Download Optimal Use of Bendamustine in Chronic Lymphocytic Leukemia

Review
Optimal Use of Bendamustine in Chronic
Lymphocytic Leukemia, Non-Hodgkin Lymphomas,
and Multiple Myeloma: Treatment Recommendations
From an International Consensus Panel
Bruce D. Cheson,1 Clemens-Martin Wendtner,2 Angelika Pieper,3
Martin Dreyling,4 Jonathan Friedberg,5 Dieter Hoelzer,6 Philippe Moreau,7
John Gribben,8 Stefan Knop,9 Marco Montillo,10 Mathias Rummel11
Abstract
Bendamustine is a novel bifunctional alkylating agent with promising activity in lymphoid malignancies and several solid tumors. Unfortunately, the early development of this agent did not provide sufficient information on which to determine an optimal systematic dose and schedule. As a result, administration of the agent has been inconsistent among
studies. The use of this drug has been increasing since it has been approved by the US Food and Drug Administration
for chronic lymphocytic leukemia and rituximab-refractory indolent B-cell non-Hodgkin lymphoma, and is expected
to increase further following anticipated European regulatory approval. Thus, a consensus meeting was convened to
develop recommendations for standardizing the administration of the drug based on the available clinical data. Recommendations were developed including dose and schedule for the various clinical indications, as a single agent and
in combination therapy, and to provide guidance for supportive measures. This report, representing the conclusions
of that meeting, should provide guidance for the clinician until definitive dose-finding studies have been conducted.
Clinical Lymphoma, Myeloma & Leukemia, Vol. 10, No. 1, 21-27, 2010; DOI: 10.3816/CLML.2010.n.002
Keywords: Alkylating agent, Non-Hodgkin’s lymphoma, Phase I trial, Refractory, Relapsed, Rituximab
Introduction
For over 40 years, bendamustine was used in the former German
Democratic Republic as monotherapy in the treatment of non1Division of Hematology-Oncology, Georgetown University Hospital, Lombardi
Comprehensive Cancer Center, Washington, DC
2Department of Hematology and Oncology, University of Cologne, Cologne, Germany
3Mundipharma, Cambridge, UK
4Department of Medicine III, University Hospital, Grosshadern, Ludwig MaximiliansUniversity, Munich, Germany
5Division of Hematology-Oncology, Wilmot Cancer Center, University of Rochester,
Rochester, NY
6Onkologikum Frankfurt, Frankfurt, Germany
7Hematology Department, University Hospital, Nantes, France
8Institute of Cancer, Department of Experimental Cancer Medicine, Barts and the
London School of Medicine, Queen Mary University, London, England
9Würzburg University, Department of Internal Medicine II, Division of HematologyOncology, Würzburg, Germany
10Divisione Ematologica, Ospedale Niguarda Ca’ Granda, Milan, Italy
11Clinic for Hematology and Oncology, Justus-Liebig-University, Giessen, Germany
Submitted: Jul 17, 2009; Revised: Sep 15, 2009; Accepted: Oct 18, 2009
Address for correspondence: Bruce D. Cheson, MD, Georgetown University Hospital,
3800 Reservoir Rd, NW, Washington, DC 20007
Fax: 202-444-1229; e-mail: [email protected]
Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL),
multiple myeloma (MM), Hodgkin lymphoma (HL), breast cancer,
and small-cell lung cancer. Following the German reunification,
further studies with bendamustine resulted in its regulatory approval
for the treatment of patients with indolent NHL, CLL, and MM,
as well as breast cancer and HL. Based on preliminary encouraging
data, other study groups initiated additional trials of bendamustine to
confirm its efficacy. Randomized data demonstrating the superiority
of bendamustine over chlorambucil in CLL led to its Food and Drug
Administration (FDA) approval for that indication.1 Recent US
studies confirmed single-agent activity for bendamustine in follicular,
low-grade, and transformed NHL,2,3 leading to its FDA approval in
rituximab-refractory indolent B-cell NHL.4
Despite the increasing number of studies demonstrating efficacy
for this agent, many questions remain unanswered. The mechanism
of action is just becoming understood.5 The optimal dose and
schedule, and the appropriate use of supportive measures have varied
widely among studies, with no guidance as to its proper administration. Throughout its development, bendamustine has been administered in a variety of doses and schedules that have been primarily
This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA.
