Bendamustine s Emerging Role in the Management of Lymphoid Malignancies

Bendamustine s Emerging Role in the Management of Lymphoid Malignancies Mathias J. Rummel a and Stephanie A. Gregory b The potent alkylating agent bendamustine has demonstrated substantial efficacy in patients with non-hodgkin lymphomas (NHLs), including chronic lymphocytic leukemia (CLL), follicular lymphoma, and mantle cell lymphoma. Due to incomplete cross-reactivity between bendamustine and other chemotherapeutic agents, bendamustine has been extensively tested in the relapsed/refractory setting. Bendamustine is highly effective in rituximab-refractory NHL and in patients whose disease is refractory to chemotherapy, including other alkylating agents. It has also demonstrated considerable efficacy in previously untreated NHLs, both alone and in combination with rituximab or other chemotherapeutic agents. Studies suggest complete responses and durability of remission achieved with bendamustine are superior to those achieved with standard regimens. However, longer follow-up is needed to fully establish long-term response duration. Additionally, bendamustine is associated with hematologic toxicity and risk of infection, which must be carefully monitored and managed. This is particularly important in elderly patients with advanced disease. Increased understanding of the mechanisms of action of bendamustine and the efficacy of bendamustine in combination with rituximab in newly diagnosed or relapsed/refractory CLL and indolent lymphomas led to investigation of other combinations. Ongoing studies are examining bendamustine with bortezomib, lenalidomide, temsirolimus, ofatumumab, alemtuzumab, and other novel agents. Bendamustine is also undergoing clinical investigation in patients with relapsed/refractory diffuse large B-cell lymphomas, a patient population with limited therapeutic options currently. This review will summarize current clinical data regarding the efficacy and safety of bendamustine in patients with lymphoma and highlight ongoing clinical trials expanding the role of this alkylating agent in the treatment of hematologic malignancies. Semin Hematol 48:S24 S36. 2011 Elsevier Inc. All rights reserved. UNMET MEDICAL NEEDS IN LYMPHOID MALIGNANCIES a Universitätsklinikum, Giessen, Germany. b Rush University Medical Center/Rush University, Chicago, IL. Publication of this article was supported by Cephalon, Inc. Address correspondence to Stephanie A. Gregory, MD, Section of Hematology, Rush University Medical Center/Rush University, 1725 W Harrison St, Suite 834, Chicago, IL 60612. E-mail: Stephanie_A_Gregory@ rush.edu 0037-1963/$ - see front matter 2011 Elsevier Inc. All rights reserved. doi:10.1053/j.seminhematol.2011.03.004 Although tremendous progress has been made in the past 30 years, the majority of patients with indolent B-cell malignancies will eventually relapse and die of their disease. Therefore, continued efforts to improve on existing therapies are needed to find more effective and less toxic regimens that can provide durable long-term remissions, prolong survival, and improve quality of life. A major obstacle to effective therapy in these patients is the risk of myelosuppression and life-threatening infection, particularly in elderly patients and those who have been extensively treated with myelotoxic agents. Given the incomplete cross-reactivity between bendamustine and other alkylating agents, bendamustine was initially tested in the relapsed/refractory setting, where it is clearly effective as a single agent. Preclinical studies have also shown that the combination of bendamustine plus rituximab has synergistic antitumor activity against various leukemia and lymphoma cell lines. 1,2 Rituximab sensitized CD20 B-cell lymphoma lines to chemotherapy-induced apoptosis in vitro, and this effect was observed with a variety of chemotherapy agents, including bendamustine. 1 Therefore, combinations with rituximab are actively being investigated. Clinical trials have shown that this combination is highly effective in patients with indolent lymphoma, including those who are rituximab-naïve, rituximabpretreated, or rituximab-refractory. The promising efficacy and safety profile of bendamustine in the relapsed/refractory setting has generated great interest in exploring the potential role of bendamustine as initial S24 Seminars in Hematology, Vol 48, No 2, Suppl 1, April 2011, pp S24 S36

