Alemtuzumab in the treatment of chronic lymphocytic lymphoma Drug Profile

Drug Profile
Alemtuzumab in the
treatment of chronic
lymphocytic lymphoma
Expert Rev. Anticancer Ther. 8(4), 525–533 (2008)
Kevin Boyd and
Claire E Dearden†
†
Author for correspondence
Department of
Haemato-Oncology, The
Royal Marsden Hospital and
Institute of Cancer Research,
Downs Road, Sutton, Surrey
SM2 5PT, UK
Tel.: +44 208 661 3116
Fax: +44 208 642 9634
claire.dearden@rmh.nhs.uk
Alemtuzumab was the first monoclonal antibody to be humanized, a process which embeds
rodent sequence fragments in a human IgG framework. The antibody target is CD52, an
antigen expressed on normal lymphocytes as well as many T- and B-cell neoplasms. It therefore
has a potential broad application across a spectrum of B- and T-cell malignancies as well as use
as an immunosuppressant drug in, for example, bone marrow transplantation. The original
licensing in the USA and Europe was for the treatment of fludarabine-refractory chronic
lymphocytic leukemia (CLL). However, recent trials using alemtuzumab as a first-line agent for
CLL have shown superior response rates compared with traditional alkylator therapy and this
has led to US FDA approval for first-line treatment for CLL. It seems to be particularly useful in
patients with CLL who have deletion of the TP53 tumor suppressor gene, a subset of disease
that responds poorly to other currently available chemotherapeutics.
KEYWORDS: alemtuzumab • campath • CD52 • chronic lymphocytic leukemia • CLL • front-line • maintenance
• monoclonal antibody • T-PLL
Chronic lymphocytic leukemia (CLL) is the
most common leukemia in adults in the western world with an annual incidence of 3–5
cases per 100,000 per year. CLL affects twice
as many males as females with a median age at
diagnosis of 67 years. It is characterized by the
accumulation of clonal mature B lymphocytes
in the blood, bone marrow, lymph nodes and
spleen. The clinical course of patients with
CLL is highly variable. Many survive for decades with little disease progression and no
requirement for therapy. Others progress rapidly with enlarging lymphadenopathy and
organomegaly, bone marrow failure and systemic malaise, including night sweats and
weight loss.
Chemotherapy is usually reserved for
patients with systemic symptoms or progressive disease, as evidenced by progressive cytopenias or significant organ or lymph node
enlargement. Current chemotherapy options
include alkylating agents such as chlorambucil,
purine analogues such as fludarabine and corticosteroids. Rituximab, a monoclonal antibody directed against CD20, has also been
shown to have activity. Of these, only chlorambucil has a license in CLL. No treatment,
www.future-drugs.com
10.1586/14737140.8.4.525
with the exception of bone marrow transplantation, is curative. The aim of treatment is a
complete response (CR), defined as no disease
detected in the bone marrow biopsy by histological assessment, no lymphadenopathy or
organomegaly and normalization of the
peripheral blood count (lymphocytes < 4.0 ×
109/l, neutrophils > 1.5×109/l, Hb >
11.0 g/dl, platelets >100×109/l). Patients who
achieve remissions characterized by negative
disease assessed by a sensitive flow cytometric
method have a longer progression-free survival
(PFS) and better overall survival (OS) [1]. Single-agent chlorambucil has CR rates of less
than 10% and fludarabine approximately
20%, whilst combinations such as fludarabine
and cyclophosphamide improve this to
approximately 40% [2]. To date, the highest
CR rates have been obtained with the combination of fludarabine, cyclophosphamide and
rituximab [3]. No randomized trial has shown
a survival benefit. This has been attributed to
the ability of refractory or relapsed patients to
cross-over and achieve a response with the
other trial therapy. However, patients who are
refractory to both alkylator agents and
fludarabine have a very poor prognosis with a
© 2008 Future Drugs Ltd
ISSN 1473-7140
525
Drug Profile
Boyd & Dearden
median survival of 10 months. There is a real clinical need
for effective therapeutic agents in this group, and it was these
patients who were first targeted in trials of alemtuzumab
(Campath-1H, MabCampath; BayerSchering).