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Clinical Lymphoma, Myeloma & Leukemia February 2010
| 21
Bendamustine for CLL, NHL, and MM: Treatment Recommendations
Table 1 Published Single-Agent Bendamustine Doses
and Schedules
Disease
Dose, mg/m2
Schedule
Dose/Cycle, mg/m2
1506
Days 1, 2 every 28 days
300
1608
Days 1, 8 every 28 days
320
1809
Days 1, 2 every 21 days
360
26010
Day 1 every 21 days
260
Solid Tumor
Recommended
Dose, mg/m2
Dose/Cycle,
mg/m2
Dose-Limiting Toxicity
60 every
week × 88
240
Fatigue, dry mouth, fever
160, days 1, 2
every 3 weeks6
320
Thrombocytopenia
140, days 1, 8
every 4 weeks9
320
Fatigue, dry mouth, diarrhea,
cardiac arrhythmia
260, day 1
every 3 weeks10
260
Fatigue, cardiac
200
Febrile neutropenia
100, days 1, 2
every 3-4 weeks16
200
Bilirubinemia, diarrhea,
anemia, thrombocytopenia
70, days 1, 2
every 4 weeks12
140
Hyperuricemia, pneumonia,
leukopenia, infection, anemia,
liver enzymes, thrombocytopenia
Solid Tumor
NHL
50-6011
Days 1-5 every 28 days
250-300
1202,3,13
Days 1, 2 every 21 days
240
MM
CLL
50-6015
Days 1-5 every 28 days
250-300
50-6011
Days 1, 2 every 28 days
100-120
7012
Days 1, 2 every 28 days
140
1001,14,16
Days 1, 2 every 28 days
200
MM
50-6011
Days 1-5 every 21 days
250-300
10018
Days 1, 2 every 28 days
200
15017
Days 1, 2 every 28 days
300
Abbreviations: CLL = chronic lymphocytic leukemia; MM = multiple myeloma;
NHL = non-Hodgkin lymphoma
developed empirically and with no clear drug development strategy
(Table 1).2,6-18 As bendamustine becomes more widely used, it is
important for clinicians to have information on how to administer
the drug with safety and effectiveness. In November 2008, an international group of investigators with extensive experience using this
agent met to develop recommendations for treating patients with
bendamustine. This report represents the consensus of that meeting.
Background
Pharmacokinetics
Limited pharmacokinetic data are available to direct the dose and
schedule of bendamustine. Rasschaert et al administered the drug once
every 3 weeks and found a tmax of 35 minutes with a mean elimination
half-life of 49.1 min, volume of distribution of 18.31 m−2 and a clearance of 265 mL min−1 m−2, with no evidence for dose dependency.
The amount detected in the urine was highly variable.9 The pharmacokinetics of bendamustine administered days 1 and 2 every 3 weeks
produced virtually identical results, suggesting a lack of schedule
dependency.9 Owen et al19 conducted a population pharmacokinetic
analysis of bendamustine in patients with indolent NHL treated with
120 mg/m2 day 1 and 2 every 3 weeks. Plasma concentrations declined
in a triphasic manner, with a rapid distribution phase, an intermediate
phase, and a terminal decline. They determined the intermediate t1/2
of 40 minutes to be the most pharmacologically relevant because the
initial phases accounted for 99% of the bendamustine area under the
curve (AUC). Cmax was 6 μg/mL. Accumulation was not expected,
thus, single-dose pharmacokinetics reflected multidosing schedules. Of
interest was that neither mild-to-moderate renal nor mild liver impairment altered pharmacokinetics.