Bendamustine for lymphoid malignancies S25 therapy. It has been approved in chronic lymphocytic leukemia (CLL) as first-line therapy, and studies are ongoing in the front-line setting for both follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), in elderly lymphoma patients who have relapsed after CHOP-R (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab), and in elderly patients with CLL. In mantle cell lymphoma (MCL), better combination regimens are needed, and the role of bendamustine as a component of combination therapy is being evaluated. CHRONIC LYMPHOCYTIC LEUKEMIA The role of bendamustine in the treatment of CLL continues to evolve. Early studies of single-agent bendamustine were conducted in patients with relapsed/ refractory disease. In an early phase II study that enrolled 23 patients (10 relapsed/refractory and 13 previously untreated), bendamustine was administered at a dose of 50 mg/m 2 or 60 mg/m 2 (depending on age) for 5 consecutive days every 28-day cycle. 3 The overall response rate was 75%, and 36% of patients had a complete response (CR), but this regimen was quite myelotoxic. Grade 3/4 leukopenia was reported in 51% of patients and three patients (13%) died of sepsis. Subsequently, several single-agent studies investigated doses of 70 mg/m 2 or 100 mg/m 2, day 1 and 2 every 28-day cycle, and demonstrated overall response rates ranging from 56% to 67% with CR in 13% to 29% of treated patients (Table 1). 3 13 In a phase I/II dosefinding study conducted by the German CLL Study Group (GCLLSG) in a heavily pretreated population (N 16), which included eight patients previously treated with fludarabine, the dose had to be de-escalated because of a high rate of infection, and 70 mg/m 2 was determined to be the maximum tolerated dose (MTD). 6 Nevertheless, nine of 16 patients (56%) achieved a response, including two CRs (13%), and the median duration of response was 43 months. A similar phase I/II dose-finding study found that fludarabinenaïve patients (N 15) could tolerate 100 mg/m 2, and this regimen yielded a 60% response rate with 27% CR. 7 Among six patients treated with 100 mg/m 2, four had a CR and two had a partial response (PR), and the median duration of CR was 22 months (range, 18 27 months). These studies set the stage for a randomized phase II trial directly comparing bendamustine (100 mg/m 2, days 1 and 2 every 28 days) with fludarabine (25 mg/m 2, days 1 5 every 28 days) in 96 fludarabine-naïve patients who had relapsed after one prior therapy (primarily chlorambucil). The overall response rate was 78% (29% CR) in the bendamustine arm compared with 65% (10% CR) in the fludarabine arm. Median progression-free survival (PFS) was also slightly better in the bendamustine arm (83 weeks v 64 weeks). Although bendamustine was associated with a higher incidence of hematologic toxicity, the rate of grade 3/4 infection was the same in both arms (15%). These results suggest that bendamustine has activity similar to that of fludarabine with a similar safety profile in patients who have relapsed after initial treatment with chlorambucil. Therefore, bendamustine is a reasonable alternative to fludarabine as second-line therapy for CLL. Bendamustine has also demonstrated good singleagent activity in previously untreated CLL. Knauf et al 9 reported a randomized, open-label, phase III trial comparing bendamustine (100 mg/m 2, days 1 and 2 every 28 days) with chlorambucil (0.8 mg/kg, days 1 and 15 every 28 days) in 319 previously untreated patients with advanced (Binet stage B or C) CLL. Patients 75 years of age received a maximum of six cycles of chemotherapy. Randomized patients (162 to bendamustine and 157 to chlorambucil) had a median age of 64 years; 70% had Binet stage B disease, and the remainder had Binet stage C disease. Treatment was well tolerated, and dose-intensity was similar in both treatment arms. The overall response rate was 68% (31% CR) in the bendamustine arm compared with 31% (2% CR) in the chlorambucil arm (P.0001) by blinded independent review. Bendamustine also significantly improved PFS compared to chlorambucil (Figure 1). 9 At a median follow-up of 54 months, median PFS was 21.2 months in the bendamustine arm compared to 8.8 months in the chlorambucil arm (P.0001). 14 This updated analysis also showed that bendamustine significantly prolonged median time to next treatment. Although bendamustine resulted in more grade 3/4 hematologic toxicity, particularly lymphopenia, the rate of grade 3/4 infection was relatively low in both arms (8% with bendamustine v 3% with chlorambucil). These results, which were the basis for US Food and Drug Administration (FDA) approval, indicate that bendamustine is a good first-line treatment option for CLL and is reasonably well tolerated in this setting. The 68% overall response rate achieved with bendamustine is comparable to that achieved with fludarabine monotherapy in previously untreated patients, 15 18 and the 31% CR rate is higher than that typically observed with fludarabine monotherapy. 9,18,19 The high CR rate achieved with bendamustine is particularly important given the evidence that CRs achieved with fludarabinecontaining regimens are associated with prolonged PFS. 20 23 The low rate of serious infections in this study (8% in the bendamustine arm) also compares favorably with fludarabine monotherapy. 15 It is noteworthy that infections associated with bendamustine typically occur in the context of transient neutropenia, whereas fludarabine can result in prolonged T-cell depletion. 24 A critical question in CLL is how bendamustine plus rituximab compares with fludarabine plus rituximab or fludarabine/cyclophosphamide/rituximab (FCR). To date, the majority of studies of bendamustine plus rituximab have been in the relapsed/refrac-

