Myelofibrosis The Physician’s Guide to ders e Disor

The National Organization for Rare Disorders
NORD Guides for Physicians
The Physician’s Guide to
Myelofibrosis
Visit website at:
nordphysicianguides.org/myelofibrosis/
For more information about NORD’s programs and services, contact:
National Organization for Rare Disorders (NORD)
PO Box 1968
Danbury, CT 06813-1968
Phone: (203) 744-0100
Toll free: (800) 999-NORD
Fax: (203) 798-2291
Website: www.rarediseases.org
Email: orphan@rarediseases.org
NORD’s Rare Disease Database and Organizational Database may be
accessed at www.rarediseases.org.
Contents ©2012 National Organization for Rare Disorders®
What is Myelofibrosis?
Myelofibrosis (MF) is classified as a chronic myeloproliferative neoplasm
(MPN). These are a group of heterogeneous hematopoietic stem cell
malignancies that include chronic myelogenous leukemia (CML), essential
thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis
(PMF). CML is categorized as a Philadelphia chromosome-positive MPN due
to the presence of the BCR-ABL1 proto-oncogene. ET, PV and PMF comprise
the Philadelphia chromosome-negative MPNs. ET and PV can evolve into
MF, termed post-ET/PV MF. These cases, together with PMF, are collectively
referred to as MF. In 2008, the World Health Organization (WHO) modified
the terminology of myeloproliferative disorders (MPDs) to MPNs to correctly
reflect the malignant nature of these related hematologic cancers.
Cytogenetic and molecular studies indicate that MF is a clonal hematologic
malignancy originating in primitive hematopoietic cells capable of
producing lymphoid and myeloid cells. The accumulation of bone marrow
reticulin and collagen fibrosis that typifies this cancer represents a secondary
reaction of non-clonal bone marrow fibroblasts. MF can have a hypercellular
pre-fibrotic phase and then later in the course develop severe cytopenias,
progressive symptomatic splenomegaly, and worsening bone marrow
fibrosis. Recent advances in the understanding of the pathobiology of MF
have highlighted the presence of genetic mutations, epigenetic alterations,
hyperactive signalling pathways, and a heightened inflammatory state.
Symptoms & Signs
MF is characterized by constitutional symptoms (fevers, night sweats,
weight loss), bone marrow myeloproliferation and fibrosis, worsening
cytopenias, leukoerythroblastosis (presence of peripheral blood nucleated
erythrocytes and early myeloid forms), and progressive symptomatic
splenomegaly. Extra-medullary hematopoiesis (EMH) is the result of
1
abnormal trafficking of hematopoietic stem cells (HSC) from the bone
marrow to organs such as the spleen, liver, and lung causing organomegaly
and sometimes organ dysfunction.
Common MF symptoms include bone pain, debilitating fatigue, pruritus,
and bowel irregularity (see Table 2) Dyspnea can be due to anemia,
pulmonary emboli, congestive heart failure, and/or the development of
pulmonary artery hypertension secondary to EMH. Splenomegaly can
result in early satiety that further adds to weight loss, abdominal bloating,
and severe left upper quadrant abdominal pain from splenic infarcts.
Figure 1 depicts the classic body habitus of a cachectic MF patient with
massive hepatosplenomagly that is outlined with marker on the patient’s
abdominal wall. Portal hypertension is common in patients with MF and can
result from massive splenomegaly (Banti’s syndrome) or contribute to the
development of splenomegaly in some patients. Portal vein thrombosis is
also associated with portal hypertension in some patients with MF.
An increased rate of thrombotic complications is associated with
MF and can occur in the venous circulation (cerebral venous sinus
thrombosis, splanchnic vein thrombosis, deep vein thrombosis, pulmonary
thromboembolism) or arterial circulation (stroke, transient ischemic attacks,
retinal artery occlusion, myocardial infarction, and peripheral arterial
disease). Conversely, bleeding episodes can also complicate the clinical
course of MF patients and can be attributed to either thrombocytopenia
or qualitative platelet dysfunction. Peripheral blood count abnormalities
2
are often noted at time of diagnosis and can include leukocytosis or
leukopenia, anemia and thrombocytosis or thrombocytopenia.
Figure 1
Many patients develop clinically relevant anemia through the course of
their disease and require red blood cell transfusion support. Patients with
thrombocytopenia are at an increased risk of bleeding and ecchymosis
and gastrointestinal bleeding is not uncommon. Some patients develop
profound transfusion dependent thrombocytopenia and in some cases
become refractory to platelet transfusions.
Causes
The true incidence of MF is not known but estimated to be approximately
1-1.5/100,000 people and is likely higher due to underdiagnosing and
underreporting. The median age at diagnosis is approximately 65, but MF
can be diagnosed in patients of all ages. The disorder is rare in children.