Introduction to alemtuzumab
Alemtuzumab is a chimeric molecule produced by taking hypervariable regions derived from rat IgG that are responsible for antigen recognition and splicing them into a human IgG1 framework in order to reduce immunogenicity. The resulting antibody
is cultured in a mammalian cell suspension culture (Chinese
hamster ovary). The antibody recognizes CD52, a 21–28 kDa
cell surface glycoprotein attached to the cell surface membrane by
a glycosylphosphatidylinositol (GPI) anchor (FIGURE 1). CD52 is
expressed on B and T lymphocytes, natural killer cells, eosinophils and macrophages. It is not found on hemopoietic stem
cells, erythrocytes and platelets, minimizing toxicity to these parts
of the hemopoietic system. The physiological function of CD52
has not been fully elucidated.
Pharmacology
The dosing schedule starts with an escalating regimen of 3, 10
and 30 mg given on successive days in order to minimize infusion-related side effects. Initially recommended as a 2 h intravenous infusion, it has since been shown to be effective when
given by subcutaneous injection, which can ameliorate infusional side effects as well as being more convenient for the outpatient. It takes significantly longer to achieve the same serum
blood concentration by subcutaneous injection [4], so this route
Sialic acid
Carbohydrate
Sialic acid
Gal
GlcNAc
Man
Alemtuzumab
binding site
Fuc
Peptide scaffold
Ethanolamine
PO4
Alemtuzumab
epitope
GPI anchor
Mannose
Inositol ±
core
palmitate
PO4
PO4
Ethanolamine
Lipid
Figure 1. Molecular structure of CD52 antigen.
GPI: Glycosylphosphatidylinositol.
526
NH2
of administration is not suitable for more aggressive diseases such
as prolymphocytic leukemia. Alemtuzumab displays nonlinear
elimination kinetics [5]. Distribution of the drug occurs mainly in
the extracellular fluid and plasma compartments. Systemic clearance decreases with repeated administration, primarily due to
decreased receptor-mediated clearance as the number of CD52+
cells falls. As the plasma concentration increases, the rate of elimination approaches zero-order kinetics. The median t½ after the
first dose is around 8 h, increasing to 6 days after the last dose.
It has been estimated that the average lymphocyte has
500,000 CD52 antigens, and an adult with CLL has 1013
lymphocytes [6]. Using these figures, a total dose of over 1 g is
needed to saturate all binding sites. Dosing regimens have traditionally used 12 weeks of treatment, which approximates a
total dose of 1 g. Few studies have varied the dosing schedule
or the duration of treatment to explore potentially superior
regimens. One study using the subcutaneous route of administration in treatment-naive patients did increase the duration
of treatment to 18 weeks and showed continuing response
during 12–18 weeks, demonstrating that there may be scope
to optimize the dosing regimen [7].
Alemtuzumab attaches to the C-terminal peptide and part of
the GPI anchor. The method by which it then effects cellular
killing in vivo is not fully understood. Antibody dependent cellular cytotoxicity and the activation of the complement cascade
are both thought to play a role. It has also been shown in vitro
to directly induce apoptosis [8].
Alemtuzumab in fludarabine-refractory/relapsed CLL
Multiple Phase II trials using alemtuzumab in previously
treated patients have been published [9–14]. There are no
Phase III trials in this patient group, which partly reflects the
paucity of effective therapeutic options to use in a control arm,
with responses to most salvage agents being less than 20%.