Table 1. Reported Studies of Bendamustine in Chronic Lymphocytic Leukemia 3 13 Author Phase Dose, mg/m 2, Regimen N Single-agent studies Kath 3 2 Age 70: 60 Age 70: 50 d1 5, every 28d 10 13 Patient Population Treated Untreated % Patients Median ORR CR PFS or TTP Median OS 75 36 NA 13.6 mo Aivado 4 2 100 d1 2, every 28d 23 R/R 67 29 6 mo NA Bremer 5 2 60 d1 5, every 28d 15 R/R 93 7 NR 32 mo Bergmann 6 1/2 70 d1 2, every 28d 16 R/R 56 13 NA 43 mo Lissitchkov 7 1/2 100 d1 2, every 28d 15 R/R 60 27 NA NA Niederle 8 2 B: 100 d1 2, every 28d F: 25 d1 5, every 28d Knauf 9 3 B: 100 d1 2, every 28d C: 0.8 mg/kg d1, 15 every 28d Combination studies Koppler 10 1/2 B: 80 240 over 2 3 d, every 29d M: 8 10 d1 Fischer 11 2 B: 70 d1 2, every 28d R: 375 cycle 1 then 500 Weide 12 1/2 B: 80 d1 2, every 28d M: 10 d1 R: 375 wk 2 5 Fischer 13 2 B: 70 d1 2, every 28d R: 375 cycle 1 then 500 96 R/R 78 65 319 Untreated 68 39 29 10 30 2 83 wk 64 wk 21 mo 9mo 22 R/R 86 27 10 mo 39 mo 81 R/R 77.4 14.5 NA NA 21 R/R 95 23 17 mo NA 117 Previously untreated NR NA 91 33 NR NA B bendamustine; C chlorambucil; CR complete response; d day; ; F fludarabine; M mitoxantrone; NA not available; NR not reached; ORR overall response; OS overall survival; PFS progression-free survival; R rituximab; R/R relapsed/refractory; TTP time to progression. S26 M.J. Rummel and S.A. Gregory

Bendamustine for lymphoid malignancies S27 Progression-Free Survival No. left: BEN CLB 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 162 157 116 59 94 29 Time Since Treatment, months 73 6 54 2 tory setting, and no comparative trials have been reported. Bendamustine has been combined with mitoxantrone and/or rituximab in three single-arm studies (Table 1). 10 12 The first of these studies combined escalating doses of bendamustine (80 mg/m 2 to 240 mg/m 2 divided over 2 3 days every 29-day cycle) with mitoxantrone (8 mg/m 2 to 10 mg/m 2, day 1). 10 Among 22 patients enrolled, the majority received either 150 mg/m 2 (n 8) or 240 mg/m 2 (n 6) bendamustine, and the recommended phase II dose was 150 mg/m 2. The overall response rate was 86% (27% CR). However, at 150 mg/m 2, seven of eight patients had grade 3/4 neutropenia, and two patients developed infections, suggesting that this dose may be too high in the relapsed/refractory setting. A phase I/II pilot study has also tested the triple combination of bendamustine (80 mg/m 2, days 1 and 2) with mitoxantrone (10 mg/m 2, day 1) and rituximab (375 mg/m 2 weeks 2 5) in 54 patients with B-cell malignancies. 12 The first cycle was 36 days, but all subsequent cycles were the standard 28 days. Treatment was continued only until patients had an objective response, and the majority achieved a response after two cycles. Among 21 patients with CLL, 95% had an objective response, including a CR in 23% of patients, and hematologic toxicity was manageable. Subsequently, the GCLLSG conducted a multicenter phase II study to test the combination of bendamustine (70 mg/m 2, days 1 and 2) with rituximab (375 mg/m 2 in the first cycle and 500 mg/m 2 in subsequent cycles on day 0) in 81 patients with relapsed/refractory CLL. 11 This dosing regimen was fairly well tolerated with only 12% of patients developing grade 3 leukopenia/neutropenia. However, three patients (4%) died of infec- 42 1 BEN (N = 162; median, 21.6) CLB (N = 157; median, 8.3) Censored observations 6 12 18 24 30 36 42 48 54 60 Figure 1. Kaplan-Meier estimate of progression-free survival based on independent radiologic assessment (intentto-treat population). BEN bendamustine; CLB chlorambucil. Reprinted with permission. 2009 American Society of Clinical Oncology. All rights reserved. Knauf WU, et al. J Clin Oncol 2009;27:4378 84. 9 23 1 10 0 7 0 3 0 0 0 tious complications secondary to neutropenia. Among 62 evaluable patients, the overall response rate was 77% (14.5% CR), including seven of nine patients (78%) with fludarabine-refractory disease. The majority of patients in the different genetic subgroups responded, including high-risk patients with 17p deletion (44% overall response rate). This study established the recommended dosing for this combination in relapsed/ refractory CLL and showed that this combination is effective (with good activity in high-risk CLL) and is reasonably well tolerated. However, further follow-up is needed to establish response duration and long-term safety, and the potential for infectious complications needs to be managed carefully. This study has now been followed with a similar GCLLSG protocol in previously untreated CLL. A total of 117 previously untreated patients with predominantly stage Binet B or C disease were treated with bendamustine (90 mg/m 2, days 1 and 2 every 28-day cycle) plus rituximab (at the same dose as the previous trial) for up to six cycles. 