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Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References
  9. Appendix

Although bendamustine plus rituximab has demonstrated efficacy in indolent B cell non-Hodgkin’s lymphoma (B-NHL), data for this combination in aggressive B-NHL are extremely limited. The present dose-escalation study evaluated the safety, efficacy, and pharmacokinetics of bendamustine hydrochloride in combination with rituximab in patients with relapsed/refractory, CD20-positive, aggressive B-NHL. Patients received rituximab 375 mg/m2, i.v., on Day 1 and bendamustine at either 90 (Cohort 1) or 120 mg/m2 (Cohort 2), i.v., on Days 2 and 3 of a 21-day cycle. The primary endpoint was the proportion of patients experiencing dose-limiting toxicity (DLT). Secondary endpoints were adverse events (AE), the overall response rate (ORR), and pharmacokinetic parameters. Nine patients received rituximab plus bendamustine: three in Cohort 1 and six in Cohort 2. Histologies included diffuse large B cell lymphoma (= 5), mantle cell lymphoma (= 2), and transformed lymphoma (= 2). No DLT was observed at either dose level. Grade 3/4 hematologic AE included lymphocytopenia, leukocytopenia, and neutropenia (= 9 each; 100%), and thrombocytopenia (= 2; 22%). No Grade 3/4 gastrointestinal AE were reported. The ORR was 33% (one partial response) in Cohort 1 and 100% (five complete and one partial response) in Cohort 2. The maximum drug concentration and area under the blood concentration–time curve for bendamustine increased dose dependently, with time to maximum blood concentration = 1.0 h in both cohorts; these pharmacokinetic data were similar to those reported previously for single-agent bendamustine in patients with indolent B-NHL. In conclusion, bendamustine 120 mg/m2 plus rituximab 375 mg/m2 was feasible and generally well tolerated, with promising efficacy in relapsed or refractory aggressive B-NHL. (Cancer Sci 2011; 102: 1687–1692)

Bendamustine is a benzimidazole nitrogen mustard compound with structural similarities to alkylating agents and purine analogs. It has been shown to act as a bifunctional alkylator, forming both inter- and intrastrand DNA cross-links, which produce DNA damage that is more extensive and more durable than that caused by cyclophosphamide or bis-chloronitrosourea (BCNU; carmustine) but similar to that of melphalan.(1)

Bendamustine has a unique mechanism of action. In a study of 60 human tumor cell lines, bendamustine showed a pattern of antitumor activity that was distinct from other alkylating compounds tested.(2) Unlike other alkylators, bendamustine was able to induce cell death through both apoptosis and mitotic catastrophe.(2) Additional in vitro studies have shown a lack of cross-resistance between bendamustine and other chemotherapeutic agents, including other alkylators.(1)

Bendamustine demonstrates clinical activity against a variety of human cancers, including non-Hodgkin’s lymphoma (NHL).(3–11) The efficacy of bendamustine (120 mg/m2) in indolent B cell NHL (B-NHL) was shown in a US multicenter, single-arm study of 100 patients with rituximab-refractory disease, which resulted in an overall response rate (ORR) of 75% (17% complete responses [CR]) and a median duration of response of 9.2 months.(12) We also evaluated the efficacy and safety of bendamustine in Phase I and Phase II studies in Japanese patients with relapsed or refractory indolent B-NHL and mantle cell lymphoma (MCL) and reported ORR of 89% (8/9) and 91% (63/69), respectively.(9,10) In those two studies, objective responses were observed for all patients with MCL (= 12).(9,10)

Two Phase II studies have demonstrated the efficacy of single-agent bendamustine in small numbers of patients with relapsed or refractory aggressive NHL. One study reported responses in eight of 18 (44%) patients with diffuse large B cell lymphoma (DLBCL; = 12) or other aggressive lymphomas, including 10 patients who were refractory to prior chemotherapies.(7) The second study reported responses in 10 of 15 patients (67%) with rituximab-refractory, transformed B-NHL, with a median response duration of 2.3 months.(11)