22
Table 2 Single-Agent Bendamustine Phase I Trials
| Clinical Lymphoma, Myeloma & Leukemia
February 2010
100, days 1, 2
every 4 weeks18
CLL
Abbreviations: CLL = chronic lymphocytic leukemia; MM = multiple myeloma;
NHL = non-Hodgkin lymphoma
Phase I Studies in Solid Tumors
Schöffski et al8 conducted a phase I trial with intravenous
bendamustine in patients with solid tumors starting at 80 mg/m2
weekly (Table 2). Two patients experienced dose-limiting toxicity
at the starting dose (fever, mouth dryness, fatigue) and 60 mg/m2
was determined to be the phase II dose. Schöffski et al7 identified
a maximum tolerated dose (MTD) of 160 mg/m2 on days 1 and 8
of an every-4-week schedule. Rasschaert et al10 conducted a phase I
trial with an initial dose of bendamustine of 160 mg/m2 once every
3 weeks, and escalated by increments of 20 mg/m2. At 280 mg/m2,
grade 4 thrombocytopenia, grade 3 fatigue, and grade 2 cardiotoxicity were encountered; the latter two were considered dose-limiting.
These investigators recommended 260 mg/m2 administered every
3 weeks for subsequent trials. In another phase I study from the same
investigators, the starting dose of bendamustine was 120 mg/m2 days
1 and 2 every 3 weeks and the dose escalated by 20 mg/m2. The
MTD was 180 mg/m2 and thrombocytopenia was dose limiting.9
Phase I Studies in Hematologic Malignancies
Few single-agent phase I studies have been conducted in CLL
and myeloma, and none in NHL (Table 2).12,16,18 It appears that
myelosuppression appears less in patients with solid tumors versus
those with myeloma, with CLL patients tolerating the lowest doses.
Dose and Schedule Considerations
Factors determining the dose and schedule of bendamustine
must take into account whether the drug is being used as initial
therapy or in the relapsed/refractory setting, whether it is being
delivered as a single agent or in combination with other drugs (primarily rituximab, and the other drugs in those combinations) and
a number of patient and disease characteristics.
Bruce D. Cheson et al
Chronic Lymphocytic Leukemia
Based on the results of a phase I trial in patients with fludarabinenaive, relapsed, and refractory CLL, Lissitchkov et al recommended
a dose of 100 mg/m2 on days 1 and 2 every 4 weeks.16 However,
the German CLL Study Group recommended 70 mg/m2 on days 1
and 2 every 4 weeks for relapsed patients either as a single agent12
or in combination with rituximab.20 An explanation for the differences between these studies is that most patients in the latter series
had previously received fludarabine and, therefore, might have had
more compromised bone marrow reserves.12,20
Data on which to base dosing recommendations are more
limited for bendamustine in previously untreated patients. Knauf
et al1 conducted a trial which patients without previous therapy
for their CLL were randomized to receive either bendamustine
100 mg/m2 days 1 and 2 every 4 weeks, or chlorambucil 0.8 mg/kg
days 1 and 15 of a 28-day cycle. Bendamustine was associated with
a higher complete response (32% vs. 2%) and overall response rate
(ORR; 67% vs. 30%), and a longer progression-free survival (PFS;
21.5 months vs. 8.3 months). There was no substantial difference
in the rate of serious infections between the two arms: neutropenia,
23% and 11% for bendamustine and chlorambucil, respectively;
thrombocytopenia, 12% and 9%; infections, 6% and 3%; skin
toxicity, 4% and 3%; and anemia, 3% and 1%. The FDA approval
for bendamustine at 100 mg/m2 on days 1 and 2 every 4 weeks was
based on this randomized trial (Table 3).
Rituximab appears to increase the myelotoxicity of chemotherapy drugs such as fludarabine, especially when the antibody is
delivered concurrently.21 Therefore, when bendamustine is used in
combination with rituximab as initial treatment for CLL, a dose of
90 mg/m2 days 1 and 2 every 4 weeks is recommended (Table 3).
For patients with relapsed or refractory disease, a starting dose of
70 mg/m2 days 1 and 2 every 4 weeks is recommended for bendamustine when combined with rituximab.20 In a recent phase II trial
of the German CLL Study Group using this combination, a response
rate of 77% including 14% CRs was documented in a heavily pretreated population.20 The dose of bendamustine can be escalated to
90 mg/m2 days 1 and 2 if the lower dose is well tolerated.
Non-Hodgkin Lymphoma
Single-Agent Bendamustine as Initial Therapy of
Follicular and Low-Grade Non-Hodgkin Lymphoma
Given the widespread use of rituximab-based combinations in
B-cell NHL, bendamustine is not expected to be used extensively
as a single agent for initial treatment.
