non-Hodgkin-Lymphomen von intermediärem oder hohem
Malignitätsgrad in Kombination mit anderen zytostatischen Arzneimitteln.
– im Kindesalter:
in Kombination mit anderen zytostatischen Arzneimitteln
– primär im Zentralnervensystem lokalisierte Non-Hodgkin-Lymphome vor einer
Radiotherapie
Akute lymphatische Leukämien (ALL)
Methotrexat in hoher Dosierung wird angewendet zur Behandlung der akuten
lymphatischen Leukämie im Kindes- und Erwachsenenalter jeweils in Kombination mit
anderen
zytostatischen Arzneimitteln.
Methotrexat in hoher Dosierung hat sich im Rahmen unterschiedlicher Therapieprotokolle
insbesondere zur systemischen Vorbeugung und Behandlung der Meningeosis
leucaemica als wirksam erwiesen.
(Mustertext für Methotrexat-Dinatrium, Muster-Nr. 8000240,, Stand der Information November
2009)
Doxorubicinhydrochlorid
• kleinzelliges Bronchialkarzinom (SCLC)
• Mammakarzinom
• fortgeschrittenes Ovarialkarzinom
• zur intravesikalen Rezidivprophylaxe oberflächlicher Harnblasenkarzinome nach TUR
bei Patienten mit hohem Rezidivrisiko
• zur systemischen Behandlung lokal fortgeschrittener oder metastasierter Harnblasenkarzinome
• neoadjuvante und adjuvante Therapie des Osteosarkoms
• fortgeschrittenes Weichteilsarkom des Erwachsenenalters
• Ewing-Sarkom
• Frühstadium des Hodgkin-Lymphoms (Stadium I – II) bei schlechter Prognose
• fortgeschrittenes (StadiumIII – IV) Hodgkin-Lymphom
• hochmaligne Non-Hodgkin-Lymphome
• Remissionsinduktion bei akuter lymphatischer Leukämie
• Remissionsinduktion bei akuter myeloischer Leukämie
• fortgeschrittenes Multiples Myelom
• fortgeschrittenes oder rezidiviertes Endometriumkarzinom
• Wilms-Tumor (im Stadium II bei hochmalignen Varianten, alle fortgeschrittenen Stadien [III–IV])
• fortgeschrittenes papilläres / follikuläres Schilddrüsenkarzinom
• anaplastisches Schilddrüsenkarzinom
• fortgeschrittenes Neuroblastom
• fortgeschrittenes Magenkarzinom
®
(Fachinformation für ADRIBLASTIN Lösung 10 mg, Pharmacia GmbH, Stand der Information
Oktober 2009)
Cytarabin
Cytarabin wird eingesetzt zur Hochdosistherapie bei:
– refraktären (anderweitig therapieresistenten) Non-Hodgkin-Lymphomen
– refraktärer akuter nichtlymphatischer Leukämie
– refraktärer akuter lymphoblastischer Leukämie
– Rezidiven akuter Leukämien
– Leukämien mit besonderem Risiko
– sekundären Leukämien nach vorausgegangener Chemotherapie und/oder Bestrahlung
– manifester Leukämie nach Transformation von Präleukämien
– Konsolidierung der Remission akuter, nichtlymphatischer Leukämien bei Patienten
unter 60 Jahren
(Fachinformation für Alexan® 50mg/ml, EBEWE Pharma, Stand der Information Januar 2012)
Ifosfamid
Hodentumoren
Zur Kombinationschemotherapie bei Patienten mit fortgeschrittenen Tumoren in den
Stadien II bis IV nach TNM-Klassifikation (Seminome und Nicht-Seminome), welche
nicht oder nicht genügend auf eine Initialchemotherapie ansprechen.
Zervixkarzinom
Palliative Cisplatin/Ifosfamid Kombinations-Chemo-Therapie (alleinig, ohne weitere
Kombinationspartner) des Zervixkarzinoms im FIGO StadiumIV B (wenn eine kurative
Therapie der Erkrankung durch Chirurgie oder Radiotherapie nicht möglich ist) – als
Alternative zur palliativen Radiotherapie.
Mammakarzinom
Zur Palliativtherapie bei fortgeschrittenen, therapierefraktären bzw. rezidivierenden
Mammakarzinomen.
Nicht-kleinzellige Bronchialkarzinome
Zur Einzel- oder Kombinationschemotherapie von Patienten mit inoperablen oder
metastasierten Tumoren.
Kleinzelliges Bronchialkarzinom
Zur Kombinationschemotherapie.
Weichteilsarkome (inkl. Osteosarkom und Rhabdomyosarkom)
Zur Einzel- oder Kombinationschemotherapie des Rhabdomyosarkoms oder des
Osteosarkoms nach Versagen der Standardtherapien. Zur Einzel- oder
Kombinationschemotherapie anderer Weichteilsarkome nach Versagen der Chirurgie und
Strahlentherapie.
Ewing-Sarkom
Zur Kombinationschemotherapie nach Versagen der zytostatischen Primärtherapie.
Zur Kombinationschemotherapie bei Patienten mit hochmalignen Non-HodgkinLymphomen, welche nicht oder nur unzureichend auf die Initialtherapie ansprechen. Zur
Kombinationstherapie von Patienten mit rezidivierten Tumoren.
Morbus Hodgkin
Zur Behandlung von Patienten mit primär progredienten Verläufen und Frührezidiven
des Morbus Hodgkin (Dauer der kompletten Remission kürzer als ein Jahr) nach
Versagen der chemotherapeutischen bzw. radio-chemotherapeutischen Primärtherapie –
im Rahmen anerkannter Kombinations-Chemotherapie-Regime, wie z. B. dem MINE
Protokoll.
(Fachinformation für Holoxan®, Baxter Oncology GmbH, Stand der Information November 2008)
Bleomycinsulfat
Bleomycin wird fast immer in Kombination mit anderen Zytostatika und/oder einer
Strahlentherapie verabreicht.
Bleomycin ist indiziert fur die Behandlung von:
- Plattenepithelkarzinomen (SCC) von Kopf und Hals, äußeren Genitalen und Zervix
- Hodgkin-Lymphomen
- Non-Hodgkin-Lymphomen von intermediärer und hoher Malignitat bei Erwachsenen
- Hoden-Karzinom (Seminomen und Nichtseminomen)
- intrapleurale Therapie von malignen Pleuraergussen.
(Fachinformation Bleomycin-TEVA®, TEVA GmbH, Stand der Information August 2010)
Vindesinsulfat
Kombinationschemotherapie: Remissionseinleitung und Konsoldierung bei akuter
lymphatischer Leukämie.
Kombinationschemotherapie: Blastenschub bei chronischer myeloischer Leukämie.
Kombinationschemotherapie: Morbus Hodgkin nach Versagen der Standardtherapie
(nicht vollständiges Ansprechen auf die Therapie bzw. Wiederauftreten der Erkrankung).
Kombinationschemotherapie: lokal fortgeschrittenes oder metastasiertes nichtkleinzelliges Bronchialkarzinom (Stadium IIIB oder IV).
Kombinationschemotherapie: aggressives Non-Hodgkin-Lymphom (Stadium I oder II).
(elektronische Einreichung lt. AMIS für: Eldisine 5 mg Pulver zur Herstellung einer
Injektionslösung, Stand: Oktober 2010)
Bendamustinhydrochlorid
Primärtherapie bei chronisch-lymphatischer Leukämie (Binet-StadiumB oder C) bei
Patienten, bei denen eine Fludarabin-Kombinations- Chemotherapie ungeeignet ist.
Monotherapie bei indolenten Non-Hodgkin- Lymphomen bei Patienten mit Progression
während oder innerhalb von 6 Monaten nach Behandlung mit Rituximab oder mit einer
Rituximab-haltigen Therapie.
Primärtherapie bei multiplem Myelom (Stadium II nach Durie-Salmon mit Progression
oder StadiumIII) in Kombination mit Prednison, bei Patienten, die älter als 65 Jahre und
nicht für eine autologe Stammzellen-Transplantation (HDT/ASCT) geeignet sind und die
bereits bei Diagnosestellung eine klinische Neuropathie aufweisen, wodurch eine
Behandlung mit Thalidomid oder Bortezomib ausgeschlossen ist.
(Fachinformation für Levact® 2,5 mg/ml, Mundipharma, Stand der Information Dezember 2010)
Trofosfamid
Therapie von Non-Hodgkin-Lymphomen nach Versagen von Standardtherapie
(Fachinformation für Ixoten®, Baxter Oncology Gmbh, Stand der Information November 2008)
Vinblastinsulfat
Vinblastin wird manchmal in der Monotherapie, üblicherweise jedoch in Kombination mit
anderen Zytostatika und/oder Strahlentherapie zur Behandlung der folgenden malignen
Erkrankungen angewendet:
– maligne Non-Hodgkin-Lymphome
– Morbus Hodgkin
– fortgeschrittenes Hodenkarzinom
– rezidivierendes oder metastasierendes Mammakarzinom (wenn eine Behandlung mit
Anthracyclinen nicht erfolgreich war)
– Langerhans-Zell-Histiozystosis (Histiozystosis X).
(Fachinformation für Vinblastinsulfat-TEVA®, TEVA GmbH, Stand der Information September
2009)
Anlage 1a
Suchvorgang #1 : 100 Treffer
Sortierung: alphabetisch nach Erstautor
1. Cancer. 1999 Oct 1;86(7):1368-76.
Chemotherapy with etoposide, vincristine, doxorubicin, bolus
cyclophosphamide,
and oral prednisone in patients with refractory cutaneous T-cell lymphoma.
Akpek G, Koh HK, Bogen S, O'Hara C, Foss FM.
Section of Hematology and Oncology, Department of Medicine, Johns Hopkins
Oncology Center, Baltimore, Maryland 21287-8985, USA.
BACKGROUND: This Phase II study was undertaken to assess the efficacy and
toxicity of chemotherapy with etoposide, vincristine, doxorubicin, bolus
cyclophosphamide, and oral prednisone (EPOCH regimen) in patients with
advanced,
refractory cutaneous T-cell lymphoma (CTCL).
METHODS: Fifteen patients were treated with a 96-hour continuous infusion
of
etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral
prednisone,
followed by granulocyte-colony stimulating factor support and
trimethoprim/sulfamethoxazole prophylaxis. The median age of the patients
was 53
years (range, 17-82 years). Six patients had Sézary syndrome (SS), four
patients
had visceral involvement, and four patients had anaplastic large cell
morphology,
three with Ki-1 (CD30) positivity. All patients had disease that was
refractory
to prior chemotherapy or electron beam irradiation and eight of these
patients
had received cyclophosphamide, doxorubicin, vincristine, and prednisone.
Seven
patients had received prior interferon therapy and nine patients had
received
fludarabine and/or 2-CDA.
RESULTS: After a median of 5 cycles (range, 1-9 cycles), 4 patients
achieved a
complete response (27%) and 8 patients achieved a partial response (53%)
for an
overall response rate of 80% (95% confidence interval, 52-96%). Three
patients
with visceral involvement, two of three patients with anaplastic large cell
morphology, and one patient with human T-cell lymphoma virus
leukemia/lymphoma
did not respond. All 12 responders had improvement in skin disease; 2 of 6
patients with SS had complete disappearance of circulating Sézary cells.
The
median progression free survival was 8.0 months (range, 3-22 months). After
a
median follow-up of 11.4 months (range, 2-56+ months), the median patient
survival was 13.5 months. Grade 3 or 4 hematologic toxicity occurred in 8
patients (61%); 5 of these 8 patients had febrile neutropenia. Six patients
developed staphylococcal bacteremia, two patients had disseminated herpes
infection, and one patient had Pneumocystis carinii pneumonia. Grade 3
neurotoxicity occurred in one patient. Two patients had a significant
decrease in
left ventricular ejection fraction and one patient had supraventricular
tachycardia.
CONCLUSIONS: EPOCH chemotherapy has a high response rate with acceptable
toxicity
in patients with advanced and refractory CTCL.
Copyright 1999 American Cancer Society.
PMID: 10506727
[PubMed - indexed for MEDLINE]
2. Mymensingh Med J. 2011 Jul;20(3):497-500.
Sezary syndrome.
Ali CM, Sikdar TK, Sultana N, Hoque MR, Ahmed N, Parvez Z, Kamal B, Rahman
F.
Department of Dermatology, Dhaka Medical College, Dhaka, Bangladesh.
Sezary syndrome is a rare form of primary cutaneous T cell lymphoma. A male
patient of 37 years old was reported with multiple subcutaneous swelling at
different parts of the body which were asymptomatic for the last 2 years.
But he
had persistent generalized itching, induration in skin surface and erythema
for
months. The disease was diagnosed by the presence of Sezary cells in the
skin
biopsy, peripheral blood smears and epidermotrophism of lymphocytes. The
patient
was treated by CHOP (Cyclophosphamide, Doxorubicin, Vincristine and
Prednisolone)
therapy.
PMID: 21804519
3. J Am Acad Dermatol. 2011 Oct;65(4):855-62. Epub 2011 May 6.
Evaluation of cutaneous angioimmunoblastic T-cell lymphoma.
Balaraman B, Conley JA, Sheinbein DM.
Washington University, Saint Louis, Missouri, USA.
BACKGROUND: Angioimmunoblastic T-cell lymphoma (AITL) accounts for 18% of
peripheral T-cell lymphomas worldwide. Skin involvement occurs in up to 50%
of
patients but poses a diagnostic dilemma because of the limited number of
reported
cases and subsequent lack of established diagnostic criteria.
OBJECTIVE: The purpose of this review is to examine common clinical,
histologic,
and molecular findings in cases of AITL with the hope of improving the
diagnostic
accuracy of this challenging condition.
METHODS: We present a case of AITL and conducted a review of the
literature.
RESULTS: The common clinical and histologic features in cases of AITL are
nonspecific. However, newer immunohistochemical stains and gene
rearrangement
studies appear very promising at improving diagnostic capabilities.
LIMITATIONS: There was a paucity of reported cases of AITL in the
literature, and
this review is retrospective.
CONCLUSION: AITL presents with nonspecific clinical and histologic
findings, but
immunohistochemical stains and gene rearrangements can help establish the
diagnosis.
Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby,
Inc.
All rights reserved.
PMID: 21550134
4. Acta Derm Venereol. 2009;89(4):427-9.
Thoracic subcutaneous infiltration: an unusual presentation of subcutaneous
panniculitis-like T-cell lymphoma.
Ballanger F, Barbarot S, Le Gouill S, Gaillard F, Cassagnau E, Lodé L,
Dréno B,
Stalder JF.
PMID: 19688166
5. Rev Stomatol Chir Maxillofac. 2007 Jun;108(3):228-30. Epub 2007 Mar 30.
[Cervicofacial cellulitis revealing cutaneous lymphomas].
[Article in French]
Benbouzid MA, Bencheikh R, Benhammou A, El Edghiri H, Boulaich M, Essakali
L,
Kzadri M.
Service d'ORL et de chirurgie maxillofaciale, hôpital des spécialités, CHU
Rabat-Salé, Maroc.
INTRODUCTION: The cervicofacial localization of cutaneous lymphomas is
rare.
These lymphomas usually present as a long-lasting and treatment-refractory
papule
or nodule. Lymphomas can also be revealed by cervicofacial cellulitis.
CASES: We report 2 cases of cervicofacial cellulitis revealing a cutaneous
lymphoma. The diagnosis was proved by multiple biopsies, performed because
there
was no clinical improvement in spite of an aggressive and adequate
antibiotherapy. Our 2 patients were treated by radio and chemotherapy.
DISCUSSION: Cutaneous lymphomas are lymphocytic proliferations stemming
from
cutaneous lymphoid tissue, without nodal, medullary, or visceral
localization.
Their clinical presentation is quite polymorphic, and cellulitis is one of
the
modes of revelation, especially forehead and neck localization. They have
no
portal of entry and are resistant to treatment. The diagnosis relies on
histology, and biopsies must be performed if there is a suspicion of
lymphoma.
The treatment is radio and chemotherapy, and the evolution depends on the
tumoral
stage.
PMID: 17399753
6. Dermatol Online J. 2006 Mar 30;12(3):2.
Role of slit skin smear examination in cutaneous T-cell lymphomas and other
chronic dermatoses.
Bindu B, Kurien A, Shenoi SD, Prabhu S.
Department of Skin and STD, Kasturba Medical College, Manipal, Karnataka,
India.
The purpose of this study was to evaluate the utility of slit-skin smear
examination in the diagnosis of various chronic dermatoses. The study
included 24
patients with chronic dermatoses who presented to the skin outpatient
department.
Ten patients had idiopathic erythroderma, seven were diagnosed with
airborne
contact dermatitis, four had cutaneous T-cell lymphoma, two had chronic
actinic
dermatoses, and a single patient had panniculitis. Slit skin smears were
obtained
from all patients, stained with Leishman stain, and examined under
microscope.
Out of 24 patients, all four cases of cutaneous T-cell lymphoma showed
abnormal
cells suggestive of lymphomatous infiltration, two patients with airborne
contact
dermatitis showed reactive lymphocytes, and two idiopathic erythroderma
cases
showed numerous eosinophils in the smear. Slit skin smear examination is a
simple
rapid, decisive test in the diagnosis of cutaneous T-cell lymphoma. It is a
useful screening test, especially in Sezary syndrome and diseases with
specific
skin infiltrate.
PMID: 16638416
7. J Clin Oncol. 2003 Nov 15;21(22):4251-2.
Uncommon hematologic malignancies. Case 3. Parotid swelling during
treatment for
transformed mycosis fungoides.
Bird BR, Daly PA.
St. James's Hospital and Trinity College, Dublin, Ireland.
PMID: 14615457
8. Am J Dermatopathol. 2009 Dec;31(8):834-7.
A dyshidrosis-like variant of adult T-cell leukemia/lymphoma with
clinicopathological aspects of mycosis fungoides. A case report.
Bittencourt AL, Mota K, Oliveira RF, Farré L.
Department of Pathology, Federal University of Bahia, Salvador, Bahia,
Brazil.
Adult T-cell leukemia/lymphoma (ATL) is an aggressive type of
leukemia/lymphoma
associated with the human T-cell lymphotropic virus (HTLV-I). We describe
an
adult male patient clinically and pathologically diagnosed as mycosis
fungoides
and treated with chemotherapy after which complete involution of the
lesions
occurred. The disease relapsed with confluent dyshidrosis-like vesicles on
the
palmoplantar regions, followed by disseminated vesiculopapules and
associated
lymphocytosis. A serological test performed at this time revealed HTLV-I
infection, and a diagnosis of chronic ATL was made. Monoclonal integration
of
HTLV-I was detected in peripheral blood mononuclear cells by inverse long
polymerase chain reaction. A skin biopsy revealed spongiosis, Pautrier
abscesses,
and intraepidermal vesicles with atypical lymphocytes and an infiltration
of
small and atypical CD4 lymphocytes in the superficial dermis. Proliferative
index
(Ki-67) was 70%. This is the first reported vesicular cutaneous ATL with
confirmation of HTLV-I proviral integration. The delay that occurred in
diagnosing ATL was due to the fact that mycosis fungoides and ATL may
present the
same clinical, histopathological, and immunohistochemical features.
PMID: 19770630
9. J Dtsch Dermatol Ges. 2003 Oct;1(10):785-9.
Bexarotene--an alternative therapy for progressive cutaneous T-cell
lymphoma?
First experiences.
Bohmeyer J, Stadler R, Kremer A, Nashan D, Muche M, Gellrich S, Luger T,
Sterry
W.
Department of Dermatology, Medical Centre Minden.
BACKGROUND: A standard therapy for advanced cutaneous T-cell lymphomas has
not
yet been defined. Bexarotene is a new retinoid x receptor-specific retinoid
that
has been approved for systemic second-line therapy for cutaneous T-cell
lymphomas
in the USA and Europe. In order to evaluate the efficacy of bexarotene in
cutaneous T-cell lymphomas, a pilot trial was initiated.
PATIENTS AND METHODS: In a pilot project 10 patients with advanced
cutaneous
T-cell lymphomas, who had received a variety of previous treatments, were
treated
with bexarotene at the departments of dermatology in Münster, Minden and
Charité
Berlin, Germany. The patients received bexarotene at a dose of 300 mg/m2
body
surface daily. According to the percentage of tumour reduction and affected
body
surface, the response rates were divided in complete and partial remission,
stable disease and progressive disease. Laboratory parameters i.e.
cholesterol,
triglycerides transaminases, T3, T4, and TSH were screened regularly.
RESULTS: In 2 patients a short partial remission was achieved; however,
after a
few weeks progression followed. In 4 patients a lasting stabilisation was
obtained. The other 4 patients showed a progressive disease during therapy.
6
patients developed hypertriglyceridemia with levels up to 2000 mg/dl;
therapy had
to be suspended in 3 patients because of these adverse drug events.
CONCLUSION: Weighing benefits and risks, bexarotene can at present not be
recommended as standard therapy in the treatment of patients with
progressive
cutaneous lymphomas.
PMID: 16281814
10. J Am Acad Dermatol. 1987 Jan;16(1 Pt 1):45-60.
Combined total body electron beam irradiation and chemotherapy for mycosis
fungoides.
Braverman IM, Yager NB, Chen M, Cadman EC, Hait WN, Maynard T.
Since 1979 a protocol of total body electron beam therapy (3,600 rads; 6
MeV),
followed by six monthly cycles of chemotherapy (doxorubicin, 30 mg/M2 given
intravenously once monthly, and cyclophosphamide, 100 mg/M2 given orally
each day
for 14 days), has been used to treat fifty patients with mycosis fungoides
(primarily Stages I and II). A group of twenty-four patients, treated by
identical high-dose electron beam therapy alone, served as control
subjects.
Actuarial analysis by the Kaplan-Meier method and statistical analysis by
the
generalized Wilcoxon test of Gehan demonstrated a significant difference (p
=
0.008) in the probability of Stages I and II patients' remaining in
complete
clinical remission when combination therapy was compared with high-dose
electron
beam therapy alone. No statistically significant difference was
demonstrated in
patients in Stages III and IV mycosis fungoides. Although 60% of patients
were in
"complete clinical remission," the longest follow-up being 75 months, all
continued to show karyotypic abnormalities of circulating lymphocytes, and
70%
had intermittently and abnormally elevated blood levels of Sézary cells.