The cause of MF is as yet unknown, however, chronic exposure to several
industrial solvents, including benzene and toluene, has been associated
with development of MF. Additionally, Japanese people exposed to radiation
from the atomic bomb at Hiroshima were found to be at a significantly
increased risk of developing MF as well as other hematologic malignancies.
MF has been reported in every ethnic background. There appears to be a
higher risk of developing MF in Ashkenazi Jewish populations even when
controlling for environment.
3
In 2005, separate laboratories reported the finding of a gain of function point
mutation in the Janus kinase 2 gene (JAK2). The JAK2V617F mutation is located
in exon 14 at position 617 of the JAK2 gene and affects the pseudokinase
domain (JH2) of this non-receptor tyrosine kinase rendering the enzyme
constitutively active. JAK2 is associated with thrombopoietin and erythropoietin
receptor signaling and phosphorylated JAK2 activates signal transducers and
activators of transcription (STATs) which then in turn dimerize and translocate
to the nucleus. STATs act as transcription factors (TFs) regulating the expression
of cytokine inducible genes that are pivotal in cell differentiation, proliferation,
and survival. JAK2V617F can be found in approximately 96%, 50%, and 50%
of patients with PV, ET, and MF. More recently it has been appreciated that even
in those MPN patients that lack JAK2V617F, hyperactive JAK-STAT signaling
is present and can be attributed to other identified mutations (JAK2 exon 12,
MPL515L/K, LNK) or yet unrecognized lesions.
In the last several years a growing appreciation of the complex pathobiologic
mechanisms underlying MF has developed based on a deeper understanding
of genetic determinants of normal hematopoiesis and acquired mutations
detected in the hematopoietic compartment of MF patients. Mutations in genes
that activate the JAK-STAT pathway (JAK2, MPL, LNK) and alter epigenetic
regulation (TET2, DNMT3a, EZH2, IDH 1/2, SUZ12) have been implicated in
MF pathogenesis. Given the low frequency in which the non-JAK2V617F
mutations occur in patients with MF, the true relevance of each of these genetic
and epigenetic lesions remains unclear and is subject of much laboratory
and translational research. The order in which these events are acquired and
their co-existence can affect MF phenotype, and may in part, explain the
heterogeneity in clinical course. Current and future therapeutic trials in MF will
test novel agents that exploit these targets as well as evaluate these biomarkers
in terms of their prognostic power and their ability to predict response to
different therapies.
Prognosis
Patients with MF have a median survival of 5-6 years from time of
diagnosis. MF patients are at an increased risk of arterial and venous
thrombosis with a predilection for the splanchnic vasculature which
contributes to significant morbidity and mortality in this disease. There is
an approximate 10-20% risk of transformation to acute leukemia over the
first decade from time of MF diagnosis. Leukemic transformation of MF is
termed MF-BP (blast phase) and is associated with a dismal prognosis with a
median survival of approximately 3-5 months even with anthracycline-based
induction chemotherapy.
4
The clinical course of MF can be variable and often patients should be
risk stratified for survival at time of diagnosis in order to best select the
appropriate treatment approach for a given patient. The Lille classification
was the first such widely used prognostic scoring system based on white
blood cell count and hemoglobin at time of PMF diagnosis. A white blood
cell count (WBC) of either >30 x 109/L or <4 x 109/L earns a point and
hemoglobin <10g/dL earns a point. Low (0 points), intermediate (1 point),
or high risk (2 points) disease is associated with median survivals of 93, 26,
and 13 months, respectively (Table 3).
More recently, newer scoring systems based on a composite of multiple
prognostic variables have been created and validated for use in clinical
practice. The International Prognostic Scoring System (IPSS) was developed
by the International Working Group for Myelofibrosis Research and
Treatment (IWG-MRT) and incorporates five statistically significant MF clinical
features derived from multivariate analysis. Age > 65 years, leukocyte count
>25×109/L, hemoglobin <10g/dL, peripheral blood blast percentage ≥1%,
and the presence of constitutional symptoms are each assigned a point.
Four risk groups with independent median survivals of 135, 95, 48, 27
months, can be calculated for low risk (0 points), intermediate-1 (1 point),
intermediate-2 (2 points), and high risk MF patients (≥3 points), respectively.
The IPSS score was designed to be calculated at time of diagnosis and
the newer dynamic IPSS (DIPSS) can be used to calculate an individual MF
patient’s risk group status at any point in their clinical course.
The prognostic significance of JAK2V617F remains unclear. The presence
of JAK2V617F does not appear to influence thrombosis risk, risk for
leukemic transformation, or survival in several large retrospective studies.
JAK2V617F appears to be associated with a higher hemoglobin and less
need for transfusion in MF patients, as well as older age, thrombocytopenia
and increased peripheral blood blasts. Interestingly, the presence of low
JAK2V617F allele burden (when compared to high allele burden or the
absence of the mutation) may have prognostic significance as it has been
5
shown to predict for shorter overall and leukemia-free survival. Karyotypic
abnormalities are present in approximately 30-50% of MF patients
and unfavourable chromosomal (complex abnormalities or sole or two
abnormalities that include +8, -7/7q-, i7/7q-, i(17q), -5/5q-, 12p-, inv(3)
or 11q23 rearrangements) have been incorporated in the DIPSS plus as a
negative prognostic indicator.