Rituximab is a monoclonal antibody that binds specifically to surface CD20 on human B lymphocytes, leading to B cell depletion. In vitro combination therapy with rituximab and bendamustine induces apoptosis in CD20-positive follicular lymphoma and NHL cell lines and enhances the antitumor activity of rituximab.(13) The efficacy and tolerability of the bendamustine–rituximab combination has been demonstrated in two Phase II studies of patients with relapsed/refractory indolent B-NHL. In the first (German) study, 57 of 63 patients (90%) achieved an objective response, including CR in 60% of patients, and the median progression-free survival was 24 months.(8) In the second (US) study in 67 patients with relapsed and refractory MCL and low-grade NHL, an ORR of 92% was reported, including CR in 55% of patients.(14) In patients with MCL, the ORR ranged from 75% (50% CR)(8) to 92% (59% CR).(14)

The combination of cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP) is the standard of care in newly diagnosed, aggressive B-NHL, including DLBCL.(15,16) Because bendamustine does not demonstrate cross-resistance with these drugs, it was hypothesized that the combination of bendamustine and rituximab would be effective in previously treated, aggressive B-NHL.

The primary objectives of the present study were to: (i) evaluate the safety of bendamustine in patients with relapsed or refractory aggressive B-NHL when administered via i.v. infusion for 2 consecutive days in combination with rituximab; and (ii) determine a bendamustine dose for subsequent Phase II studies. The secondary objectives of the present study were to investigate the antitumor effects of bendamustine plus rituximab and to describe the pharmacokinetic profile of unchanged bendamustine.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References
  9. Appendix

Trial design and endpoints.  A multicenter, open-label, dose-escalation study was conducted between December 2008 and February 2010. The study was performed in compliance with the Declaration of Helsinki and the Good Clinical Practice Ministerial Ordinance and Guidelines for Clinical Evaluation of Anti-Tumor Drugs, and was approved by the institutional review board at each participating institution. All patients provided written informed consent prior to participating in the study.

The primary endpoint was the number of patients who experienced dose-limiting toxicity (DLT), defined as any adverse event (AE) reported during the first treatment cycle that had a possible causal relationship with the study drugs and met any of the following criteria: (i) Grade 4 neutropenia (neutrophil count <500 cells/mm3) with a fever of 38°C or higher for more than 1 week; (ii) platelet count <10 000 cells/mm3 or a hemorrhagic tendency requiring platelet transfusion; (iii) other Grade 4 hematologic toxicity, excluding decreased lymphocytes and changes in the leukocyte differential count; and (iv) other Grade ≥3 non-hematologic toxicity. Secondary endpoints included the frequency of AE, the ORR, the CR rate, and pharmacokinetic parameters.

Patient eligibility.  Patients 20–75 years of age with measurable, histopathologically confirmed, CD20-positive, aggressive B-NHL (DLBCL, MCL, transformed lymphoma, or Grade 3 follicular lymphoma) were eligible for inclusion in the study if they had failed to achieve a CR or had relapsed after achieving a CR or partial response (PR) with one to two prior chemotherapies or antibody therapies. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0–1, a life expectancy ≥3 months, and functional major organs (defined as neutrophils ≥1500 cells/mm3, platelets ≥100 000 cells/mm3, alanine aminotransferase [ALT] and aspartate aminotransferase [AST] <2.5-fold the upper limit of normal [×ULN], total bilirubin and serum creatinine <1.5 × ULN, arterial oxygen partial pressure ≥65 mmHg, and no abnormal electrocardiogram findings requiring treatment).

Patients were excluded from the study for any of the following reasons: cancer treatment within the 3 weeks prior to the study; primary central nervous system lymphoma; serious active infection; serious hepatic, renal, cardiac, gastrointestinal, or pulmonary disorders; positive status for hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus antibody; other active cancer or a history of another malignancy in the preceding 5 years (except for basal cell carcinoma of the skin, squamous cell carcinoma, and carcinoma in situ of the cervix); autoimmune hemolytic anemia; serious hemorrhagic tendency; pregnancy or lactation; or unwillingness to use birth control. Patients were also excluded if they had ever received bendamustine or radioimmunotherapy; had received a cytokine preparation or blood transfusion within 2 weeks prior to screening, or an investigational drug within 3 months of enrollment; displayed symptoms of allergy or intolerance to rituximab, bendamustine, or analogous drugs, or premedications; or were receiving sulfamethoxazole–trimethoprim combination therapy or acyclovir to prevent opportunistic infections.