PMID: 3100583
11. Oncol Rep. 2001 Jan-Feb;8(1):197-9.
Mycosis fungoides and pregnancy.
Castelo-Branco C, Torné A, Cararach V, Iglesias X.
Institute of Obstetrics, Gynecology and Neonatology, Hospital Clínic,
Faculty of
Medicine, University of Barcelona, Barcelona, Spain.
Mycosis fungoides is a cutaneous T-cell lymphoma, a subgroup of nonHodgkin's
lymphomas, characterized by skin infiltration and occasionally systemic
involvement. The association of pregnancy and mycosis fungoides has not
been
described previously. A case of mycosis fungoides, stage IVb, in a pregnant
woman
is reported. Prior to pregnancy, the patient received adriamycin,
cyclophosphamide, vincristine prednisolone (CHOP) and bleomycin and total
body
irradiation. Around the concepcional period she presented a cutaneous
relapse
palliated with photon radiotherapy. No obstetrics complications were
observed
during gestation. At 39 week's gestation a cesarean section was performed
and a
healthy 2900 g boy was delivered. Mycosis fungoides did not worsen during
pregnancy and postpartum period. In conclusion mycosis fungoides did not
adversely affect pregnancy outcome and gestation did not worsen the
malignancy
course. This case report may be valuable in managing patients with mycosis
fungoides who are currently pregnant or are contemplating pregnancy.
PMID: 11115598
12. Dermatology. 2011;222(4):297-303. Epub 2011 May 21.
Two atypical cases of cutaneous gamma/delta T-cell lymphomas.
Caudron A, Bouaziz JD, Battistella M, Sibon D, Lok C, Leclech C, Ortonne N,
Molinier-Frenkel V, Bagot M.
Department of Dermatology, AP-HP, Saint-Louis Hospital, Paris, France.
acaudron02@gmail.com
Cutaneous γ/δ T-cell lymphoma (CGD-TCL) is a recent entity described in the
newly
revised World Health Organization-European Organization for Research and
Treatment of Cancer classification of cutaneous lymphomas, and is
characterized
by the γ/δ T-cell receptor expression on atypical lymphocytes. Only a few
cases
of primary CGD-TCL have been reported, with an extremely aggressive course
(median survival time of 15 months). We describe 2 atypical cases of CGDTCL. The
first case was initially misdiagnosed as an inflammatory panniculitis due
to the
granulomatous infiltrate on the skin biopsy specimen. Diagnosis was
confirmed
using δ PCR that revealed γ/δ T-cell clonal expansion. The evolution was
marked
by predominant γ/δ T-cell infiltrate with diffuse body fat involvement as
seen on
positron emission tomography-computed tomography. The second case is the
first
described Epstein-Barr virus (EBV)-associated CGD-TCL with a rapidly fatal
evolution. CGD-TCL is also a heterogeneous entity and δ PCR and EBV-encoded
RNA
probe to detect an EBV latent infection may help diagnose and characterize
these
cutaneous lymphomas.
Copyright © 2011 S. Karger AG, Basel.
PMID: 21606639
13. Int J Oncol. 2005 Jun;26(6):1559-62.
Cutaneous CD56 positive natural killer and cytotoxic T-cell lymphomas.
Chattopadhyay A, Slater DN, Hancock BW.
Weston Park Hospital, Sheffield, S10 2SJ, UK.
We report two cases of CD56 positive natural killer (NK) cell and cytotoxic
T-cell cutaneous lymphomas and review the literature on these rare forms of
non-Hodgkin's lymphoma. The first case was diagnosed to have extra nodal
NK/T-cell lymphoma, nasal-type. She had a rapid downhill clinical course
and died
within 3 months of presentation. She had been started on systemic
chemotherapy
but did not respond. The second case was diagnosed as subcutaneous
panniculitis-like T-cell lymphoma, CD56 positive variant. She presented
with skin
nodules that were quiescent for 10 years. Then the course of the disease
suddenly
changed and progressed rapidly. She had systemic chemotherapy and initially
had a
complete response, but she relapsed within 1 month of completion of
chemotherapy.
She then had partial response with further chemotherapy but relapsed
rapidly. She
died within 15 months of her lymphoma changing to its aggressive form.
These
cases illustrate the often poor prognosis of cutaneous CD56 positive
lymphomas.
PMID: 15870869
14. J Clin Pathol. 2008 Jun;61(6):770-2.
Rare provisional entity: primary cutaneous aggressive epidermotropic CD8+
cytotoxic T-cell lymphoma in a young woman.
Csomor J, Bognár A, Benedek S, Sinkó J, Fekete S, Krenács L, Matolcsy A,
Reiniger
L.
1st Department of Pathology and Experimental Cancer Research, Faculty of
Medicine, Semmelweis University, Budapest, Hungary.
Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma
is a
rare and provisional entity, characterised by cutaneous involvement and
aggressive clinical behaviour. The case is here presented of a young woman
with
concurrent cutaneous and systemic involvement. Despite multi-agent
chemotherapy,
only partial remission could be achieved, and the patient died from
therapy-resistant respiratory and circulatory failure. This case report is
intended to add to the data collected on this rare entity, with only about
20
cases as yet described.
PMID: 18505891
15. J Cutan Med Surg. 2003 May-Jun;7(3):247-9.
Unusual presentation of angiocentric T-cell lymphoma mimicking perianal
abscess.
Dashkovsky I, Cozacov JC.
Department of Surgery, Sieff Government Hospital, Safed, Israel.
drigor88@hotmail.com
BACKGROUND: Subcutaneous angiocentric T cell is a common form of cutaneous
lymphoma localized within subcutis mimicking lobular panniculitis. It is
rarely
manifested as perianal skin lesion.
OBJECTIVE: To suggest that perianal T-cell lymphoma is a rare entity that
should
be included in the differential diagnosis of perianal infiltrate mimicking
perianal abscess.
METHODS AND RESULTS: A 65-year-old woman presented with painful perianal
infiltrate mimicking a perianal abscess. The pain lasted seven days and
there was
no evidence of fever. Bacterial examination of tissue of the infiltrate
discovered Staphylococcus aureus. Angiocentric T-cell lymphoma was
demonstrated
on biopsy.
CONCLUSION: Our case represented sequela of subcutaneous angiocentric Tcell
malignant lymphoma with a complication of a secondary infection mimicking
perianal abscess. In patients presenting with a perianal infiltrate without
abscess, a malignant condition should be considered a differential
diagnosis and
a biopsy should be performed.
PMID: 12717588
16. Clin Exp Dermatol. 2003 Nov;28(6):620-4.
Co-existent primary cutaneous anaplastic large cell lymphoma and
lymphomatoid
papulosis.
Dawn G, Morrison A, Morton R, Bilsland D, Jackson R.
Department of Dermatology, Southern General Hospital, Glasgow, Scotland.
gmitali@eggconnect.net
We describe the case of a 37-year-old female with a history of psoriasiform
dermatitis who presented with multicentric primary cutaneous CD30-positive
anaplastic large T cell lymphoma (ALCL). Despite aggressive systemic
therapy, the
patient suffered multiple relapses and the lymphoma spread to cervical and
inguinal lymph nodes. Later in her clinical course it was appreciated that
she
was also suffering from lymphomatoid papulosis (LyP). The case illustrates
the
overlapping clinical, histological and immunophenotypic features of ALCL
and LyP,
conditions which represent a spectrum of CD30-positive lymphoproliferative
disease. A multidisciplinary approach between dermatologist, oncologist and
pathologist is essential for the optimal management of these complex
conditions.
PMID: 14616830
17. Br Med J (Clin Res Ed). 1987 Oct 10;295(6603):873-5.
Membrane phenotype and response to deoxycoformycin in mature T cell
malignancies.
Dearden CE, Matutes E, Hoffbrand AV, Ganeshaguru K, Brozovic M, Williams
HJ,
Traub N, Mills M, Linch DC, Catovsky D.
Medical Research Council Leukaemia Unit, Hammersmith Hospital, London.
The adenosine deaminase inhibitor deoxycoformycin was used in low doses to
treat
19 patients with clinically aggressive T cell malignancy with a mature
membrane
phenotype. The patients comprised eight with prolymphocytic leukaemia, two
with
chronic lymphocytic leukaemia, four with adult T cell leukaemia-lymphoma,
three
with Sézary syndrome, and two with T cell lymphoma. Two thirds of the
patients
had been resistant or minimally responsive to combination chemotherapy.
Complete
remission was obtained in five patients (two with prolymphocytic leukaemia
and
one each with chronic lymphocytic leukaemia, adult T cell leukaemialymphoma, and
Sézary syndrome) and partial remission in two others. Unmaintained complete
remission lasting more than one year was seen in three patients. Responses
were
obtained only in patients with CD4+,CD8-membrane markers (seven out of 10),
and
no responses were recorded in any of the nine patients with a different
phenotype. In this series remission appeared to correlate with the membrane
phenotype of the neoplastic cell and not with the cytopathological
diagnosis.
Future studies should establish the biochemical basis for the greater
sensitivity
of CD4+ lymphoid cells to deoxycoformycin.
PMCID: PMC1247926
PMID: 2890401 [PubMed - indexed for MEDLINE]
18. Br J Dermatol. 2005 Jul;153(1):183-5.
Pegylated liposomal doxorubicin in stage IVB mycosis fungoides.
Di Lorenzo G, Di Trolio R, Delfino M, De Placido S.
Dipartimento di Patologia Sistematica, Clinica Dermatologica, Università di
Napoli Federico II, Naples, Italy. giuseppedilorenzoncol@hotmail.com
BACKGROUND: Previous studies have shown that pegylated liposomal
doxorubicin (LD)
is effective in the treatment of relapsing or recalcitrant cutaneous T-cell
lymphoma.
OBJECTIVES: To evaluate the activity and toxicity of LD in patients with
stage
IVB mycosis fungoides (MF).
METHODS: In this retrospective study, we evaluated outcomes and recorded
adverse
effects in 10 patients with MF (seven men and three women) with
extracutaneous
involvement. Patients were treated with LD 20 mg m(-2) administered
intravenously
every 4 weeks.
RESULTS: All patients received at least two cycles of LD, three patients
received
four cycles and one patient received six cycles. Three patients (30%) had a
partial response and two patients had stable disease. Grade 1-2 leucopenia
occurred in three of the 10 patients, and grade 4 leucopenia in one. Three
patients had grade 2 palmoplantar erythrodysaesthesia.
CONCLUSIONS: This study demonstrates that LD is beneficial in terms of
activity
and toxicity in stage IVB MF. These observations should be verified in
larger
studies.
PMID: 16029347
19. Hematology. 2007 Apr;12(2):155-7.
Rapid leukaemic evolution in a cutaneous blastic NK-cell lymphoma initially
diagnosed as pseudolymphoma.
Di Mario A, Garzia M, d'Alò F, Rumi C, Massini G, Bellesi S, Zini G.
Istituto di Ematologia, Università Cattolica del Sacro Cuore, Rome, Italy.
PMID: 17454197
20. Int J Hematol. 2009 Sep;90(2):226-9. Epub 2009 Jun 23.
Differential diagnosis and treatment of primary, cutaneous, anaplastic
large cell
lymphoma: not always an easy task.
Diamantidis MD, Papadopoulos A, Kaiafa G, Ntaios G, Karayannopoulou G,
Kostopoulos I, Girtovitis F, Saouli Z, Kontoninas Z, Raptis ID, Savopoulos
C,
Hatzitolios A.
Department of Hematology, First Propedeutic Department of Internal
Medicine,
Aristotle University of Thessaloniki, AHEPA Hospital, 1 S. Kiriakidi
Street,
Thessaloniki, Greece. diamantidis79@yahoo.gr
Primary cutaneous anaplastic large cell lymphoma (PC-ALCL) is a rare and
distinct
neoplasm appearing de novo on the skin. We present a case of a 75-year-old
man
diagnosed with PC-ALCL in his left femoral region. We describe the
morphology of
lesions along with the differential diagnosis, treatment, clinical course
and
prognosis. We further discuss parameters concerning treatment that should
be
considered when a PC-ALCL is diagnosed. Our case report demonstrates the
complexity in classification, staging, differential diagnosis and therapy
selection of PC-ALCLs. It is crucial to emphasize the importance of
clinical
criteria in diagnosing a PC-ALCL in combination with immunohistochemistry.
PMID: 19548068
21. Ann Dermatol Venereol. 2006 Dec;133(12):991-4.
[Aggressive T cytotoxic CD8+ epidermotropic cutaneous lymphoma: a case in a
patient with Steinert's myotonic dystrophy].
[Article in French]
Du-Thanh A, Durand L, Costes V, Guillot B, Dereure O.
Service de Dermatologie, Laboratoire d'Anatomie Pathologique, CHRU
Montpellier.
INTRODUCTION: Primary cutaneous "aggressive" CD8-positive epidermotropic
cytotoxic T-cell lymphoma is a rare subset of cutaneous cytotoxic T/NK
lymphomas
that clearly differs from mycosis fungoides, whether CD4+ or CD8+, by the
presence of rapidly evolving tumoral cutaneous lesions, foci of
keratinocytes
necrosis, a cytotoxic T phenotype and a poor prognosis.
CASE REPORT: A 33-year-old man with Steinert's myotonic dystrophy was
referred
for evaluation of rapidly worsening cutaneous tumors along with marked
deterioration of general status. Clinical, histological and
immunohistological
data led to the diagnosis of primary cutaneous CD8+ epidermotropic
cytotoxic
T-cell lymphoma. CHOP chemotherapy was effective despite cardiac toxicity
in the
setting of Steinert's dystrophy, but the patient relapsed and died of
pulmonary
sepsis after chemotherapy was resumed.
DISCUSSION: The treatment of primary cutaneous epidermotropic CD8+
cytotoxic
T-cell lymphoma is not codified. CHOP chemotherapy is usually the firstline
therapy but relapses are frequent with median survival of no more than 34
months.
In our patient, an additional difficulty was the cardiac toxicity of
cytostatic
drugs linked to the myopathy which prevented the use of high dosages,
requiring a
change of therapeutic regimen.
PMID: 17185931
22. Leuk Lymphoma. 1998 Nov;31(5-6):583-8.
Systemic polychemotherapy in the treatment of primary cutaneous lymphomas:
a
clinical follow-up study of 81 patients treated with COP or CHOP.
Fierro MT, Quaglino P, Savoia P, Verrone A, Bernengo MG.
Department of Medical and Surgical Specialties, University of Turin, Italy.
The efficacy of systemic polychemotherapy in the treatment of primary
cutaneous
B-cell lymphomas (CBCL) or T-cell lymphomas (CTCL) is still controversial.
A
series of 81 patients (46 primary CBCL and 35 CTCL) were treated with COP
or CHOP
regimens. In primary CBCL, the overall objective response rate (RR) was
98%, with
an 89% CR rate and a 33% relapse-rate. Five-year disease-free survival was
70%,
5-year survival 97%. Patients with leg or widespread lesions showed a
higher
relapse-rate (55% vs 26%) than those with trunk or head lesions. The
overall
objective RR was 40% in CTCL patients, with a 23% CR rate; median response
duration was 5.7 months, median survival 19 months. The results confirm
both the
good prognosis of primary CBCL and the efficacy of polychemotherapy. CHOP
regimen
is to be preferred to COP in as much as it reduces relapse rates.
Conversely,
there are no indications for the use of COP/CHOP regimens as first-line
chemotherapy in CTCL patients.
PMID: 9922049
23. Dermatol Online J. 2010 Feb 15;16(2):6.
An unusual ulcer in an 8-year-old girl.
Friedman A, Abadi M, Wu K, Fisher M, Abadi J.
Division of Dermatology, Department of Medicine, Albert Einstein College of
Medicine, Bronx, New York, USA. ajf0424@yahoo.com
PMID: 20178702
24. Int J Hematol. 2002 Jan;75(1):67-71.
Therapy-related myelodysplastic syndrome in a case of cutaneous adult Tcell
lymphoma.
Fukuda N, Shinohara K, Ota I, Muraki K, Shimohakamada Y.
Department of Medicine, Yamaguchi Prefecture Central Hospital, Hofu, Japan.
We report a case of therapy-related myelodysplastic syndrome (t-MDS) in
adult
T-cell lymphoma. A 69-year-old man suffered from cutaneous adult T-cell
lymphoma,
which was treated with radiation to the skin and combination chemotherapy
of
CHOP-V-MMV and VEPA-B. After 14 months of these therapies, anemia and
thrombocytopenia appeared, and bone marrow aspiration smears showed
immature
myeloblasts, dysplastic erythroblasts, and micromegakaryocytes. Therapyrelated
MDS of refractory anemia with an excess of blasts was diagnosed.
Cytogenetic
study of the bone marrow cells showed 5q- and additional abnormalities.
Rearrangement of the MLL gene was observed in the bone marrow cells.
Mutations of
N-ras codons at 12,13, and 61, p53 tumor suppressor gene, and monoclonal
integration of human T-lymphotrophic virus -1 provirus DNA were not
observed in
the bone marrow cells. The patient died of pneumonia 21 months after
diagnosis of
cutaneous adult T-cell lymphoma.
PMID: 11843294
25. JOP. 2008 Nov 3;9(6):719-24.
Obstructive jaundice in a patient with mycosis fungoides metastatic to the
pancreas. EUS findings.
Gottlieb K, Anders K, Kaya H.
Endoscopic Ultrasound, Deaconess Medical Center Department of Pathology,
Cancer
Care Northwest, Spokane, WA, USA. klausg@u.washington.edu
CONTEXT: Cutaneous T-cell lymphomas such as mycosis fungoides are uncommon
neoplasms with a long and often relatively indolent course. Some eventually
metastasize to lymph nodes or visceral organs but there are to our
knowledge only
two prior reports which describe clinically relevant pancreas involvement.
CASE REPORT: We present the case of a 52-year-old man with mycosis
fungoides who
developed abdominal pain and jaundice. Endoscopic ultrasound guided-fine
needle
aspiration biopsies of a peculiar infiltrative appearing mass in the head
of the
pancreas revealed T-cell lymphoma cells.
CONCLUSION: There is an increased incidence of second primaries in
cutaneous
T-cell lymphomas and a biopsy diagnosis of new intra-abdominal masses is
essential.
PMID: 18981554
26. Cancer Treat Rep. 1979 Apr;63(4):647-53.
Combination chemotherapy for mycosis fungoides: a Southwest Oncology Group
study.
Grozea PN, Jones SE, McKelvey EM, Coltman CA Jr, Fisher R, Haskins CL.
Between 1972 and 1977, the Southwest Oncology Group studied the following
three
chemotherapy programs for the treatment of patients with advanced forms of
mycosis fungoides: (a) cyclophosphamide, adriamycin, vincristine, and
prednisone
(CHOP) (seven patients); (b) adriamycin, vincristine, and prednisone (HOP)
(five
patients); and (c) cyclophosphamide, vincristine, prednisone, and bleomycin
(COP
plus bleomycin) (12 patients). Among the 24 evaluable patients there was an
overall objective response rate of 95% with seven (29%) achieving a
complete
remission. With the adriamycin-containing chemotherapy, five (42%) of 12
patients
achieved a complete remission compared to two (17%) of 12 patients treated
with
COP plus bleomycin. The median duration of remission (partial plus
complete) was
longer with the COP plus bleomycin combination (median, 47 weeks) than with
the
adriamycin-containing combinations (median, 22 weeks; P = 0.03). The median
survival for all 24 evaluable patients was 95 weeks and was similar
regardless of
remission-induction therapy. In summary, combination chemotherapy proved to
be
effective palliative therapy for advanced mycosis fungoides.
PMID: 87277
27. J Am Acad Dermatol. 2011 Nov;65(5):1063-4.
Adult T-cell lymphoma/leukemia presenting as pagetoid reticulosis of the
palms
and soles.
Grubb B, Henderson DB, Pandya AG.
PMID: 22000876
28. J Eur Acad Dermatol Venereol. 2003 Mar;17(2):219-22.
Cytotoxic gamma/delta subcutaneous panniculitis-like T-cell lymphoma:
report of a
case with pulmonary involvement unresponsive to therapy.
Guizzardi M, Hendrickx IA, Mancini LL, Monti M.
Department of Dermatology, Istituto Clinico Humanitas, University of Milan,
Milan, Italy.
Peripheral subcutaneous panniculitis-like T-cell lymphoma (PSPTCL) is a
rare form
of cutaneous lymphoma recently proposed as a distinct clinicopathological
entity.
It usually presents with multiple indurated subcutaneous plaques or
tumours, most
commonly located on the extremities and trunk and clinically mimicking
lobular
panniculitis. Associated constitutional symptoms due to haemophagocytic
syndrome
may advance or, more often, complicate the clinical course in about 40-70%
of
cases. Finding of TIA-1+ and perforin + cytolytic granules in atypical
pleomorphic lymphocytes suggests PSPTCL origin from granular cells of Tcell or
natural killer cell phenotype. Cells have a CD3+ CD4+ CD8- or CD3+ CD4CD8+
T-cell phenotype. Moreover, these lymphomas can express natural killer cell
associated antigens, such as CD56, especially in gamma/delta variants.
PSPTCL
following an indolent clinical course with recurrent self-healing lesions
have
been described. The prognosis of most PSPTCL is poor even when treated with
aggressive chemotherapy. This paper reports a case of PCTCL in a young
woman with
T-cytotoxic differentiation, with rapid progression unresponsive to several
treatments.
PMID: 12705758
29. Eur J Haematol. 2004 May;72(5):377-8.
Treatment with alemtuzumab in a case of refractory primary cutaneous
CD30-negative CD8-positive cytotoxic large T-cell lymphoma.
Gutierrez A, Rodriguez J, Ramos R, Gines J, Sampol A, Galmes B, Besalduch
J.
PMID: 15059077
30. J Am Acad Dermatol. 1997 Nov;37(5 Pt 2):832-5.
Subcutaneous T-cell lymphoma treated with systemic chemotherapy, autologous
stem
cell support, and limb amputation.
Haycox CL, Back AL, Raugi GJ, Piepkorn M.
Division of Dermatology, University of Washington, Seattle 98195-6524, USA.