Diagnosis
Patients with MF often, but not always, present to their physician with
vague complaints that can range from profound fatigue, dyspnea, bone
pain or abdominal discomfort. On occasion, patients are discovered to have
asymptomatic MF on routine blood work by abnormal blood counts alone
and this may motivate further evaluation. It is not unusual for patients to
undergo sometimes extensive testing before referral to a hematologist.
Figure 2
A complete blood count (CBC) and differential is a necessary and often the
first step in establishing the diagnosis of MF. Manual review of the peripheral
blood to assess for the presence of leukoerythroblastosis and other
morphologic changes in myeloid and erythroid cells is important (Figure 2).
A complete comprehensive metabolic panel, coagulation profile, iron studies,
B12, folate, reticulocyte count, and should also be obtained. Further laboratory
evaluation is often needed and is dictated by competing co-morbidities and
complaints. Presently, mutational analyses for the presence of JAK2V617F,
JAK2 exon 12, JAK2 exon 13, MPL515L/K, and in some commercial labs,
TET2 are available for testing. Although the detection of molecular markers
can help establish clonality, which is a hallmark of malignancy, they are not
6
able to adequately predict prognosis or determine therapy in MF.
A bone marrow biopsy and aspiration is an integral part of the evaluation
of a patient with MF. Often bone marrow aspiration is unobtainable due to
extensive marrow fibrosis or excessive marrow cellularity. Flow cytometry
and cytogenetic analysis are preferably performed on the aspirate specimen,
but in cases where an aspirate is not available, it can be informative when
performed on the peripheral blood. Additionally, the bone marrow biopsy
should be submitted for iron, reticulin, and collagen stains and is best
read by an experienced hematopathologist. Overall marrow cellularity,
megakaryocyte atypia, myeloid to erythroid ratio, reticulin and collagen
fibrosis, and percentage of myeloblasts should be reported and are important
in establishing the diagnosis of MF. Bone marrow fibrosis grading systems exist
and scores should be reported as well. The marrow cellularity can be variable,
and can range from hypo- to hyper-cellular with characteristic atypical
hyperlobated megakaryocytes that can be found singly and in clusters
(Figure 3A). The development of bone marrow reticulin and collagen fibrosis
can replace hematopoiesis and profoundly alter the hematopoietic niche
(Figure 3B).The presence of ≥ 20% myeloblasts in the aspirate or peripheral
blood is by definition MF-BP and these patients should pursue clinical trial
or HSCT immediately.
Figure 3A
Figure 3B
7
The physical exam is also important in establishing the diagnosis of MF with
special attention to palpable hepatosplenomegaly. Although not necessary,
imaging of the abdomen with ultrasound, CT scan, or MRI can document
and confirm organomegaly. Imaging of the chest or echocardiography is
sometimes necessary to assess for heart dysfunction, pulmonary hypertension,
and the presence of pulmonary EMH or thromboembolic disease.
The WHO and the International Working Group for the Treatment of
Myelofibrosis (IWG-MRT) has developed major and minor criteria for the
diagnosis of PMF and post-PV/ET MF, respectively (Table 1 A and Table 1 B).
These criteria are very helpful in establishing a diagnosis and can easily be
used by hematologists/oncologists in the community.
It is important to note that the finding of bone marrow fibrosis is not specific to MF and can be seen in many other conditions such as
myelodysplastic syndrome, hairy cell leukemia, tuberculosis, metastatic
carcinomas (e.g. prostate, lung, breast), lymphoma, and non-malignant
conditions such as autoimmune disorders and infectious causes like
tuberculosis.
8
Treatment
MF is a chronic progressive disease that does not spontaneously remit.
The only therapeutic modality that currently offers the potential for cure is
hematopoietic stem cell transplantation (HSCT). Medical management with
oral agents has mostly been palliative and until recently no single agent was
FDA-approved for the treatment of patients with MF. Ruxolitinib (Jakafi) is
9
the only FDA-approved agent for the treatment of MF patients regardless
of their JAK2 mutational status. Ruxolitinib is a first in class, oral agent,
taken twice daily on a continuous basis, and has been shown to inhibit the
hyperactive JAK-STAT pathway in MF hematopoietic cells.