Single-Agent Bendamustine in Relapsed and Refractory
Follicular and Low-Grade Non-Hodgkin Lymphoma
Based on a single-agent pivotal trial,3 and supported by similar
results from another phase II study,2 bendamustine was approved
by the FDA for patients with rituximab-refractory, relapsed/refractory follicular and low-grade NHL at a dose of 120 mg/m2 days
1 and 2 every 3 weeks. When the two studies are pooled, there
were 176 patients for which safety and efficacy data are available.22 Of these, 34% were refractory to their last chemotherapy.
Bendamustine was to be delayed for grade 4 hematologic toxicity
Table 3 Consensus Panel Dose Recommendations for
Bendamustine Therapy
Indication
Dose, mg/m2
Days 1, 2a
CLL
Initial therapy, single agent
100
Initial therapy, with rituximab
90
Relapsed/refractory, single agent (fludarabine naive)
Relapsed/refractory, with rituximab
70 (100)
70b
Follicular/Low-Grade NHL
Initial therapy, with rituximab
90
Relapsed/refractory, single agent
120
Relapsed/refractory, with rituximab
90
Aggressive B-NHL
Relapsed/refractory, single agent
120
Relapsed/refractory, with rituximab
90
T-Cell, NK, Hodgkin Lymphoma
Relapsed/refractory
Unknown
Multiple Myeloma
Relapsed/refractory
100
aAll
are every 4 weeks except aggressive B-cell, which is every 3 weeks.
to 90 mg/m2 if tolerated.
Abbreviations: CLL = chronic lymphocytic leukemia; NHL = non-Hodgkin lymphoma;
NK = natural killer
bEscalate
or clinically significant grade 2 or worse nonhematologic toxicity
and therapy resumed when toxicity has decreased to no worse than
grade 1 or an absolute neutrophil count of at least 1000/mm3. The
dose of bendamustine was to be decreased to 90 mg/m2 for grade
4 hematologic toxicity or grade 3 or worse nonhematologic toxicity. In the setting of recurrent grade 4 myelosuppression or grade
3 nonhematologic toxicity, the dose was reduced to 60 mg/m2.
Ninety patients (56%) received the intended 6 or more cycles of
bendamustine; early withdrawals were because of adverse events
(28%), mostly myelosuppression (18%) or disease progression
(12%). Dose reductions occurred in 25% of patients and 60%
experienced at least 1 treatment delay. Grade 3-4 hematologic
adverse events included neutropenia (34%), thrombocytopenia
(15%), and anemia (10%). Overall there were 34 opportunistic infections in 32 patients (10 Herpes zoster, 5 H. simplex, 10
Candida, 5 cytomegalovirus, 2 Pneumocystis jiroveci pneumonia, 1
atypical mycobacterial infection, 1 tuberculosis). Grade 3/4 nonhematologic toxicities included nausea (4%), vomiting (2%), fatigue
(14%), and diarrhea (5%). Kahl et al3 reported grade 3-4 nausea
in 4%, vomiting in 2%, fatigue in 14%, and diarrhea in 5%. Forty
patients discontinued therapy because of adverse events (27) disease progression (10), or patient decision (1). Dose reductions for
adverse events occurred in 24% of patients; 20% from 120 mg/m2,
and 4% to 60 mg/m2. Overall, 68% of patients had dose reductions, delays, or did not receive both doses in a cycle. Friedberg et
al2 noted grade 3/4 nausea, vomiting, and fatigue in 4%, 4%, and
7%, respectively. They felt that the drug was well tolerated, but
Clinical Lymphoma, Myeloma & Leukemia February 2010
| 23
Bendamustine for CLL, NHL, and MM: Treatment Recommendations
20% of cycles were delayed, 3-7 days in 9% of cycles and 8-14 days
in 6% of cycles. Delays of 3 weeks or longer occurred in fewer
than 5% of cycles. In 20% of patients, the dose was reduced from
120 mg/m2 to 90 mg/m2, and in 5% from 90 mg/m2 to 60 mg/m2.