Subcutaneous T-cell lymphoma is an unusual variant of peripheral T-cell
lymphoma
in which the malignant infiltrate preferentially involves the subcutis. The
disease is often initially misdiagnosed as a benign inflammatory
panniculitis or
a granulomatous disease. We describe subcutaneous T-cell lymphoma in a
39-year-old man who was treated with systemic chemotherapy, autologous stem
cell
support, and amputation of the limb primarily involved with the
lymphomatous
infiltrate. This is the first report of amputation being included in the
treatment regimen of subcutaneous T-cell lymphoma. Because preferential
involvement of the extremities often occurs in patients with subcutaneous
T-cell
lymphoma, surgical debulking of refractory disease by partial or complete
limb
amputation may be a useful therapeutic adjunct.
PMID: 9366846
31. Cancer. 1985 May 1;55(9 Suppl):2176-83.
The role of radiation therapy in the management of the non-Hodgkin's
lymphomas.
Hoppe RT.
Radiation therapy has a broad range of applications in the management of
patients
with non-Hodgkin's lymphoma. It has curative potential for patients with
Stage I
to II low-grade lymphoma (small lymphocytic, follicular small cleaved, and
follicular mixed) and has substantial palliative efficacy in patients with
more
advanced stage low-grade lymphoma. Low-dose whole-body irradiation may be
used as
palliative therapy even in patients with bone marrow involvement by these
lymphomas. In the management of the large cell lymphomas (diffuse large
cell,
diffuse mixed, and immunoblastic), radiation alone has curative potential
in only
the most favorable early-stage presentations. However, since radiation can
achieve significant responses in these tumors, it should be considered for
inclusion in combined-modality programs. Reports that have appeared in the
literature as well as results of treatment at Stanford that bear upon these
issues are reviewed.
PMID: 2579725
32. J Cutan Pathol. 2008 Nov;35(11):1063-7. Epub 2008 Jun 9.
Transformation of cutaneous gamma/delta T-cell lymphoma following 15 years
of
indolent behavior.
Hosler GA, Liégeois N, Anhalt GJ, Moresi JM.
Department of Dermatology, Johns Hopkins University, Baltimore, MD, USA.
gregory.hosler@propathlab.com
Subcutaneous gamma/delta (gamma/delta) T-cell lymphoma is a rare lymphoma,
characterized by its unique immunophenotype and clinical course. It has
been
shown to behave more aggressively than its counterpart bearing the
alpha/beta
receptor and has recently been removed from the subcutaneous panniculitislike
T-cell lymphoma category for this very reason. We present a case of a
patient
with a 15-year running diagnosis of panniculitis. Following these years of
indolent behavior, the disease began an aggressive clinical course and she
was
diagnosed with gamma/delta T-cell lymphoma. Molecular analysis identified a
T-cell clone, which through retrospective analysis, was also shown to be
present
in the patient's original biopsy material. We present this case as a rare
example
of initial indolent behavior in a lymphoma typically considered very
aggressive.
PMID: 18544066
33. Ai Zheng. 2009 Oct;28(10):1093-9.
[Clinical analysis of 19 cases of subcutaneous panniculitis T-cell lymphoma
with
literature review].
[Article in Chinese]
Huang JJ, Cai MY, Ye S, Li ZM, Huang HQ, Lin TY.
State Key Laboratory of Oncology in South China, Guangzhou, Guangdong
510060, P.
R. China.
BACKGROUND AND OBJECTIVE: Subcutaneous panniculitis T-cell lymphoma (SPTCL)
is a
rare subtype of primary cutaneous lymphoma. This study was to analyze the
clinical characteristics, treatment and prognosis of SPTCL.
METHODS: Clinical data of 19 SPTCL patients, treated at Cancer Center and
the
First Affiliated Hospital of Sun Yat-sen University from January 2001 to
July
2007, were analyzed.
RESULTS: The median age of the patients was 36 years. Seven patients had
skin-excluded extra-nodal involvement; ten had lactate dehydragenase (LDH)
elevation before treatment; one had hemophagocytic syndrome. Most of the
parents
received chemotherapy, including CHOP regimen, modified-alternative triple
therapy (m-ATT), and Hyper-CVAD/HD-MA regimen. The median follow-up was 56
months. The median survival was 40 months, and the 2-year expected overall
survival rate was 56%. Eight patients who received treatment of intensive
chemotherapy had continous remission of 17-70 months; six of them underwent
radiotherapy after chemotherapy. Univariate analysis (log-rank test) showed
that
sex, B symptoms, skin-excluded extra-nodal involvement, and pre-treatment
blood
cell count and LDH level affected the prognosis.
CONCLUSIONS: SPTCL might be cured by high dose chemotherapy combined with
whole
body irradiation. The regimens which are effective without crossing
resistance or
more intensive may improve the response rate and overall survival.
PMID: 19799820
34. Clin Lymphoma. 2002 Mar;2(4):238-41.
Testicular lymphoma: a literature review and report of a case with a
zoster-like
cutaneous recurrence.
Ingram RM, Williams ME, Fintel WA, Ross M.
Division of Hematology/Oncology and Adult Stem Cell Transplantation
Program,
University of Virginia Health System, Charlottesville, VA 22908, USA.
rmi8n@virginia.edu
Testicular lymphoma accounts for approximately 1% of all cases of nonHodgkin's
lymphoma. This distinct clinical entity can have an aggressive course with
a high
rate of systemic relapse. We describe a unique case of a diffuse large Bcell
lymphoma, T-cell-rich variant with cutaneous dermatomal zosteriform
recurrence
presenting as neuralgia. This case represents a unique pattern of treatment
failure in this aggressive extranodal lymphoma.
PMID: 11970763
35. Intern Med. 2006;45(9):641-7. Epub 2006 Jun 1.
Coexistent B-cell lymphoma and cutaneous T-cell lymphoma.
Inokuchi T, Shincho M, Moriwaki Y, Ka T, Takahashi S, Tsutsumi Z, Lin Y,
Hirota
S, Yamamoto T.
Division of Endocrinology and Metabolism, Department of Internal Medicine,
Hyogo
College of Medicine, Nishinomiya.
A 78-year-old man with a history of mycosis fungoides was referred for
evaluation
of a right adrenal mass. A physical examination showed the left cervical
lymph
node to be palpable, which was later shown to be caused by a diffuse large
B-cell
lymphoma. The patient was diagnosed with concurrent mycosis fungoides and a
diffuse large B-cell lymphoma. Three courses of chemotherapy were
performed,
however, the patient died of advanced disease. Autopsy findings showed that
the
right adrenal and soft tissue masses had an identical B-cell origin.
Although the
exact mechanism remains unclear, the pathogenesis of this rare association
is
discussed.
PMID: 16755097
36. Dermatology. 2004;209(3):243-5.
Nasal-type NK/T-cell lymphoma successfully treated with ProMACE-CytaBOM
therapy.
Isogai R, Kawada A, Hashimoto K, Aragane Y, Tezuka T, Maeda Y, Kanamaru A.
PMID: 15459544
37. Dermatol Online J. 2008 Sep 15;14(9):6.
Folliculotropic mycosis fungoides and a leonine clinical appearance of the
face.
Ito T, Yamamoto T, Matsumoto Y, Wakamatsu J, Kato Y, Tsuboi R.
Department of Dermatology, Tokyo Medical University, Tokyo, Japan.
itoto@niaid.nih.gov
A 73-year-old man presented with a two year history of multiple nodules and
follicular papules accompanied by slight itching on the face and the
forearm. A
physical examination showed multiple, soft, erythematous nodules on the
forehead,
cheek, and jaw, contributing to a generally leonine appearance of the face.
Histopathological examination from the forehead revealed dense, massive
concentrations of atypical lymphocytes in the dermis, and the forearm
showed
infiltration of atypical lymphocytes predominantly around the follicles. We
diagnosed this condition as folliculotropic cutaneous T cell lymphoma
(CTCL).
EPOCH therapy was very effective and the lesions of the forehead and
forearm
showed a decrease in tumor elevation; the histology showed a precipitous
decrease
in the number of the atypical lymphocytes.
PMID: 19061588
38. Acta Haematol. 2008;120(1):14-8. Epub 2008 Aug 21.
Durable remission of Sézary syndrome after unrelated bone marrow
transplantation
by reduced-intensity conditioning.
Kahata K, Hashino S, Takahata M, Fujisawa F, Kondo T, Kobayashi S, Fujita
Y,
Shimizu H, Imamura M, Asaka M.
Department of Gastroenterology and Hematology, Hokkaido University Graduate
School of Medicine, Sapporo, Japan. kahatak@med.hokudai.ac.jp
A 22-year-old Japanese man was diagnosed with Sézary syndrome with large
cell
transformation. His skin lesions persisted after treatment with 7 cycles of
CHOP
(cyclophosphamide, doxorubicin, vincristine and prednisone), psoralen and
ultraviolet light A, and total skin electron beam irradiation. He
subsequently
underwent allogeneic bone marrow transplantation by reduced-intensity
conditioning from a human leukocyte antigen-identical unrelated donor. He
developed grade II of acute graft-versus-host disease and extensive-type
chronic
graft-versus-host disease. He has no signs of disease 36 months after the
transplantation. The prognosis of patients with advanced stage of mycosis
fungoides or Sézary syndrome is very poor. Allogeneic hematopoietic stem
cell
transplantation, especially by reduced-intensity conditioning, is expected
to
become a curative treatment option, and graft-versus-tumor effect might
play a
critical role for sustained remission.
Copyright 2008 S. Karger AG, Basel.
PMID: 18716396
39. N Engl J Med. 1989 Dec 28;321(26):1784-90.
A randomized trial comparing combination electron-beam radiation and
chemotherapy
with topical therapy in the initial treatment of mycosis fungoides.
Kaye FJ, Bunn PA Jr, Steinberg SM, Stocker JL, Ihde DC, Fischmann AB,
Glatstein
EJ, Schechter GP, Phelps RM, Foss FM, et al.
National Cancer Institute-Navy Medical Oncology Branch, Bethesda, Md 20814.
Comment in
N Engl J Med. 1989 Dec 28;321(26):1822-4.
N Engl J Med. 1990 May 17;322(20):1470-1.
Mycosis fungoides is a T-cell lymphoma that arises in the skin and
progresses at
highly variable rates. Nonradomized studies have suggested that early
aggressive
therapy may improve the prognosis in this usually fatal disease. We studied
103
patients with mycosis fungoides, who, after complete staging, were randomly
assigned to receive either combination therapy, consisting of 3000 cGy of
electron-beam radiation to the skin combined with parenteral chemotherapy
with
cyclophosphamide, doxorubicin, etoposide, and vincristine (n = 52) or
sequential
topical treatment (n = 51). The prognostic factors were well balanced in
the two
groups. Combined therapy produced considerable toxicity: 12 patients
required
hospitalization for fever and transient neutropenia, 5 had congestive heart
failure, and 2 were later found to have acute nonlymphocytic leukemia.
Patients
receiving combined therapy had a significantly higher rate of complete
response,
documented by biopsy, than patients receiving conservative therapy (38
percent
vs. 18 percent; P = 0.032). After a median follow-up of 75 months, however,
there
was no significant difference between the treatment groups in disease-free
or
overall survival. We conclude that early aggressive therapy with radiation
and
chemotherapy does not improve the prognosis for patients with mycosis
fungoides
as compared with conservative treatment beginning with sequential topical
therapies.
PMID: 2594037
40. Mayo Clin Proc. 2008 Mar;83(3):351-4.
39-year-old woman with fever and weight loss.
Keane AM, Kasten MJ.
St. Vincent's University Hospital, Dublin, Ireland.
PMID: 18316004
41. Dermatology. 1994;189(2):188-92.
Lymphomatoid papulosis and Hodgkin's disease: report of a case.
Koeppel MC, Horschowski N, Terrier G, Andrac L, Stoppa AM, Signoret R,
Sayag J.
Department of Dermatology, Institut Paoli-Calmettes, Marseille, France.
The authors report the case of a 67-year-old-man who presented with stage
IIIAa
Hodgkin's disease (HD) almost 17 years after developing CD30+ type A
lymphomatoid
papulosis (LP). Combination chemotherapy resulted in a complete remission
of the
HD for 2 years, although the LP continued relentlessly as before. A
possible link
between HD and LP is discussed in the light of similar cases reported in
the
literature.
PMID: 7521232
42. Bone Marrow Transplant. 1997 Jul;20(2):171-3.
Effective high-dose chemotherapy followed by autologous peripheral blood
stem
cell transplantation in a patient with the aggressive form of cytophagic
histiocytic panniculitis.
Koizumi K, Sawada K, Nishio M, Katagiri E, Fukae J, Fukada Y, Tarumi T,
Notoya A,
Shimizu T, Abe R, Kobayashi H, Koike T.
Department of Internal Medicine II, Hokkaido University School of Medicine,
Sapporo, Japan.
A 20-year-old Japanese man developed generalized, subcutaneous, painless
nodules,
fever, abnormal liver function, serosal effusions, hepatosplenomegaly,
lymphadenopathy and anemia. Skin biopsies revealed lobular panniculitis
with a
morphologically benign histiocytic infiltration and prominent phagocytosis.
Atypical T lymphocytes were also present in the skin and liver. The
diagnosis
given was aggressive cytophagic histiocytic panniculitis (CHP) or
aggressive
subcutaneous panniculitic T cell lymphoma (SPTCL). He received
cyclophosphamide,
doxorubicin, and vincristine on day 1, prednisolone on days 1-5, and
etoposide on
days 1, 3 and 5 (CHOP-E), with the support of granulocyte colonystimulating
factor. This regimen was repeated every 2 weeks and complete clinical
remission
(CCR) was attained after three cycles of CHOP-E. As the clinical course of
aggressive CHP is recurrent and often fatal, he was given high-dose
chemotherapy
followed by autologous peripheral blood stem cell transplantation (APBSCT),
after
five cycles of CHOP-E. He has remained in CCR for 12 months after APBSCT.
High-dose chemotherapy followed by APBSCT is considered to be one of the
most
beneficial therapies for patients with aggressive CHP and aggressive phase
SPTCL.
PMID: 9244423
43. Int J Dermatol. 2009 Dec;48(12):1338-42.
Cutaneous natural killer (NK) / T-cell lymphoma: nasal type with extensive
facial
destruction.
Kost Al M, Kost Alová M, Belada D, Laco J.
2nd Department of Internal Medicine, Teaching Hospital, Hradec Králové,
Czech
Republic.
PMID: 19930492
44. Int J Dermatol. 2003 Sep;42(9):710-4.
Nasal-type natural killer cell lymphoma preceded by benign panniculitis
arising
in an asymptomatic HTLV-1 carrier.
Kunisada M, Adachi A, Matsumoto S, Ogawa Y, Horikawa T, Iwatsuki K.
Department of Dermatology, Hyogo Prefectural Kakogawa Hospital, Kakogawa,
Japan.
We report a case of an Epstein-Barr virus (EBV)-associated nasal-type
natural
killer cell lymphoma (NKCL) preceded by benign panniculitis, which arose in
a
48-year-old woman with an asymptomatic human T-cell leukemia/lymphoma virus
type-1 (HTLV-1) infection. A biopsy of the initial panniculitis lesion
demonstrated lobular panniculitis with a germinal center composed of benign
mononuclear cells with a phenotype of CD4+CD45RO+CD5sCD3+ cCD3 epsilon + Tcell
intracellular antigen-1 (TIA-1)- and granzyme B-. One year after oral
prednisolone therapy, the patient developed subcutaneous nodules composed
of
atypical lymphoid cells with a phenotype of CD4-CD45RO+CD56+sCD3-cCD3
epsilon +
(TIA-1)+ and granzyme B+. In the initial panniculitis lesion, neither EBVencoded
RNA (EBER-1) nor clonal proliferation of EBV-infected cells was identified.
In
later lesions, however, a large number of atypical cells were positive for
EBER-1, and a clonal expansion of EBV-infected cells was detected. No
clonal
rearrangement of T-cell receptor-alpha, -beta, or -gamma genes was found in
either specimen. This patient was an asymptomatic carrier of human T-cell
leukemia/lymphoma virus type-1 (HTLV-1) without clonal integration of
proviral
HTLV-1 in neither the peripheral blood nor the skin lesions. These
observations
suggest that EBV-associated NKCL occurred subsequently in the clinical
course of
benign panniculitis under the influence of immunosuppression caused by
prednisolone treatment and HTLV-1 infection.
PMID: 12956685
45. Leuk Lymphoma. 2009 Oct;50(10):1715-7.
CD56-negative extranodal nasal type of natural killer/T-cell lymphoma with
extranasal skin involvement.
Lan MX, Zhen ZX, Ming WH.
PMID: 19863343
46. J Dermatol. 1999 Jul;26(7):465-8.
A case of pre-Sézary syndrome preceded by hand lesions.
Lee NH, Lee SW, Choi EH, Lee WS, Ahn SK.
Department of Dermatology, Yonsei University Wonju College of Medicine,
Wonju,
Korea.
Pre-Sézary syndrome is an erythroderma with a chronic course, clinical
findings
of Sézary syndrome, lymphocytic subepidermal band infiltration at times,
and
repeated cycles of circulating Sézary cells of less than 1,000 cells/mm3.
Duration of the pre-existing skin diseases preceding pre-Sézary
erythroderma
varies from a few weeks to 20 years. Before the erythroderma develops,
these
patients are diagnosed with contact dermatitis, neurodermatitis, chronic
dermatitis, atopic dermatitis, or asteatotic eczema. Hand lesion also
precedes
the pre-Sézary erythroderma. This condition has been controlled by three
cycles
of chemotherapy consisting of vincristine, cytoxan, doxorubicin, and
prednisolone. We describe a case of pre-Sézary syndrome preceded by hand
lesion
and treated with chemotherapy.
PMID: 10458089
47. Cancer. 1977 May;39(5):1967-70.
Adriamycin therapy in advanced mycosis fungoides.
Levi JA, Diggs CH, Wiernik PH.
Thirteen patients with advanced mycosis fungoides received induction
therapy with
Adriamycin, 60/m2 I.V. repeated at 21-day intervals. Ten patients had
extensive
skin tumors; all patients had lymph node enlargement with mycosis fungoides
involvement in eight; four patients had biopsy-proven visceral involvement.
Only
two patients had received no prior therapy. The overall response rate with
Adriamycin therapy was 85% with three patients (23%) achieving a biopsyproven
complete remission and five patients (39%) partial remissions. The median
number
of courses to maximum response was two (range two to four). The principle
toxicity was myelosuppression, but this was not severe and the entire group
received more than 90% of the intended doses of Adriamycin. One patient
developed
probable Adriamycin cariotoxicity. Maintenance therapy for patients
achieving a
remission was methotrexate 15 mg/m2 I.M. twice weekly and cyclophosphamide
750
mg/m2 I.V. every 21 days. The median duration of complete remission was 32+
weeks
(range 16+-40+ weeks) while the median duration of partial remission was 18
weeks
(range 8-111+ weeks). Adriamycin has proven to be an effective induction
agent in
the treatment of advanced mycosis fungoides and its incorporation into
combination chemotherapy regimens is warranted.
PMID: 858126
48. Pathol Res Pract. 2011 Jan 15;207(1):55-9. Epub 2010 Jun 22.
Primary cutaneous blastic plasmacytoid dendritic cell neoplasm without
extracutaneous manifestation: case report and review of the literature.
Li Y, Li Z, Lin HL, Chen XH, Li B.
Department of Pathology, the First Affiliated Hospital, Sun Yat-sen
University,
58# Zhongshan Road II, Guangzhou, Guangdong 510080, China.
Blastic plasmacytoid dendritic cell (BPDC) neoplasm is a rare, highly
aggressive
hematopoietic malignancy with involvement of bone marrow and peripheral
blood. We
present 2 cases of primary cutaneous BPDC neoplasm without extracutaneous
manifestation during the course of disease. A 36-year-old and a 51-year-old
male
presented with erythematous patches, purple plaques, and nodules on the
head,
trunk, and extremities. Skin biopsies revealed that the lesions of both
cases
were composed of diffusely medium-sized monomorphic blastoid cells
infiltrating
into the dermis and subcutis. The neoplastic cells were strongly positive
for
CD4, CD56, CD123, and TdT, whereas other T-cell markers and EBV markers
were not
expressed. The patients underwent polychemotherapy with hyper-CVAD regimen
and
obtained a remarkable clinical response with regression of skin lesions. No
sign
of recurrence and extracutaneous manifestation was found during the period
of
follow-up. We presume that the favorable prognosis of our cases might
result from
the presentation only with a skin lesion, diffuse TdT expression in tumor
cells,
and aggressive chemotherapy with hyper-CVAD regimens. Laboratory
examination for
blood and bone marrow should be performed every 3-6 months during the first
period of follow-up to monitor the progression of disease even if the
patients
had complete remission at initial chemotherapy.
Crown Copyright © 2010. Published by Elsevier GmbH. All rights reserved.
PMID: 20573459
49. J Cutan Med Surg. 2008 Nov-Dec;12(6):299-301.
A young man with fever and skin nodules.
Lomaga MA, Walsh S.
Division of Dermatology, University of Toronto, Sunnybrook Health Sciences
Centre, Toronto, ON.
BACKGROUND: There are two rare variants of cutaneous T-cell lymphoma (CTCL)
that
primarily involve the subcutis. These include subcutaneous panniculitislike
T-cell lymphoma (SPTL) and cutaneous gamma/delta T-cell lymphoma.
OBJECTIVE: This case report describes the clinical presentation, diagnosis,
and
treatment of a young man with probable SPTL. A review of recent literature
outlining the differences between SPTL and cutaneous gamma/delta T-cell
lymphoma
is discussed.
CONCLUSION: The differential diagnosis in patients presenting with
subcutaneous
nodules and constitutional symptoms should include CTCL.
PMID: 19317953
Pegylated liposomal doxorubicin in the treatment of mycosis fungoides.
Lybaek D, Iversen L.
PMID: 17106606
51. Cancer Radiother. 1998 Jul-Aug;2(4):404-7.
[Cutaneous lymphoma in Tunisia: clinical profile and therapeutic results].
[Article in French]
Maalej M, Frikha H, Daoud J, Sellami D, Ben Romdhane K, Kamoun MR, Souissi
R, Ben
Osmen A, Zahaf A, Nouira R, Bouaouina N, Ben Abdallah M.
Institut Salah Azaiz, Tunis, Tunisie.
PURPOSE: The aim of this retrospective study was to investigate therapeutic
result of cutaneous lymphoma in Tunisia.
