June 2013, Vol 4 No 4
Novel Approaches in the Treatment of Hematologic Malignancies Utilizing Bendamustine
This is the fourth article in a 4-part series on bendamustine. While the previous articles discussed the efficacy and safety of bendamustine for patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) in the registration studies cited in the US product labeling, this article discusses ongoing clinical investigations of the agent in a wide range of therapeutic areas.
At the 54th Annual Meeting of the American Society of Hematology (ASH 2012), 29 abstracts were presented describing the use of bendamustine as a treatment for a number of lymphoid malignancies. Bendamustine, both alone and in combination with rituximab or other chemotherapeutic agents, has demonstrated substantial efficacy in a number of lymphoid malignancies, and ongoing studies are examining bendamustine with bortezomib, lenalidomide, ofatumumab, and other novel agents.1
Bendamustine Plus Rituximab
The results of a German multicenter phase 2 study to evaluate the efficacy and safety of bendamustine in combination with rituximab in patients with relapsed/refractory CLL have been published.2 The primary end point of this study was overall response rate (ORR). Secondary end points included toxicity, quality and duration of response, event-free survival (EFS), minimal residual disease levels, and ORR in biologically defined risk groups. Eighty-three patients with relapsed/refractory B-cell CLL were initially enrolled in the study between March 2006 and June 2007. Seventy-eight patients (male, n=51) with a median age of 66.5 years (range, 42-86 years) received at least 1 dose of treatment and established the intent-to-treat (ITT) population for analysis. Twenty-nine of these 78 patients (37%) were ?70 years of age. Five patients were excluded from the study due to missing informed consents (n=3) or diagnosis other than CLL (n=2). Patients had to be ?18 years to enroll in the study, and inclusion criteria consisted of at least 1 but not more than 3 previous treatments for CLL, WHO performance status of 0 to 2, life expectancy of at least 12 weeks, and adequate renal and liver function. The median number of prior treatments was 2, which included 2 protocol violators (4 previous treatments, n=1; 5 previous treatments, n=1). Twenty-two of the 78 ITT patients (28%) were refractory to fludarabine. Sixty-three patients (81%) had received prior fludarabine monotherapy and/or a fludarabine-containing regimen. Seven patients (9%) had received previous rituximab-containing therapies, and 5 patients (6%) were previously administered alemtuzumab- containing regimens. Patient response rates for the ITT population (n=78) are presented in Figure 1.
For the ITT population, median EFS (after a median follow-up of 24 months) was 14.7 months (95% CI, 14.1-20.1 months). The median overall survival (OS) was 33.9 months (95% CI, 25.5-42.1 months), and the median progression-free survival (PFS) was 15.2 months (95% CI, 12.5-17.9 months). Median EFS for the subsets of Binet stages A, B, and C patients was reached at 27.5, 20.5, and 13.8 months, respectively. Overall, of 46 responders, the median duration of response was 15.2 months (95% CI, 12.1-18.3 months).
Additional analyses were done for the subgroup of patients previously treated with fludarabine (n=72). In those patients who were fludarabine naive (n=12), the ORR was 100%, with a complete response (CR) achieved in 33%. In those patients who were fludarabine sensitive (n=38), the ORR was 61%, with 8% CR. Finally, in those patients who were fludarabine refractory (n=22), the ORR was 46% with no CRs reported. Five of the 7 patients (71%) who had received previous rituximab therapy achieved a partial response (PR). Six of 10 patients (60%) who had received prior therapy with an antibody-containing regimen were observed to have a PR.
Toxicities were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. In the ITT population (n=78), 46 patients (59%) had at least 1 reported adverse event (AE) grade ?3, most commonly myelosuppression, which occurred in 39 patients (50%); neutropenia in 18 patients (23%); thrombocytopenia in 22 patients (28%); and anemia in 13 patients (17%). The most common nonhematologic toxicity reported was grade 3 infection, which occurred in 10 patients (13%); no grade 4 infections were reported. Dose reductions of >10% of the study dose in either of the 2 drugs were applied in 29 patients (37%) mainly due to the onset of treatment-related neutropenia. Other dose modifications included 19 patients (24%) with a dose reduction of rituximab alone; 18 patients (23%) with a dose reduction of bendamustine alone; and 5 patients (6%) with a dose reduction of both rituximab and bendamustine. A total of 34 patients (44%) discontinued treatment early due to withdrawal of consent (n=9), toxicity (n=15), progressive disease (n=8), or other (n=2). After the median follow-up time of 24 months, 28 deaths had occurred, 21 of which were deemed unrelated to treatment with study drug. Three of 7 patient deaths (4%) were considered related to study drug therapy, including 1 patient with preexisting Richter’s transformation. All 3 deaths were the result of infections during the first 2 courses of therapy (septicemia [n=2]; pneumonia [n=1]).