In the COMFORT-1 and COMFORT-2 (COntrolled MyeloFibrosis study with Oral
JAK inhibitor Treatment) studies, ruxolitinib was shown to be superior when
compared to placebo and best available therapy, respectively, in achieving the
primary endpoint of proportion of treated patients achieving a spleen volume
reduction of at least 35% by 24 weeks or at 48 weeks, respectively. In a crossover design, with intention to treat analysis, patients with intermediate-2/
high risk MF by IPSS were randomized in a double-blinded fashion to receive
ruxolitinib or placebo. In both trials, ruxolitinib therapy achieved the primary
endpoint of spleen volume reduction and also demonstrated superiority
in symptom improvement as assessed by the myeloproliferative neoplasm
symptom assessment form (MPN-SAF) in COMFORT-1. Ruxolitinib has a favorable clinical side effect profile and grade 1/2
headache, dizziness, and bruising were the most common adverse
events noted in COMFORT-1 and almost all were grade 1/2. Reversible
thrombocytopenia is the dose limiting toxicity of this agent and patients
should be aware of the potential for worsening anemia, which is most
pronounced during the first three months of therapy. Dosing of ruxolitinib
is based on the platelet count and careful monitoring of blood counts with
dose adjustments for treatment emergent thrombocytopenia is important
to ensure patient safety. In ad hoc analysis, ruxolitinib demonstrated a
modest statistically significant survival advantage over placebo in the
COMFORT-1 study. Reversal of markedly elevated inflammatory cytokines
with ruxolitinib therapy has been postulated to drive improvement in many
of the MF related symptoms. The improvement in performance status of
MF patients with ruxolitinib treatment may in part explain the survival
advantage seen in this phase III trial.
See Table 4 for a list of therapies used in the treatment of MF and which
aspects of the disease are addressed. Therapeutic approaches to address
the myeloproliferation (leukocytosis, thrombocytosis) and organomegaly
(splenomegaly and hepatomegaly) associated with MF include
chemotherapeutic agents such as hydroxyurea, melphalan, busulfan,
and cladribine. Hydroxyurea is an oral agent that inhibits ribonucleotide
reductase, thereby reducing the production of deoxyribonucleotides.
Hydroxyurea is one of the most commonly used initial agents in patients
10
with MF and can be very effective in controlling elevated leukocytes and
platelets, ameliorating spleen discomfort and at times improving anemia if
driven by splenic sequestration. Worsening cytopenias, mucositis, malleolus
ulcers, rash and gastrointestinal toxicities are potential side effects that
require monitoring by the treating physician.
Symptomatic splenomegaly (and/or hepatomegaly) can be controlled with
chemotherapy as well and the same agents used to control leukocytosis/
thrombocytosis are also given to address extramedullary hematopoiesis
of the spleen/liver/lung/skin or other organs that cause symptoms.
Radiotherapy can be employed to address symptomatic splenomegaly
refractory to medical management or in cases of EMH affecting the lung,
peritoneum, or impinging on nerves.
Anemia is common in MF patients and can be multifactorial in origin (iron
deficiency, B12 deficiency, folate deficiency, ineffective erythropoiesis,
splenic sequestration, and hemolysis) and has been demonstrated to be a
definitive negative prognostic indicator. Many patients develop red blood
cell transfusion dependence and long term transfusion therapy can lead
to the development of iron overload. The role of iron chelation therapy
has not yet been adequately defined in this disease. Multiple approaches
to alleviate anemia have been evaluated over the last several decades.
Erythropoiesis stimulating agents (ESA) have also been used to improve
anemia in MF patients that have not already been heavily transfused and do
not have elevated endogenous erythropoietin levels. Immunomodulatory
11
agents such as thalidomide and lenalidomide alone or in combination with
prednisone have been reported to have anemia response rates of 20-50%
depending on the clinical trial. Danazol is a synthetic attenuated androgen
that can be a reasonable approach in some patients with anemia and should
be avoided in young women, men with active prostate conditions, and
in patients with significant liver dysfunction. Occasionally corticosteroids
given for short periods of time can be effective if the anemia is due to an
autoimmune hemolytic process.
HSCT is the only treatment modality that offers the potential of cure at the risk
of transplant related complications and graft versus host disease (GVHD). HSCT
with myeloablative conditioning is associated with transplant-related mortality
and morbidity that requires careful consideration for appropriate patient
candidates. Reduced intensity conditioning (RIC) is associated with less transplant
related morbidity but a potentially higher rate of engraftment failure.
Patients with low/intermediate-1 risk MF by IPSS should either be followed
closely for signs of disease progression or treated with conventional agents
(thalidomide, lenalidomide, danazol, hydroxyurea) or ruxolitinib to address
disease features listed in Table 4. Patients that have intermediate-2/high risk
disease should be considered for treatment with ruxolitinib or experimental
therapy and those less than 65 years of age with preferably a matched
sibling donor or matched unrelated donor should be considered for stem cell
transplant. HSCT clinical trials are currently evaluating RIC approaches as well
as pre-conditioning with ruxolitinib therapy. Transplant approaches utilizing
alternative graft sources such as cord blood and haploidentical donors will
also be explored in the near future. Patients with MF should preferably be
transplanted at centers with significant experience with this particular patient
population.