The pivotal study was a prospective, nonrandomized, multicenter international trial enrolling 93 patients who had
received at least one alkylating agent and who were judged to
be refractory to fludarabine [10]. The patient cohort all had
advanced disease at the time of trial entry with a poor prognosis and few other treatment options. Alemtuzumab was administered intravenously at 30 mg three-times weekly. Overall
response rate (ORR) was 33% (CR 2%; partial remission [PR]
31%). Median time to progression was 4.7 months overall and
9.5 months for responders. Overall median survival was
16 months and 32 months for responders. It was noted that
whilst dramatic improvement was often seen in the blood and
bone marrow, there was rarely any significant clearance of
lymph node disease. Other single arm trials using the same
dosing regimen yielded similar results and are summarized in
TABLE 1. The early trials also showed a high incidence of infective complications, including Pneumocystis carinii and cytomegalovirus (CMV), emphasizing the need for the routine use
of prophylactic antiviral and antimicrobial agents.
Expert Rev. Anticancer Ther. 8(4), (2008)
Alemtuzumab in the treatment of chronic lymphocytic lymphoma
Drug Profile
Table 1. Summary of trials of alemtuzumab in relapsed and refractory patients with chronic
lymphocytic leukemia.
Study
n
Overall response (%)
Complete response (%)
Median response duration (months)
Ref.
Osterborg et al. (1997)
29
42
4
12
[9]
Keating et al. (2002)
93
33
2
9.5
[10]
Rai et al. (2002)
24
33
0
15.4
[11]
Ferrajoli et al. (2003)
42
31
5
18 if CR
7 if PR
[12]
Moreton et al. (2005)
91
55
36
N/A
[13]
CR: Complete response; N/A: Not applicable; PR: Partial response.
A German study enrolling patients with similar characteristics used the subcutaneous dosing route [14]. This showed that
infusional toxicity could be minimized whilst maintaining similar efficacy, with an ORR of 35% in 50 patients (CR 2%;
PR 34%) with a median PFS of 9.7 months (TABLE 1).
Alemtuzumab as first-line treatment for
progressive CLL
A pilot study of alemtuzumab as front-line therapy in nine patients
with advanced CLL showed ORRs of 89% with three patients
achieving a CR [15]. On the basis of these encouraging results the
same group expanded the patient cohort to treat 41 patients with
subcutaneous alemtuzumab given for a maximum of 18 weeks [7].
The ORR was 87%, including 19% with a CR, similar response
rates to those attained with single-agent fludarabine. Complete
responders needed the full 18 weeks to attain their best response.
At the time of trial publication the median time to treatment
failure had not been reached at 18+ months or more.
These findings prompted a prospective international randomized Phase III trial (CAM307) comparing alemtuzumab with
chlorambucil as first-line therapy in patients with progressive
CLL [16]. Patients were randomized to intravenous alemtuzumab 30 mg three-times weekly for up to 12 weeks or chlorambucil 40 mg/m2 orally once every 28 days for up to 12 cycles. A
total of 297 patients were accrued by July 2004 with the results
being published in November 2007 [16]. The ORR was 83% in
the alemtuzumab arm compared with 50% in the chlorambucil
arm, with CR rates of 24 and 2%, respectively. This translated
into a 43% lower risk of the combined end point of progression
or death in those treated with alemtuzumab. Responses in highrisk patients, notably those with deletion of 17p, were markedly
superior in the alemtuzumab arm (64% OR compared with
26% in the chlorambucil arm). Based on this trial, the US FDA
has licensed alemtuzumab for first-line treatment for CLL in the
USA. Response rates to single-agent treatment as front-line
treatment for CLL are summarized in TABLE 2 [7,16–19].
Alemtuzumab for high-risk CLL
There are several genetic abnormalities known to be associated
with different disease courses in CLL. It has long been recognized that patients with deletion of 17p, resulting in loss of the
TP53 tumor suppressor gene, fall into the worst prognostic
group with resistance to chlorambucil and fludarabine [20] but
some response to high-dose corticosteroids [21]. Several studies
have been published that have retrospectively examined the efficacy of alemtuzumab in patients with TP53 deletions [14,22,23].