Treatment and dose escalation.  Each 21-day treatment cycle consisted of rituximab (375 mg/m2, i.v.) administered on Day 1 and bendamustine (90 or 120 mg/m2, i.v.; Cohorts 1 and 2, respectively) administered over 60 min on Days 2 and 3, followed by an 18-day observation period. Patients received a maximum of six cycles. For safety reasons, hospitalization was required during the first cycle.

Three patients were to be enrolled in Cohort 1. If any DLT were observed in one or two patients, an additional three patients were enrolled into this cohort. If a DLT was observed in none of three or in two or fewer of six patients in Cohort 1, enrollment in Cohort 2 was initiated. An independent safety and data monitoring committee reviewed the data recorded from Cohort 1 following completion of the first cycle and provided guidance regarding advancement to Cohort 2. In Cohort 2, enrollment was suspended when the third patient was enrolled. Following confirmation of two or fewer DLT in the first cycle, three additional patients were enrolled in this cohort.

Rationale for doses and treatment schedule.  The regimens used in the present study were based on the efficacy and safety results of previous studies in patients with indolent B-NHL and MCL(8–10,14) and transformed(11) or aggressive B-NHL.(7)

Supportive therapy.  During each cycle, oral acetaminophen (400 mg) and chlorpheniramine maleate (2 mg) were administered prior to rituximab to prevent or alleviate infusion reactions. In addition, dexamethasone (20 mg, i.v.) was administered before bendamustine or rituximab (Days 1–3), followed by oral dexamethasone (10 mg) once daily on Days 4 and 5 of each cycle. Granisetron hydrochloride (3 mg) was administered i.v. once daily before bendamustine administration (Days 2 and 3) and followed by oral granisetron (2 mg) once daily on Days 4 and 5 of each cycle. Hydration and/or alkalization were recommended for patients at risk of tumor lysis syndrome. Granulocyte colony-stimulating factor was allowed during the first treatment cycle for patients with confirmed Grade 3 or greater neutropenia, and on Day 4 or later of Cycles 2–6. Opportunistic infection prophylaxis with oral sulfamethoxazole–trimethoprim and oral acyclovir 200 mg daily was allowed in Cycles 2–6.

Criteria for study withdrawal.  Patient participation in the study was discontinued for any of the following reasons: failure to meet criteria for proceeding to the next treatment cycle (defined as neutrophils ≥1000 cells/mm3, platelets ≥75 000 cells/mm3, ALT and AST <5 × ULN, total bilirubin <2.0 mg/dL, serum creatinine <2.0 mg/dL, and no persistent Grade ≥ 3 AE except leukocytopenia or lymphocytopenia) within 36 days after the start of the last treatment cycle; withdrawal of patient consent; deviation from the study protocol; inability to receive study drug due to AE or disease progression; death; loss to follow-up; study termination; pregnancy; or other reasons at the discretion of the investigator.

Safety and efficacy assessment.  Physical examination and laboratory testing were conducted on study drug administration days and weekly during the observation period. Any AE observed were graded according to Common Terminology Criteria for Adverse Events version 3.0.(17) Computed tomography (CT) and positron emission tomography (PET) scans were performed at the time of screening, third cycle, last cycle, and discontinuation. Tumor response was assessed based on CT/PET data by the investigator as well as by an extramural central review committee. Patients’ best responses were categorized as CR, PR, stable disease, or progressive disease according to the Revised Response Criteria for Malignant Lymphoma.(18)

Pharmacokinetic analysis.  Blood samples were collected on Day 2 of the first cycle prior to the start of the infusion, 30 min after the start of the infusion, at completion of the infusion, and then 30 min and 1 and 2 h thereafter. Plasma concentrations of bendamustine were measured by high-performance liquid chromatography tandem mass spectrometry. The maximum drug concentration (Cmax), time to maximum blood concentration (tmax), area under the blood concentration–time curve (AUC), and half-life (t½) of unchanged bendamustine were calculated by non-compartmental analysis (Model 2) using WinNonlin version 5.0.1 software (Pharsight, Mountain View, CA, USA).