PATIENTS AND METHODS: Between January 1969 and June 1994, 100 patients with
cutaneous lymphoma were referred either to Salah Azaiz Institute or the
other
University Hospitals of Tunisia. Fifty-one patients had epidermotropic
lymphoma
and 49 non-epidermotropic lesions. Eighty-seven patients received complete
treatment. Puvatherapy and other local dermatologic treatments were used
for
early stage mycosis fungoïdes. Thirty-two patients benefited from
radiotherapy,
with curative dose in 28 cases. Chemotherapy including anthracyclin agents
was
used for high grade lymphoma. Thirteen patients had association of
radiotherapy
and chemotherapy.
RESULTS: Five-year survival rates were 50% for patients with epidermotropic
lesions and 56% for patients with non-epidermotropic cutaneous lymphoma.
Statistical study has not identified any significant prognosis factor.
CONCLUSION: Radiotherapy and chemotherapy are both effective. Treatment
should
depend on stage and histologic type.
PMID: 9755755
52. Am J Clin Pathol. 2006 Jul;126(1):14-22.
Primary CD20+CD10+CD8+ T-cell lymphoma of the skin with IgH and TCR beta
gene
rearrangement.
Magro CM, Seilstad KH, Porcu P, Morrison CD.
Department of Pathology, The Ohio State University, Columbus, USA.
Most cutaneous T-cell lymphomas are derived from mature postthymic T cells
of the
CD4 subtype. When other less common profiles are encountered, a diagnostic
challenge is posed. Accurate categorization is critical because of the
specificity of therapeutic regimens, including biologics. A 65-year-old
woman was
seen in 2001 because of a thigh mass manifesting an unusual phenotype
eventually
categorized as a mature postthymic CD8+ T-cell lymphoma with CD10 and weak
CD20
expression. Molecular studies revealed T-cell receptor and heavy chain
immunoglobulin rearrangement. Her cutaneous disease progressed despite
several
cycles of chemotherapy and radiation therapy. However, a therapeutic trial
with
denileukin diftitox resulted in a striking response. The importance of this
case
lies in the novel phenotype and dual T- and B-cell rearrangements. Rather
than
representing an aberrant phenotype, this tumor may represent the malignant
counterpart of a benign population of weakly CD20+ T cells of the CD8
subset.
PMID: 16753590
53. J Pediatr Hematol Oncol. 2008 Jul;30(7):558-61.
Subcutaneous panniculitislike T-cell lymphoma with hemophagocytosis:
complete
remission with BFM-90 protocol.
Medhi K, Kumar R, Rishi A, Kumar L, Bakhshi S.
Department of Medical Oncology, Institute Rotary Cancer Hospital, All India
Institute of Medical Sciences, New Delhi, India. sambakh@hotmail.com
SUMMARY: Subcutaneous panniculitislike T-cell lymphoma (SPTCL) is an
uncommon
type of cutaneous lymphoma. In many cases, SPTCL is accompanied by
hemophagocytic
syndrome (HPS), resulting in prominent systemic symptoms. The natural
history,
optimal treatment strategy, and prognostic factors associated with this
malignancy are not well defined. We report an 11-year-old boy of SPTCL with
HPS
who was initially treated with conventional cyclophosphamide, doxorubicin,
vincristine, and prednisone chemotherapy, but progressed later on therapy.
Subsequently, the child was treated with multiagent combination
chemotherapy as
per BFM-90 protocol and achieved complete remission, and has remained so
for 3
years. This report suggests the value of this particular multiagent
combination
chemotherapy regimen in the treatment of patients with SPTCL and HPS.
PMID: 18797207
Combination chemotherapy in the tumour stage of mycosis fungoides with
cyclophosphamide, vincristine, vp-16, adriamycin and prednisolone (cop,
chop,
cavop): a report from the Scandinavian mycosis fungoides study group.
Molin L, Thomsen K, Volden G, Groth O, Hellbe L, Holst R, Knudsen EA, Roupe
G,
Schmidt H.
Combination chemotherapy with cyclophosphamide, vincristine, VP-16,
adriamycin
and prednisolone was given in 9 cases of mycosis fungoides in the tumor
stage; 3
of these patients received COP, one received CHOP, and 5 CAVOP. Complete
remission was obtained in one case and partial remission in 5, the response
rate
thus being 6/9. It was impossible, however, to maintain remission. The
treatment
was reduced or withdrawn owing to toxic effects in 4 cases. These forms of
combination chemotherapy are beneficial in non-Hodgkin lymphomas but do not
seem
to be of value in the tumour stage of mycosis fungoides.
PMID: 6162347
55. Gan To Kagaku Ryoho. 1997 Jan;24(1):23-9.
[Primary cutaneous lymphoma--mycosis fungoides].
[Article in Japanese]
Nagatani T, Okazawa H, Mizuno H, Yanagi N, Miyazawa M, Baba N.
Department of Dermatology, Yokohama City University School of Medicine,
Japan.
Malignant lymphoma of the skin is a type of extranodal lymphoma with a
benign
prognosis, in which the main organ involved is the skin. Some 80-90% of the
cases
in Japan show a T-cell phenotype. Mycosis fungoides and Sézary syndrome are
common T-cell lymphomas of the skin. The tumor cells of mycosis fungoides,
small
and medium-sized cells with cerebriform nuclei, are detected in an
epidermo-dermo
junction. The tumor cells show CD3, CD4 and CLA, (cutaneous lymphocyte
associated
antigen) positivity. Various forms of topical therapy, such as topical
steroid,
photochemotherapy (PUVA), and interferons, have been indicated for the
good-risk
group (stages I A, I B and II A). Electron-beam irradiation, various
chemotherapy, such as low-dose etoposide, low-dose MTX and CPT-11 and deoxy
coformycin (DCF) plus IFNs, have been indicated for intermediate-risk group
(stage II B, III and IV A). BRMs plus low-dose etoposide, electron-beam
irradiation and a multiagent combination chemotherapy, such as MACOP-B, MBACOD
or ProMACE-CytaBOM, have been indicated for the high-risk group (stages IV
A and
IV B). Cutaneous B cell lymphoma (CBCL) can be diagnosed using a molecular
biological assay. The tumor cells of CBCL do not express T-cell antigens
such as
CD2, CD3 and CD43 and show B-cell antigens such as sIg, CD19, CD20 and
CD22.
Electron-beam irradiation has been indicated for early-stage CBCL (stages I
and
II). An effective multiagent combination chemotherapy, such as MACOP-B, MBACOD
or ProMACE-CytaBOM, is required for patients with advanced stage CBCL
(stages III
and IV).
PMID: 9020941
56. Acta Haematol. 2009;121(4):239-42. Epub 2009 Jun 29.
Autologous peripheral blood stem cell transplantation to treat CHOPrefractory
aggressive subcutaneous panniculitis-like T cell lymphoma.
Nakahashi H, Tsukamoto N, Yamane A, Saitoh T, Uchiumi H, Handa H, Karasawa
M,
Murakami H, Kojima M, Nojima Y.
Department of Medicine and Clinical Science, Gunma University Graduate
School of
Medicine, Maebashi, Gunma, Japan.
PMID: 19556752
57. Arch Dermatol. 2006 Jun;142(6):793-5.
Mycosis fungoides bullosa.
Natsuga K, Shimizu T, Abe R, Kodama K, Shimizu H.
PMID: 16785397
58. Dermatol Online J. 2003 Oct;9(4):42.
Subcutaneous T-cell lymphoma.
Nguyen NQ.
Ronald O. Perelman Department of Dermatology, New York University, USA.
A 70-year-old woman presents with a 2-year history of intermittent,
subcutaneous
nodules. The patient was otherwise asymptomatic. A biopsy specimen was
consistent
with a subcutaneous T-cell lymphoma, a rare subset of peripheral T-cell
lymphoma;
when accompanied by the hemocphagocytic syndrome, it can be rapidly fatal.
The
histopathologic characteristics and nature of the disease are discussed.
PMID: 14594615
59. Clin Lymphoma Myeloma. 2008 Dec;8 Suppl 5:S166-7.
At long last, it's finally 'T' time.
O'Connor OA.
PMID: 19073523
60. Gan To Kagaku Ryoho. 1997 Jul;24(9):1074-8.
[Recent progress in the management of malignant lymphoma].
Ohnishi K.
Dept. of Medicine III, Hamamatsu University School of Medicine, Japan.
In this article recent lymphoma-related topics were reviewed. REAL
classification, a new histopathological classification of lymphoid
neoplasm, has
been controversial in terms of clinical usefulness. However, mantle cell
lymphoma
in the classification has been well established as one histopathological
entity,
and considered an intermediate grade lymphoma in prognosis. In gastric MALT
lymphoma, Helicobacter pylori might provide the antigenic stimulus for its
growth. The eradication of H. pylori causes regression of MALT lymphoma,
and
anti-H. pylori treatment should be given for this type of lymphoma. The
international prognostic index has made it possible to make a different
therapeutic plan according to the risk group. The results of new therapies,
such
as purine nucleoside analogs for low grade B cell lymphoma and high dose
chemoradiotherapy for high grade aggressive lymphoma, were reviewed.
PMID: 9239159
61. Acta Chir Plast. 2005;47(3):65-6.
T-cell lymphoma presenting as a rapidly enlarging tumor on the lower
eyelid.
Onesti MG, Mazzocchi M, De Leo A, Scuderi N.
Department of Plastic and Reconstructive Surgery, University of Rome "La
Sapienza", Rome, Italy.
Lymphoma or leukemia skin lesions as a secondary site of disease are quite
common; however, to discover a cutaneous Hodgkin or non-Hodgkin lymphoma is
very
unusual. To find a cutaneous T-cell lymphoma on the skin of the face is a
rarity.
Because the condition is so rare and difficult to diagnose and treat, we
report
the case of a young man with a T-cell lymphoma with atypical and anaplastic
cells
on the lower eyelid. The patient was treated with 4 cycles of chemotherapy,
and
radiotherapy, and the tumor was resolved after 6 weeks. Our case was
clinically
suggestive of a rapidly enlarging malignant lymphoma on the eyelid. If the
lymphomas are detected at an early stage the prognosis for survival is
favorable.
A few forms of treatment are possible, either surgical treatment, or
radiotherapy
and chemotherapy, where response to the treatment is better.
PMID: 16173513
62. Rinsho Ketsueki. 1993 Jun;34(6):723-7.
[Parapsoriasis en plaque suspected of progression to mycosis fungoides
associated
with extranodal malignant B cell lymphoma of the cheek].
Onizuka T, Satou S, Koike M, Ishiyama T, Tomoyasu S, Tsuruoka N, Ohta H,
Fujisawa
R, Yamaguchi A, Tashiro T.
Department of Hematology, Showa University.
A 59-year-old female, clinically diagnosed as having parapsoriasis en
plaque for
ten years, was referred on June 1991 to the Department of Oral Surgery in
the
Dental School of showa University with a complaint of painless swelling of
the
left malar area. The swelling was found to have been caused by a tumor.
Since the
excised tumor was suspected to be a malignant lymphoma, she was admitted to
our
hospital. The specimen was subsequently confirmed to be a malignant
lymphoma of
the diffuse large cell type according to the LSG classification, and was
immunologically confirmed to be a B cell lymphoma. In addition, the excised
skin
was suspected of incipient mycosis fungoides. She was classified as having
stage
IE disease according to her bone marrow biopsy and other examinations. she
was
treated with combination of chemotherapy (CHOP) and radiation therapy. This
subject was interesting because her tumor probably resulted from a
parapsoriasis
en plaque skin lesion.
PMID: 8366574
63. Taiwan J Obstet Gynecol. 2010 Mar;49(1):69-71.
Vaginal obliteration in a woman with a history of cutaneous T-cell
lymphoma: the
results of combined chemotherapy-induced gonadal toxicity and lymphoma
relapse.
Pan CC, Lee WL.
Department of Obstetrics and Gynecology, National Yang-Ming University
Hospital,
Ilan, Taiwan.
OBJECTIVE: Although ovarian failure commonly occurs following chemotherapy,
the
relation between menopause or related sexual activity in this failure is
often
overlooked. We report a case that emphasizes a clinically rare
complication, the
complete obliteration of the vagina.
CASE REPORT: A 42-year-old married woman with a history of
Mayer-Rokitansky-Küster-Hauser syndrome, an established neovagina, and
complete
clinical remission of cutaneous T-cell lymphoma (stage T4) treated with
bleomycin, cyclophosphamide, doxorubicin, vincristine and prednisolone had
suffered from abdominal pain. Imaging studies (computed tomography) and
laboratory evaluations indicating a suspicious pelvic abscess with
leukocytosis
(16,800/mm(3)) and elevated serum C-reactive protein (18.4 mg/L) levels.
The
patient underwent intensive medical treatment and surgical intervention,
but died
2 months later. Pathology showed widespread lymphoma throughout the
perineal
area, including the neovagina, deep pelvic cavity and the entire abdominal
cavity.
CONCLUSION: Physicians should be greatly concerned about the frequency and
severity of treatment-associated acute and long-term complications, such as
gonadal toxicity. In this case, vaginal obliteration was an early sign of
tumor
recurrence, although menopause may have contributed to the vaginal
obliteration.
PMID: 20466296
64. Clin Lymphoma. 2004 Dec;5(3):190-3.
Lymphomatoid papulosis from childhood with anaplastic large-cell lymphoma
of the
small bowel.
Perna AG, Jones DM, Duvic M.
Department of Pathology, Baylor College of Medicine, One Baylor Plaza,
Houston,
TX 77030, USA. ap692395@bcm.tmc.edu
Lymphomatoid papulosis (LyP) is a lymphoproliferative disorder that exists
on a
spectrum of diseases with cutaneous CD30+ anaplastic large-cell lymphoma
(ALCL).
Multiple treatment options are available, although none are curative. The
typical
age of onset for LyP is in the third and fourth decades, but it has been
seen
occasionally in children. Lymphomatoid papulosis is associated with primary
cutaneous ALCL and other lymphoproliferative malignancies, but is rarely
associated with extranodal systemic ALCL. A 43-year-old man developed
lymphomatoid papulosis lesions at 3 years of age, which persisted into
adulthood,
and he later developed ALCL of the duodenum. Treatment with standard CHOP
(cyclophosphamide/doxorubicin/vincristine/prednisolone) chemotherapy
resulted in
complete remission of his gastrointestinal lymphoma and temporary
improvement of
his skin lesions. However, the LyP relapsed and proved refractory to
psoralen
plus ultraviolet-A phototherapy, and was only temporarily and partially
responsive to bexarotene and denileukin diftitox.
PMID: 15636695
65. J Am Acad Dermatol. 2001 Jan;44(1):149-50.
Pegylated liposomal doxorubicin in the treatment of cutaneous T-cell
lymphoma.
Prince HM, Seymour JF, Ryan G, McCormack C.
Comment on
J Am Acad Dermatol. 2000 Jan;42(1 Pt 1):40-6.
PMID: 11148501
66. Haematologica. 2007 May;92(5):686-9.
Pegylated liposomal doxorubicin in the treatment of primary cutaneous Tcell
lymphomas.
Pulini S, Rupoli S, Goteri G, Pimpinelli N, Alterini R, Tassetti A,
Scortechini
AR, Offidani M, Mulattieri S, Stronati A, Brandozzi G, Giacchetti A,
Mozzicafreddo G, Ricotti G, Filosa G, Bettacchi A, Simonacci M, Novelli N,
Leoni
P.
Clinic of Hematology, Polytechnic University of the Marche, Medical School,
Ospedali Riuniti Umberto I, G.M. Lancisi-G. Salesi, Ancona, Italy.
stpulini@bigfoot.com
Pegylated liposomal doxorubicin (Peg-Doxo) is a promising drug for
advanced/recalcitrant primary cutaneous T-cell lymphomas (CTCLs). This
prospective phase II trial enrolled 19 patients. We observed overall and
complete
response rates of 84.2% and 42.1% (with no significant differences between
stage
I-IIA and IIB-IV patients), and 11% grade III/IV toxicity. After a maximum
46
month-follow-up, median overall (OS), event-free (EFS) and progression-free
(PFS)
survival were 34, 18 and 19 months. OS, EFS and PFS rates at 46 months were
44%,
30% and 37% respectively. Peg-Doxo seems to be an active and safe principle
that
should be used in plurirelapsed, early stage-MF and in combination with
other
chemotherapeutic agents in advanced and aggressive CTCLs.
PMID: 17488695
67. Actas Dermosifiliogr. 2008 Sep;99(7):560-4.
[Autologous hematopoietic stem cell transplantation followed by oral
bexarotene
in a patient with advanced mycosis fungoides].
[Article in Spanish]
Pérez-Barrio S, Izu R, García-Ruiz JC, Acebo E, Martínez de Lagrán Z, DíazPérez
JL.
Servicio de Dermatología. Hospital de Cruces. Baracaldo. Vizcaya. España.
spbarrio@hotmail.com
We describe the case of a 17-year-old patient with rapidly progressing and
aggressive mycosis fungoides, with multiple cutaneous tumors and large cell
transformation. She was initially treated with 3 cycles of high-dose
chemotherapy
with mega-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)
without response, leading to the decision to undertake autologous
hematopoietic
stem cell transplantation. Partial remission of the disease was achieved
with
this treatment and subsequent introduction of oral bexarotene led to
complete
remission, which has been maintained for more than 3 years with good
tolerance of
oral therapy. We discuss the advantages and disadvantages of autologous
hematopoietic stem cell transplantation and the use of oral bexarotene.
PMID: 18682170
Prospective multicenter study of pegylated liposomal doxorubicin treatment
in
patients with advanced or refractory mycosis fungoides or Sézary syndrome.
Quereux G, Marques S, Nguyen JM, Bedane C, D'incan M, Dereure O, Puzenat E,
Claudy A, Martin L, Joly P, Delaunay M, Beylot-Barry M, Vabres P, Celerier
P,
Sasolas B, Grange F, Khammari A, Dreno B.
Departments of Dermatology, Centre Hospitalier Universitaire, Nantes,
France.
Comment in
Arch Dermatol. 2008 Jun;144(6):786-7.
OBJECTIVE: To assess the rate of objective response to pegylated liposomal
doxorubicin hydrochloride (Caelyx) in patients with advanced or refractory
cutaneous T-cell lymphoma (CTCL).
DESIGN: Prospective, open, multicenter study.
SETTING: Thirteen dermatology departments in France.
PATIENTS: Twenty-five patients with either (1) stage II to stage IV CTCL
previously unsuccessfully treated with at least 2 lines of treatments or
(2)
histologically transformed epidermotropic CTCL requiring chemotherapy.
INTERVENTION: Administration of Caelyx intravenously once every 4 weeks at
a dose
of 40 mg/m(2).
MAIN OUTCOME MEASURES: The response to treatment was evaluated by clinical
evaluation.
RESULTS: At the end of treatment, we observed an objective response
(primary end
point) in 56% of the patients (14 of 25): 5 complete responses and 9
partial
responses. The median overall survival time was 43.7 months. For the 14
patients
who experienced an objective response, the median progression-free survival
time
after the end of treatment was 5 months.
CONCLUSIONS: This prospective study demonstrates the effectiveness of
Caelyx in
treating CTCL, with an overall response rate of 56% in spite of the high
proportion of patients with advanced-stage disease. Responses were observed
in 2
subpopulations of patients in which the prognosis is known to be poorer:
Sézary
syndrome (overall response rate, 60%) and transformed CTCL (overall
response
rate, 50%). Moreover, this study shows that dose escalation to 40 mg/m(2)
does
not seem to improve the effectiveness but increases toxic effects
(especially
hematologic toxic effects) compared with the dose previously tested of 20
mg/m(2).
PMID: 18559761
69. Acta Derm Venereol. 2010 Nov;90(6):616-20.
Sudden onset of an aggressive cutaneous lymphoma in a young patient with
psoriasis: role of immunosuppressants.
Quéreux G, Renaut JJ, Peuvrel L, Knol AC, Brocard A, Dréno B.
Nantes University Hospital, INSERM, Nantes, France.
Psoriasis is thought to be associated with an increased risk of lymphoma.
We
report here the first case of an aggressive primary cutaneous pleomorphic
T-cell
lymphoma in a patient with psoriasis. The 36-year-old patient, who had
previously
been treated successively with methotrexate, ciclosporin and etanercept,
presented with rapidly growing nodules on the leg. A biopsy confirmed a
stage IVa
primary cutaneous pleomorphic T-cell lymphoma. Despite treatment with
pegylated
liposomal doxorubicin, the disease progressed and the patient died 5 months
later. This case of pleomorphic T-cell lymphoma was remarkable in both its
extremely rapid onset and the aggressive nature of the disease. The onset
of this
disease in a patient with psoriasis who had been previously treated with
immunosuppressive drugs and a tumour necrosis factor (TNF)-α blocker is of
major
interest. Only eight cases of cutaneous lymphomas associated with treatment
with
TNF-α blockers have been published previously. Most of these eight cases
related
to anti-TNFα antibodies; only two were linked to etanercept.
PMID: 21057746
70. J Pediatr Hematol Oncol. 2001 Jun-Jul;23(5):321-3.
Lymphomatoid papulosis and Ki-1+ anaplastic large cell lymphoma occurring
concurrently in a pediatric patient.
Rifkin S, Valderrama E, Lipton JM, Karayalcin G.
Division of Pediatric Hematology/Oncology and Stem Cell Transplantation,
Schneider Children's Hospital, Albert Einstein College of Medicine at the
Long
Island Jewish Medical Center, New Hyde Park, New York 11040, USA.
srifkin@lij.edu
Lymphomatoid papulosis (LyP) is a benign, self-healing, papular eruption
that can
wax and wane over the course of time. Transformation to T-cell lymphoma has
been
well documented in 10% to 20% of adults with LyP, but there are have been
no
cases reported in patients younger than age 26 years. We describe the first
pediatric patient, a 16-year-old girl, who had clinical features of LyP and
concurrently was found to have a lesion diagnosed as Ki-1+ anaplastic large
cell
lymphoma. After treatment with chemotherapy, she has been in continuous
remission
for 16 months.
PMID: 11464993
71. Clin Cancer Res. 2006 Mar 1;12(5):1547-55.
Increased MDR1 expression in normal and malignant peripheral blood
mononuclear
cells obtained from patients receiving depsipeptide (FR901228, FK228,
NSC630176).
Robey RW, Zhan Z, Piekarz RL, Kayastha GL, Fojo T, Bates SE.