13 Based on 110 evaluable patients, the overall response rate was 91% (33% CR), and at 18 months, 76% of patients remained in remission. These results compare favorably with the FCR regimen in previously untreated CLL. 19 As in the previous study, three of seven high-risk patients with 17p deletion (43%) had a PR. Hematologic toxicity was manageable with grade 3/4 leukopenia in 15% of cycles and grade 3/4 neutropenia in 6.5% of cycles. Grade 3 infections occurred in only 5% of cycles; however, two patients died of infectious complications. Studies are ongoing to further explore the potential benefit of bendamustine in CLL (Table 2). Most notably, the GCLLSG is currently conducting a large, randomized, multicenter, phase III trial comparing bendamustine 90 mg/m 2 (on days 1 and 2) plus rituximab 375 mg/m 2 administered intravenously (on day 0 of course 1 and on day 1 of courses 2 6) (BR) with FCR in 550 previously untreated CLL patients (NCT00769522). The primary endpoint is PFS at 24 months, and this trial will also assess duration of response, overall survival, minimal residual disease, benefit in biologic subgroups, safety, and quality of life as secondary endpoints. A similar large, randomized, multicenter trial is comparing bendamustine plus rituximab with chlorambucil plus rituximab in 600 previously untreated patients with CLL, and objective response rate is the primary endpoint (NCT01056510). These are just two of many ongoing studies investigating a variety of combinations with bendamustine in CLL (Table 2). These include combinations with rituximab, alemtuzumab, ofatumumab, and several novel agents. Of particular interest is a phase I/II dose-finding study being conducted at The University of Texas, M.D. Anderson Cancer Center that will investigate the combination of fludarabine, bendamustine, and rituximab (FBR) in patients with previously treated CLL. Preclinical evidence suggests that the combination of benda-

S28 M.J. Rummel and S.A. Gregory Table 2. Ongoing Studies of Bendamustine in Chronic Lymphocytic Leukemia Phase NCT ID Condition Treatment Arms 1 NCT00864942 CLL, NHL Bendamustine (B) lenalidomide (L) rituximab (R) for CLL; BLR for NHL; BL for NHL, BL for CLL 1 NCT01088048 Relapsed/refractory Bendamustine rituximab CAL-101 indolent NHL or v rituximab CAL-101 v CLL bendamustine CAL-101 v ofatumumab CAL-101 Estimated Enrollment 96 1 NCT00947388 Refractory CLL Bendamustine alemtuzumab 24 1 NCT00868413 Relapsed/refractory ABT-263 36 CLL fludarabine/cyclophosphamide/rituximab v ABT-263 bendamustine/rituximab 1/2 NCT01096992 CLL Bendamustine fludarabine 82 rituximab (FBR) 1/2 NCT00951457 Pretreated CLL Bendamustine alemtuzumab 25 1/2 NCT01188681 Relapsed CLL Bendamustine TRU-016 (v 112 bendamustine in phase II) 1/2 NCT00426855* Relapsed/refractory Bendamustine bortezomib 12 indolent NHL or B-CLL 2 NCT00758693 Previously untreated CLL ( 65 yrs of age) 96 Bendamustine rituximab 42 2 NCT01010568 Previously treated Bendamustine ofatumumab 40 CLL 2 NCT01125787 Previously Bendamustine ofatumumab 39 untreated CLL 2 NCT01131247 Relapsed/refractory Bendamustine ofatumumab 37 CLL 2 NCT00974233 Relapsed/refractory Bendamustine/rituximab induction CT 34 CLL and SLL lenalidomide maintenance 2 NCT00274989 Relapsed CLL Bendamustine rituximab 61 2 NCT00939328 Refractory B-cell Bendamustine rituximab 49 CLL 2 NCT00274963 Relapsed/refractory Bendamustine mitoxantrone 60 CLL 3 NCT00769522 Previously untreated CLL Fludarabine cyclophosphamide rituximab v bendamustine 550 rituximab 4 NCT01056510 CLL Rituximab bendamustine v rituximab chlorambucil CLL chronic lymphocytic leukemia; CT chemotherapy; NHL non-hodgkin lymphoma. *Study has been completed. Study was terminated. 660 mustine with a purine analogue may have additive or synergistic activity. 25 The starting dose of bendamustine will be 20 mg/m 2 on days 1, 2, and 3 of each 28-day cycle, which will be administered after fludarabine (20 mg/m 2 ), and rituximab will be given at standard doses. An important clinical question is whether bendamustine plus rituximab is effective and well tolerated in elderly patients with CLL who are at higher risk for infectious complications. A recent study of reduceddose FCR in previously untreated elderly patients with CLL showed that this regimen was effective and well tolerated. 26 Grade 3/4 neutropenia occurred in only

Bendamustine for lymphoid malignancies S29 13% of cycles, and there were no septic deaths. Unfortunately, the available data with bendamustine in this setting are limited, and the only phase II study directly addressing this question in previously untreated patients 65 years of age (NCT00758693) was terminated due to poor accrual. FOLLICULAR AND MANTLE CELL LYMPHOMA Bendamustine is highly effective in relapsed/refractory indolent non-hodgkin lymphoma (NHL) and MCL, including patients who are refractory to rituximab and those previously treated with other alkylating agents (Table 3). 27 36 Therefore, bendamustine is now widely used in this setting and provides another effective treatment option for patients who progress after CHOP-R. Previously, the only treatment options available to these patients were radioimmunotherapy or a clinical trial. In this setting, the standard single-agent bendamustine dosing regimen is 120 mg/m 2 days 1 and 2 every 21 days. An early phase II study of this regimen in 58 patients with relapsed/refractory indolent lymphomas demonstrated a 73% response rate (11% CR) among 52 evaluable patients and a median time to progression of 16 months. 