The numbers in each series were small, but ORRs approximated
50% (TABLE 3), impressive results in such a refractory patient
group. As disease in lymph nodes responds poorly to alemtuzumab the combination of high dose methylprednisolone plus
alemtuzumab has been used with good results in patients with
TP53 deletion and bulky lymphadenopathy (TABLE 3) [24].
Table 2. Response rates for single agent front-line therapy for chronic lymphocytic leukemia.
Drug
Study
Overall response (%)
Complete response (%)
Ref.
Alemtuzumab (iv.)
Hillmen
83
24
[16]
Alemtuzumab (sc.)
Lundin
87
19
[7]
Fludarabine
Rai
63
20
[17]
Cladribine
Robak
78
21
[18]
Chlorambucil
Hillmen
55
2
[16]
Rituximab
Hainsworth
51
4
[19]
iv.: Intravenous; sc.: Subcutaneous.
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Drug Profile
Boyd & Dearden
Table 3. Alemtuzumab in patients with deletions of TP53.
Study
n
Number with TP53 deletions
Overall response in TP53 deleted group (%)
Stilgenbauer et al. (2004)
50
13
53.8
[14]
Lozanski et al. (2004)
36
15
40
[22]
Osuji et al. (2005)
28
8
50
[23]
Alemtuzumab as consolidation
Two facts provide the rationale for the use of alemtuzumab as
consolidation following conventional chemotherapy: Firstly,
patients who achieve a CR and have no disease detectable by fourcolor flow cytometry have longer PFS and OS [1,13]. Secondly,
alemtuzumab is most effective at clearing disease from the blood
and bone marrow. A Cancer and Leukemia Group B (CALGB)
study treated 56 patients with previously untreated CLL with four
courses of fludarabine followed by a rest period of 2 months and
then alemtuzumab consolidation (30 mg three-times weekly for
6 weeks) [25]. This small study reported an ORR of 92% (CR rate
42%; PR rate 50%). Two other smaller Phase II studies have been
published with varying consolidation regimens (TABLE 4), both of
which demonstrated the feasibility of this approach with
improved responses in around 50% of patients [26,27].
There has only been one Phase III trial, conducted by the German study group [28,29]. This trial randomized patients who had
been treated with fludarabine +/- cyclophosphamide to alemtuzumab at the standard dose for 12 weeks or no further treatment.
The study was terminated prematurely after 21 patients had been
recruited because of severe infection in seven of 11 patients in the
alemtuzumab arm compared with two minor infections in the
control arm. However, despite the small number of patients, a significantly prolonged PFS (p = 0.036) was demonstrated in those
treated with alemtuzumab (27.7 months versus median not
reached). It is likely that the high infection rate was related to the
increase in myelo- and immunosuppression seen particularly
because the interval between completing chemotherapy and the
initiation of alemtuzumab was relatively short. This has led to the
modification of subsequent protocols.
Ref.
Alemtuzumab as in vivo purging prior to
autologous transplantation
CD52 is not expressed on hemopoietic stem cells [30] and alemtuzumab, as seen above, is effective at eradicating minimal residual disease (MRD). Therefore, there is rationale in its use as an
in vivo purge to reduce the risk of contamination of autologously
harvested stem cells by CLL. This approach has been reported on
in a small group of patients [27] whose initial treatment was consolidated by 6 weeks of alemtuzumab. Of 26 patients, 24 were
then successfully harvested using a cytarabine/granulocyte-colony-stimulating factor regimen. In total, 18 of these patients
were subsequently autografted with 17 remaining in CR after
28 months follow-up. This demonstrates the feasibility of stem
cell harvesting after alemtuzumab therapy.