Bendamustine Plus Rituximab and Fludarabine
Preliminary results were presented at ASH 2012 from a phase 1/2 dose escalation study using bendamustine concomitantly with fludarabine and rituximab for the treatment of 35 evaluable patients (median age 62 years; median 3 prior therapies [range, 1-6]) with active CLL.3 Patients received escalating doses of bendamustine at 20, 30, 40, or 50 mg/m2 IV on days 1, 2, and 3 with fludarabine 20 mg/m2 IV administered 2 hours prior to bendamustine on days 2 and 3. Rituximab 375 to 500 mg/m2 IV was given on day 3. Courses were repeated every 28 days. Among the 35 evaluable patients, 71% achieved an objective response, including 26% who achieved a CR or a CR with incomplete recovery of cytopenias. Myelosuppression was the most common treatment-related toxicity considering all courses given (n=106). Grade 3 neutropenia occurred in 26% of courses and grade 4 in 29%. Grade 3 thrombocytopenia occurred in 14% of courses and grade 4 in 9%. Grade 3 anemia occurred in 15% of courses and grade 4 in 2%. There were no treatment-related deaths.
Bendamustine Plus Alemtuzumab
The results of an Italian multicenter, single-arm, open- label, dose-escalation study of bendamustine combined with alemtuzumab in 43 evaluable patients with relapsed/refractory CLL were also presented at ASH 2012.4 Median age was 67 years; 64% were male; all had Binet stage B or C; median number of prior therapies was 2 (range, 1-4); 84% had previously received fludarabine-based treatment, and 70% had received monoclonal antibodies as monotherapy or in combination. Results showed a 70% ORR, including 26% CR and 44% PR. Median time to progression in responders was reached after a median follow-up of 15.5 months. Grade 3/4 neutropenia occurred in 33% of courses, thrombocytopenia and anemia in 7% and 4%, respectively. Febrile neutropenia developed in 15% of courses.
Bendamustine and bendamustine-containing regimens are currently being investigated in 21 clinical studies in patients with CLL (Table 1).5
Results of a prospective, multicenter, randomized, phase 3 study (German Study Group for Indolent Lymphomas [StiL]) that compared 6 cycles of bendamustine-rituximab (BR; n=261) with 6 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; n=253) as first-line treatment in 514 patients with indolent lymphomas, including a subset of patients (18% of enrolled patients) with mantle cell lymphoma (MCL), showed that patients treated with BR had significantly higher PFS as well as improved tolerability compared with those who received R-CHOP.6 At ASH 2012, Rummel and colleagues presented results of a subanalysis of the StiL study that examined the impact of response quality on PFS and OS.7 The ORR for patients receiving BR was 92.7%, and for R-CHOP, 91.3%. CRs were achieved by 39.8% of patients in the BR arm and by 30% of those in the R-CHOP arm (P=.021). The achievement of CR was associated with a significantly prolonged PFS and OS (Table 2). Patients in CR following first-line treatment had a significantly longer PFS and OS compared with those achieving a PR.
Bendamustine-Rituximab Versus R-CHOP/R-CVP
Also at ASH 2012, Flinn and colleagues presented results of an open-label, randomized phase 3 study (BRIGHT) of BR compared with R-CHOP or rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) in the first-line treatment of 447 patients with advanced indolent NHL or MCL.8 Of 447 randomized patients, 436 received treatment (BR, n=221; R-CHOP/R-CVP, n=215 [R-CHOP, n=99; R-CVP, n=116]) and were evaluable for safety. Dose delays were more common for BR-treated patients (35% vs 19%), and dose reductions were more common for patients receiving R-CHOP/R-CVP (29% vs 22%). The AE profile of BR was distinct from that of R-CHOP/R-CVP. The most common AEs reported in patients receiving BR and R-CHOP/R-CVP, respectively, were nausea (139 vs 102 patients), fatigue (113 vs 107), neutropenia (76 vs 85), constipation (65 vs 90), and alopecia (8 vs 74). Grade 3/4 hematologic toxicities for BR and R-CHOP/R-CVP were lymphopenia (137 vs 64), neutropenia (98 vs 151), leukopenia (84 vs 116), thrombocytopenia (16 vs 15), and anemia (6 vs 9), respectively. The most frequent investigator-reported nonhematologic grade 3/4 AEs for BR and R-CHOP/R-CVP were infusion-related reactions (13 vs 8 patients). Six deaths occurred among patients receiving BR (causes of death were pneumonia, respiratory failure, and sepsis; acute respiratory failure; cardiac arrest; pneumonia; chronic obstructive pulmonary disease; lung cancer), and 1 patient receiving R-CHOP/R-CVP died due to sepsis. A total of 419 patients (BR, n=213, 61% men, median 60 years of age; R-CHOP/R-CVP, n=206 [R-CHOP, n=97; R-CVP, n=109], 59% men, median 58 years of age) were evaluable for efficacy. In both groups, 64% of patients were classified as ECOG performance status 0, 83% of patients had indolent NHL, and 62% of patients had stage IV disease. Assessment by an independent review committee showed that in patients with advanced indolent NHL and MCL, high ORRs were attained in both treatment groups: 94% for BR and 84% for R-CHOP/R-CVP. BR produced a CR rate that was noninferior to that of R-CHOP/R-CVP (Figure 2). In the subgroup of patients with MCL, BR produces a significantly higher CR rate (51% vs 24%; P=.018).
