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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 | 25 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. References 1. Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 2009; 27:4378-84. 2. Friedberg JW, Cohen P, Chen L, et al. Bendamustine in patients with rituximab refractory and alkylator-refractory, indolent and transformed non-Hodgkin’s lymphoma: Results from a phase II multicenter single-agent study. J Clin Oncol 2008; 28:204-10. 3. Kahl BS, Bartlett NL, Leonard JP, et al. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a multicenter study. Cancer 2009; 116:106-14. 4. Cheson BD, Rummel MJ. Bendamustine: rebirth of an old drug. J Clin Oncol 2009; 27:1492-1501. 5. 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