Investigational Therapies
Experimental therapies remain a very important treatment option for many
patients with MF. Since MF originates at the level of the hematopoietic stem
cell (HSC), the identification of novel drugs that target the MF HSC is likely
the most effective path to potentially curative pharmacological strategies.
Table 5 lists a number of experimental agents that are being evaluated in
phase I, II, and III studies. Centers that offer these trials can be found at
www.clinicaltrials.gov.
Signaling pathways that remain essential to HSC function, proliferation and
survival are potential drug targets. Modifying the chromatin structure in MF
12
HSCs is also an attractive therapeutic approach based on scientific rationale
and supported by preclinical studies. Histone deacetylase inhibitors (HDACi)
such as panobinostat, givinostat, and pracinostat are being tested in phase
II studies and have already proven to be effective in reducing splenomegaly
and in small numbers of patients after long term administration at low
doses have demonstrated the ability to improve bone marrow morphology
and reduce bone marrow fibrosis. Further studies with these agents are
ongoing. Studies combining ruxolitinib with lenalidomide, panobinostat,
danazol, and other agents are now being started or are ongoing and the
results are highly anticipated. Ultimately, treatment with combinations of
agents with differing mechanisms of action will likely build upon current
therapeutic success in achieving clinically relevant responses through
pathobiological modification.
References
1. Abdel-Wahab O, Pardanani A, Bernard OA, Finazzi G, Crispino JD, Gisslinger H, et al.
Unraveling the genetic underpinnings of myeloproliferative neoplasms and understanding their
13
effect on disease course and response to therapy: proceedings from the 6th International PostASH Symposium. American journal of hematology. 2012;87(5):562-8. Epub 2012/03/31.
2. Barosi G, Elliott M, Canepa L, Ballerini F, Piccaluga PP, Visani G, et al. Thalidomide in
myelofibrosis with myeloid metaplasia: a pooled-analysis of individual patient data from five
studies. Leuk Lymphoma. 2002;43(12):2301-7. Epub 2003/03/05.
3. Barosi G, Mesa RA, Thiele J, Cervantes F, Campbell PJ, Verstovsek S, et al. Proposed criteria
for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis:
a consensus statement from the International Working Group for Myelofibrosis Research and
Treatment. Leukemia. 2008;22(2):437-8. Epub 2007/08/31.
4. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation
of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365(9464):105461. Epub 2005/03/23.
5. Begna KH, Pardanani A, Mesa R, Litzow MR, Hogan WJ, Hanson CA, et al. Long-term
outcome of pomalidomide therapy in myelofibrosis. American journal of hematology.
2012;87(1):66-8. Epub 2011/11/15.
6. Cervantes F, Alvarez-Larran A, Domingo A, Arellano-Rodrigo E, Montserrat E. Efficacy and
tolerability of danazol as a treatment for the anaemia of myelofibrosis with myeloid metaplasia:
long-term results in 30 patients. Br J Haematol. 2005;129(6):771-5. Epub 2005/06/15.
7. Cervantes F, Alvarez-Larran A, Hernandez-Boluda JC, Sureda A, Torrebadell M, Montserrat E.
Erythropoietin treatment of the anaemia of myelofibrosis with myeloid metaplasia: results in 20
patients and review of the literature. Br J Haematol. 2004;127(4):399-403. Epub 2004/11/04.
8. Cervantes F, Dupriez B, Passamonti F, Vannucchi AM, Morra E, Reilly JT, et al. Improving
survival trends in primary myelofibrosis: an international study. Journal of clinical oncology
: official journal of the American Society of Clinical Oncology. 2012;30(24):2981-7. Epub
2012/07/25.
9. Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Morra E, et al. New prognostic
scoring system for primary myelofibrosis based on a study of the International Working Group for
Myelofibrosis Research and Treatment. Blood. 2009;113(13):2895-901. Epub 2008/11/08.
10.Cervantes F, Passamonti F, Barosi G. Life expectancy and prognostic factors in the classic BCR/
ABL-negative myeloproliferative disorders. Leukemia. 2008;22(5):905-14. Epub 2008/04/04.
11.Dingli D, Schwager SM, Mesa RA, Li CY, Dewald GW, Tefferi A. Presence of unfavorable
cytogenetic abnormalities is the strongest predictor of poor survival in secondary myelofibrosis.
Cancer. 2006;106(9):1985-9. Epub 2006/03/29.
12.Dupriez B, Morel P, Demory JL, Lai JL, Simon M, Plantier I, et al. Prognostic factors in
agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood.
1996;88(3):1013-8. Epub 1996/08/01.
13.Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S, et al. DIPSS plus:
a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that
incorporates prognostic information from karyotype, platelet count, and transfusion status.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology.
2011;29(4):392-7. Epub 2010/12/15.
14.Gregory SA, Mesa RA, Hoffman R, Shammo JM. Clinical and laboratory features of
14
myelofibrosis and limitations of current therapies. Clinical advances in hematology & oncology :
H&O. 2011;9(9 Suppl 22):1-16. Epub 2012/03/08.