At ASH 2012, Knauf and colleagues presented results (obtained from a large prospective registry that collects data on the treatment of patients with lymphoid B-cell neoplasms as administered in hematology outpatient centers in Germany) from 645 patients who received systemic first-line treatment for indolent NHL.9 Results showed that rituximab was part of the first-line treatment in 94% (n=606) of patients with indolent NHL, while bendamustine was part of the first-line treatment in 71% (n=455) of patients with indolent NHL. In 66% (n=428) of patients, the combination of bendamustine and rituximab (BR) was used. Only 2% (n=10) of patients received bendamustine as monotherapy. The use of BR increased from 62% in 2009 to 68% in 2011, while the rate of R-CHOP decreased from 19% in 2009 to 15% in 2011. BR was used more often than R-CHOP in elderly patients (mean age 67.3 years vs 60.9 years). In patients <66 years, BR was also the preferred treatment (BR 60% vs R-CHOP 23%). Among the 121 patients in the registry who received second-line treatment for indolent NHL, rituximab was part of the treatment in 84% (n=102) of patients, and bendamustine was part of the second-line treatment in 68% (n=82) of patients. In 60% (n=72) of patients, the combination of BR was used. Only 7% (n=9) of patients received bendamustine as monotherapy. R-CHOP was used as second-line therapy in 7% (n=9) of patients with indolent NHL. These results indicate that in Germany, R-CHOP can no longer be considered as “standard of care” for patients with indolent NHL. The authors also point out that these data also show that results from clinical trials are quickly implemented into daily practice.
Bendamustine, Rituximab, and Bortezomib
The combination of bendamustine, rituximab, and bortezomib (BRB) was assessed in a phase 2 study in 55 patients with previously untreated low-grade lymphoma (follicular center cell lymphoma, 69%; marginal zone lymphoma, 15%; small lymphocytic lymphoma [SLL], 9%; or lymphoplasmacytic lymphoma, 7%).10 After a median follow-up of 13 months (range, 6-26 months), 78% of patients had completed 6 cycles of BRB, and 56% had continued to receive maintenance rituximab. Five patients (9%) discontinued treatment due to toxicity (1 due to grade 2 neuropathy, 1 due to grade 2 atrial fibrillation, 1 due to grade 3 pancreatitis, 1 due to grade 3 diarrhea, and 1 due to grade 3 rash). The remaining 5 patients discontinued prematurely (1 patient died due to stroke, 1 discontinued due to wound complication, 1 was lost to follow-up, 2 discontinued due to request). Treatment-related grade 3/4 hematologic toxicities were neutropenia (25%), febrile neutropenia (2%), thrombocytopenia (5%), and anemia (4%). The most common grade 3 treatment-related nonhematologic AEs were neuropathy (9%), diarrhea (7%), fatigue (7%), constipation (5%), and rash (5%). At the time of the data cutoff, 3 patients (5.5%) had progressed or relapsed and 3 patients (5.5%) had died. An objective response was achieved in 89% of patients, including CR 47% and PR 42%.
Idelalisib (GS-1101) Plus Rituximab and/or Bendamustine
Fowler and colleagues presented results of a phase 1 study of combinations of the phosphatidylinositol 3-kinase-delta inhibitor idelalisib with rituximab (IR; n=30), bendamustine (IB; n=33), or bendamustine plus rituximab (IBR; n=13) in 76 patients with previously treated (median 3 prior therapies) indolent NHL (follicular lymphoma, 74%; SLL, 20%; or marginal zone lymphoma, 6%).11 Grade ?3 AEs and laboratory abnormalities were generally consistent with those expected with each of the single agents (Table 3).
Lymph node shrinkage was rapid, and all evaluable patients had reductions in lymphadenopathy (Table 4), resulting in ORRs of 77%, 85%, and 77% for the IR, IB, and IBR regimens, respectively, including CRs in 13%, 16%, and 30% of patients, respectively. With median follow-up duration ranging from 28 to 48 weeks, 1-year PFS rates were 82%, 90%, and 78% for the 3 groups, respectively.