Overall, almost half of the patients did not receive the intended
therapy dose. Thus, whereas the dose of 120 mg/m2 appears to be
safe and efficacious, the consensus of the panel was that the same
dose should be administered every 4 weeks to reduce hematologic
toxicity, dose modifications, or treatment delays, but likely with
comparable efficacy (Table 3).
Bendamustine Combined With Rituximab in Follicular
and Low-Grade Non-Hodgkin Lymphoma
The recommended dose of bendamustine in combination with
rituximab is 90 mg/m2 days 1 and 2 based on the data in the
relapsed setting.23,24 Rummel et al first reported on 63 patients
with relapsed or refractory lymphomas (median age, 63 years)25
with either follicular lymphoma (24), mantle cell (16), immunocytoma (17), or marginal zone lymphoma (6). Bendamustine/
rituximab (B-R) was administered every 4 weeks for up to 4 cycles.
Additional doses of rituximab were administered 1 week before
the first cycle and 4 weeks after the last cycle. The ORR was
90%, including 60% CRs. The median PFS for all patients was
24 months (range, 5-44+ months). The probability of survival
after 4 years was 55%. Hematologic toxicity included grade 3 or 4
leukopenia (16% of cycles), thrombocytopenia (3% of cycles), and
anemia (1% of cycles). No organ toxicity was reported.
Robinson et al24 used a similar regimen for 4-6 cycles to treat
67 patients with relapsed follicular, low-grade, and mantle cell
NHL who were not rituximab refractory. Previous rituximab had
been administered to 56% of patients. The ORR was 92% including 55% complete response (CR)/unconfirmed CR (CRu) with no
difference between patients with indolent and mantle cell disease or
by the number of previous regimens (1 vs. > 1). The PFS was similar between mantle cell and indolent histologies, number of previous regimens, or previous rituximab therapy. Myelosuppression was
the major toxicity with 36% of patients experiencing grade 3 or 4
neutropenia, and 9% experiencing grade 3 or 4 thrombocytopenia.
Based on these two studies, the recommended dose of B-R in follicular, low-grade, and mantle cell lymphomas is 90 mg/m2 days 1
and 2 every 4 weeks for relapsed patients.
This combination has also been evaluated as initial therapy.
Rummel et al25 conducted a study in previously untreated follicular and mantle cell NHL in which bendamustine (90 mg/m2
days 1 and 2 every 4 weeks) and rituximab was compared with
rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) resulting in a response rate of 93% in both arms,
with 40% complete remissions and a longer PFS with bendamustine (54.8 months vs. 34.8 months). The bendamustine arm was
associated with less toxicity, notably alopecia, myelosuppression,
and infections. The consensus was that this dose was appropriate
for both first-line therapy and for relapsed patients as the higher
single-agent dose of 120 mg/m2 approved for rituximab-refractory
patients was unlikely to achieve better results, but would increase
the risk of severe myelotoxicity (Table 3). This dose was recommended for further study in untreated patients.
24
| Clinical Lymphoma, Myeloma & Leukemia
February 2010
Aggressive Non-Hodgkin Lymphoma
The only published data with bendamustine in aggressive NHL
are by Weidmann et al26, who used a dose of 120 mg/m2 on days 1
and 2 every 3 weeks in relapsed and refractory patients and achieved
a response rate of 44% including 16% complete remissions. Toxicity
was reported to be low with no nonhematologic grade 4 adverse
events, and grade 3 in fewer than 10% of treatment cycles. Grade 4
anemia, thrombocytopenia, and granulocytopenia occurred in 3.3%,
8.3%, and 6.7% of cycles, respectively. Bendamustine therapy had to
be discontinued in 2 patients because of prolonged grade 4 thrombocytopenia and leukopenia. There were no treatment-associated
deaths. Dose delays or reductions occurred in 21.7% of treatment
cycles. No patients received myeloid growth factors.
Further study is warranted in patients with relapsed or refractory
aggressive NHL not eligible for high-dose therapy. Based on the
data published by Weidmann et al26 and the data in indolent NHL,
when bendamustine is administered as a single agent the dose
should be 120 mg/m2 days 1 and 2 delivered every 3 weeks because
of the aggressive nature of this lymphoma. There are no published
data combining bendamustine with rituximab in this setting; however, when combined with rituximab, a starting dose of 90 mg/m2
days 1 and 2 every 3 weeks was recommended by the consensus
panel until additional information becomes available (Table 3).