Cancer Therapeutics Branch, Center for Cancer Research, NIH, National
Cancer
Institute, Bethesda, Maryland 20892, USA. robeyr@mail.nih.gov
The increased expression of markers associated with a differentiated
phenotype,
such as P-glycoprotein (Pgp), follows treatment with histone deacetylase
inhibitors. Because depsipeptide (FR901228, FK228, NSC630176) is a
substrate for
Pgp, up-regulation of the gene that encodes it, MDR1, would mean that
depsipeptide induces its own mechanism of resistance. To examine the effect
of
depsipeptide on expression of ATP-binding cassette transporters associated
with
multidrug resistance, the kidney cancer cell lines 108, 121, 127, and 143
were
treated with depsipeptide and evaluated by quantitative reverse
transcription-PCR. Increased levels of MDR1 (1.3- to 6.3-fold) and ABCG2
(3.2- to
11.1-fold) but not MRP1 (0.9- to 1.3-fold) were observed. The induced Pgp
transported the fluorescent substrates rhodamine 123, bisantrene, calceinAM,
BODIPY-vinblastine, and BODIPY-paclitaxel. In normal peripheral blood
mononuclear
cells (PBMC) and circulating tumor cells obtained from patients receiving
depsipeptide, increased levels of histone H3 acetylation were found. We
next
examined MDR1 levels in normal and malignant PBMCs obtained from 15
patients
enrolled in clinical trials with depsipeptide and detected up to a 6-fold
increase in normal PBMCs and up to an 8-fold increase in circulating tumor
cells
after depsipeptide administration. In one patient with Sézary syndrome,
increased
MDR1 gene expression was accompanied by increased cell surface Pgp
expression in
circulating Sézary cells as determined by measurement of MRK-16 staining by
flow
cytometry. These studies suggest that depsipeptide induces its own
mechanism of
resistance and thus provide a basis for clinical trials evaluating
depsipeptide
in combination with a Pgp inhibitor.
PMID: 16533780
72. Leuk Lymphoma. 2009 Aug;50(8):1369-71.
Paraneoplastic cerebellar degeneration: initial presentation in a patient
with
anaplastic T-cell lymphoma, associated with ichthyosiform cutaneous
lesions.
Rodis DG, Liatsos GD, Moulakakis A, Pirounaki M, Tasidou A.
PMID: 19544138
73. Leuk Lymphoma. 2007 Mar;48(3):560-3.
Cyclosporin in subcutaneous panniculitis-like T-cell lymphoma.
Rojnuckarin P, Nakorn TN, Assanasen T, Wannakrairot P, Intragumtornchai T.
Department of Medicine, Faculty of Medicine, Chulalongkorn University,
Bangkok,
Thailland.
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of
hematologic malignancy characterized by lesions in subcutaneous fat
associated
with systemic symptoms. The standard treatment of the disease, currently,
is not
established, but CHOP or CHOP-like regimens are usually given. We report,
herein,
4 cases of SPTCL diagnosed by histopathology and immunohistochemistry who
were
refractory to CHOP and/or ESHAP and/or fludarabine-based regimen, but
showed
rapid improvement within weeks after oral cyclosporin 4 mg/kg/day. Three
sustained complete remission for the durations of 8 - 9 months offtreatments.
T-cell receptor gene rearrangement revealed polyclonality in 3 cases and
monoclonality in 1 case. Our data suggest the benefit of incorporating
cyclosporin into the treatment regimen for SPTCL.
PMID: 17454599
74. Cancer. 1985 Aug 1;56(3):649-51.
Rapid pulmonary dissemination in mycosis fungoides simulating pneumonia. A
case
report and review of the literature.
Rubin DL, Blank N.
Mycosis fungoides is a neoplastic disease with extranodal dissemination
most
frequently to the lung. The roentgenographic and clinical manifestations in
these
patients may simulate pneumonia and delay appropriate treatment.
Disseminated
disease is thought to occur in the setting of involvement of the peripheral
blood
with the neoplastic cells. A case of rapid pulmonary involvement with
mycosis
fungoides which simulated pneumonia is presented in which there was no
peripheral
blood manifestation of the disease.
PMID: 3839162
75. Hematology Am Soc Hematol Educ Program. 2008:280-8.
Prognosis and primary therapy in peripheral T-cell lymphomas.
Savage KJ.
British Columbia Cancer Agency, Vancouver, BC, Canada.
ksavage@bccancer.bc.ca
Peripheral NK/T-cell neoplasms are an uncommon group of diseases that show
distinct racial and geographic variation. The prognostic significance of
the
T-cell phenotype has been clearly defined in recent studies by using modern
lymphoma classification systems. However, within this heterogenous group of
neoplasms, some have a more favorable prognosis, such as ALK-positive
anaplastic
large-cell leukemia (ALCL) and primary cutaneous ALCL, and some have
ultimately
fatal courses with standard chemotherapy programs (e.g., hepatosplenic
gammadelta
T-cell lymphomas). Further, unlike the benefits observed with CHOP
chemotherapy
in the treatment of diffuse large B-cell lymphoma (DLBCL), peripheral Tcell
lymphomas (PTCL), other than ALK-positive ALCL, are relatively
chemoresistant to
this regimen. Given disease rarity and biological heterogeneity, advances
in
diagnosis, prognosis and treatment have lagged behind DLBCL. Recently,
however,
studies are emerging that focus specifically on PTCLs with the ultimate
goal of
better understanding disease biology and developing more effective
therapies.
PMID: 19074097
76. Strahlentherapie. 1977 May;153(5):283-92.
[Chemotherapy in non-Hodgkin's lymphomas (author's transl)].
[Article in German]
Schmidt CG.
The type of therapy in non-Hodgkin's lymphomas (NHL) depends on the state
of the
disease and on histological classification. As in Hodgkin's lymphoma
radiotherapy
is indicated with localized disease, whereas chemotherapy is given in
disseminated cases. In contrast to Hodgkin's lymphoma chemotherapy is
indicated
earlier (already in most stage II cases), since dissemination may occur
outside
the typical lymph node areas. Division of NHLs according to higher or lower
degree of malignancy is possible histologically on the basis of the Kiel
classification as well as of the Rappaport classification. Low-grade
malignant
lymphomas are treated best with conventional doses of an alkylating agent.
An
intensive combined chemotherapy is not indicated. Because of the tendency
to
early and frequent relapses a cyclic maintenance therapy with an alkylating
agent
is incidated. High-grade malignant lymphomas have to be treated with
agressive
combination chemotherapy in order to get the patient into complete
remission with
the possibility for a long relapse-free interval. Up to now there is no
indication that any of the published chemotherapy combinations is
definitely
superior to the others. It is most important to apply the therapy
consequently
for at least six months. The value of a maintenance therapy is not yet
proven.
PMID: 69343
77. Leuk Lymphoma. 2009 Aug;50(8):1389-91.
Sustained response of primary cutaneous CD30 positive anaplastic large cell
lymphoma to bexarotene and photopheresis.
Sheehy O, Catherwood M, Pettengell R, Morris TC.
PMID: 19544141
78. Dermatol Online J. 2008 Nov 15;14(11):5.
CD4+/CD56+ Hematodermic neoplasm (plasmacytoid dendritic cell tumor).
Shiman M, Marchione R, Ricotti C, Romanelli P, Alonso-Llamazares J.
Department of Dermatology and Cutaneous Surgery, University of Miami Miller
School of Medicine, Miami, Florida, USA.
A 60-year-old male presented with multiple, purplish-red, nodules and
plaques.
After a complete work-up, he was diagnosed with CD4+/CD56+ hematodermic
neoplasm.
We review the clinical, pathological, and immunohistochemical features of
this
disease. CD4+/CD56+ hematodermic neoplasm, which is also known as blastic
natural
killer-cell lymphoma, is a rare, aggressive neoplasm with a strong
predilection
for skin involvement.
PMID: 19094843
79. Int J Cardiol. 2007 Apr 25;117(2):e84-5. Epub 2007 Feb 27.
Intracardiac right ventricular metastatic tumor of malignant T-cell
lymphoma.
Sibbing D, Barthel P, Abbrederis K, Dennig K, Gaa J.
PMID: 17331600
80. Int J Dermatol. 1998 Jul;37(7):541-3.
Lymphomatoid papulosis followed by Hodgkin's disease.
Silva MM, Morais JC, Spector N, Maceira J, Sousa MA, Filgueira AL.
Department of Pathology, University Hospital, Federal University of Rio de
Janeiro, Brazil.
PMID: 9679697
81. Actas Dermosifiliogr. 2010 Nov;101(9):810-2.
[Primary cutaneous CD30+ large T-Cell lymphoma with lymph node and cerebral
metastases].
[Article in Spanish]
Simal E, Hörndler C, Porta N, Baldellou R.
Comment in
Actas Dermosifiliogr. 2011 May;102(4):308-9; author reply 309.
PMID: 21034717
82. Indian J Dermatol Venereol Leprol. 2008 Mar-Apr;74(2):151-3.
Subcutaneous panniculitis-like T-cell cutaneous lymphoma.
Singh A, Kumar J, Kapur S, Ramesh V.
Institute of Pathology (ICMR), New Delhi, India. dravninder@yahoo.co.in
Subcutaneous panniculitis-like T cell lymphoma (SPTCL) is a rare cytotoxic
T-cell
lymphoma classified in the World Health Organization-European Organization
for
Research and Treatment of Cancer (WHO-EORTC) classification as a unique
extranodal lymphoma with characteristic by T cell receptor (TCR) gene
rearrangement. We report here a case of SPTCL in a 22 year-old woman who
had
presented with variably sized multiple nodules on both her legs. Initial
differential diagnoses considered were panniculitis and lupus panniculitis.
The
histopathology showed a predominantly subcutaneous lobular infiltrate with
atypical lymphocytes, karyorrhexis and rimming of adipocytes by lymphoid
cells.
Immunohistochemistry showed CD4-, CD8+, CD56- T-cell phenotype. Although
TCR
rearrangement studies were not done, the above T-cell phenotype and sparing
of
epidermis and dermis suggested the possibility of an SPTCL alpha/beta type.
The
patient received five cycles of a cyclophosphamide, doxorubicin,
vincristine and
prednisone (CHOP) regimen which resulted in the regression in her skin
lesions
and constitutional symptoms.
PMID: 18388378
83. Oncology (Williston Park). 2007 Feb;21(2 Suppl 1):29-32.
Optimal combination with PUVA: rationale and clinical trial update.
Stadler R.
Department of Dermatology, Medical Centre Minden, Germany.
hautklinik@klinikum-minden.de
Cutaneous T-cell lymphoma (CTCL) is relatively benign in its early stages,
but
survival rates decrease dramatically as the disease progresses. As no
curative
therapies are currently available, the goal of therapy is preventing or
delaying
progression from early disease stages while minimizing long-term toxicity.
No
single agent, including psoralen plus ultraviolet A (PUVA), can control
disease
progression fully, so combination therapy is needed to improve response
rates. In
addition, low-dose combination therapy may improve treatment safety and
tolerability. A combination of PUVA and interferon (IFN) alpha in early
disease
has been shown to be effective and well tolerated. Likewise, small studies
of
PUVA and bexarotene (Targretin) indicate good efficacy for this
combination.
Reduced doses of these combinations may also be effective as maintenance
therapies following complete remission. Other treatment combinations shown
to be
effective in early disease stages include bexarotene with IFNalpha and
bexarotene
with denileukin diftitox (Ontak). In advanced stages of CTCL,
liposomal-encapsulated doxorubicin or extracorporeal photopheresis may be
combined with bexarotene or IFNalpha.
PMID: 17474357
Clinical research in cutaneous T-cell lymphoma moving forward.
Sterry W, Heinzerling L.
Comment in
Arch Dermatol. 2009 Feb;145(2):209-10.
Comment on
PMID: 18559771
85. J Cutan Pathol. 2008 Jun;35(6):579-84. Epub 2007 Nov 12.
CD4+/CD56+ hematodermic neoplasm: report of a rare variant with a T-cell
receptor
gene rearrangement.
Stetsenko GY, McFarlane R, Kalus A, Olerud J, Cherian S, Fromm J, George E,
Argenyi Z.
Department of Pathology, University of Washington, Seattle, WA 98195-6100,
USA.
gstetsen@u.washington.edu
CD4+/CD56+ hematodermic neoplasm (HN), formerly known as a blastic natural
killer
(NK) cell lymphoma, is a rare subtype of a cutaneous dendritic cell
neoplasm
notable for highly aggressive behavior. The characteristic features are:
expression of the T-helper/inducer cell marker CD4 and the NK-cell marker
CD56 in
the absence of other T cell or NK-cell specific markers. In particular, CD3
(surface or cytoplasmic) and CD2 are not expressed. Although T-cell
receptor
(TCR) genes are generally reported to be in a germline configuration, we
present
an unusual variant of a CD4+/CD56+ HN with a clonal rearrangement of TCR
genes.
This feature of a CD4+/CD56+ HN has been only rarely reported. Recognition
of the
presence of clonal TCR gene rearrangements in a small subset of CD4+/CD56+
HN is
important to avoid misdiagnosis of this entity as an unusual variant of a
cutaneous T-cell lymphoma.
PMID: 18005171
86. Dermatol Online J. 2010 Apr 15;16(4):8.
A case of CD4+/CD56+ hematodermic neoplasm (plasmacytoid dendritic cell
neoplasm).
Su O, Onsun N, Demirkesen C, Aydin Y, Pirmit S, Gereli M.
Department of Dermatology, Vakif Gureba Teaching and Research Hospital,
Istanbul,
Turkey.
CD4+/CD56+ hematodermic neoplasm (blastic plasmacytoid dendritic cell
neoplasm)
involving the skin is relatively rare and has been of significant interest
in the
recent literature. We report here a 64-year-old male who presented with
multiple
purple-red nodules and plaques on his face, back, and chest. Histological
examination of skin biopsies showed an intense hematolymphoid infiltration
in the
dermis and in the subcutaneous tissue. Stains were positive for CD4 (weak),
CD56,
and terminal deoxynucleotidyl transferase (TdT). These cells were negative
for
CD2, CD3, CD5, CD10, CD20, CD30, CD68, and T cell intracellular antigen
(TIA). In
situ hybridization (ISH) for Epstein-Barr virus was negative and the
diagnosis
was blastic NK cell lymphoma. The patient was treated with a hyper-CVAD
regimen
(cyclophosphamide, vincristine, doxorubicine, dexamethasone, methotrexate,
and
cytarabine).This treatment regimen achieved partial remission but the
patient
died eight months after the diagnosis. The patient presented with
exclusively
cutaneous involvement at the beginning but progressed rapidly and died
shortly
after despite aggressive chemotherapy. Due to its rarity, we present here a
case
of CD4+/CD56+ hematodermic neoplasm.
PMID: 20409415
87. J Am Acad Dermatol. 1998 May;38(5 Pt 2):803-5.
Follicular mucinosis as a presenting sign of acute myeloblastic leukemia.
Sumner WT, Grichnik JM, Shea CR, Moore JO, Miller WS, Burton CS.
Department of Medicine, Duke University Medical Center, Durham, NC 27710,
USA.
Follicular mucinosis is often associated with mycosis fungoides and has
been
rarely observed to occur with other neoplastic and inflammatory conditions.
We
describe a 60-year-old patient with follicular mucinosis who later
developed
acute myelogenous leukemia. This is the first reported case of follicular
mucinosis as a presenting sign of acute myeloblastic leukemia in the
absence of
mycosis fungoides or leukemia cutis.
PMID: 9591790
88. Med Pediatr Oncol. 2001 Dec;37(6):549-52.
Subcutaneous panniculitic T-cell lymphoma in childhood: successful response
to
chemotherapy.
Thomson AB, McKenzie KJ, Jackson R, Wallace WH.
Royal Hospital for Sick Children, Edinburgh, Scotland, United Kingdom.
PMID: 11745897
89. J Eur Acad Dermatol Venereol. 2003 Jan;17(1):80-2.
Long-term remission of recalcitrant tumour-stage mycosis fungoides
following
chemotherapy with pegylated liposomal doxorubicin.
Tsatalas C, Martinis G, Margaritis D, Spanoudakis E, Kotsianidis I,
Karpouzis A,
Bourikas G.
Department of Haematology, School of Medicine, Democritus University of
Thrace,
Alexandroupolis, Greece. ktsatala@med.duth.gr
Advanced stage mycosis fungoides (MF) generally has a poor prognosis, and
currently there is no standard treatment available. Here we report the case
of a
young woman with recalcitrant tumour-stage MF (T3, stage IIb) whose disease
was
unresponsive to several therapeutic modalities, but who has showed
sustained
clinical response to pegylated liposomal doxorubucin. No severe infectious
complications have been observed. The use of this drug in tumour-stage MF
should
be investigated further.
PMID: 12602979
90. Int J Radiat Oncol Biol Phys. 1995 Jul 15;32(4):987-95.
Systemic chemotherapy and extracorporeal photochemotherapy for T3 and T4
cutaneous T-cell lymphoma patients who have achieved a complete response to
total
skin electron beam therapy.
Wilson LD, Licata AL, Braverman IM, Edelson RL, Heald PW, Feldman AM,
Kacinski
BM.
Yale University School of Medicine, Department of Therapeutic Radiology,
New
Haven, CT, USA.
PURPOSE: To evaluate the impact of systemic adjuvant therapies on relapsefree
(RFS) and overall survival (OS) of cutaneous T-cell lymphoma (CTCL)
patients
treated with total skin electron beam therapy (TSEBT).
METHODS AND MATERIALS: Between 1974 and 1990, TSEBT (36 Gy at 1 Gy/day; 9
weeks;
6 MeV electrons) was administered with curative intent to a total of 163
CTCL
(mycosis fungoides) patients using six fields supplemented by orthovoltage
boosts
(120 kvp, 1 Gy x 20) to the perineum, soles of feet, and apical scalp (120
kvp, 2
Gy x 3). In this group, all patients who achieved a clinical complete
response or
a good partial response were offered one of two competing regimens of
either
adjuvant doxorubicin/cyclophosphamide or adjuvant extracorporeal
photochemotherapy (ECP).
RESULTS: When the results for the group who achieved a complete response
(CR) to
TSEBT were analyzed, OS for T1 and T2 patients was excellent (85-90% at 510
years) and not improved by either adjuvant regimen. However, T3 and T4
patients
who received either adjuvant doxorubicin/cyclophosphamide (75% at 3 years)
or
adjuvant ECP (100% at 3 years) had better overall survival than those who
received neither adjuvant regimen (approximately 50% at 5 years). The
difference
between the OS curves for those who received ECP vs. those who received no
adjuvant therapy approached statistical significance (p < 0.06), while a
significant survival benefit from the addition of chemotherapy for TSEBT
complete
responders was not observed. Neither adjuvant therapy provided benefit with
respect to relapse free survival after TSEBT.
CONCLUSIONS: These results suggest that an adjuvant nontoxic regimen of
extracorporeal photochemotherapy may prolong survival in advanced stage
CTCL
patients who have achieved a complete remission after TSEBT. The
combination of
doxorubicin/cyclophosphamide had no significant impact on overall survival
in
those patients who achieved CR to TSEBT, and neither adjuvant therapy had
an
impact on relapse free survival for all T-stages. Such results are the
basis for
the current development of a prospective, randomized trial studying the
impact of
ECP after TSEBT in patients with advanced stage CTCL.
PMID: 7607973
91. Cancer. 2003 Sep 1;98(5):993-1001.
Multicenter study of pegylated liposomal doxorubicin in patients with
cutaneous
T-cell lymphoma.
Wollina U, Dummer R, Brockmeyer NH, Konrad H, Busch JO, Kaatz M, Knopf B,
Koch
HJ, Hauschild A.
Department of Dermatology, Hospital Dresden-Friedrichstadt,
Friedrichstrasse 41,
01067 Dresden, Germany. wollina-uw@khdf.de
BACKGROUND: In single center studies and case reports, it was shown that
pegylated liposomal doxorubicin (PEG-DOXO) was effective as second-line
therapy
for patients with cutaneous T-cell lymphoma (CTCL). The objective of this
study
was to evaluate the efficacy and toxicity of single-agent PEG-DOXO as
second-line
chemotherapy in patients with CTCL.
METHODS: A retrospective, multicenter study was performed evaluating 34
patients
(31 male patients and 3 female patients). Twenty-seven patients received
PEG-DOXO
20 mg/m(2), 5 patients received PEG-DOXO 20-30 mg/m(2), and 2 patients
received
PEG-DOXO 40 mg/m(2). PEG-DOXO was administered intravenously every 2 weeks
in 6
patients, every 2-3 weeks in 4 patients, and every 4 weeks in 23 patients.
One
patient received only a single course of PEG-DOXO. Outcomes were evaluated,
and
adverse effects were recorded.
RESULTS: Thirty-four patients received at least 1 cycle of PEG-DOXO.
Disease was
classified as mycosis fungoides in 28 patients, mycosis fungoides with
follicular
mucinosis in 2 patients, small or medium-sized pleomorphic CTCL in 2
patients,
Sèzary syndrome in 1 patient, and CD30 positive CTCL in 1 patient. Fifteen
patients achieved a complete response (CR), including patients who achieved
a CR
and patients who achieved a CR defined by clinical criteria only with no
biopsy
(CRu), and 15 patients achieved a partial response (PR), resulting in a
response
rate (CRs, CRus, and PRs) of 88.2%. Two patients dropped out: one patient
after a
single PEG-DOXO infusion because of Grade 3 capillary leakage syndrome and
one
patient after two cycles because of a suicide attempt that was not related
to
treatment or to CTCL. All other patients received at least four cycles of
PEG-DOXO. Overall survival was 17.8 months +/- 10.5 months (n = 33
patients),
event-free survival was 12.0 months +/- 9.5 months, and disease-free
survival was
13.3 +/- 10.5 months (n = 16 patients). Adverse effects were seen in 14 of
34
patients (41.2%); they were temporary and generally mild. Only 6 patients
had
Grade 3 or 4 adverse effects.
CONCLUSIONS: This multicenter study provided evidence of high efficacy of
PEG-DOXO monotherapy with a low rate of severe adverse effects compared
with
other chemotherapy protocols in patients with CTCL.