Alemtuzumab in combination with other
therapies in CLL
The efficacy of alemtuzumab as monotherapy and its inability to
eradicate bulky nodal disease has led to several small Phase II
studies combining it with other chemotherapy, all in the
relapsed/refractory patient setting. Early results combining alemtuzumab with the current gold standard of fludarabine and
cyclophosphamide were reported at the American Society of
Haematology meeting in December 2007 [31]. In 19 patients eligible for evaluation, the ORR was 79% (CR 37%, PR 37%,
nodular PR 5%). There was one death due to infection (mycobacterium tuberculosum). A total of 36 patients have been
treated with fludarabine plus alemtuzumab, with an ORR of
83% (CR 30%, PR 53%) and a median OS of 35.6 months [32].
Table 4. Alemtuzumab as consolidation therapy.
Study
n
Median interval from
chemotherapy to maintenance
Regime
Improved response (overall
response %)
Rai et al. (2003)
28
2 months
30 mg iv. TIW
6 weeks
66
[25]
O’Brien et al. (2005)
41
6 months
10 mg iv. TIW
4 weeks
30 mg iv. TIW
4 weeks
39
[26]
Montillo et al. (2006)
Ref.
56
34
8 weeks
10 mg sc. TIW
6 weeks
51
[27]
Schweighofer et al. (2006) 21
67 days
30 mg iv. TIW
12 weeks
45 (improved PFS, increased infections)
[29]
iv.: Intravenous; PFS: Progression-free survival; sc.: Subcutaneous; TIW: Three-times weekly.
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Expert Rev. Anticancer Ther. 8(4), (2008)
Alemtuzumab in the treatment of chronic lymphocytic lymphoma
The regimen was well tolerated. Based on this study a Phase III
trial comparing fludarabine to fludarabine + alemtuzumab is
underway. Alemtuzumab and rituximab have been used in combination with reasonable response rates but disappointing times
to disease progression and a median OS of only 11 months [33].
Alemtuzumab has also been combined with fludarabine, cyclophosphamide and rituxumab with an ORR of 52% (CR 14%,
PR 38%) [34]. A Phase II study using the same regimen in highrisk previously untreated patients is underway at the MD
Anderson Cancer Center (TX, USA). All these regimens show
that it is feasible to combine alemtuzumab with other therapies
with an acceptable side-effect profile and improved response
rates compared with alemtuzumab when used alone.
Alemtuzumab & T-cell malignancies
T-cell malignancies are rare, accounting for less than 15% of all
lymphoid neoplasms. Although the range of disorders is wide,
the rate of expression of CD52 is high, although not ubiquitous
[35–37]. Alemtuzumab has been used with some benefit in the
following diseases:
T-cell prolymphocytic leukemia
T-cell prolymphocytic leukemia (T-PLL) is an aggressive malignancy presenting with organomegaly, skin lesions, serous effusions and rapidly rising peripheral blood lymphocyte counts. It
does not respond well to conventional chemotherapy regimens,
the best results being with the purine analogue 2´-deoxycoformycin, with response rates of approximately 40%. Median survival is around 6–12 months. Two studies have reported the use
of alemtuzumab in patients refractory to other treatments [38,39].
In the first study of 39 patients there was a 76% response rate
(60% CR, 16% PR) with a median survival of 16 months in
those who attained a CR. As in CLL, bone marrow and blood
showed good clearance of disease but patients with serous effusions, hepatic or CNS involvement had a poor response. In the
second study, a retrospective analysis of 76 refractory patients in
the USA, the ORR was 50%. There are also data in a small series
of patients where alemtuzumab was used as a first-line therapy [40].
All patients (11/11) achieved a CR.
Cutaneous T-cell lymphoma
A Phase II study in patients with advanced mycosis fungoides
(MF) or Sezary syndrome (the leukemic manifestation of MF)
yielded an ORR of 55% (32% CR, 23% PR) [41]. The median
time to treatment failure was 12 months. Several other smaller
Phase II studies have confirmed alemtuzumab’s efficacy in this
disease [42–44].