27 More recently, Friedberg et al 28 reported a phase II study of the same dosing regimen in 76 rituximab-refractory patients with predominantly stage III/IV indolent (80%) or transformed (20%) NHL. Patients who had progressed within 6 months of their first dose of rituximab (either primary or maintenance therapy) or chemotherapy plus rituximab were eligible. In addition, 32% of patients were refractory to their last chemotherapy regimen. Enrolled patients had a Follicular Lymphoma International Prognostic Index (FLIPI) classification of low-risk (26%), intermediate-risk (30%), high-risk (33%), or unknown (11%). Among 74 evaluable patients, the overall response rate was 77% (15% CR and 19% unconfirmed CR [CRu]). The response rate was also quite high in the subset of patients who were refractory to chemotherapy (61% overall and 13% CR). Median PFS was 8.3 months among patients with an indolent histology. This phase II study in patients with rituximab-refractory FL set the stage for the pivotal phase III trial of single-agent bendamustine in this patient population. This study enrolled 100 patients with indolent NHL, including FL (62%), CLL or small lymphocytic lymphoma (SLL) (26%), and marginal-zone NHL (21%), and the majority (76%) had stage III/IV disease. 29 Their FLIPI scores were low-risk (29%), intermediate-risk (42%), and high-risk (29%). These patients were heavily pretreated with a median of three prior regimens, including two prior rituximab-containing regimens, and 36% were refractory to their last chemotherapy regimen. The overall response rate as assessed by the independent review committee was 75% (17% CR or CRu) and did not vary appreciably based on FLIPI category or histology. Among patients who were refractory to their last chemotherapy, 61% had a response to bendamustine. Median PFS was 9 months for the overall study population (11.5 months for chemotherapy-sensitive patients and 7.5 months for chemotherapy-refractory patients). Grade 3/4 neutropenia occurred in 61% of patients but was manageable with growth factor support in 38% of patients. Thrombocytopenia was the most common reason for premature study discontinuation. Grade 3 infections occurred in 21 patients, but there were no deaths due to infection. Taken together, these studies demonstrated that bendamustine is highly effective in rituximab-refractory NHL and in patients whose disease is refractory to chemotherapy, including other alkylating agents. This is important because resistance to both rituximab and alkylating agents often develops concurrently in patients treated with chemoimmunotherapy. The activity of bendamustine in this setting is also comparable to that of radioimmunotherapy with either 131 I-tositumomab or 90 Y-ibritomomab. 37,38 Combinations of bendamustine with either fludarabine or rituximab have also been reported in patients with relapsed/refractory indolent lymphoma (Table 3). In a multicenter phase I/II dose-escalation study conducted by the East German Society of Hematology Oncology, bendamustine (30 mg/m 2 to 50 mg/m 2 days 1 3, every 28 days) was combined with fludarabine (30 mg/m 2 ) in 29 patients. 30 All patients had stage III/IV disease and had received prior chemotherapy with or without addition of rituximab or radioimmunotherapy. Among 19 evaluable patients, the overall response rate was 77% (45% CR). As expected, the major dose-limiting toxicity was hematologic, and the MTD for this combination was determined to be 30 mg/m 2 of both drugs. However, given the observed additive hematologic toxicity, this regimen may not be feasible. Equally impressive results have been achieved with combinations of bendamustine plus rituximab, and this combination is reasonably well tolerated. Two phase II studies have combined bendamustine (90 mg/m 2 days 2 3 every 28 days) with rituximab (375 mg/m 2 day 1) and both reported similar results. A study conducted by the Study Group indolent Lymphomas (StiL) enrolled 63 rituximab-naïve patients with FL (n 24), MCL (n 16), lymphoplasmacytic lymphoma (n 17), or marginal-zone lymphoma (n 6). 31 The overall response rate was 90% (60% CR) for the entire patient population, and among the 16 patients with MCL the response rate was 75% (50% CR). All 17 patients with lymphoplasmacytic lymphoma achieved a response. Median PFS for all patients was 24 months. Grade 3/4 leukopenia occurred in only 16% of cycles. These data were subsequently confirmed and extended in a multicenter trial conducted in the United States in 66 patients with FL (n 40), CLL/SLL (n 10), lymphop-