PMID: 12942567
92. J Cancer Res Clin Oncol. 2002 Feb;128(2):103-10. Epub 2001 Nov 16.
Galectin fingerprinting by immuno- and lectin histochemistry in cutaneous
lymphoma.
Wollina U, Graefe T, Feldrappe S, André S, Wasano K, Kaltner H, Zick Y,
Gabius
HJ.
Department of Dermatology and Dermatological Allergology,
Friedrich-Schiller-University, Jena, Germany. Wollina-Uw@khdf.de
Owing to their relevance for growth regulation and cell adhesion monitoring
the
expression of galectins (endogenous beta-galactoside-binding lectins) and
their
binding sites has relevance for tumor biology. Using galectin-type-specific
reagents (non-crossreactive antibodies for proto-type galectin-1, chimeratype
galectin-3 and tandem-repeat-type galectins-4 and -8, and labeled
galectins-1,
-3, and -4) we determined galectin expression in cutaneous T cell lymphomas
(CTCL) and controls. In addition to commonly studied galectins-1 and -3,
tandem-repeat-type galectins could be detected, i.e., galectin-8 in six
from 15
cases and galectin-4 in one of 15 cases. In view of relevant ligands such
as
bcl-2 or integrins the presence of galectins-3 and -8 seems to be possibly
related to loss of proliferation control and change in cell adhesion
properties
that are involved in clonal expansion and epidermal spread of malignant T
cell
clones. Successful chemotherapy of CTCL alters galectin expression
selectively as
shown for liposomal doxorubicin.
PMID: 11862481
93. Ann N Y Acad Sci. 2001 Sep;941:214-6.
Pegylated doxorubicin for primary cutaneous T cell lymphoma: a report on
ten
Wollina U, Graefe T, Kaatz M.
Department of Dermatology and Allergology, Friedrich Schiller University of
Jena,
Germany. Wollina-Uw@khdf.de
PMID: 11594577
94. J Cancer Res Clin Oncol. 2001 Feb;127(2):128-34.
Pegylated doxorubicin for primary cutaneous T-cell lymphoma: a report on
ten
Jena,
Germany. uwol@derma.uni-jena.de
PURPOSE: Pegylated liposomal doxorubicin (PEG-DOXO) was found to be
effective in
primary cutaneous T-cell lymphomas (CTCL). The present observation reports
on
follow-up and relapse-free interval in patients with CTCL.
METHODS: Ten patients (one female, nine male) aged 50-78 years (mean 66.7
years)
with relapsing or recalcitrant CTCL, stage I b (n = 3), II a (2), II b (3),
IV a
(1), and IV b (1) were treated with PEG-DOXO 20 mg m(-2) once a month with
an
upper limit of 400 mg or eight infusions to induce a clinical response.
There was
one drop out after a single infusion because of a capillary leak syndrome.
RESULTS: In nine patients with PEG-DOXO the best response was a complete
response
(CR) in five patients and a partial response (PR) in four patients. The
final
outcome was CR in six, PR in two, stable disease (SD) in one, and
progressive
disease (PD) in another patient. The overall response rate (CR + PR) was
80% (of
ten patients). The follow-up was 2-22 months (mean 12.8+/-7.1 months). The
overall survival was calculated as 19.8+/-7.4 months with eight out of ten
patients still alive. Response duration was 15.2+/-3.9 months, disease-free
survival 13.3+/-6.1 months, event-free survival 16.7+/-9.0 months, and
progression-free survival 18.2+/-6.5 months. Four patients (stage I b and
II b)
achieved 12-19 months of disease-free survival. The follow-up after the
first
course with PEG- DOXO was 2-22 months (mean 12.8+/-7.1 months). The
survival rate
after 12 months of follow-up was 80% (n = 5). One patient free of relapse
died
after 12 months because of pulmonary embolism not related to disease or
treatment. Another patient died 1 month after a second course of PEG-DOXO
in an
advanced tumor stage of CTCL. The most frequent side effects of treatment
were
anemia and lymphopenia without the need of supportive treatment or
dose-reduction. Only one patient developed toxicity of grade 4 (anemia).
CONCLUSIONS: These results indicate that patients with relapsing or
recalcitrant
CTCL can achieve an 80% response rate with PEG-DOXO and long-term
remissions.
PMID: 11216914
Treatment of relapsing or recalcitrant cutaneous T-cell lymphoma with
pegylated
Wollina U, Graefe T, Karte K.
Department of Dermatology, Friedrich-Schiller-University, Germany.
Comment in
J Am Acad Dermatol. 2001 Jan;44(1):149-50.
BACKGROUND: Pegylated liposomes are stable, long-circulating carriers
useful for
delivering doxorubicin to tumor sites with a lower toxicity than the free
drug.
Free doxorubicin is used in several treatment protocols for non-Hodgkin's
lymphoma. Although pegylated liposomal doxorubicin is currently used in the
treatment of Kaposi's sarcoma, no data are available for tumors, such as
primary
cutaneous T-cell lymphomas (CTCLs).
OBJECTIVE: Our purpose was to determine the efficacy and toxicity of
pegylated
liposomal doxorubicin in patients with relapsing or recalcitrant CTCL. The
cumulative dose was limited to 320 mg.
METHODS: A prospective pilot study was performed. Six patients (1 woman and
5
men) aged 59 to 78 years with relapsing or recalcitrant CTCL of the mycosis
fungoides type, stage (Ib/IIb), were treated with pegylated liposomal
doxorubicin
to induce a clinical response. The drug was administered at a dosage of 20
mg
m(-2) once a month. Four patients received 8 doses, and 2 patients received
6
doses.
RESULTS: The best response was a complete response in 4 patients and a
partial
response in 2 patients. The final outcome was a complete response in 4, a
partial
response in 1, and progressive disease in 1 patient (overall response rate,
83%).
The responders showed a decrease of lymphocytic infiltrates and activated T
lymphocytes in skin biopsy specimens. Side effects were seen temporarily,
ranging
from grade 0 to grade 3. The most frequent side effects were mild anemia
and
lymphopenia. There was no need of additional therapy because of side
effects.
CONCLUSION: These results indicate that patients with relapsing or
recalcitrant
CTCL can achieve a high response rate with pegylated liposomal doxorubicin
and
that a monthly dose is a well-tolerated regimen.
PMID: 10607318
96. Zhonghua Bing Li Xue Za Zhi. 2011 Apr;40(4):267-8.
[Granulomatous slack skin with anaplastic large cell lymphoma: report of a
case].
[Article in Chinese]
Xie JJ, Zhou ZQ, Wang Y, Li Y, Zhang RY, Ren YB, Chen B, Zhou GY.
PMID: 21616005
97. Eur J Dermatol. 2011 Jul-Aug;21(4):609-10.
CD8-positive primary cutaneous anaplastic large cell lymphoma presenting as
multiple scrotal nodules and plaques.
Xu H, Qian J, Wei J, Zhao Y, Zhou C, Chen D, Zhang J.
PMID: 21680287
98. Australas J Dermatol. 2001 Aug;42(3):183-7.
Subcutaneous panniculitic T-cell lymphoma and cytophagic histiocytic
panniculitis.
Yung A, Snow J, Jarrett P.
Department of Dermatology, Waikato Hospital, Hamilton and Dermatology Unit,
Greenlane Hospital, Auckland, New Zealand. ants_ange@hotmail.com
A 43-year-old Maori man presented with a 1 month history of malaise, weight
loss,
anorexia, arthralgia, recurrent fever and tender erythematous subcutaneous
skin
lesions. Histological examination of an incisional biopsy of a lesion
revealed a
lobular panniculitis with an inflammatory infiltrate of atypical
lymphocytes and
evidence of cytophagocytosis consistent with a diagnosis of subcutaneous Tcell
lymphoma. The systemic symptoms and skin lesions resolved spontaneously
within 3
weeks, only to recur 2 months later, requiring treatment with oral
prednisolone.
T-cell gene rearrangement studies demonstrated a monoclonal T-cell receptor
(gamma-chain) gene rearrangement, further supporting the diagnosis of
subcutaneous panniculitic T-cell lymphoma. Treatment with chemotherapy
(cyclophosphamide, doxorubicin, vincristine and prednisone) led to
remission of
symptoms. Four months after completing chemotherapy, the patient remained
asymptomatic with a few indurated subcutaneous plaques on the chest. Biopsy
of
these areas revealed lobular panniculitis, lymphocytic infiltrate without
cytological atypia, abundant lipophages and fibrosis and sclerosis
consistent
with a healing response. He remains well 24 months following chemotherapy.
PMID: 11488712
99. Cancer. 1986 Dec 15;58(12):2611-6.
Treatment of advanced stage mycosis fungoides with bleomycin, doxorubicin,
and
methotrexate with topical nitrogen mustard (BAM-M).
Zakem MH, Davis BR, Adelstein DJ, Hines JD.
Ten patients with advanced stage (TNM IIB-IVB) mycosis fungoides were
treated
with a combination chemotherapy program consisting of bleomycin and
methotrexate
weekly, doxorubicin every 3 weeks, and topical nitrogen mustard daily (BAMM).
Seven patients obtained histologically documented complete remissions
ranging
from 4 to 105+ months in duration. Median survival is 16.5+ months. Three
patients in whom splenomegaly was detected during their staging evaluation
underwent splenectomy. These three patients have had unmaintained diseasefree
survivals of 36+, 100+, and 105+ months. This study indicates that BAM-M is
effective therapy for advanced stage mycosis fungoides and suggests that
the
therapeutic role of splenectomy should be evaluated further.
PMID: 2430687
100. J Natl Med Assoc. 2007 Oct;99(10):1190-2.
Subcutaneous panniculitis-like T-cell lymphoma in a patient with long-term
remission with standard chemotherapy.
Zhang H, Gupta R, Wang JC, Lipton JF, Huang YW.
Division of Hematology/Oncology, Department of Medicine, Maimonides Medical
Center Brooklyn, NY 11219, USA.
Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is a very rare
postthymic
T-cell non-Hodgkin's lymphoma with poor prognosis. There is not a standard
treatment for this disease. Here we describe the first case of SPTL with
unusual
periorbital involvement, pancytopenia, hepatic dysfunction and
coagulopathy,
which was successfully treated with a chemotherapy regimen of
cyclophosphamide,
hydroxydaunomycin (doxorubicin), Oncovin (vincristine) and prednisone
(CHOP). Our
case demonstrates that although the natural history of SPTL is aggressive,
patients may respond effectively to combination chemotherapy. Early
recognition
of the classic subcutaneous lesions and its associated systemic signs, such
as
unusual periorbital involvement, liver dysfunction and hemophagocytic
syndrome,
is very important in managing this aggressive lymphoma. Immunohistochemical
and
genetic studies are helpful in confirming the diagnosis. Early initiation
of
aggressive chemotherapy is recommended for better clinical outcome.
PMCID: PMC2574403
Anlage 1aa
10 für die Fragestellung relevante Publikationen aus Suchschritt #1:
1. Pegylated doxorubicin for primary cutaneous T-cell lymphoma: a report on ten patients
with follow-up.
J Cancer Res Clin Oncol. 2001 Feb;127(2):128-34.
Related citations
2. Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell
lymphoma.
Wollina U, Dummer R, Brockmeyer NH, Konrad H, Busch JO, Kaatz M, Knopf B, Koch
HJ, Hauschild A.
Cancer. 2003 Sep 1;98(5):993-1001.
PMID: 12942567 [PubMed - indexed for MEDLINE] Free Article
Related citations
3. Long-term remission of recalcitrant tumour-stage mycosis fungoides following
Tsatalas C, Martinis G, Margaritis D, Spanoudakis E, Kotsianidis I, Karpouzis A, Bourikas
G.
J Eur Acad Dermatol Venereol. 2003 Jan;17(1):80-2.
Related citations
4. Pegylated doxorubicin for primary cutaneous T cell lymphoma: a report on ten patients
with follow-up.
Ann N Y Acad Sci. 2001 Sep;941:214-6. No abstract available.
Related citations
5. Pegylated liposomal doxorubicin in the treatment of cutaneous T-cell lymphoma.
J Am Acad Dermatol. 2001 Jan;44(1):149-50. No abstract available.
Related citations
6. Treatment of relapsing or recalcitrant cutaneous T-cell lymphoma with pegylated liposomal
doxorubicin.
Related citations
7. Pegylated liposomal doxorubicin in the treatment of mycosis fungoides.
Acta Derm Venereol. 2006;86(6):545-7. No abstract available.
Related citations
8. Pegylated liposomal doxorubicin in stage IVB mycosis fungoides.
Br J Dermatol. 2005 Jul;153(1):183-5.
Related citations
9. Prospective multicenter study of pegylated liposomal doxorubicin treatment in patients
with advanced or refractory mycosis fungoides or Sézary syndrome.
Quereux G, Marques S, Nguyen JM, Bedane C, D'incan M, Dereure O, Puzenat E, Claudy
A, Martin L, Joly P, Delaunay M, Beylot-Barry M, Vabres P, Celerier P, Sasolas B, Grange
F, Khammari A, Dreno B.
Related citations
10. Pegylated liposomal doxorubicin in the treatment of primary cutaneous T-cell
lymphomas.
Pulini S, Rupoli S, Goteri G, Pimpinelli N, Alterini R, Tassetti A, Scortechini AR,
Offidani M, Mulattieri S, Stronati A, Brandozzi G, Giacchetti A, Mozzicafreddo G,
Ricotti G, Filosa G, Bettacchi A, Simonacci M, Novelli N, Leoni P.
Haematologica. 2007 May;92(5):686-9.
Related citations
Anlage 1b
Suchvorgang #2 : 13 Treffer
1. J Clin Oncol. 2003 Nov 15;21(22):4251-2.
Uncommon hematologic malignancies. Case 3. Parotid swelling during
treatment for
transformed mycosis fungoides.
Bird BR, Daly PA.
St. James's Hospital and Trinity College, Dublin, Ireland.
PMID: 14615457
2. Br J Dermatol. 2005 Jul;153(1):183-5.
doxorubicin (LD)
lymphoma.
stage
adverse
extracutaneous
intravenously
every 4 weeks.
received
activity
larger
studies.
PMID: 16029347
3. Cancer. 1977 May;39(5):1967-70.
Thirteen patients with advanced mycosis fungoides received induction
therapy with
Adriamycin, 60/m2 I.V. repeated at 21-day intervals. Ten patients had
extensive
skin tumors; all patients had lymph node enlargement with mycosis fungoides
involvement in eight; four patients had biopsy-proven visceral involvement.
Only
two patients had received no prior therapy. The overall response rate with
Adriamycin therapy was 85% with three patients (23%) achieving a biopsyproven
complete remission and five patients (39%) partial remissions. The median
number
of courses to maximum response was two (range two to four). The principle
toxicity was myelosuppression, but this was not severe and the entire group
received more than 90% of the intended doses of Adriamycin. One patient
developed
probable Adriamycin cariotoxicity. Maintenance therapy for patients
achieving a
remission was methotrexate 15 mg/m2 I.M. twice weekly and cyclophosphamide
750
mg/m2 I.V. every 21 days. The median duration of complete remission was 32+
weeks
(range 16+-40+ weeks) while the median duration of partial remission was 18
weeks
(range 8-111+ weeks). Adriamycin has proven to be an effective induction
agent in
the treatment of advanced mycosis fungoides and its incorporation into
combination chemotherapy regimens is warranted.
PMID: 858126
PMID: 17106606
lymphoma.
Comment on
PMID: 11148501
lymphomas.
Scortechini
Leoni
P.
complete
stage
46
(PFS)
44%,
that
other
PMID: 17488695
in
P,
France.
Comment in
(2)
a dose
of 40 mg/m(2).
evaluation.
(primary end
partial
patients
time
Caelyx in
in 2
Sézary
response
does
(especially
mg/m(2).
PMID: 18559761
Comment in
Comment on
PMID: 18559771
following
Karpouzis A,
Bourikas G.
10. Cancer. 2003 Sep 1;98(5):993-1001.
cutaneous
T-cell lymphoma.
Koch
HJ, Hauschild A.
therapy
study
second-line
patients
PEG-DOXO
received
in 6
One
and
Disease was
follicular
patients,
a CR
biopsy
response
after a
one
to
patients),
survival was
34
had
with
PMID: 12942567
11. Ann N Y Acad Sci. 2001 Sep;941:214-6.
Pegylated doxorubicin for primary cutaneous T cell lymphoma: a report on
ten
Jena,
Germany. Wollina-Uw@khdf.de
PMID: 11594577
ten
Jena,
effective in
on
years)
IV a
an
There was
response
final
progressive
80% (of
II b)
first
survival rate
died
in an
were
recalcitrant
remissions.
PMID: 11216914
pegylated
Comment in
useful for
drug.
primary
pegylated
5
doxorubicin
mg
6
doses.
partial
partial
83%).
ranging
and
effects.
recalcitrant
and
PMID: 10607318
Anlage 1c
Suchvorgang #4: 15 Treffer
1. Am J Clin Dermatol. 2002;3(3):193-215.
Treatment of cutaneous T cell lymphoma: current status and future
directions.
Apisarnthanarax N, Talpur R, Duvic M.
Division of Internal Medicine, Department of Dermatology, University of
Texas, MD
Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
The treatment of cutaneous T cell lymphoma (CTCL), which includes mycosis
fungoides and Sezary syndrome, has been in a state of continual change over
recent decades, as new therapies are constantly emerging in the search for
more
effective treatments for the disease. However, prognosis and survival of
patients
with CTCL remains dependent upon overall clinical stage (stage IA-IVB) at
presentation, as well as response to therapy. Past therapies have been
limited by
toxicity or the lack of consistently durable responses, and few treatments
have
been shown to actually alter survival, especially in the late stages of
disease.
Even aggressive chemotherapy has not been shown to improve overall survival
compared to conservative sequential therapy in advanced disease, and adds
the
risk of immunosuppressive complications. Over the last decade,
extracorporeal
photopheresis has been the only single treatment that has been shown to
improve
survival in patients with Sezary syndrome, although its true efficacy and
place
in combination therapy remain unclear. Much of the focus of current
research has
been on combinations of skin-directed therapies and biological response
modifiers, which improve response rates. The results of various trials over
the
years have also brought into favor the use of post-remission maintenance
therapy
with topical corticosteroids, topical mechlorethamine (nitrogen mustard),
interferon-alpha, or phototherapy to prevent disease relapse. Recent novel
developments in CTCL therapy include oral bexarotene, a retinoid X
receptor-selective retinoid that has activity in all stages of CTCL, and
the
topical gel formulation of bexarotene, which plays a role in treating
localized
lesions. US Food and Drug Administration (FDA)-approved, oral systemic
bexarotene
has the advantage of a 48% overall response rate at a dosage of 300
mg/m(2)/day,
and avoids immunosuppression and risk of central line and catheter-related
infectious complications that are associated with other systemic therapies.
Monitoring of triglycerides and use of concomitant lipid-lowering agents
and
thyroid replacement is required in most patients. Also recently FDAapproved,
denileukin diftitox is the first of a novel class of fusion toxin proteins
and is
selective for interleukin-2R (CD25+) T cells, targeting the malignant T
cell
clones in CTCL. Denileukin diftitox is associated with capillary leak
syndrome in
20 to 30% of patients, which may be ameliorated by hydration and
corticosteroids.
Higher response rates are possible by combining bexarotene with "statin"
drugs
and active CTCL therapies. Studies are being conducted on combining
bexarotene
and denileukin diftitox with other modalities. Biological response modifier
therapies that are in current or future investigational trials include
topical
tazarotene, pegylated interferon, interleukin-2, and interleukin-12. At the
forefront of systemic chemotherapy development, pegylated liposomal
doxorubicin,
gemcitabine, and pentostatin appear to have the greatest potential for
success in
CTCL therapy. Bone marrow transplantation, which is currently limited by
the risk
of graft-versus-host disease, offers the greatest potential for disease
cure.
Further developments for CTCL may include more selective immunomodulatory
agents,
vaccines, and monoclonal antibodies.
PMID: 11978140
2. Br J Dermatol. 2005 Jul;153(1):183-5.
doxorubicin (LD)
lymphoma.
stage
adverse
extracutaneous
intravenously
every 4 weeks.
received
activity
larger
studies.
PMID: 16029347
3. Semin Oncol. 2006 Feb;33(1 Suppl 3):S33-6.
Future perspectives in the treatment of cutaneous T-cell lymphoma (CTCL).
Dummer R.
Department of Dermatology, University Hospital of Zurich, Switzerland.
reinhard.dummer@usz.ch
Over the last 20 years the treatment of cutaneous T-cell lymphoma has been
in a
state of continual change. New therapies are constantly emerging as the
search
continues for more effective and tolerable disease-specific agents that
satisfy
medical needs. Therapies under investigation include topical retinoids,
fusion
molecules like denileukin diftitox, pegylated interferon, interleukin-2,
and
interleukin-12. Pegylated liposomal doxorubicin, gemcitabine, and
chlorodeoxyadenosine also appear to have clinical potential. Other
identified
agents include vaccines and monoclonal antibodies. This article reviews
some of
the most recent clinical innovations.
PMID: 16516674
4. Clin Lymphoma Myeloma. 2008 Dec;8 Suppl 5:S187-92.
Novel therapies for cutaneous T-cell lymphomas.
Horwitz SM.
Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York, NY
10021,
USA. horwitzs@mskcc.org
Cutaneous T-cell lymphomas (CTCLs) are a group of uncommon mature T-cell
lymphomas presenting primarily or exclusively in the skin. The most common
subtype, mycosis fungoides and its leukemic variant Sézary syndrome,
frequently
behave as a chronic lymphoma with good prognosis for early-stage disease
and
shortened survival only for patients in advanced stages. Historically,
these
patients have experienced excessive toxicity from chemotherapy without
durable
benefit, leading to current conservative treatment strategies. An
increasing
number of novel therapies are available or in development. These newer
therapies
often have unique mechanisms of action and different toxicities with less
myelosuppression than traditional cytotoxic chemotherapy. Among these novel
systemic therapies are so-called biologic therapies such as retinoids like
bexarotene, the fusion toxin denileukin diftitox, lenalidomide, and tolllike
receptor agonists. Other important novel or emerging agents include the
histone
deacetylase inhibitors; a novel antifolate, pralatrexate; the proteasome
inhibitor bortezomib; and the purine nucleoside phosphorylase inhibitor
forodesine. Even agents considered to be conventional chemotherapy, such as
gemcitabine or pegylated liposomal doxorubicin, have demonstrated activity
in
CTCL at relatively lower doses with less myelosuppression. The mechanisms
of
action of the novel agents are reviewed as well as available clinical data.