Other Lymphoma Histologies
There are currently no data on the use of bendamustine in
T-cell NHL, natural killer NHL, or Hodgkin lymphoma. A reasonable starting dose of bendamustine for dose-finding clinical trials
in relapsed and refractory patients is 90 mg/m2 on days 1 and 2
every 4 weeks, which can be escalated to 120 mg/m2 in subsequent
cycles, as tolerated (Table 3).
Bendamustine Combination
Regimens
Limited data exist on bendamustine combined with other agents.
Weide et al27 combined bendamustine at 90 mg/m2 days 1 and 2 with
mitoxantrone 10 mg/m2 on day 1 with rituximab 375 mg/m2 on day 8.
They treated 66 patients with relapsed or refractory indolent and mantle
cell NHL, only 39% of whom had received previous rituximab, only
14% were refractory to previous therapy, and 83% had received 1-2 previous therapies. The response rate was 89% with 35% CRs. Progressionfree survival was 17 months for follicular and 22 months for mantle cell
lymphoma. These results do not appear to be different from those that
can be achieved without mitoxantrone.23,24 Adverse effects included
grade 3-4 granulocytopenia in 46% and thrombocytopenia in 16%.
Bendamustine has also been combined with bortezomib and
rituximab in the phase I VERTICAL trial.28 Patients received
five 35-day cycles of bortezomib at 1.6 mg/m2 with rituximab at
375 mg/m2 days 1, 8, 15, 22, and escalating doses of bendamustine
starting at 50 mg/m2. There were 16 patients with a median of 3
previous regimens. Rash was the single dose-limiting toxicity (DLT)
at 70 mg/m2, grade 3 thrombocytopenia at 90 mg/m2. The latter
dose was selected for the phase II study, which is near completion.
Empirical combinations of bendamustine with other myelosuppressive agents are strongly discouraged outside of a clinical trial
until safety data from phase I studies are available.
Bruce D. Cheson et al
Multiple Myeloma
Most of the available data for bendamustine in MM are for combination regimens, rather than for single-agent studies.
Pönisch et al17 randomized 131 patients to bendamustine
(150 mg/m2 days 1 and 2) or melphalan (15 mg/m2 day 1) every
4 weeks; both arms received prednisolone (60 mg/m2 daily on
days 1-4). Crossover was permitted within 3 months for progression. The ORR was 75% for the bendamustine/prednisolone
(BP) arm and 70% for melphalan/prednisolone (MP). However,
bendamustine achieved CRs in 32% compared with 13% after
melphalan (P = .007), with a shorter time to maximum response
with bendamustine; 6.8 cycles for BP, but 8.6 cycles with MP
(P < .02). Time to treatment failure was longer for bendamustine
at 14 months compared with 10 months for melphalan (P < .02),
with no difference in OS. The toxicities of the two arms were
comparable including 12% infections, 24% anemia, 30%-40%
leukopenia, and 10%-15% thrombocytopenia. The exception
was 12% grade 3-4 nausea and vomiting with BP that was not
observed with MP. The same group evaluated a combination of
fixed doses of bendamustine (60 mg/m2 on days 1, 8, and 15)
and prednisolone (100 mg days 1, 8, 15, and 22) with escalating
doses of thalidomide (50 mg, 100 mg, and 200 mg daily; BPT
protocol) in patients with relapsed MM.29 Twenty-eight intensively pretreated patients were enrolled and received a median of
5.5 four-week cycles of BPT. Formally, the MTD was not reached
even at a daily thalidomide dose of 200 mg. The ORR (CR, very
good partial response [PR], PR) was 85%, with a median PFS of
11 months. Although no prophylactic anticoagulation was used,
there were no events of thromboembolism. Mild-to-moderate
peripheral neuropathy occurred in 75% with mild somnolence in
11% of patients; grade 3-4 neuropathy was not observed. These
data compare favorably to the dose-escalation trial of Knop et al19
including 31 patients progressing following a previous autologous stem cell transplantation, escalating from a starting dose of
60 mg/m2 by 10 mg/m2 increments, with activity at each dose
level. They concluded that the MTD was 100 mg/m2 based on a
single patient with febrile neutropenia (Table 3).