The authors concluded that idelalisib-based combination therapy with rituximab and/or bendamustine offers major and rapid reductions in lymphadenopathy, and that all 3 regimens provide durable tumor control. They recommended that phase 3 combination trials of idelalisib with rituximab- and/or bendamustine-containing regimens be conducted in patients with indolent NHL.
Bendamustine Plus Ofatumumab
When combined with bendamustine in NHL, ofatumumab may have comparable efficacy to rituximab. Initial results of a phase 2 study of bendamustine plus ofatumumab in 45 evaluable patients with untreated indolent B-cell NHL (follicular lymphoma, n=36; marginal zone lymphoma, n=13; lymphoplasmacytic lymphoma, n=13) showed an ORR of 98%, including 60% CR.12 Seven patients withdrew from the study due to AEs. At the time of this analysis, the most commonly observed grade 3/4 AEs were neutropenia and fatigue. Serious AEs were reported in 13 patients (27%).
Bendamustine and bendamustine-containing regimens are currently being investigated in 17 clinical studies in patients with indolent NHLs (Table 5).5
Mantle Cell Lymphoma
Bendamustine, Rituximab, and Cytarabine
The safety and efficacy of bendamustine in combination with rituximab and cytarabine have been evaluated in a recently published prospective, phase 2 study in 40 patients (median age 70 years) with previously untreated (50%), relapsed (15%), or refractory (35%) MCL.13 Among the previously untreated patients, the ORR was 100%, including 95% CR. Among the relapsed/refractory patients, the ORR was 80%, including 70% CR. The 2-year PFS rate was 95% in the previously untreated group and 70% in the relapsed/refractory group. Transient grade 3/4 thrombocytopenia occurred in 87% of patients and febrile neutropenia occurred in 12% of patients.
Bendamustine-containing regimens are currently being investigated in 17 clinical studies in patients with MCL (Table 6).5
Bendamustine Plus Rituximab
At the 2010 American Society of Clinical Oncology Annual Meeting, Vacirca and colleagues presented initial results of their open-label, single-arm phase 2 study examining BR in CD20-positive patients with relapsed/refractory diffuse large B-cell lymphoma who were ineligible for autologous stem cell transplant (ASCT).14 At the time of that presentation, the ORR for 26 evaluable patients was 58%, including 19% CR. Grade 3/4 AEs are shown in Table 7.
Bendamustine and bendamustine-containing regimens are currently being investigated in 8 clinical studies in patients with aggressive NHL (Table 8).5
Mian and colleagues from Italy recently published a report on 2 patients with Hodgkin lymphoma in whom bendamustine was successfully used as salvage treatment for relapse after allogeneic bone marrow transplantation.15 Corazzelli and colleagues, also from Italy, reported on 41 patients with Hodgkin lymphoma that recurred after stem cell transplantation who were treated with bendamustine.16 At first assessment (after 2-4 cycles), the ORR was 78%, including 12 CRs (29%) and 20 PRs (49%). Upon treatment prolongation to 6 to 8 courses, 40% of PRs progressed, yielding a final ORR of 58% with 31% CR. Eight patients (2 with CRs and 6 with PRs) subsequently underwent ASCT. The median PFS exceeded 11 months and the median OS exceeded 21 months. Among the group that had reached a CR, the median disease-free survival time was more than 9 months, with a relapse rate of only 30%. No life-threatening or unexpected AEs occurred.
A retrospective study evaluated the efficacy and toxicity of bendamustine in 28 patients (median 5 prior therapies) with refractory/relapsed Hodgkin lymphoma after ASCT used as part of a French compassionate use program.17 The ORR was 50%, including 29% CR. The median PFS for all patients was 5.7 months; for patients who achieved a CR, the median PFS was 10.2 months. During the first 6 cycles, 2 patients experienced febrile neutropenia and 4 patients had grade 3/4 thrombocytopenia.
In the United States, Moskowitz and colleagues recently published the results of a phase 2 study that evaluated the efficacy of bendamustine in 34 evaluable patients (median 4 prior therapies) with relapsed/refractory Hodgkin lymphoma who were ineligible for ASCT (25%) or for whom this treatment failed (75%).18 The ORR was 56%, including 12 CRs. The median response duration was 5 months. Five patients (20% of those eligible) proceeded to ASCT after treatment with bendamustine. The most commonly reported grade ?3 AEs were thrombocytopenia (20%), anemia (14%), and infection (14%).