Other T-cell malignancies
There are case reports of the use of alemtuzumab in adult
T-cell lymphoma/leukemia [45]. Small studies have shown efficacy of alemtuzumab in peripheral T-cell lymphoma, both as
monotherapy [46] and with combination chemotherapy [47].
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Drug Profile
Bone-marrow transplantation
Alemtuzumab was originally developed at Cambridge University,
UK, as a tool for depleting T cells from donor bone marrow in an
attempt to reduce graft-versus-host disease (GvHD), and therefore warrants brief mention here. T-cell depletion of the donor
bone marrow may cause graft rejection so alemtuzumab is given
to the recipient to produce T-cell depletion in order to provide
the optimum environment for engraftment and to reduce
GvHD. Alemtuzumab has been used in a variety of regimens collectively known as reduced-intensity-conditioning regimens as
they rely primarily on immune suppression rather than myeloablation to allow engraftment, and graft-versus-leukemia effect to
suppress disease. There is evidence of the tolerability and efficacy
of these alemtuzumab-containing regimens in CLL [48], myeloma
[49], non-Hodgkin’s lymphoma [50], Hodgkin’s lymphoma [51] and
acute myeloid leukemia/myelodysplasia [52].
Safety & tolerability
The main side effects of alemtuzumab are infectious complications, cytopenias and infusion-related events.
The increased risk of infection is the most concerning sideeffect of alemtuzumab. Increased rates of viral (especially CMV),
bacterial and fungal infections have been documented in all trials using this agent. The cause of this is the profound and prolonged depletion of T and B lymphocytes, although transient
neutropenia may also contribute. In the early Phase II studies on
relapsed/refractory patients there was no routine prophylaxis
against infection and infectious complication rates were high. In
the largest Phase II study [10] infection rates were 55% during
the trial. Septicemia occurred in 15%, with causative organisms
such as E. coli and pseudomonas identified. Viral infections were
also frequent with six of 93 patients reactivating herpes simplex
and seven of 93 reactivating CMV. Other opportunistic infections documented were Pneumocystis carinii pneumonia (PCP),
Aspergillus pneumonia, Cryptococcal pneumonia and Listeria
meningitis. There were five on-study deaths caused by infection.
Since then, routine prophylaxis with an anti-PCP and antiviral
agent, which should continue until lymphopenia resolves, has
become mandatory. There is no doubt that host factors play a
major role, with heavily pretreated patients with advanced disease being especially susceptible to infections. As such, the infection rates in the more recent trials using alemtuzumab as initial
treatment are more comparable to conventional regimens. In the
Phase III study comparing alemtuzumab with chlorambucil [16]
there were increased infectious complications in the alemtuzumab arm (76 vs 50%), but these were almost entirely attributable to CMV reactivation with comparable rates of bacterial
infection and no increased treatment-related mortality in the
alemtuzumab arm.
CMV reactivation remains a particular concern and warrants
special mention. All patients commencing treatment with
alemtuzumab should have serological assessment for previous
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Boyd & Dearden
exposure to CMV. Those who are CMV IgG positive are at
high risk of viral reactivation and require careful management.
This is usually done by weekly monitoring of CMV viral copy
number and pre-emptive treatment if there is a rise in copy
number. We use an arbitrary threshold of 3000 copies/ml to
instigate treatment. Ganciclovir (Cymevene, Roche) and its
pro-drug, valganciclovir (Valcyte, Roche), foscarnet (Foscavir,
AstraZeneca) and cidofovir (Vistide, Gilead, Pfizer) all have
efficacy against CMV. This usually prevents symptomatic reactivation. Inadequate monitoring or treatment risks symptomatic, life-threatening disease with pneumonia, colitis and
retinitis. One study has used prophylactic valganciclovir with
virtual elimination of CMV reactivation [53], but this is a costly
strategy which may also increase the risk of viral resistance and
contribute to neutropenia.