Further evaluation of bendamustine combinations in MM
appears warranted and are currently being tested with new, active
agents, such as bortezomib.30
Duration of Bendamustine Therapy
The optimal number of treatment cycles for bendamustinebased regimens has not been determined. Patients who fail to
respond following 2 cycles should be considered for alternate
treatments. Six cycles is probably adequate for previously untreated
patients. In the relapsed/refractory setting, 4-6 cycles can be delivered as tolerated. Until additional safety data become available,
only 4 cycles should be used in patients previously treated with
bendamustine as retreatment following previous bendamustine.
Supportive Measures
Antiemetic Therapy
Partly because of the limited data and its approval in March 2008
in the United States, bendamustine is not listed in the Multinational
Association of Supportive Care in Cancer (MASCC) guidelines as
Table 4 Dose Reductions With Bendamustine
Disease Status
Dose Reduction, mg/m2 Days 1, 2
CLL: First-line
Single agent
100 to 70
Rituximab combination
90 to 60
CLL: Relapsed/Refractory
Single agent
100 to 70
Rituximab combination
70 to 50a
NHL: Single Agent
120 to 90 to 60
Rituximab combination
90 to 60
aDoses
< 50 mg/m2 are considered subtherapeutic, and dose delays are preferred.
Abbreviations: CLL = chronic lymphocytic leukemia; NHL = non-Hodgkin lymphoma
to its emetogenic risk. However, bendamustine has a moderate risk
of emesis following administration. In recent studies, about 70%
of treated patients experience nausea, and 40% experience vomiting; however, these toxicities were grade 3 or worse in fewer than
4% of patients.2,3 Also, the distinction between acute and delayed
emesis has not been well studied. Because bendamustine is usually
administered over 2 consecutive days as an outpatient treatment,
the potential exists for underreporting adverse effects during the
days following therapy. In some patients the emesis might last a
week whereas others might experience delayed emesis. All patients
treated with bendamustine should receive antiemetic treatment
with a 5-HT3 antagonist. For patients with persistent nausea, palonosetron given on day 1, or with the addition of aprepitant might
be necessary. Steroids are generally not needed.
Immunosuppression and Infections
Bendamustine appears to induce fewer infections than regimens such as R-CHOP in follicular and mantle cell lymphoma,25
and no more than chlorambucil in CLL.1 In the 242 patients
treated on the US clinical trials with single-agent bendamustine
or in combination with rituximab,2,3,24 the incidence of fungal,
herpes, or cytomegalovirus infections was 3.3%, 6.6%, and 2.5%,
respectively. Nevertheless, delayed H. zoster might occur; whether
it is as a consequence of the treatment or the disease is unclear.
Thus, as a general recommendation, no antimicrobial prophylaxis
is indicated, though individual patients with recurring infections
or receiving concurrent immunosuppressive agents may be considered for such treatment. Similarly, prophylactic growth factor
use is not warranted.
Tumor Lysis Syndrome
Fludarabine as a single agent has been reported to induce tumor
lysis syndrome (TLS) in approximately 0.4% of patients.31 This
complication is similarly uncommon with bendamustine.1,3,12,32
In the pivotal trial in rituximab-refractory NHL3 there were 2
episodes in 100 patients.22 In the initial treatment of patients with
CLL, Knauf et al1 noted that 1% of 162 patients treated with
bendamustine developed this complication. Given the low incidence, TLS prophylaxis is not routinely indicated, except perhaps
in patients with impaired renal function.12
Clinical Lymphoma, Myeloma & Leukemia February 2010
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Bendamustine for CLL, NHL, and MM: Treatment Recommendations
Autoimmune Hemolytic Anemia
Stem Cell Collection
Unlike fludarabine, bendamustine does not appear to induce
autoimmune hemolytic anemia or thrombocytopenia and might
even reverse these complications. In the randomized trial of bendamustine versus chlorambucil, which did not exclude patients who
were direct antiglobulin test positive,1 1% of patients in both arms
developed autoimmune hemolytic anemia. Therefore, there is no
contraindication to using the drug in patients who have a positive
direct antiglobulin test or with ongoing hemolysis.