Table 3. Reported Studies of Bendamustine in Indolent NHL and MCL 27 36 Author Phase Dose, mg/m 2, Regimen N Patient Population % patients Median ORR CR PFS or TTP Single-agent studies Heider 27 2 120 d1 2, every 21d 58 R/R (I) 73 11 16 mo 36 mo Friedberg 28 2 120 d1 2, every 21d 76 Rituximab-refractory (I) 77 34 8 mo NA Kahl 29 3 120 d1 2, every 21d 100 Rituximab-refractory (I) 75 17 9 mo NA Combination studies Koenigsmann 30 1/2 B: 30 50 d1 3 29 R/R (I) 77 45 NA NA F: 30 d1 3, every 28d Rummel 31 2 B: 90 d1 2 63 R/R (I) 90 60 24 mo NR R: 375 d1, every 28d (16 MCL) 75 50 Robinson 32 2 B: 90 d1 2 66 Relapsed 92 55 23 mo NA R: 375 d1, every 28d Weide 33 2 B: 90 d1 2 M: 10 d1 R: 375 d8, every 28d Randomized studies Rummel 34 3 B: 90 d1 2 R: 375 d1, every 28d F: 25 d1 3 R: 375 d1, every 28d Rummel 35 3 B: 90 d1 2 R: 375 d1, every 28d Herold 36 BOP vs COP 3 B: 60 d1 5 V:2d1 P: 100 d1 5, every 21d (12 MCL) 57 R/R (I) (18 MCL) 219 Relapsed (indolent) ( 20% MCL) Median OS 92 42 89 35 19 mo 33 mo 83.5 38.5 30 mo NR 52.5 16.2 11 mo NR 549 Previously untreated (indolent) ( 18% MCL) 94 40 55 mo NR CHOP-R every 21d 94 31 31 mo NR 164 Previously untreated (indolent) 66 22 84 mo 76 mo (43 MCL) C: 400 d1 5 V:2d1 P: 100 d1 5, every 21d 76 20 28 54 (A) aggressive; C cyclophosphamide; B bendamustine; CR complete response; d day; F fludarabine; (I) indolent; M mitoxantrone; NA not available; NR not reached; ORR overall response; OS overall survival; P prednisone; PFS progression-free survival; R rituximab; R/R relapsed/refractory; TTP time to progression; V vincristine. S30 M.J. Rummel and S.A. Gregory

Bendamustine for lymphoid malignancies S31 Figure 2. Kaplan-Meier estimate of progression-free survival among patients with relapsed/refractory indolent lymphoma treated with bendamustine plus rituximab. Reprinted with permission. 2008 American Society of Clinical Oncology. All rights reserved. Robinson KS, et al. J Clin Oncol 2008;26:4473 9. 32 lasmacytic lymphoma (n 2), marginal zone NHL (n 2), or MCL (n 12) who had relapsed after chemotherapy with or without rituximab but were not rituximab-refractory. 32 Patients were evenly distributed between FLIPI risk groups. This study demonstrated a 92% overall response rate (55% CR) in the entire patient population, and the response rate did not vary appreciably by histology. Notably, patients who had been previously treated with rituximab had an 86% overall response rate (35% CR). Median PFS in the entire study population was 23 months (Figure 2), 32 which was similar to that observed in the previous study. Finally, Weide et al 33 combined bendamustine (90 mg/m 2 days 1 2, every 28 days) with mitoxantrone (10 mg/m 2 day 1) and rituximab (375 mg/m 2 day 8) in patients with relapsed/refractory indolent lymphoma. This regimen was also highly active, but the authors concluded that the addition of mitoxantrone only served to increase hematologic toxicity to unacceptable levels without improving efficacy. Based on these encouraging results in the relapsed/ refractory setting, the StiL initiated two large, randomized, phase III trials of bendamustine (90 mg/m 2 days 1 2 every 28 days) plus rituximab (375 mg/m 2 day 1). The first of these trials compared B-R with fludarabine (25 mg/m 2 days 1 3) plus rituximab (F-R) in patients with relapsed follicular, indolent, or mantle cell lymphoma. 34 A total of 219 patients were randomized, and 208 patients were evaluable. The majority of patients had stage IV disease and all patients had received a median of one prior therapy (range, 1 7). Treatment arms were well balanced for all prognostic variables, including histologic subtype ( 46% FL and 20% MCL) and FLIPI score. At a median follow-up of 33 months, B-R significantly improved PFS by 50% compared with F-R (median, 30 v 11 months; hazard ratio 0.51; P.0001), and response rates were also significantly higher with B-R. The second of these trials compared B-R with standard CHOP-R (21-day cycles) in previously untreated patients with indolent NHL and MCL. The first interim analysis was reported in 2007, 39 and the final results of this trial, at a median follow-up of 32 months, were presented at the 2009 American Society of Hematology Annual Meeting and Exposition. 35 This trial enrolled 549 patients with predominantly stage IV disease, and the treatment groups were well balanced for all baseline characteristics. Approximately 55% of patients had FL, approximately 20% had MCL, and the remaining 25% had other indolent lymphomas. Median age was 64 years (range, 31 83 years). Although the overall response rate was similar in the B-R and CHOP-R arms (93.8% and 93.5%, respectively), the CR rate was significantly higher in the B-R arm (40.1% compared with 30.8% for CHOP-R; P.03), and the median PFS was significantly longer in the B-R arm (54.8 months v 34.8 months for CHOP-R; P.0002). No difference in survival has been observed thus far, but the overall survival analysis is not yet mature. Further follow-up of this ongoing study will be required to address whether B-R improves survival compared with CHOP-R. Nevertheless, bendamustine plus rituximab yielded more durable responses and improved PFS compared with CHOP-R in previously untreated patients with indolent lymphomas. Moreover, bendamustine plus rituximab was better tolerated. In particular, CHOP-R was associated with a significantly higher incidence of grade 3/4 neutropenia and leukopenia and more infectious complications compared with bendamustine plus rituximab. Based on these results, bendamustine plus rituximab has the