T and B lymphocytes are rapidly depleted with immune
reconstitution being slow [54]. Lymphopenia is often still
present a year after treatment with opportunistic infection
remaining a risk during this time. Neutropenia is most common in weeks 5 and 6, whilst thrombocytopenia is most
common during the first 2 weeks of treatment. Both are
usually transient.
As with other monoclonal antibodies, infusion can produce a cytokine release syndrome characterized by fever, rigors, nausea, vomiting, skin rash and occasionally hypotension. This is the result of release of TNF-α, IFN-γ, IL-6
and IL-10 mediated by natural killer cells [55]. The symptoms are reduced by escalating the dose at initiation (3, 10
and 30 mg) and by premedication with paracetamol or
acetaminophen, an antihistamine and corticosteroids if there
has been a previous severe reaction. Subcutaneous administration may also ameliorate this effect, although it can cause
local injection site erythema. Infusion-related side effects
usually decrease with time with few symptoms prevailing
beyond week 4. Very rarely will they lead to the permanent
discontinuation of treatment.
There is controversy as to whether alemtuzumab carries the
risk of cardiotoxicity. An initial report found cardiac toxicity in
4 of 8 patients treated with alemtuzumab for T-cell disorders,
manifesting as arrhythmias and congestive cardiac failure [56].
However, these reports were not confirmed by a larger European study in a similar patient group [57]. In some trials in
patients with CLL, increased rates of cardiac events have been
suggested [10] including the recent randomized study comparing chlorambucil with alemtuzumab [16] which noted four serious cardiac events in the alemtuzumab arm compared with
none in the chlorambucil arm.
Expert commentary
A review of alemtuzumab was published in this journal 6 years
ago, shortly after its license for use in fludarabine-refractory
CLL was granted. Things have progressed in the intervening
years and it has very recently received licensing in the USA for
530
initial treatment for CLL, the only drug other than chlorambucil to be licensed for this indication. Alemtuzumab
remains the most effective agent in the relapsed/refractory
group of patients with CLL when used as monotherapy with
response rates of greater than 30%. It is most effective for disease in the bone marrow, blood and spleen. Bulky lymphadenopathy is not cleared so easily, so combining alemtuzumab
with other agents known to be effective in clearing lymph node
disease may produce synergy. Small trials with a variety of regimens show the feasibility of this approach and promise further
improvements in response rates.
New data shows alemtuzumab to be superior to chlorambucil
as first-line treatment for CLL with manageable toxicity. This
has led to the extension of the license for this indication. The
current gold standard from randomized controlled trials is the
combination of fludarabine and cyclophosphamide, although
improved response rates have been reported with the addition
of rituximab to the fludarabine and cyclophosphamide regimen
in Phase II trials with the data from Phase III trials pending. As
yet it is unknown how alemtuzumab will fit into the treatment
algorithm as more data is needed on the use of alemtuzumab in
front-line combination regimens.
The indication for which alemtuzumab may become accepted
as standard front-line therapy for CLL is in the high-risk cytogenetic group exhibiting TP53 deletion. Here it can either be
used alone or in combination with high-dose corticosteroids if
the patient has significant lymphadenopathy.
In addition, alemtuzumab has been shown to be effective in
eradicating MRD and thus prolonging the PFS in patients.
As trials have shown that patients who are MRD negative
have improved OS, this has become the aim of treatment.
The fact that the only Phase III trial for alemtuzumab as
maintenance had to be terminated early due to a high infectious complication rate means that this approach cannot be
advocated outside the scope of a controlled trial. The high
infection rate in the German trial may be explicable by the
timing, dose and duration of maintenance alemtuzumab,
with the key conclusion being that the time interval between
the discontinuation of chemotherapy and the initiation of
alemtuzumab consolidation should be longer. Other regimens
therefore need to be explored. The feasibility of autologous
harvesting after alemtuzumab therapy has been demonstrated. However, concerns about high rates of secondary
myelodysplasia and acute myeloid leukemia in patients with
CLL who receive autologous transplants, plus the question of
how much an autograft adds to the prognosis of a patient
already in CR and MRD negative, are likely to prevent this
approach being widely taken up.