The effect on stem cell collection has not been carefully determined; however, successful autologous stem cell transplantation has
been performed following treatment with bendamustine.35
Other Adverse Effects
Effects on fertility have not been carefully studied. The fact
that bendamustine is an alkylating agent raises concerns about
the potential for secondary myelodysplastic syndrome or acute
myeloid leukemia. Although rarely reported, longer follow-up is
needed to determine whether this problem is a potential adverse
effect of bendamustine.
Drug Interactions
There are no known drug-drug interactions.
Conclusion
Bendamustine has clearly demonstrated activity in a variety of lymphoid malignancies and is generally well tolerated.
Unfortunately, the development of this agent has not been systematic. Future clinical trials need to focus on identifying the optimal
dose and schedule of this agent alone and in combination with
other cytotoxic and biologic agents. In the meantime, these recommendations will facilitate the safe and effective use of this drug in
the treatment of patients with lymphoid malignancies.
Disclosures
Dose Modification
Patients who experience serious adverse effects, such as grade 3
or worse myelosuppression with febrile neutropenia, may be considered for myeloid growth factor support in subsequent cycles. If
this approach is not successful, a dose delay or reduction is indicated
(Table 4). Similar dose reductions are recommended for patients
who experience grade 3-4 or prolonged thrombocytopenia. Doses
below 50 mg/m2 are considered to be subtherapeutic and treatment
delay is preferred.
Organ Dysfunction
The current recommendation is to use bendamustine with caution in patients with mild-to-moderate renal or hepatic impairment. Patient with more severe renal impairment have not been
systematically studied, and optimal dosing strategies are needed.
In a small cohort of patients with myeloma and end-stage renal
failure, a dosage of bendamustine of 120 mg/m2 on day 1 at 4-week
intervals was administered safely.33 Nevertheless, until more data
are available, it is recommended that the drug should not be used in
patients with a creatinine clearance < 40 mL/min or with an aspartate aminotransferase level or alanine aminotransferase level > 2.5
times or bilirubin > 3 times the upper limit of normal.34 Otherwise,
patients with more severe dysfunction have not been systematically
studied, and optimal dosing strategies are needed.
At the currently recommended doses, no other organ toxicity
has been reported; therefore, bendamustine can be safely given to
patients with a reduced cardiac ejection fraction.
Other Adverse Effects
Friedberg et al2 noted an infusion reaction syndrome in 7 of
74 patients characterized by fevers, hypotension, back and muscle
pain, chills, and rigors within 24 hours of administration of the
drug, up to the third cycle. Three patients also experienced a transient elevation in serum creatinine. Kahl et al noted this in 1% of
patients.3 The syndrome resolved with discontinuation of the drug
or with corticosteroids.
26
| Clinical Lymphoma, Myeloma & Leukemia
February 2010
Stefan Knop has served as a consultant or been on an advisory or research panel for Mundipharma Laboratories GmbH.
Martin Dreyling has received research funding from Mundipharma
Laboratories GmbH. Clemenes-Martin Wendtner has received
research funding from Bayer Pharmaceuticals Corporation,
GlaxoSmithKline, Fresenius Medical Care AG & Co. KGaA,
Mundipharma Laboratories GmbH, and Roche Pharmaceuticals;
and has served as a consultant or been on an advisory or research
panel for Celgene Corporation, Genentech, Inc., GlaxoSmithKline,
Mundipharma Laboratories GmbH, and Roche Pharmaceuticals.
Philippe Moreau has served on a Speaker’s Bureau for Mundipharma
Laboratories GmbH. Marco Montillo has served as a consultant or
been on an advisory or research panel for Genzyme Corporation,
GlaxoSmithKline, Mundipharma Laboratories GmbH, and Roche
Pharmaceuticals. Bruce D. Cheson has served as a consultant or
been on an advisory or research panel for Cephalon, Inc. Jonathan
W. Friedberg has received research funding from Cephalon, Inc.
and has served as a consultant or been on an advisory or research
panel for Mundipharma Laboratories GmbH. John Gribben has
served on a Speaker’s Bureau for Genzyme Corporation, Napp
Pharmaceuticals Limited, and Roche Pharmaceuticals.
The remaining authors report no relevant relationships.
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