15.Guardiola P, Anderson JE, Bandini G, Cervantes F, Runde V, Arcese W, et al. Allogeneic
stem cell transplantation for agnogenic myeloid metaplasia: a European Group for Blood and
Marrow Transplantation, Societe Francaise de Greffe de Moelle, Gruppo Italiano per il Trapianto
del Midollo Osseo, and Fred Hutchinson Cancer Research Center Collaborative Study. Blood.
1999;93(9):2831-8. Epub 1999/04/27.
16.Guglielmelli P, Barosi G, Rambaldi A, Marchioli R, Masciulli A, Tozzi L, et al. Safety and
efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with
myelofibrosis. Blood. 2011;118(8):2069-76. Epub 2011/07/05.
17.Gupta V, Hari P, Hoffman R. Allogeneic hematopoietic cell transplantation for myelofibrosis in
the era of JAK inhibitors. Blood. 2012;120(7):1367-79. Epub 2012/06/16.
18.Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK
inhibition with ruxolitinib versus best available therapy for myelofibrosis. The New England journal
of medicine. 2012;366(9):787-98. Epub 2012/03/02.
19.Hexner E, Goldberg JD, Prchal JT, Demakos EP, Swierczek S, Weinberg RS, et al. A Multicenter,
Open Label Phase I/II Study of CEP701 (Lestaurtinib) in Adults with Myelofibrosis; a Report On
Phase I: A Study of the Myeloproliferative Disorders Research Consortium (MPD-RC). ASH Annual
Meeting Abstracts. 2009;114(22):754-.
20.Hoffman R, Rondelli D. Biology and treatment of primary myelofibrosis. Hematology / the
Education Program of the American Society of Hematology American Society of Hematology
Education Program. 2007:346-54. Epub 2007/11/21.
21.Ianotto JC, Kiladjian JJ, Demory JL, Roy L, Boyer F, Rey J, et al. PEG-IFN-alpha-2a therapy in
patients with myelofibrosis: a study of the French Groupe d’Etudes des Myelofibroses (GEM) and
France Intergroupe des syndromes Myeloproliferatifs (FIM). Br J Haematol. 2009;146(2):223-5.
Epub 2009/06/24.
22.James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, et al. A unique
clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature.
2005;434(7037):1144-8. Epub 2005/03/29.
23.Komrokji RS, Wadleigh M, Seymour JF, Roberts AW, To LB, Zhu HJ, et al. Results of a Phase
2 Study of Pacritinib (SB1518), a Novel Oral JAK2 Inhibitor, In Patients with Primary, PostPolycythemia Vera, and Post-Essential Thrombocythemia Myelofibrosis. ASH Annual Meeting
Abstracts. 2011;118(21):282-.
24.Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function
mutation of JAK2 in myeloproliferative disorders. The New England journal of medicine.
2005;352(17):1779-90. Epub 2005/04/29.
25.Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al. Activating mutation
in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid
metaplasia with myelofibrosis. Cancer cell. 2005;7(4):387-97. Epub 2005/04/20.
26.Marchetti M, Barosi G, Balestri F, Viarengo G, Gentili S, Barulli S, et al. Low-dose thalidomide
ameliorates cytopenias and splenomegaly in myelofibrosis with myeloid metaplasia: a phase II
trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology.
2004;22(3):424-31. Epub 2004/01/31.
15
27.Mascarenhas J, Hoffman R. Risk adapted approach to the treatment of primary myelofibrosis.
Hematology Education: the education program for the annual congress of the European
Hematology Association. 2009;3:192-9.
28.Mascarenhas J, Hoffman R. Ruxolitinib: the first FDA approved therapy for the treatment of
myelofibrosis. Clinical cancer research : an official journal of the American Association for Cancer
Research. 2012;18(11):3008-14. Epub 2012/04/05.
29.Mascarenhas J, Mercado A, Rodriguez A, Lu M, Kalvin C, Li X, et al. Prolonged Low Dose
Therapy with a Pan-Deacetylase Inhibtor, Panobinostat (LBH589), in Patients with Myelofibrosis.
ASH Annual Meeting Abstracts. 2011;118(21):794-.
30.Mesa R, Yao, X, Cripe, LD, Li, CY, Tefferi A, Tallman, MS. Lenalidomide and Prednisone for
Primary and Post Polycythemia Vera/ Essential Thrombocythemia Myelofibrosis (MF): An Eastern
Cooperative Oncology Group (ECOG) Phase II Trial. Blood (ASH Annual Meeting Abstracts). 2008.
31.Mesa RA, Elliott MA, Schroeder G, Tefferi A. Durable responses to thalidomide-based drug
therapy for myelofibrosis with myeloid metaplasia. Mayo Clinic proceedings Mayo Clinic.