As
the role of these new agents is better understood, particularly with regard
to
nonoverlapping toxicities, combination strategies might emerge. Evaluation
through carefully designed clinical trials should lead to better, safer,
and more
effective treatment strategies in the future.
PMID: 19073526
5. Am J Clin Dermatol. 2006;7(3):155-69.
Management of refractory early-stage cutaneous T-cell lymphoma.
Huber MA, Staib G, Pehamberger H, Scharffetter-Kochanek K.
Department of Dermatology, Division of General Dermatology, Vienna Medical
University, Vienna, Austria. margit.huber@meduniwien.ac.at
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin's
lymphomas that manifest primarily in the skin. Mycosis fungoides is
recognized as
the most common type of CTCL. Patients with early-stage CTCL usually have a
benign and chronic disease course. However, although there is a wide array
of
therapeutic options for early-stage CTCL, not all patients respond to these
individual therapies, resulting in refractory cutaneous disease over time.
Refractory early-stage CTCL poses an important therapeutic challenge, as
one of
the principal treatment goals is to keep the disease confined to the skin,
thereby preventing disease progression. Much of the focus of current
research has
been on the evaluation of already available skin-directed therapies and
biologic
response modifiers and combination regimens thereof, such as the
combination of
psoralen and UVA (PUVA) with interferon-alpha or retinoids. Recent novel
developments include oral bexarotene, a retinoid X receptor-selective
retinoid
that has activity in all stages of CTCL and has been shown to be effective
in
patients with refractory early-stage disease as well as advanced-stage
disease.
Likewise, the topical gel formulation of bexarotene has proved to be an
important
therapeutic option in patients with refractory or relapsed lesions. Oral
bexarotene and topical bexarotene have been approved by the US FDA for the
treatment of refractory CTCL. Systemic chemotherapy is typically reserved
for
advanced-stage CTCL and is usually not recommended for early-stage, skinlimited
disease. However, recent exploratory studies indicate that low-dose
methotrexate
may represent an overall well tolerated therapy in a subset of patients
with
refractory early-stage CTCL, as may pegylated liposomal doxorubicin, which
is
currently being investigated in this specific clinical setting. Another
recently
FDA-approved therapy is the interleukin-2 fusion toxin denileukin diftitox,
which
is now well established to play a role in the treatment of refractory CTCL,
including early-stage extensive plaque disease. The value of other agents,
such
as topical tazarotene, topical methotrexate, and topical imiquimod, and of
novel
immunomodulatory approaches including monoclonal antibodies, still needs to
be
assessed for refractory early-stage CTCL.
PMID: 16734503
PMID: 17106606
lymphoma.
Comment on
PMID: 11148501
lymphomas.
Scortechini
Leoni
P.
complete
stage
46
(PFS)
44%,
that
other
PMID: 17488695
in
P,
France.
Comment in
(2)
a dose
of 40 mg/m(2).
evaluation.
(primary end
partial
patients
time
Caelyx in
in 2
Sézary
response
does
(especially
mg/m(2).
PMID: 18559761
10. Acta Derm Venereol. 2010 Nov;90(6):616-20.
Sudden onset of an aggressive cutaneous lymphoma in a young patient with
psoriasis: role of immunosuppressants.
Quéreux G, Renaut JJ, Peuvrel L, Knol AC, Brocard A, Dréno B.
Nantes University Hospital, INSERM, Nantes, France.
Psoriasis is thought to be associated with an increased risk of lymphoma.
We
report here the first case of an aggressive primary cutaneous pleomorphic
T-cell
lymphoma in a patient with psoriasis. The 36-year-old patient, who had
previously
been treated successively with methotrexate, ciclosporin and etanercept,
presented with rapidly growing nodules on the leg. A biopsy confirmed a
stage IVa
primary cutaneous pleomorphic T-cell lymphoma. Despite treatment with
pegylated
liposomal doxorubicin, the disease progressed and the patient died 5 months
later. This case of pleomorphic T-cell lymphoma was remarkable in both its
extremely rapid onset and the aggressive nature of the disease. The onset
of this
disease in a patient with psoriasis who had been previously treated with
immunosuppressive drugs and a tumour necrosis factor (TNF)-α blocker is of
major
interest. Only eight cases of cutaneous lymphomas associated with treatment
with
TNF-α blockers have been published previously. Most of these eight cases
related
to anti-TNFα antibodies; only two were linked to etanercept.
PMID: 21057746
Comment in
Comment on
PMID: 18559771
following
Karpouzis A,
Bourikas G.
Department of Haematology, School of Medicine, Democritus University of
Thrace,
Alexandroupolis, Greece. ktsatala@med.duth.gr
Advanced stage mycosis fungoides (MF) generally has a poor prognosis, and
currently there is no standard treatment available. Here we report the case
of a
young woman with recalcitrant tumour-stage MF (T3, stage IIb) whose disease
was
unresponsive to several therapeutic modalities, but who has showed
sustained
clinical response to pegylated liposomal doxorubucin. No severe infectious
complications have been observed. The use of this drug in tumour-stage MF
should
be investigated further.
PMID: 12602979
13. Cancer. 2003 Sep 1;98(5):993-1001.
cutaneous
T-cell lymphoma.
Koch
HJ, Hauschild A.
therapy
study
second-line
patients
PEG-DOXO
received
in 6
One
and
Disease was
follicular
patients,
a CR
biopsy
response
after a
one
to
patients),
survival was
34
had
with
PMID: 12942567
ten
Jena,
effective in
on
years)
IV a
an
There was
response
final
progressive
80% (of
II b)
first
survival rate
died
in an
were
recalcitrant
remissions.
PMID: 11216914
pegylated
Comment in
useful for
drug.
primary
pegylated
5
doxorubicin
mg
6
doses.
partial
partial
83%).
ranging
and
effects.
recalcitrant
and
PMID: 10607318
Anlage 1d
Suchvorgang # 5: 1 Treffer
Pegylated liposomal doxorubicin in the treatment of primary cutaneous Tcell lymphomas.
Scortechini
Leoni
P.
complete
stage
46
(PFS)
44%,
that
other
PMID: 17488695
Anlage 2a
Stand der Bearbeitung
08.03.2012
Nr. Feld
Hinweise für die Bearbeitung
1
Quelle
2
Studientyp vom Autor bezeichnet als
Quereux G
Prospective multicenter study of pegylated liposomal
doxorubicin treatment in
Prospektive, offene, multizentrische Studie
3
Studientyp nach Durchsicht
Zuordnung zu einem der folgenden Studientypen:
□ Therapiestudie mit randomisierter Gruppenzuteilung
□ Therapiestudie mit nicht-randomisierter Gruppenzuteilung
x Therapiestudie mit Vergleichen über Zeit und Ort (z. B.
historische Kontrollen)
□ Therapiestudie ohne Vergleichsgruppen (auch Beobachtungsstudien und Anwendungsbeobachtungen)
□ Fall-Kontrollstudien
□ Fallserie
□ Fallbericht / Kasuistik (case report)
□ Nicht eindeutig zuzuordnen
Falls Therapiestudie:
□ mit Placebokontrolle(n): nein
□ mit Aktivkontrolle(n): nein
□ mit Dosisgruppen: nein
□ sonstige Kontrollgruppe(n): nein
4
Formale Evidenzkriterien
gemäß SIGN
□ 1++: Qualitativ hochwertige Metaanalyse bzw. systematischer Review von RCTs oder RCT mit sehr geringem
Risiko von Bias
□ 1+: Gut durchgeführte Metaanalyse bzw. systematischer
Review von RCTs oder RCT mit geringem Risiko von
Bias
□ 1-: Metaanalyse bzw. systematischer Review von RCTs
oder RCT mit hohem Risiko von Bias
□ 2++: Qualitativ hochwertiger systematischer Review von
Fallkontroll- oder Kohortenstudien
oder
Qualitativ hochwertige Fallkontroll- oder Kohortenstudie
mit sehr geringem Risiko von Confounding, Bias oder
Zufallsschwankungen und hoher Wahrscheinlichkeit, so
dass der Zusammenhang kausal ist
x 2+: Gut durchgeführte Fallkontroll- oder Kohortenstudie
mit niedrigem Risiko von Confounding, Bias oder Zufallsschwankungen und einer mittleren Wahrscheinlichkeit, so dass der Zusammenhang kausal ist
□ 2-: Fallkontroll- oder Kohortenstudie mit hohem Risiko
von Confounding, Bias oder Zufallsschwankungen und
einem signifikanten Risiko, so dass der Zusammenhang
1
nicht kausal ist
□ 3: Andere Studien wie Einzelfallberichte, Fallserien
□ 4: Expertenmeinung
5
Bezugsrahmen
Nennung des Auftraggebers und der für die Durchführung
des Berichts verantwortlichen Institution
Funding: Nantes University Hospital
Die Prüfsubstanz Caelyx wurde von der Fa. ScheringPlough gestellt
Gibt es Hinweise auf relevante Interessenkonflikte?
Rolle des Sponsors: Der Sponsor hatte keinen Einfluß auf
das Design der Studie, die Durchführung, die Analyse und
Interpretation der Daten oder der Erstellung des Manuskriptes.
6
Indikation
Therapie refraktärer kutaner T-Zell-Lymphome mit liposomalem pegyliertem Doxorubicin
7
Primäre Fragestellung /
primäre Zielsetzung(en)
Primäre Zielsetzung ist die Untersuchung der objektiven
Ansprechrate von pegyliertem liposomalen Doxorubicin bei
Patienten mit refraktären kutanen T-Zell-Lymphomen
8
Relevante Ein- und Ausschlusskriterien
wichtigste Einschlußkriterien:
Primär kutanes T-Zell-Lymphom Stadium II-IV mit mind.
2 Vortherapien
oder
histol. transformiertes epidermotropes kutanes T-ZellLymphom mit Indikation einer Chemotherapie
wichtigste Ausschlußkriterien:
Herzinsuffizienz
Zweitkarzinom
aktive Infektion
Vorbehandlung mit Doxorubicin; kum. Dosis > 300 mg/qm
9
Prüfintervention
Art der Therapie:
Liposomales pegyliertes Doxorubicin 40 mg/qm i.v. alle 4
Wochen
Dauer der Therapie: bis max. 8 Zyklen
10
Vergleichsintervention
historische Kontrollen:
2 retrospektive Studien mit liposomalem Doxorubicin
Fludarabin
Methotrexat
Gemcitabine
Polychemotherapie
11
Evtl. weitere Behandlungsgruppen
keine
12
Subgruppen
Enthält die Studie Subgruppen, die für die Fragestellung an
die Kommission relevant sind ?
□ keine relevanten Subgruppen
□ prospektiv geplante Subgruppenauswertung
x post hoc definierte oder in Auswertung gefundene Subgruppen:
Sezary-Syndrom: n = 10
transformierte kutane T-Zell-Lymphome: n = 10
2
13
Studiendesign
Prüfung der Therapie ohne Kontrollen
Anzahl der Behandlungsarme:
1
Typus:
□ Parallelgruppendesign
□ Cross-Over Design
□ Prae-Post-Vergleich
□ Sonstige:.........................
Geplante Fallzahl ( falls angegeben):
nicht angegeben
Wurde eine Fallzahlplanung (Power-Kalkulation) durchgeführt?
nein
Waren Interimanalysen geplant?
nein
14
Zentren
Anzahl der Zentren:
13
Vergleichbarkeit der Studiendurchführung in den einzelnen
Zentren gegeben:
ist gegeben
15
Randomisierung
Keine Randomisierung!
16
Verblindung der Behandlung
x Keine Verblindung (offene Behandlung)
□ Patienten verblindet
□ Behandler verblindet
□ Beurteiler verblindet ( z.B. bei Bildgebung)
17
Beobachtungsdauer
nicht angegeben
18
Primäre Zielkriterien
primärer Endpunkt: objektive Ansprechrate
Wurden relevante patientennahe Zielkriterien verwendet?
Ja: medianes Gesamtüberleben
Mit welchen Instrumenten und in welcher Form erfolgte die
Erfassung der Zielkriterien:
klinische Untersuchung zu definierten Zeitpunkten
19
Sekundäre Zielkriterien
nicht angegeben
20
Statistische Methoden für
die Analyse der primären
Endpunkte
Kaplan-Meyer- Kurve und log-rank-Test
Signifikanz-/Konfidenzniveau
alpha-Fehler: 5%
21
Anzahl der behandelten
Patienten
Erreichte Fallzahl:
25
Wurde die Studie vorzeitig beendet?
nein
3
22
Zahl und Charakteristika
der eingeschlossenen und
ausgewerteten Patienten
es liegt eine differenzierte tab. Darstellung der Patientencharakteristika vor;
n = 25; medianes Alter: 64 Jahre
10 Pat. mit Mycois fungoides (MF)
5 Pat. mit Sezary -Syndrom (SS)
5 Pat. mit histol. transformiertem SS
5 Pat. mit transformierter MF
15/25: T3
10/25: T4
Differenzierte Darstellung nach Behandlungsgruppen vorhanden?
es gibt nur 1 Behandlungsgruppe
Darstellung des Patientenflusses nach dem CONSORTFlussdiagramm
nein
Sind die Ausfälle von Studienteilnehmern (Drop-outs) dokumentiert und begründet?
2 Drop-outs wg. Progreß
1 Drop-out wg. Tod bei akutem Leber- und Nierenversagen
ohne Bezug zur Prüfmedikation
Erfolgte eine Intention-to-treat- (ITT-) Analyse?
ja
Erfolgte eine Per Protocol- (PP-) Analyse?
nein
Gibt es Hinweise auf systematische und relevante Unterschiede zwischen den Drop-outs und den gemäß Studienprotokoll behandelten Patienten?
nein
23
Vergleichbarkeit der Behandlungsgruppen
stark eingeschränkte Vergleichbarkeit der Studienergebnisse mit den histor. Kontrollen:
unterschiedl. Patientenkollektive (Stadium; Vortherapien)
unterschiedl. Methoden zur Remissionsbeurteilung
unterschiedl. Definition von Ansprechdauer und PFS
24
Ergebnisse und ihre Darstellung
es liegt eine differenzierte tab. Darstellung der Behandlungsergebnisse vor;
Gesamtansprechrate: 56% (14/25)
CR: 5 Patienten
PR: 9 Patienten
PD: 9 Patienten
medianes Overall Survival: 43,7 Monate
medianes PFS bei 14 Patienten mit CR/PR: 5,02 Monate
medianes Overall Survival bei 14 PAtienten mit CR/PR:
45,8 Monate
Subgruppen:
bei 10 Patienten mit SS: Gesamtansprechrate 60% (6/10); 1
CR
bei 10 Patienten mit transformierten kutanen T-ZellLymphomen: Gesamtansprechrate 50 (5/10); 1 CR
4
25
Unerwünschte Therapiewirkung
Sind unerwünschte Ereignisse (UEs/AEs) berichtet?
es liegt eine differenzierte tab. Darstellung der AE nach Art
und Schwere vor;
AE Grad 1 und höher: 80% d. Patienten
Die meisten Grad 1/ 2 Nebenwirkungen waren: Anämie,
Asthenie, Übelkeit und Erbrechen.
Sind schwerwiegende UEs (SUEs/SAEs) berichtet?
2 Nebenwirkungen Grad 4 beim selben Patienten: Hyperthermie und Hämophagozytose
Infektionen Grad 3 bei 3 Patienten
Wurde der Bezug zur Behandlung beurteilt?
Ja
26
Fazit der Autoren
27
Abschließende Bewertung
durch den Bearbeiter
Die Studie demonstriert die Wirksamkeit von Caelyx in der
Behandlung von primär kutenen T-Zell-Lymphomen mit
einer Gesamtansprechrate von 56%. Vor allem bei den
schwer therapiebaren Formen Sezary-Syndrom und transformierte MF zeigen sich mit 60% bzw. 50% gute Ansprechraten.
Die vorliegende Publikation wird
x berücksichtigt
□ nicht berücksichtigt
Wenn nicht berücksichtigt: Gründe angeben:
□ Klinisch relevante Patientengruppen nicht berücksichtigt
□ Klinisch relevante Alternativen zum Einsatz der
Technologie nicht berücksichtigt
□ Der in der Studie abgebildete Entwicklungsstatus
der Technologie entspricht nicht
mehr heutigen Ansprüchen
□ Keine (patienten-) relevanten Endpunkte
□ Nicht auf den deutschen Versorgungskontext übertragbar
□ Erheblich eingeschränkte Validität der Ergebnisse
aufgrund schwerwiegender
Mängel im Studiendesign
□ Es liegen aussagekräftigere Studien vor.
□ Sonstige Gründe – und zwar:
5
Anlage 2b
08.03.2012
Nr. Feld
1
Quelle
Pulini S
Pegylated liposomal doxorubicin in the treatment of
primary cutaneous T-cell lymphomas
2
prospektive, multizentrische Phase-II-Studie
3
□ Therapiestudie mit Vergleichen über Zeit und Ort (z. B.
x Therapiestudie ohne Vergleichsgruppen (auch Beobachtungsstudien und Anwendungsbeobachtungen)
□ Fallserie
4
gemäß SIGN
Risiko von Bias
Bias
oder
x 2+: Gut durchgeführte Fallkontroll- oder Kohortenstudie
nicht kausal ist
1
5
Bezugsrahmen
Ospedali Riuniti, Ancona, Italien
Funding: partially supported by AIL Onlus (Italian Association against leukemia, lymphoma and myeloma)
Ein Interessenskonflikt wird von den Autoren nicht erklärt.
6
Indikation
Therapie fortgeschrittener, relabierter und refraktärer kutaner T-Zell-Lymphome mit liposomalem pegyliertem
Doxorubicin
7
Untersuchung der Wirksamkeit von pegyliertem liposomalen Doxorubicin bei fortgeschrittenen oder relabierten/refraktären primär kutanen T-Zell-Lymphomen.
8
Wichtigste Einschlußkriterien:
Alter < 18; ECOG 0-1; fortgeschrittene, relabierte oder
refraktäre primär kutane T-Zell-Lymphome
Wichtigste Ausschlußkriterien:
Kum. Anthracyclindosis > 200 mg/qm;
Zweitneoplasie
9
Prüfintervention
Pegyliertes liposomales Doxorubicin
Dosis: 20 mg/qm über 1h i.v. alle 4 Wochen
Therapiedauer:bis zum Progreß
10
keine
11
keine
12
Subgruppen
x keine relevanten Subgruppen
□ post hoc definierte oder in Auswertung gefundene Subgruppen
13
Studiendesign
1
Typus:
□ Sonstige:.........................
Geplante Fallzahl:
keine Planung
nein
nein
2
14
Zentren
Anzahl der Zentren:
8
Zentren beurteilbar?
Nicht beurteilbar
15
Randomisierung
Keine Randomisierung!.
16
17
Beobachtungsdauer
Maximum follow-up: 46 Monate
Medianes follow-up: 22,6 Monate
18
Es erfolgt keine explizite Nennung von primären bzw.
Haupt-Zielkriterien durch die Autoren.
Im Ergebnisteil werden Therapieansprechen, overall survival (OS), event-free survival (EFS) und progression-freesurvival (PFS) berichtet.
Ja: medianes OS
Klinische Untersuchung und Bildgebung(CT) zu definierten Zeitpunkten
19
Es erfolgt keine explizite Nennung von sekundären Zielkriterien durch die Autoren.
20
Endpunkte
Fisher`s exact test
Log-rank-test
21
Patienten
Erreichte Fallzahl:
n = 19
Nein
22
es liegt eine differenzierte tab. Darstellung der Patientencharakteristika im Online-Appendix vor;
medianes Alter: 67 Jahre;
68% haben eine MF in unterschiedl. Stadien
bei 23% liegt eine Transformation in ein großzelliges Lymphom vor
16% haben ein SS
16% haben eine peripheres T-Zell-Lymphom unspecified
(PTCL-u)
alle Patienten sind vorbehandelt
mediane Zeit von Erstdiagnose bis Behandlung mit liposomalem Doxorubicin: 43 Monate
Es gibt nur 1 Behandlungsgruppe
Darstellung des Patientenflusses nach dem CONSORTFlussdiagramm
3
Nein
Es werden keine Drop-outs angegeben.
ja
nein
23
Es gibt nur 1 Behandlungsgruppe
Gibt es relevante Unterschiede zwischen den Behandlungsgruppen
□ bei Studienbeginn (Baseline)?
□ in der Durchführung der Intervention?
mediane Therapiezyklen: 6 Kurse (Range 2-8)
Gesamtansprechrate: 84,2% (16/19)
CR: 8/19 Patienten (42,1%)
VGPR: 5/19 Patienten (26,3%)
PR: 3/19 Patienten (15,8%)
Progreß: 3/19 Patienten (15,8%)
medianes OS (medianes follow-up: 22,6 Monate): 34
Monate
medians EFS (medianes follow-up: 22,6 Monate): 18
Monate
medians PFS (medianes follow-up: 22,6 Monate): 19
Monate
24
25
und Schwere vor;
Neutropenie > Grad 2: 1 Patient
Gastrointestinale Toxizität > Grad 2: 2 Patienten
PPE Grad 1: 1 Patient
Toxizität Grad 3 und 4: 2 Fälle
ja
26
Fazit der Autoren
27
Pegyliertes liposomales Doxorubicin scheint eine aktive
und sichere Substanz in der Behandlung cutaner T-ZellLymphome zu sein, welches als Monotherapie in relabierten Frühstadien und in Kombination mit anderen Zytostatika bei fortgeschrittenen Lymphomen eingesetzt werden
sollte.
x berücksichtigt
4
Anlage 2c
08.03.2012
Nr. Feld
1
Di Lorenzo G
Quelle
Pegylated liposomal doxorubicin in stage IVB mycosis fungoides
Br J Dermatol. 2005 Jul;153(1):183-5.