potential to become a new standard of care in newly diagnosed indolent NHL and MCL. A number of additional ongoing phase III studies are investigating the combination of bendamustine plus rituximab or ofatumumab in various settings, including another randomized trial comparing bendamustine-r with either CHOP-R or CVP-R (Table 4). Given the recent evidence that maintenance rituximab following response to standard CHOP-R significantly improves PFS in FL patients with high tumor burden, 40 maintenance rituximab is being studied following bendamustine-r (NCT00877214). In this phase II/III study with a planned enrollment of 874, all patients will be treated initially with bendamustine plus rituximab, and those who achieve a CR or PR will be randomized to rituximab maintenance (every 2 months) or observation. Patients with FL will receive maintenance therapy for up to 4 years, and all other histologies (mantle cell, marginal zone, and immunocytomas) will receive maintenance therapy for up to 2 years. Other combinations also appear promising, such as the regimen reported by Herold et al. 36 This randomized phase III trial in 164 patients with previously untreated indolent lymphomas, including 43 patients with MCL, compared BOP

Table 4. Ongoing Studies of Bendamustine in Indolent Non-Hodgkin Lymphoma and Mantle Cell Lymphoma Phase NCT ID Condition Treatment Arms Estimated Enrollment 1 NCT00864942 CLL, NHL Bendamustine (B) lenalidomide (L) rituximab (R) for CLL; 96 BLR for NHL; BL for NHL, BL for CLL 1 NCT01088048 Relapsed/refractory indolent NHL or CLL Bendamustine rituximab CAL-101 v rituximab CAL- 96 101 v bendamustine CAL-101 v ofatumumab CAL-101 1/2 NCT01170052 Relapsed/refractory MCL Bendamustine temsirolimus 20 1/2 NCT01078142 Relapsed FL or MCL Bendamustine temsirolimus rituximab 72 1/2 NCT00963534 MCL (adults 65 yrs of age) first line Bendamustine lenalidomide rituximab 60 1/2 NCT00426855* Relapsed/refractory indolent NHL or Bendamustine bortezomib 12 B-CLL 2 NCT00069758* Rituximab-refractory NHL Bendamustine 72 2 NCT00547534* Relapsed/refractory, indolent or MCL Bendamustine bortezomib rituximab 30 2 NCT00076349* Relapsed indolent or mantle cell NHL Bendamustine rituximab 66 2 NCT00901927 Untreated high-risk FL Bendamustine mitoxantrone rituximab (BMR) 37 2 NCT00992134 MCL Bendamustine cytarabine rituximab (R-BAC) 48 2 NCT01029730 Previously untreated low-grade Bendamustine; bortezomib; rituximab 55 lymphoma 2 NCT00636792* Relapsed or refractory FL Bendamustine bortezomib rituximab 75 2 NCT01108341 Previously untreated indolent B-cell NHL Bendamustine ofatumumab 60 2 NCT01133158 Relapsed or refractory FL Bendamustine mitoxantrone dexamethasone rituximab 60 2 NCT01127841 Relapsed/refractory FL after first-line Bendamustine rituximab 60 rituximab 2 NCT00612183* Indolent B-cell NHL or MCL Bendamustine 56 2/3 NCT00877214 Advanced follicular, indolent, and Bendamustine rituximab induction followed by 874 mantle cell lymphomas maintenance rituximab v observation 3 NCT01077518 Rituximab-refractory indolent B-cell NHL Bendamustine ofatumumab v bendamustine 388 3 NCT00139841* Indolent NHL refractory to rituximab Bendamustine 103 3 NCT01059630 Rituximab-refractory indolent NHL Bendamustine RO5072759 (GA101) v bendamustine 360 3 NCT00991211* Low malignant NHL and MCL (first line) Bendamustine rituximab v CHOP rituximab 549 3 NCT00877006 Advanced indolent NHL or MCL Bendamustine rituximab v R-CVP or R-CHOP 296 CHOP cyclophosphamide/doxorubicin/vincristine/prednisone; CLL chronic lymphocytic leukemia; CT chemotherapy; FL follicular lymphoma; MCL mantle cell lymphoma; NHL non-hodgkin lymphoma. *Study has been completed. S32 M.J. Rummel and S.A. Gregory

Bendamustine for lymphoid malignancies S33 Table 5. Ongoing Studies of Bendamustine in Diffuse Large B-Cell Lymphoma Phase NCT ID Condition Treatment Arms Estimated Enrolment 1 NCT00794638* Aggressive B-cell NHL Bendamustine rituximab 12 1/2 NCT00987493 Relapsed/refractory aggressive Bendamustine rituximab 71 B-cell lymphoma lenalidomide 2 NCT00831597 Relapsed/refractory DLBCL Bendamustine rituximab 54 2 NCT01118845 Relapsed/refractory DLBCL Bendamustine rituximab 60 2 NCT00385125 Relapsed or primary refractory aggressive B-cell NHL and anthracycline CT pretreatment Bendamustine rituximab 30 DLBCL diffuse large B-cell lymphoma; NHL non-hodgkin lymphoma. *Study has been completed. with the standard COP regimen (Table 3). In the BOP regimen, bendamustine (60 mg/m 2 days 1 5, every 21-day cycle) replaced cyclophosphamide. The standard COP regimen consisted of cyclosphophamide (400 mg/m 2 days 1 5) plus vincristine (2 mg/m 2 day 1) and prednisone (100 mg/m 2 days 1 5). Both regimens yielded similar response rates, but BOP significantly improved median PFS (84 months v 28 months; P.007) compared to COP. Again, this suggests that the durability of the remission achieved with bendamustine is superior to that achieved with standard cyclophosphamide-based regimens. Bendamustine is also being combined with bortezomib, lenalidomide, temsirolimus, ofatumumab, and several novel agents in a large number of ongoing clinical studies (Table 4). Combinations with bortezomib are particularly attractive for the treatment of MCL and other indolent lymphomas. Bortezomib has demonstrated excellent single-agent activity in patients with relapsed/refractory MCL, a patient population that presents a difficult treatment challenge. Results of the phase II PINNACLE study in 155 patients demonstrated a response rate of 33% (8% CR or CRu), 41 and longer follow-up demonstrated a median PFS of nearly 7 months and median overall survival of 24 months. 