2004;79(7):883-9. Epub 2004/07/13.
32.Mesa RA, Li CY, Ketterling RP, Schroeder GS, Knudson RA, Tefferi A. Leukemic transformation
in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood.
2005;105(3):973-7. Epub 2004/09/25.
33.Mesa RA, Powell H, Lasho T, Dewald G, McClure R, Tefferi A. JAK2(V617F) and leukemic
transformation in myelofibrosis with myeloid metaplasia. Leukemia research. 2006;30(11):145760. Epub 2006/03/28.
34.Mesa RA, Verstovsek S, Cervantes F, Barosi G, Reilly JT, Dupriez B, et al. Primary myelofibrosis
(PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia
myelofibrosis (post-ET MF), blast phase PMF (PMF-BP): Consensus on terminology by the
international working group for myelofibrosis research and treatment (IWG-MRT). Leukemia
research. 2007;31(6):737-40. Epub 2007/01/11.
35.Pardanani A, George G, Lasho T, Hogan WJ, Litzow MR, Begna K, et al. A Phase I/II Study
of CYT387, An Oral JAK-1/2 Inhibitor, In Myelofibrosis: Significant Response Rates In Anemia,
Splenomegaly, and Constitutional Symptoms. ASH Annual Meeting Abstracts. 2010;116(21):46036.Passamonti F, Cervantes F, Vannucchi AM, Morra E, Rumi E, Pereira A, et al. A dynamic
prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT
(International Working Group for Myeloproliferative Neoplasms Research and Treatment).
Blood.115(9):1703-8. Epub 2009/12/17.
37.Quintas-Cardama A, Kantarjian H, Estrov Z, Borthakur G, Cortes J, Verstovsek S. Therapy with
the histone deacetylase inhibitor pracinostat for patients with myelofibrosis. Leukemia research.
2012. Epub 2012/04/06.
38.Quintas-Cardama A, Kantarjian HM, Manshouri T, Thomas D, Cortes J, Ravandi F, et al.
Lenalidomide plus prednisone results in durable clinical, histopathologic, and molecular responses
in patients with myelofibrosis. Journal of clinical oncology : official journal of the American
Society of Clinical Oncology. 2009;27(28):4760-6. Epub 2009/09/02.
39.Rondelli D, Goldberg JD, Marchioli R, Isola L, Shore TB, Prchal JT, et al. Results of Phase II
Clinical Trial MPD-RC 101: Allogeneic Hematopoietic Stem Cell Transplantation Conditioned
with Fludarabine/Melphalan in Patients with Myelofibrosis. ASH Annual Meeting Abstracts.
2011;118(21):1750-.
16
40.Santos FP, Kantarjian HM, Jain N, Manshouri T, Thomas DA, Garcia-Manero G, et al. Phase 2
study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia
vera/essential thrombocythemia myelofibrosis. Blood.115(6):1131-6. Epub 2009/12/17.
41.Spivak JL, Hasselbalch H. Hydroxycarbamide: a user’s guide for chronic myeloproliferative
disorders. Expert review of anticancer therapy. 2011;11(3):403-14. Epub 2011/03/23.
42.Tefferi A. Primary myelofibrosis: 2012 update on diagnosis, risk stratification, and
management. American journal of hematology. 2011;86(12):1017-26. Epub 2011/11/17.
43.Tefferi A, Lasho TL, Huang J, Finke C, Mesa RA, Li CY, et al. Low JAK2V617F allele burden
in primary myelofibrosis, compared to either a higher allele burden or unmutated status, is
associated with inferior overall and leukemia-free survival. Leukemia. 2008;22(4):756-61. Epub
2008/01/25.
44.Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA, et al. Proposals and rationale
for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential
thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international
expert panel. Blood. 2007;110(4):1092-7. Epub 2007/05/10.
45.Thiele J, Kvasnicka HM. Grade of bone marrow fibrosis is associated with relevant
hematological findings-a clinicopathological study on 865 patients with chronic idiopathic
myelofibrosis. Annals of hematology. 2006;85(4):226-32. Epub 2006/01/20.
46.Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A. European consensus on
grading bone marrow fibrosis and assessment of cellularity. Haematologica. 2005;90(8):1128-32.
Epub 2005/08/05.
47.Verstovsek S, Kantarjian HM, Estrov Z, Cortes JE, Thomas DA, Kadia T, et al. Long-term
outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival
advantage in comparison to matched historical controls. Blood. 2012;120(6):1202-9. Epub
2012/06/22.
48.Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind,
placebo-controlled trial of ruxolitinib for myelofibrosis. The New England journal of medicine.
2012;366(9):799-807. Epub 2012/03/02.
49.Verstovsek S, Mesa RA, Rhoades SK, Giles JLK, Pitou C, Jones E, et al. Phase I Study of the
JAK2 V617F Inhibitor, LY2784544, in Patients with Myelofibrosis (MF), Polycythemia Vera (PV),
and Essential Thrombocythemia (ET). ASH Annual Meeting Abstracts. 2011;118(21):2814-.