Bendamustine-containing regimens are currently being investigated in 3 clinical studies in patients with Hodgkin lymphoma (Table 9).5
Phase 2 studies have demonstrated the efficacy of bendamustine in the treatment of various types of solid tumors, including small cell lung cancer,19,20 refractory soft tissue sarcoma,21 and relapsed or refractory germ cell cancer.22
Bendamustine was recently investigated in a phase 2 study in 10 women with platinum- and taxane-resistant epithelial ovarian cancer who had been treated with a median of 5 prior therapies.23 Results showed no objective tumor response; 2 patients achieved stable disease. Overall, the regimen was associated with fatigue and gastrointestinal side effects and was not well tolerated. However, the authors noted that the patients in this study experienced less bone marrow suppression than did patients in other studies. They suggested that the lack of tolerability could reflect the degree of tumor burden within the peritoneal cavity as well as the high number of prior regimens received by the patients participating in this study.
In 2005, von Minckwitz and colleagues published the results of a large study (N=364) comparing the combination of cyclophosphamide, methotrexate, and fluorouracil (CMF) with the combination of bendamustine, methotrexate, and fluorouracil (BMF) as first-line treatment for patients with metastatic breast cancer. The study showed a significant improvement in time to progression – from 6.7 months with CMF to 8.2 months with BMF (P=.0071).24 ORRs did not significantly differ between the 2 regimens. More mucositis and leukopenias were seen in the BMF group than in the CMF group.
Phase 2 studies have been conducted in Germany of single-agent bendamustine as salvage therapy for metastatic breast cancer.25-27 In 1998, Höffken and colleagues reported the results of a phase 2 pilot study of bendamustine monotherapy as salvage treatment in 37 patients with advanced breast cancer.25 Treatment consisted of 150 mg/m2 bendamustine on days 1 and 2 of a 4-week treatment course. Among the 33 patients evaluable for response, an ORR of 27% was seen. However, the toxicity profile of this regimen was high; grade 3 AEs occurred in 5 patients and grade 4 AEs occurred in 3 patients. The median time to tumor progression was 2 months (range, 1-14 months). In 2007, Reichmann and colleagues reported the results of a similar phase 2 study (N=51), in which bendamustine was administered at a lower dose (120 mg/m2).26 Of 50 evaluable patients, 10 achieved a PR. Comparison of efficacy between the 2 trials must be done with caution because of potential differences in the study populations, the size of the studies, and improvements in response assessment over time.28 Also in 2007, Eichbaum and colleagues conducted a study of weekly administration of bendamustine as salvage treatment in 34 patients with metastatic breast cancer.27 Patients received 60 mg/m2 bendamustine on days 1, 8, and 15 every 28 days for 6 cycles. Five patients (19%) achieved PRs. No grade 3 or 4 hematologic toxicities occurred. Only 3 patients experienced grade 3 nonhematologic toxicities. Steinbild and colleagues conducted a phase 2 study of bendamustine given as a flat dose of 200 mg on days 1 and 2 every 4 weeks in 22 patients with metastatic breast cancer who had been pretreated with 2 to 3 different chemotherapy regimens.29 Among 18 patients evaluable for efficacy, 3 patients (17%) achieved a PR. The main toxicities reported were nausea, weight loss, and fatigue.
Bendamustine has also been studied in combination with paclitaxel, and results show that both drugs can be given together without dose compromises. In a phase 1 study (RiTa I), the weekly doses were established at 70 mg/m2 for bendamustine and 90 mg/m2 for paclitaxel.30 A phase 2 study (RiTa II) was conducted using these recommended doses of bendamustine and paclitaxel.31 A total of 26 patients with breast cancer (27% of whom had triple-negative breast cancer) received the combination of bendamustine and paclitaxel (15 received it as first-line therapy; 11 as beyond first-line therapy). The median PFS was 7.3 months, and the median OS, 14.9 months. The 1-year PFS rate was 20.3%, and the 1-year OS rate, 71.2%. The ORR was 42.3%, including 4 CRs and 7 PRs. Among the subset of patients with triple-negative breast cancer, the ORR was 71.4%. The subset of patients who had been pretreated with anthracyclines achieved an ORR of 43.8%.
An ongoing phase 1/2 study (NCT00834678), conducted by a group from the Ohio State University Comprehensive Cancer Center, is currently investigating the combination of bendamustine with erlotinib in treating patients with stage IIIB, stage IIIC, or stage IV breast cancer.5
The efficacy of bendamustine as a first-line therapy in multiple myeloma (MM) patients not eligible for transplantation has been demonstrated in a phase 3 trial in Europe in which patients newly diagnosed were randomized to receive either a bendamustine/prednisone regimen (n=68) or standard melphalan/prednisone (n=63).32 Results showed similar ORR with the 2 regimens, but the treatment with bendamustine led to an increased CR rate (Figure 3). In addition, the maximum response was achieved more rapidly in patients treated with bendamustine (6.8 vs 8.7 cycles; P<.02).