2
Retrospektive Studie
3
□ Fallserie
□ mit Placebokontrolle: nein
□ mit Aktivkontrolle: nein
4
gemäß SIGN
Risiko von Bias
Bias
oder
□ 2+: Gut durchgeführte Fallkontroll- oder Kohortenstudie
x 2-: Fallkontroll- oder Kohortenstudie mit hohem Risiko
nicht kausal ist
1
5
Bezugsrahmen
Erstautor s.oben;
Dipartimento di Patologica Sistematica; Clinica dermatologica, Universita di Napoli, Neapel, Italien
nein
Conflicts of interest: none declared
6
Indikation
Therapie der Mycosis fungoides im Stadium IVb mit pegyliertem liposomalen Doxorubicin
7
Wirksamkeit von pegyliertem liposomalen Doxorubicin bei
MF Stadium IVb
8
histol. bestätigte MF Stadium IV b
nicht angegeben
9
Prüfintervention
Dosis: 20 mg/qm KÖF über 2h i.v. alle 4 Wochen
Therapiedauer: bis Progreß
10
Keine
11
Keine
12
Subgruppen
13
Studiendesign
Anzahl der Behandlungsarme: 1
Typus:
□ Sonstige:.........................
nicht angegeben
nein
nein
14
Zentren
Anzahl der Zentren:
unizentrisch: 1
Zentren beurteilen:
entfällt
2
15
Randomisierung
Keine Randomisierung!
16
17
Beobachtungsdauer
Eine Beobachtungsdauer wird nicht angegeben.
18
Es erfolgt keine explizite Definition der Zielkriterien (outcomes) durch die Autoren.
Im Ergebnisteil wird die Ansprechrate und das mediane
Gesamtüberleben in Monaten angegeben.
Ja, das mediane Gesamtüberleben.
Klinische Untersuchung alle 4 Wochen.
Bildgebende Untersuchung mit CT nach je 3 Therapiezyklen
19
Keine Nennung sekundärer Zielkriterien.
20
Endpunkte
Keine Nennung statistischer Methoden in der Publikation
21
Patienten
Erreichte Fallzahl:
10
Nein (retrospektive Studie)
22
10 Patienten mit histol. bestätigter MF Stadium IVb.
Patientenalter: zwischen 50 und 70 Jahren
Art und Zahl der Vortherapien sind angegeben
Metastasierungsorte (Lunge, Leber, beide) sind angegeben
nein
Darstellung des Patientenflusses nach dem CONSORTFlussdiagramm:
nein
nein
nein
Gibt es Hinweise auf systematische und relevante Unterschiede zwischen den Drop-outs und den gemäß Studienprotokoll behandelten Patienten:
In der Studie sind keine Drop-outs aufgeführt.
3
23
Nur 1 Behadlungsgruppe.
24
Progreß : 5/10 Patienten (50%)
PR: 3/10 Patienten (30%)
CR: 0/10 Patienten (0%)
SD: 2/10 Patienten: ( 20%)
Überleben: 2-8 Monate;
medianes Gesamtüberleben: nicht angegeben
25
Leukopenie Grad 1 und 2: 3 Patienten
Leukopenie Grad 4: 1 Patient
Palmoplantare Erythrodysästhesie Grad 2: 3 Patienten
nein
nein
26
Fazit der Autoren
27
Stichwortartige Zusammenfassung der Schlussfolgerungen
(conclusions) der Autoren der Studie:
Pegyliertes liposomales Doxorubicin ist wirksam und verträglich bei Patienten mit MF im Stadium IVb.
Die Ergebnisse sollten in größeren Studien verifiziert werden .
x berücksichtigt
4
Anlage 2d
08.03.2012
Nr. Feld
1
Quelle
2
Wollina U
Multicenter study of pegylated liposomal doxorubicin
in patients with cutaneous T-cell lymphoma
Cancer. 2003 Sep 1;98(5):993-1001.
retrospektive multizentrische Studie
3
□ Fallserie
4
gemäß SIGN
Risiko von Bias
Bias
oder
x 2-: Fallkontroll- oder Kohortenstudie mit hohem Risiko
nicht kausal ist
1
5
Bezugsrahmen
Uwe Wollina, Department of Dermatology, Hospital Dresden-Friedrichstadt, Dresden
The study was supported by an unrestricted grant from
Essex Pharma, Munich, Germany
6
Indikation
Therapie kutaner T-Zell-Lymphome mit liposomalem
pegyliertem Doxorubicin
7
Untersuchung der Wirksamkeit von liposomalem pegyliertem Doxorubicin als Zweitlinientherapie bei Patienten mit
primär kutanen T-Zell-Lymphomen
8
Rezidiv eines histol. gesicherten kutanen T-ZellLymphoms
schwere Herzerkrankung
kum. Anthracyclindosis > 200mg/qm
aktive Infektion
9
Prüfintervention
liposomales pegyliertes Doxorubicin i.v.über 2h:
Dosis:
20 mg/qm (20 Patienten)
20-30mg(qm (5 Patienten)
40 mg/qm (2 Patienten)
Dosisintervall: alle 2 Wochen (6 Patienten); alle 2-3 Wochen (8Patienten) oder alle 4 Wochen (19 Patienten)
10
nein
11
nein
12
Subgruppen
Subgruppen ggf. benennen
13
Studiendesign
1
Typus:
□ Sonstige:.........................
nicht angegeben
2
nein
nein
14
Zentren
Anzahl der Zentren:
7
Zentren beurteilen:
nicht beurteilbar
15
Randomisierung
keine Randomisierung!
16
17
Beobachtungsdauer
nicht angegeben
18
Von den Autoren als primäre bzw. Haupt-Zielkriterien
werden genannt:
Erreichen einer kompletten Remission (CR)
Overall survival
Failure free survival
Progression free survival
Overall survival
Erfassung der Zielkriterien (z. B. Interview, Untersuchung,
standardisierte Fragebögen, Referenzbeurteilung)?
klinische Untersuchung
19
sekundären Zielkriterien werden nicht angegeben.
20
Endpunkte
Bezeichnung der verwendeten Test- bzw. Schätzprozeduren:
nicht angegeben
Signifikanz-/Konfidenzniveau:
nicht angegeben
21
Patienten
Erreichte Fallzahl:
34
nein
22
es liegt eine differenzierte tab. Darstellung der Patientencharakteristika mit Angabe von Alter, TNPBMKlassifikation, Stadium und Vortherapie vor.
Alter: 40-80 Jahre
medianes Alter: nicht angegeben
MF: 28 Patienten
MF mit follikulärer Muzinose: 2 Patienten
pleomorphes CTCL: 2 Patienten
3
Sezary-Syndrom: 1 Patient
anaplastisches großzelliges CTLC: 1 Patient
es gibt nur 1 Behandlungsgruppe
nein
es werden 2 Drop-outs berichtet:
1 Patient mit capillary leak syndrome (Bezug zur Studienmedikation vermutet)
1 Patient mit Suizidversuch (kein Bezug zur Studienmedikation vermutet)
nein (Patient mit Suizidversuch wird nicht berücksichtigt)
ja
nein
23
24
es liegt eine differenzierte tab. Darstellung der Behandlungsergebnisse vor;
CR: 15/34 Patienten
PR: 15/34 Patienten
Gesamtansprechrate: 88,2%
Overall survival: 17,8 Monate +/- 10,5 Monate (n = 33)
Disease free survival: 13,3 Monate +/- 10,5 Monate (n =16)
25
und Schwere vor;
AE wurden bei 14/34 Patienten (41,2 %) berichtet.
AE Grad 3 und 4: bei 6 Patienten berichtet: LEukopenie,
Anämie, capillary leak syndrome, PPE
ja
26
Fazit der Autoren
Die Studie liefert Evidenz für die hohe Wirksamkeit von
liposomalem pegyliertem Doxorubicin bei geringer Nebenwirkungsrate bei Patienten mit kutanen T-ZellLymphomen.
4
Anlage 2e
Datum: 08.03.2012
Nr. Feld
1
Quelle
2
Wollina U
Treatment of relapsing or recalcitrant cutaneous T-cell
lymphoma with pegylated
Prospektive Pilotstudie
3
□ Therapiestudie ohne Vergleichsgruppen (auch Beobachtungsstudien und Anwendungsbeobachtungen)
X Fallserie
4
gemäß SIGN
Risiko von Bias
Bias
oder
nicht kausal ist
X 3: Andere Studien wie Einzelfallberichte, Fallserien
1
5
Bezugsrahmen
Uwe Wollina, Department of Dermatology, Hospital Dresden-Friedrichstadt, Dresden
Keine ersichtlichen Hinweise auf relevante Interessenkonflikte.
6
Indikation
Therapie rezidivierter oder refraktärer kutaner T-ZellLymphome mit liposomalem pegyliertem Doxorubicin
7
Untersuchung der Wirksamkeit von liposomalem pegyliertem Doxorubicin als Zweitlinientherapie bei Patienten mit
primär kutanen T-Zell-Lymphomen
8
refraktäres oder rezidiviertes histol. gesichertes kutanes TZell-Lymphom St. Ib, IIa und IIb
schwere Herzerkrankung
kum. Anthracyclindosis > 200mg/qm
aktive Infektion
9
Prüfintervention
liposomales pegyliertes Doxorubicin i.v.über 1h:
Dosis: 20 mg/qm
Intervall: alle 4 Wochen
Max. Zykluszahl: 8
10
Keine
11
Keine
12
Subgruppen
X keine relevanten Subgruppen
Subgruppen ggf. benennen
13
Studiendesign
1
Typus:
□ Sonstige:.........................
Nicht angegeben
Nein
Nein
2
14
Zentren
Anzahl der Zentren:
1
15
Randomisierung
keine Randomisierung!
16
17
Beobachtungsdauer
Dauer der Therapie
18
Von den Autoren als primäre bzw. Haupt-Zielkriterien
werden genannt:
Ansprechrate
Ansprechrate
Erfassung der Zielkriterien (z. B. Interview, Untersuchung,
standardisierte Fragebögen, Referenzbeurteilung)?
Klinische Untersuchung und Kontrollbiospie
19
Keine
20
Endpunkte
Bezeichnung der verwendeten Test- bzw. Schätzprozeduren
Signifikanz-/Konfidenzniveau:
Nicht angegeben
21
Patienten
Erreichte Fallzahl:
6
Nein
22
es liegt eine tab. Darstellung der Patientencharakteristika
mit Angabe von Alter, Geschlecht,TNPBM-Klassifikation,
Stadium und Vortherapie vor.
Nein
Es gab keine Drop-outs.
nein
nein
Entfällt (keine Drop-outs)
3
23
24
es liegt eine tab. Darstellung der Behandlungsergebnisse
vor;
2 Patienten erhielten 6 Therapiezyklen, 4 Patienten 8 Therapiezyklen.
CR: 4/6 Patienten
PR: 1/6 Patienten
PD: 1/6 Patienten
Gesamtansprechrate: 83%
25
und Schwere vor;
Lymphopenie: 3 Patienten
Anämie: 5 Patienten
Lymphopenie Grad 3: 1 Patient
Anämie Grad 3: 1 Patient
ja
26
Fazit der Autoren
27
liposomales pegyliertes Doxorubicin zeigt eine gute Wirksamkeit bei Patienten mit rezidivierten oder refraktären
kutanen T-Zell-Lymphomen mit einer Gesamtansprechrate
von 83%.
X berücksichtigt
4
Anlage 2 f
05.12.2012
Nr. Feld
1
Quelle
Prospective International Multicenter Phase II Trial
of Intravenous Pegylated Liposomal Doxorubicin
Monochemotherapy in Patients With Stage IIB,
IVA, or IVB Advanced Mycosis Fungoides: Final
Results From EORTC 21012
Reinhard Dummer, Pietro Quaglino, Ju¨rgen C.
Becker, Baktiar Hasan, Matthias Karrasch, Sean
Whittaker, Stephen Morris, Michael Weichenthal,
Rudolf Stadler, Martine Bagot, Antonio Cozzio,
Maria G. Bernengo,and Robert Knobler
J Clin Oncol 30: 4091-4097, 2012
2
Studientyp vom Autor
bezeichnet als
Prospective International Multicenter Phase II Trial
3
Studientyp nach
Durchsicht
□ Therapiestudie mit randomisierter
Gruppenzuteilung
□ Therapiestudie mit nicht-randomisierter
Gruppenzuteilung
□ Therapiestudie mit Vergleichen über Zeit und Ort (z.
B. historische Kontrollen)
X Therapiestudie ohne Vergleichsgruppen (auch
Beobachtungsstudien und
Anwendungsbeobachtungen)
□ Fallserie
□ mit Placebokontrolle(n)
□ mit Aktivkontrolle(n)
□ mit Dosisgruppen
□ sonstige Kontrollgruppe(n): Nennen
4
Formale Evidenzkriterien □ 1++: Qualitativ hochwertige Metaanalyse bzw.
gemäß SIGN
systematischer Review von RCTs oder RCT mit
sehr geringem Risiko von Bias
□ 1+: Gut durchgeführte Metaanalyse bzw.
systematischer Review von RCTs oder RCT mit
geringem Risiko von Bias
□ 1-: Metaanalyse bzw. systematischer Review von
RCTs oder RCT mit hohem Risiko von Bias
□ 2++: Qualitativ hochwertiger systematischer Review
von Fallkontroll- oder Kohortenstudien
oder
Qualitativ hochwertige Fallkontroll- oder
Kohortenstudie mit sehr geringem Risiko von
1
Nr. Feld
Confounding, Bias oder Zufallsschwankungen und
hoher Wahrscheinlichkeit, so dass der
Zusammenhang kausal ist
X 2+: Gut durchgeführte Fallkontroll- oder
Kohortenstudie mit niedrigem Risiko von
Confounding, Bias oder Zufallsschwankungen und
einer mittleren Wahrscheinlichkeit, so dass der
Zusammenhang kausal ist
□ 2-: Fallkontroll- oder Kohortenstudie mit hohem
Risiko von Confounding, Bias oder
Zufallsschwankungen und einem signifikanten
Risiko, so dass der Zusammenhang nicht kausal ist
5
Bezugsrahmen
Studie initiiert von der European Organisation for
Research and Treatment of Cancer (EORTC)
Cutaneous Lymphoma Task Force
Unterstützt durch eine Spende der Schweizerischen
Krebsliga über die European Organisation for
Research and Treatment of Cancer Charitable Trust
Unterstützt durch Schering-Plough, die das
Studienmedikament zur Verfügung gestellt hat
Unterstützt durch die Gottfried und Julia BangerterRhyner-Stiftung. Dies ist eine Schweizer Stiftung für
medizinische Forschung gegründet von einem auch
politisch aktiven Unternehmer (Nationalrat und
Mitglied des Bankrats der Nationalbank).
Ich verstehe die DISCLOSURES OF POTENTIAL
CONFLICTS OF INTEREST in der Arbeit nicht
6
Indikation
Histologisch bestätigte Mycosis fungoides ab Stadium
IIB – refraktär gegenüber oder rezidiviert nach
mindestens zwei vorherigen Therapien ohne
Erythrodermie und ohne ZNS-Befall
ECOG Null bis 2
7
Wie viele Remissionen werden erreicht?
Primärer Endpunkt: Prozentsatz erreichter Voll- und
Teilremissionen
Sekundärer Endpunkte: Toxizität der Therapie (CTC
AE version 2.0), Zeit bis zur Progression, Dauer der
Remission
8
Relevante Ein- und
Ausschlusskriterien
Einschlusskriterien: Histologisch nachgewiesene
Erkrankung, keine Therapie während der letzten
beiden Wochen vor Start der Studienmedikation,
ECOG 0-2,
Ausschlusskriterien: Systemische Steroidbehandlung
2
Nr. Feld
bei Studienbeginn, ZNS-Befall, Erythrodermie,
kumulative Anthrazyklindosis unter 200 mg/m²,
pathologische linksventrikuläre Ejektionsfraktion,
9
Prüfintervention
20 mg/m² pegyliertes liposomales Doxorubicin
(Caelyx) Tage 1+15. Neustart nächster Zyklus am
Tag 29. Therapiedauer: 6 Zyklen.
Abbruch: Bei Progression der Erkrankung, bei
exzessiver Toxizität, bei Neustart einer anderen
Therapie, bei Ablehunung durch den Patienten oder
bei Erreichen der Anthrazyklin-Maximaldosis von 400
mg/m²
10 Vergleichsintervention
Keine
11 Evtl. weitere
Behandlungsgruppen
Keine
12 Subgruppen
Enthält die Studie Subgruppen, die für die
Fragestellung an die Kommission relevant sind?
□ keine relevanten Subgruppen
X post hoc definierte oder in Auswertung
gefundene Subgruppen
Subgruppen:
"Hohe" versus "niedrige" Tumorlast,
Vorherige Chemotherapie versus keine
Zusätzlicher extrakutaner Befall versus keiner
3
13 Studiendesign
Anzahl der Behandlungsarme 1
Typus:
X Prae-Post-Vergleich
□ Sonstige:.........................
14 Zentren
Anzahl der Zentren: Neun
Vergleichbarkeit der Studiendurchführung in den
einzelnen Zentren nicht beurteilbar
15 Randomisierung
Entfällt
16 Verblindung der
Behandlung
Entfällt
17 Beobachtungsdauer
Mediane Beobachtungszeit 10.6 Monate
18 Primäre Zielkriterien
Prozentsatz erreichter Voll- und Teilremissionen.
Krankheits-Evaluation durch ein standardisiertes
Evaluationssystem für Hautläsionen.
19 Sekundäre Zielkriterien
Sekundärer Endpunkte: Toxizität der Therapie (CTC
AE version 2.0), Zeit bis zur Progression, Dauer der
Remission
20 Statistische Methoden
für die Analyse der
primären Endpunkte
One-step Fleming design. (s. Publikation)
21 Anzahl der behandelten
Patienten
49 Patienten
22 Zahl und Charakteristika Differenzierte Darstellung des Patientenflusses nach
der eingeschlossenen
CONSORT vorhanden
und ausgewerteten
Patienten
Keine Drop-outs vorhanden
23 Vergleichbarkeit der
Behandlungsgruppen
Entfällt
24 Ergebnisse und ihre
Darstellung
Vollremissionsrate 6.1%
Teilremissionsrate 34.7%
No change: 28.6%
Progression: 10.2%
Not assessable: 16.3%
Früh-Todesfälle: 2%
Mediane Zeit bis zur Progression: 7.4 Monate
25 Unerwünschte
Therapiewirkung
Grad-3/4 Toxizitäten
Insgesamt: Patientenzahl nicht angegeben
4
Blutbild: Keine
Kardiale Symptome: 1 Patient
Allergie: 1 Patient
Allgemeinsymptome: 2 Patienten
Hand-Fuß-Syndrom: 1 Patient
Andere Haut-Toxizität: 3 Patienten
GI-Toxizität: 2 Patienten
Infektion: 1 Patient
Lungenembolie: 1 Patient
Myokard-Ischämie: 1 Patient
Mittelohrentzündung: 2 Patienten
26 Fazit der Autoren
Of 49 patients, 20 were responders. Overall response:
three (6.1%) experienced CCRs, and 17 (34.7%)
experienced PRs.
PLD has an acceptable safety profile in patients with
advanced MF. The efficacy of PLD seems promising.
27 Abschließende
Bewertung durch den
Bearbeiter
Liposomales Doxorubicin hat ein akzeptables
Toxizitätsprofil und eine mäßige Wirksamkeit. Klare
Vorteile gegenüber anderen Substanzen wie
Standard-Doxorubicin sind nicht bewiesen.
5
Anlage 3
Suchstrategie: (doxorubicin[MeSH Major Topic]) AND cutaneous t-cell lymphoma[MeSH Major Topic]
Ergebnisse: 13
1.
Arch Dermatol. 2008 Jun;144(6):786-7. No abstract available.
Related citations
2.
Prospective multicenter study of pegylated liposomal doxorubicin treatment in patients with
advanced or refractory mycosis fungoides or Sézary syndrome.
Quereux G, Marques S, Nguyen JM, Bedane C, D'incan M, Dereure O, Puzenat E, Claudy A, Martin L,
Joly P, Delaunay M, Beylot-Barry M, Vabres P, Celerier P, Sasolas B, Grange F, Khammari A, Dreno B.
3.
Pegylated liposomal doxorubicin in the treatment of primary cutaneous T-cell lymphomas.
Pulini S, Rupoli S, Goteri G, Pimpinelli N, Alterini R, Tassetti A, Scortechini AR, Offidani M, Mulattieri S,
Stronati A, Brandozzi G, Giacchetti A, Mozzicafreddo G, Ricotti G, Filosa G, Bettacchi A, Simonacci M,
Novelli N, Leoni P.
Related citatio
4.
Acta Derm
Related citations
5.
Br J Dermatol. 2005 Jul;153(1):183-5.
Related citations
6.
Uncommon hematologic malignancies. Case 3. Parotid swelling during treatment for transformed
mycosis fungoides.
Bird BR, Daly PA.
J Clin Oncol. 2003 Nov 15;21(22):4251-2. No abstract available.
Related citations
7.
Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma.
Wollina U, Dummer R, Brockmeyer NH, Konrad H, Busch JO, Kaatz M, Knopf B, Koch HJ, Hauschild A.
Cancer. 2003 Sep 1;98(5):993-1001.
Related citations
8.
Long-term remission of recalcitrant tumour-stage mycosis fungoides following chemotherapy with
pegylated liposomal doxorubicin.
Tsatalas C, Martinis G, Margaritis D, Spanoudakis E, Kotsianidis I, Karpouzis A, Bourikas G.
J Eur Acad Dermatol Venereol. 2003 Jan;17(1):80-2.
Related citations
9.
Pegylated doxorubicin for primary cutaneous T cell lymphoma: a report on ten patients with followup.
Ann N Y Acad Sci. 2001 Sep;941:214-6. No abstract available.
Related citations
10.
Pegylated doxorubicin for primary cutaneous T-cell lymphoma: a report on ten patients with followup.
J Cancer Res Clin Oncol. 2001 Feb;127(2):128-34.
Related citations
11.
Pegylated liposomal doxorubicin in the treatment of cutaneous T-cell lymphoma.
J Am Acad Dermatol. 2001 Jan;44(1):149-50. No abstract available.
Related citations
12.
Treatment of relapsing or recalcitrant cutaneous T-cell lymphoma with pegylated liposomal
doxorubicin.
Related citations
13.
Cancer. 1977 May;39(5):1967-70.
Related citations

Bewertung der Expertengruppe Off-Label Fachbereich

Transcription

Similar documents

journal club - Dermatologica Helvetica

Informationen zur zweckmäßigen Vergleichstherapie

lieferengpässe für humanarzneimittel in deutschland