Resources
The following organizations are members of the MPN Coalition, a group of
organizations providing a broad range of services for patients affected by
these diseases, their families and medical professionals providing their care.
Visit their websites to learn about the specific services they provide.
A Myelofibrosis Resource Guide for Patients and Families may be
downloaded at
www.rarediseases.org/rare-disease-information/resources-tools.
17
Printed copies of the Resource Guide are available free from NORD or from
other members of the MPN Coalition.
MPN-Specific Organizations:
MPN Education Foundation
www.mpninfo.org
MPN Research Foundation
www.mpnresearchfoundation.org
Serving the Cancer Community:
CancerCare
www.cancercare.org
Cancer Support Community
www.cancersupportcommunity.org
The Leukemia & Lymphoma Society
www.LLS.org
Serving the Rare Disease Community:
National Organization for Rare Disorders (NORD)
www.rarediseases.org
Clinical Centers & Medical Experts
MPN Education Foundation Scientific Advisory Board
www.mpdinfo.org/CMPD_foundation.html
MPN Research Foundation Scientific Advisory Board
www.mpnresearchfoundation.org/MPNRF-Scientific-Advisory-Board
Myeloproliferative Disorders Research Consortium
www.mpd-rc.org/home.php
Mount Sinai School of Medicine Myeloid Malignancies Program
http://www.mssm.edu/research/institutes/tisch-cancer-institute/cancerresearch/research-programs/myeloid-malignancies
18
Acknowledgements
NORD is grateful to the following medical expert for serving as author of
this physician guide:
John Mascarenhas, MD
Myeloproliferative Disorders Program
Tisch Cancer Institute, Division of Hematology/Oncology
Mount Sinai School of Medicine
New York, NY
NORD also grateful acknowledges the members of the MPN Coalition for
their help in the creation of this guide and for the many wonderful services
they provide for patients and families affected by MPNs.
This guide was made possible by an educational grant from Incyte.
19
Patient Support
and Resources
National Organization for
Rare Disorders (NORD)
55 Kenosia Avenue
PO Box 1968
Danbury, CT 06813-1968
Phone: (203) 744-0100
Toll free: (800) 999-NORD
Fax: (203) 798-2291
www.rarediseases.org
orphan@rarediseases.org
NORD gratefully acknowledges the
assistance of the following medical
expert in the preparation of this
physician guide:
John Mascarenhas, MD
Myeloproliferative Disorders Program
Tisch Cancer Institute, Division of
Hematology/Oncology
Mount Sinai School of Medicine
New York, NY
NORD also gratefully acknowledges
the members of the MPN Coalition for
their help in the creation of this guide
and for the many wonderful services
they provide for patients and families
affected by MPNs.
This guide was made possible by an
educational grant from Incyte.
20
NORD Guides for Physicians
For information on rare disorders
and the voluntary health organizations that help people affected
by them, visit NORD’s web site at
www.rarediseases.org or call
(800) 999-NORD or
(203) 744-0100.
#1
The Pediatrician’s Guide to
Tyrosinemia Type 1
#2
The Pediatrician’s Guide to Ornithine
Transcarbamylase Deficiency...and
other Urea Cycle Disorders
#3
The Physician’s Guide to
Primary Lateral Sclerosis
#4
The Physician’s Guide to
Pompe Disease
NORD helps patients and families
affected by rare disorders by
providing:
#5
The Physician’s Guide to
Multiple System Atrophy
• Physician-reviewed information
in understandable language
#6
The Physician’s Guide to
Hereditary Ataxia
#7
The Physician’s Guide to Giant
Hypertrophic Gastritis and
Menetrier’s Disease
#8
The Physician’s Guide to Amyloidosis
#9
The Physician’s Guide to
Medullary Thyroid Cancer
#10
The Physician’s Guide to
Hereditary Angioedema (HAE)
#11
The Physician’s Guide to
The Homocystinurias
#12
The Physician’s Guide to
Treacher Collins Syndrome
#13
The Physician’s Guide to
Urea Cycle Disorders
#14
The Physician’s Guide to
Myelofibrosis
These booklets are available free of charge. To
obtain copies, call or write to NORD or download
the text from www.NORDPhysicianGuides.org.
• Referrals to support groups and
other sources of help
• Networking with other patients
and families
• Medication assistance programs
• Grants and fellowships to
encourage research on rare
diseases
• Advocacy for health-related
causes that affect the rare disease community
• Publications for physicians and
other medical professionals
Contact NORD at
orphan@rarediseases.org.
National Organization for
Rare Disorders (NORD)
PO Box 1968
Danbury, CT 06813-1968
Phone: (203) 744-0100
Toll free: (800) 999-NORD
Fax: (203) 798-2291
This booklet was made possible through
an educational grant from Incyte.