More recently, a small (N=18) study of bendamustine in combination with bortezomib and prednisone was conducted in patients with newly diagnosed MM who had severe renal failure (glomerular filtration rate <35 mL/min) at diagnosis.33 Results showed an ORR of 83% (including 3 stringent CRs [sCR], 5 near CRs [nCR], and 5 very good PRs [VGPRs]) after at least 1 cycle of chemotherapy. Thirteen patients (72%) improved their renal function after treatment.
A recent phase 2 study investigated the addition of bendamustine to melphalan conditioning for ASCT.34 At day 100 after ASCT, 79% of patients achieved an ORR, including 9 sCRs, 1 CR, and 7 VGPRs. Six patients (24%) with preexisting high-risk disease died of progressive myeloma during study follow-up, all at or beyond 100 days after ASCT. The authors concluded that bendamustine up to a dose of 225 mg/m2 added to ASCT conditioning with high-dose melphalan did not exacerbate expected toxicities.
The latest version of the National Comprehensive Cancer Network Guidelines for MM recommends bendamustine as salvage therapy, both as monotherapy and in combination with lenalidomide and dexamethasone, for patients with relapsed/refractory disease.35 In a trial by Knop and colleagues, 31 patients who had experienced relapse after high-dose chemotherapy and ASCT were enrolled to receive increasing doses of bendamustine.36 The ORR was 55%, with a median PFS of 26 weeks for all patients and 36 weeks for patients who received higher doses of bendamustine (90-100 mg/m2). Toxicity was mild and mainly hematologic. A retrospective analysis of 39 patients showed that bendamustine is effective and tolerable in patients with advanced progressive myeloma, with an ORR of 36%.37 A multicenter phase 1/2 study (N=29) investigated the combination of bendamustine, lenalidomide, and dexamethasone as treatment for patients with relapsed/refractory MM.38 Results showed that 52% (n=13) of the 25 evaluable patients achieved an objective response, including 24% (n=6) who reached a VGPR and 28% (n=7) who reached a PR (Figure 4). The median PFS was 6.1 months (95% CI, 3.7-9.4 months), and the 1-year PFS rate was 20% (95% CI, 6%-41%).
Bendamustine has also been studied in combination with prednisolone and thalidomide. In a phase 1 study in 28 patients with refractory or relapsed MM after ASCT or conventional chemotherapy, bendamustine in combination with prednisolone and thalidomide resulted in an ORR of 86%.39 Median PFS was 11 months and median OS was 19 months.
In addition, bendamustine has been studied in combination with bortezomib. In a recent open-label phase 1/2 study, the combination of bendamustine and bortezomib was assessed in 40 heavily pretreated patients with relapsed/refractory MM. The ORR was 48% (including 1 CR and 2 VGPRs).40 In another study, patients not responding to a bortezomib/dexamethasone regimen received a triple therapy consisting of bendamustine, bortezomib, and dexamethasone, which resulted in a 57% ORR.41
A recently published retrospective study assessed hematology/oncology department medical records of 78 patients with relapsed or refractory MM treated between 2005 and 2011 who received the combination of bendamustine, bortezomib, and prednisone.42 Results showed that 69% (n=54) of patients achieved an objective response (including 3 CRs, 10 nCRs, and 10 VGPRs) after at least 1 cycle of chemotherapy. Among the 45 patients without severe hematologic toxicities due to previous treatments, the median PFS was 11 months and the median OS was 50 months. However, among the 33 patients with grade 3/4 hematologic toxicities, the median PFS was 3 months and the median OS was 5 months.
Bendamustine and bendamustine-containing regimens are currently being investigated in 16 clinical studies in patients with MM (Table 10).5
As evidenced by the large number of ongoing clinical investigations of bendamustine and bendamustine-containing regimens, the oncology and hematology/oncology communities are very interested in exploring the potential of this chemotherapy drug – especially in combination with novel agents that are emerging. Therefore, a large number of studies are currently being conducted using regimens with a bendamustine backbone, and experts predict that more of these studies will be initiated in the future.43
1. Rummel MJ, Gregory SA. Bendamustine’s emerging role in the management of lymphoid malignancies. Semin Hematol. 2011;48(suppl 1):S24-S36.
2. Fischer K, Cramer P, Busch R, et al. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2011;29:3559-3566.
3. Wierda WG, Balakrishnan K, Ferrajoli A, et al. Fludarabine, bendamustine, and rituximab (FBR) chemoimmunotherapy is a safe and active regimen for relapsed/refractory CLL with in vivo mechanism of action for combination chemotherapy. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 437.
4. Tedeschi A, Rossi D, Coscia M, et al. Final report of bendamustine and alemtuzumab (BEN CAM) combination in relapsed and refractory chronic lymphocytic leukemia. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 2898.