Given the high expression of CD52 in most T-cell disorders
it is likely that there is a valuable role for alemtuzumab in
their treatment. Results obtained in T-PLL and cutaneous
T-cell lymphoma have shown improved response rates which
may translate to improved survival if more patients can then
be salvaged by allogeneic bone marrow transplantation.
Expert Rev. Anticancer Ther. 8(4), (2008)
Alemtuzumab in the treatment of chronic lymphocytic lymphoma
Five-year view
The field of CLL is set to change in two major ways in the
future. Firstly, this heterogeneous disease is likely to be stratified based on genetic abnormalities and treatments targeted to
the disease subtype. This is already the case for patients with
17p, but advances in genomics with microarray profiling may
impact this further. Secondly, there are a number of novel
agents currently undergoing Phase I and II trials, including at
least four monoclonal antibodies. There will therefore be more
treatment options in the future and the algorithm will be more
complex. However, selection of therapy will be more tailored to
the individual patient.
The role of alemtuzumab is almost certain to expand over the
next 5 years. It is likely to become established as front-line therapy
for those patients with TP53 abnormalities, and as second-line
treatment in combination regimens. It may also find its way
into routine front-line treatment as data from combination
Drug Profile
therapies matures, although expense may be an issue here, especially if used in rituxumab-containing regimens. Its role as a
consolidation drug is encouraging and needs to be further elucidated. The optimum treatment in the 5 years for the average
patient may be a fludarabine-based combination regimen followed by alemtuzumab maintenance therapy until MRD negativity is obtained. Thereafter, short courses of alemtuzumab
administered when disease is detected at MRD levels may be an
attractive strategy.
Financial & competing interests disclosure
Claire Dearden acts as a consultant and receives lecture fees from
Schering AG. The authors have no other relevant affiliations or financial
involvement with any organization or entity with a financial interest in
or financial conflict with the subject matter or materials discussed in the
manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Key issues
• Alemtuzumab is a monoclonal antibody targeting CD52, an antigen expressed on normal and malignant B and T lymphocytes.
• It has activity in chronic lymphocytic leukemia (CLL), the most common adult leukemia in the western world.
• Bone marrow, blood and spleen are effectively cleared of disease but bulky lymphadenopathy is not well treated.
• It is the most effective treatment found to date for relapsed / fludarabine-refractory patients with CLL.
• It has recently been shown to produce superior response rates compared with chlorambucil for first-line treatment for CLL.
• Its benefits are most marked in patients with CLL and deletion of the TP53 tumor suppressor gene, who respond poorly to all
other agents.
• It has efficacy in T-prolymphocytic lymphoma, cutaneous T-cell lymphomas and other T-cell disorders.
• It is also used to prevent graft-versus-host disease in bone marrow transplantation.
• The main toxicities are infusion-related cytokine reactions, infectious complications including cytomegalovirus reactivation and cytopenias.
and rituximab as initial therapy for chronic
lymphocytic leukaemia. J. Clin. Oncol.
23(18), 4079–4088 (2005)
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Affiliations
•
Kevin Boyd, MBBS, MRCP
The Royal Marsden Hospital and Institute
of Cancer Research, London, UK
Tel.: +20 8661 3116
Fax: +20 8642 9634
kboyd@doctors.org.uk
•
Claire E Dearden, MD, FRCP, FRCPath
Department of Haemato-Oncology, The
Royal Marsden Hospital and Institute of
Cancer Research, Downs Road, Sutton,
Surrey SM2 5PT, UK
Tel.: +20 8661 3116
Fax: +20 8642 9634
claire.dearden@rmh.nhs.uk
533