42 These data were the basis for FDA approval of bortezomib in relapsed/refractory MCL and provide a solid rationale for combining bendamustine with bortezomib for the treatment of indolent lymphomas. The majority of ongoing studies are looking at a triple combination of bendamustine, bortezomib, and rituximab in the relapsed/refractory setting. Lenalidomide and temsirolimus have also demonstrated good single-agent activity in relapsed/refractory MCL, 43,44 suggesting that these agents also may provide additive benefit in combination with bendamustine. Similar to CLL, an important clinical issue in the treatment of NHL and MCL is how best to manage advanced disease in elderly patients. A multicenter, phase II study of bendamustine plus rituximab in patients older than 75 years of age has been reported. 45 Eligible patients could receive up to four cycles of bendamustine (90 mg/m 2 days 1 and 2 every 28 days) and six cycles of rituximab (375 mg/m 2 day 1). Among 41 patients enrolled, median age was 79 years, and 26 patients were evaluable for response. The overall response rate was 88% (35% CR), and hematologic toxicity was manageable. This study suggests that this regimen can be used in elderly patients without excessive dose-limiting toxicity and without compromising efficacy. A phase I/II study is currently investigating a combination of bendamustine plus lenalidomide and rituximab in elderly patients ( 65 years of age) with MCL (NCT00963534). Additional studies are needed to better define the role of bendamustine in elderly patients with indolent lymphomas. DIFFUSE LARGE B-CELL LYMPHOMA Standard first-line therapy for DLBCL is typically CHOP-R or a similar regimen. Therefore, based on the demonstrated benefit of bendamustine plus rituximab compared with CHOP-R in patients with indolent lymphomas, there is great interest in establishing the benefit of this regimen in DLBCL. Currently, there are several ongoing studies of bendamustine plus rituximab, primarily in the relapsed/refractory setting (Table 5). These patients have limited treatment options after progression. To date, preliminary data have been reported for one ongoing phase II study in a planned 54 patients for whom at least one prior therapy failed. Based on data from 26 evaluable patients treated with bendamustine (120 mg/m 2 days 1 and 2 every 28 days) plus rituximab (375 mg/m 2 day 1), the overall response rate was 58% (19% CR). 46 This regimen was well tolerated; grade 3 or 4 neutropenia occurred in 12 of 34 patients (35%) evaluable for safety. Therefore, bendamustine could play an important role

S34 M.J. Rummel and S.A. Gregory in the treatment of relapsed/refractory DLBCL, in patients who are not eligible for stem cell transplantation, and in elderly patients. There is a great need for effective and well tolerated salvage therapy for DLBCL. FUTURE DIRECTIONS FOR BENDAMUSTINE DEVELOPMENT A wide range of combination strategies are actively being investigated in CLL, NHL, and MCL (Tables 2 and 4). These include combinations of bendamustine with other chemotherapy agents, with targeted agents, and with monoclonal antibodies and other biologic agents. In some cases, these combination approaches are empiric, based on existing combination regimens that have demonstrated clinical activity, or simply aim to achieve additive benefit by combining two drugs with proven single-agent activity. In other cases these combination approaches are rationally designed based on evidence of potential interactions between agents that could lead to therapeutic synergy. For example, preclinical studies suggest that combining bendamustine with rituximab may have synergistic activity, and this combination has been shown to be highly effective in the clinic even in patients with rituximab-refractory disease. However, to better design rational combinations, it is important to clearly define the precise antitumor mechanisms that could lead to therapeutic synergy. On the basis of our current understanding of the mechanism of action of bendamustine, it has been suggested that combining bendamustine with purine analogues might inhibit DNA repair or that combining it with agents that inhibit the cell cycle could enhance mitotic catastrophe. These hypotheses still need to be proven in clinical practice but provide a framework to guide the design of new combination strategies. A better understanding of the precise mechanism of action of bendamustine will be critical to guide these efforts in the future. STATEMENT OF CONFLICT OF INTEREST M.J. 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