5. US National Institutes of Health. ClinicalTrials.gov. www.clinicaltrials.gov. Accessed April 9, 2013.
6. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): updated results from the StiL NHL1 study. J Clin Oncol. 2012;30(suppl). Abstract 3.
7. Rummel MJ, Niederle N, Maschmeyer G, et al. Subanalysis of the StiL NHL 1-2003 study: achievement of complete response with bendamustine-rituximab (B-R) and CHOP-R in the first-line treatment of indolent and mantle cell lymphomas results in superior survival compared to partial response. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 2724.
8. Flinn IW, Van der Jagt RH, Kahl BS, et al. An open-label, randomized study of bendamustine and rituximab (BR) compared with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in first-line treatment of patients with advanced indolent non-Hodgkin’s lymphoma (NHL) or mantle cell lymphoma (MCL): the Bright study. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 902.
9. Knauf WU, Abenhardt W, Nusch A, et al. Bendamustine-rituximab replaces R-CHOP as “standard of care” in the treatment of indolent non-Hodgkin lymphoma in German hematology outpatient centres. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 3666.
10. Flinn IW, Thompson DS, Boccia RV, et al. Bendamustine, bortezomib, and rituximab in patients with previously untreated low grade lymphoma: a phase II trial of the Sarah Cannon Research Institute. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 1624.
11. Fowler NH, de Vos S, Schreeder MT, et al. Combinations of the phosphatidylinositol 3-kinase-delta (PI3K?) inhibitor Gs-1101 (CAL-101) with rituximab and/or bendamustine are tolerable and highly active in previously treated, indolent non-Hodgkin lymphoma: results from a phase I study. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 3645.
12. Fowler NH, Kahanic SP, Forero A, et al. Results of a phase II study with bendamustine and ofatumumab in untreated indolent B-cell non-Hodgkin’s lymphoma. Blood (ASH Annual Meeting Abstracts). 2011;118. Abstract 778.
13. Visco C, Finotto S, Zambello R, et al. Combination of rituximab, bendamustine, and cytarabine for patients with mantle-cell non-Hodgkin lymphoma ineligible for intensive regimens or autologous transplantation. J Clin Oncol. 2013;31:1442-1449.
14. Vacirca JL, Acs PI, Shimkus BJ, et al. Bendamustine/rituximab in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2010;28(suppl). Abstract 8041.
15. Mian M, Farsad M, Pescosta N, et al. Bendamustine salvage for the treatment of relapsed Hodgkin’s lymphoma after allogeneic bone marrow transplantation. Ann Hematol. 2013;92:121-123.
16. Corazzelli G, Angrilli F, D’Arco A, et al. Efficacy and safety of bendamustine for the treatment of patients with recurring Hodgkin lymphoma. Br J Haematol. 2013;160:207-215.
17. Ghesquières H, Stamatoullas A, Casasnovas O, et al. Clinical experience of bendamustine in relapsed or refractory Hodgkin lymphoma: a retrospective analysis of the French compassionate use program in 28 patients [published online ahead of print March 13, 2013]. Leuk Lymphoma.
18. Moskowitz AJ, Hamlin PA Jr, Perales MA, et al. Phase II study of bendamustine in relapsed and refractory Hodgkin lymphoma. J Clin Oncol. 2013;31:456-460.
19. Koster W, Heider A, Niederle N, et al. Phase II trial with carboplatin and bendamustine in patients with extensive stage small-cell lung cancer. J Thorac Oncol. 2007;2:312-316.
20. Schmittel A, Knödler M, Hortig P, et al. Phase II trial of second-line bendamustine chemotherapy in relapsed small cell lung cancer patients. Lung Cancer. 2007;55:109-113.
21. Hartmann JT, Mayer F, Schleicher J, et al. Bendamustine hydrochloride in patients with refractory soft tissue sarcoma: a noncomparative multicenter phase 2 study of the German sarcoma group (AIO-001). Cancer. 2007;110:861-866.
22. Kollmannsberger C, Gerl A, Schleucher N, et al. Phase II study of bendamustine in patients with relapsed or cisplatin-refractory germ cell cancer. Anticancer Drugs. 2000;11:535-539.
23. Baker AF, Roe DJ, Laughren C, et al. Investigation of bendamustine HCL in a phase 2 study in women with resistant ovarian cancer. Invest New Drugs. 2013;31:160-166.
24. von Minckwitz G, Chernozemsky I, Sirakova L, et al. Bendamustine prolongs progression-free survival in metastatic breast cancer (MBC): a phase III prospective, randomized, multicenter trial of bendamustine hydrochloride, methotrexate and 5-fluorouracil (BMF) versus cyclophosphamide, methotrexate and 5-fluorouracil (CMF) as first-line treatment of MBC. Anticancer Drugs. 2005;16:871-877.
25. Höffken K, Merkle K, Schöenfelder M, et al. Bendamustine as salvage treatment in patients with advanced progressive breast cancer: a phase II study. J Cancer Res Clin Oncol. 1998;124:627-632.
26. Reichmann U, Bokemeyer C, Wallwiener D, et al. Salvage chemotherapy for metastatic breast cancer: results of a phase II study with bendamustine. Ann Oncol. 2007;18:1981-1984.
27. Eichbaum MH, Schuetz F, Khbeis T, et al. Weekly administration of bendamustine as salvage therapy in metastatic breast cancer: final results of a phase II study. Anticancer Drugs. 2007;18:963-968.
28. von Minckwitz G, Linder M, Loibl S. The reawakening of bendamustine – also in breast cancer? Onkologie. 2009;32:462-463.
29. Steinbild S, Frost A, Häring B, et al. Phase II study with 3rd- or 4th-line bendamustine (flat dose) therapy in patients with metastatic breast cancer. Onkologie. 2009;32:488-492.
30. Loibl S, Murmann C, Schwedler K, et al. Phase I dose finding study evaluating the combination of bendamustine with weekly paclitaxel in patients with pre-treated metastatic breast cancer: RiTa trial. Cancer Chemother Pharmacol. 2009;63:953-958.
31. Loibl S, Doering G, Müller L, et al. Multicenter phase II study with weekly bendamustine and paclitaxel as first- or later-line therapy in patients with metastatic breast cancer: RiTa II trial. Breast Care (Basel). 2011;6:457-461.
32. Pönisch W, Mitrou PS, Merkle K, et al; East German Study Group of Hematology and Oncology (OSHO). Treatment of bendamustine and prednisone in patients with newly diagnosed multiple myeloma results in superior complete response rate, prolonged time to treatment failure and improved quality of life compared to treatment with melphalan and prednisone – a randomized phase III study of the East German Study Group of Hematology and Oncology (OSHO). J Cancer Res Clin Oncol. 2006;132:205-212.
33. Pönisch W, Andrea M, Wagner I, et al. Successful treatment of patients with newly diagnosed/untreated multiple myeloma and advanced renal failure using bortezomib in combination with bendamustine and prednisone. J Cancer Res Clin Oncol. 2012;138 :1405-1412.
34. Mark TM, Reid W, Niesvizky R, et al. A phase 1 study of bendamustine and melphalan conditioning for autologous stem cell transplantation in multiple myeloma. Biol Blood Marrow Transplant. 2013;19:831-837.
35. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Multiple Myeloma. Version 2.2013. www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf. Accessed April 4, 2013.
36. Knop S, Straka C, Haen M, et al. The efficacy and toxicity of bendamustine in recurrent multiple myeloma after high-dose chemotherapy. Haematologica. 2005;90:1287-1288.
37. Michael M, Bruns I, Bölke E, et al. Bendamustine in patients with relapsed or refractory multiple myeloma. Eur J Med Res. 2010;15:13-19.
38. Lentzsch S, O’Sullivan A, Kennedy RC, et al. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood. 2012;119:4608-4613.
39. Pönisch W, Rozanski M, Goldschmidt H, et al. Combined bendamustine, prednisolone and thalidomide for refractory or relapsed multiple myeloma after autologous stem-cell transplantation or conventional chemotherapy: results of a phase I clinical trial. Br J Haematol. 2008;143:191-200.
40. Berenson JR, Yellin O, Bessudo A, et al. Phase I/II trial assessing bendamustine plus bortezomib combination therapy for the treatment of patients with relapsed or refractory multiple myeloma. Br J Haematol. 2013;160:321-330.
41. Fenk R, Michael M, Zohren F, et al. Escalation therapy with bortezomib, dexamethasone and bendamustine for patients with relapsed or refractory multiple myeloma. Leuk Lymphoma. 2007;48:2345-2351.
42. Pönisch W, Bourgeois M, Moll B, et al. Combined bendamustine, prednisone and bortezomib (BPV) in patients with relapsed or refractory multiple myeloma. J Cancer Res Clin Oncol. 2013;139:499-508.
43. Gribben J. Bendamustine for non-Hodgkin lymphoma. Interview by Louise Rishton. Expert Rev Hematol. 2013;6:123-125.
At the 54th Annual Meeting of the American Society of Hematology, a number of abstracts were presented demonstrating the efficacy and toxicities of bendamustine either alone or in combination with other agents for the treatment of several lymphoid malignancies such as chronic lymphocytic leukemia (CLL) and indolent as well as [ Read More ]
Bendamustine has demonstrated activity as monotherapy and in combination for patients with lymphoid and hematologic as well as solid tumors. In the United States, bendamustine has been approved by the FDA for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) who have progressed during or within 6 months [ Read More ]