Statistical analysis.  Baseline patient and disease characteristics were summarized using descriptive statistics. The incidence of DLT and 90% confidence intervals were calculated based on binomial probability for each treatment group. Summary statistics were calculated for hematologic toxicities and non-hematologic toxicities. The ORR was calculated as the proportion of patients who achieved a CR or PR.

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References
  9. Appendix

Patient disposition and baseline characteristics.  Nine patients were enrolled at four study centers: three received bendamustine at 90 mg/m2 (Cohort 1) and six received bendamustine at 120 mg/m2 (Cohort 2). These patients constituted the full analysis set (FAS; Fig. 1). There were two protocol violations. One patient in Cohort 1 (Patient 1-1) deviated from the inclusion criteria: this patient was enrolled based on a clinical diagnosis of DLBCL, but upon rebiopsy after completion of study treatment, the patient was found to have adenocarcinoma. One patient in Cohort 2 (Patient 2-4) did not meet the criteria to begin the next treatment cycle: this patient had persistent Grade 3 hypokalemia after Cycle 3, but proceeded to start the fourth cycle. Treatment in this patient was discontinued during the fourth cycle. These two patients were excluded from the per-protocol set.

image

Figure 1.  Patient disposition in the study arms.

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The median age of enrolled patients was 65 years (range 56–74 years); five patients were male and four were female. Baseline characteristics are presented in Table 1. Disease histologies included DLBCL, MCL, and transformed lymphoma. Eight patients (89%) had received prior treatment with R-CHOP and all patients had received prior rituximab.

Table 1.   Baseline characteristics of patients with aggressive B cell non-Hodgkin’s lymphoma treated with bendamustine plus rituximab
Patient no.Histology†Disease stage‡IPI risk groupPrior treatment
  1. †World Health Organization classification.(19)‡Ann Arbor classification.(20) CHASE, cyclophosphamide, cytarabine, etoposide, and dexamethasone; CHASER, cyclophosphamide, cytarabine, etoposide, dexamethasone, and rituximab; DLBCL, diffuse large B cell lymphoma; IPI, International Prognostic Index; MCL, mantle cell lymphoma; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CMOPP, rituximab plus cyclophosphamide, vincristine, procarbazine, and prednisone; R-F, rituximab plus fludarabine; R-HyperCVAD/MA, rituximab plus fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with methotrexate and cytarabine; TL, transformed lymphoma.

Dose level 1: 90 mg/m2, i.v., bendamustine plus 375 mg/m2, i.v., rituximab
 1-1DLBCLIIIHigh-intermediateR-CHOP × 8
CHASER × 2
 1-2DLBCLIVLow-intermediateR-CHOP × 8
CHASE × 2
 1-3DLBCLILow-intermediateR-CHOP × 6
Dose level 2: 120 mg/m2, i.v., bendamustine plus 375 mg/m2, i.v., rituximab
 2-1DLBCLIILowR-CHOP × 8
 2-2DLBCLILowR-CHOP × 8
 2-3TLIILow-intermediateR-CHOP × 3
R-CMOPP × 8
 2-4MCLIILowR-CHOP × 6
 2-5TLIIILow-intermediateR-CHOP × 8
R-F × 3
 2-6MCLIVLow-intermediateR-HyperCVAD/MA × 4

Safety.  Safety analyses were conducted on the FAS. A total of 38 treatment cycles was administered (10 in Cohort 1 and 28 in Cohort 2); all patients completed three or more treatment cycles and two patients (both in Cohort 2) completed six cycles. All patients experienced at least one delay of treatment to allow for recovery from AE (most commonly neutrophil counts <1000 cells/mm3), in compliance with the protocol. In Cohort 1, the median cycle duration was 22 days (range 21–28 days) for Cycle 1, 21 days (range 21–35) for Cycle 2, and 28 days for Cycle 3 (= 1). In Cohort 2, the median cycle duration was 21 days (range 21–28 days) for Cycles 1, 2, and 4, and 28 days (range 21–41 days) for Cycles 3 and 5.

Although all nine patients experienced AE, bendamustine was generally well tolerated. No DLT was observed with either dose of bendamustine (Table 2). No deaths were reported. Grade 3/4 hematologic AE included lymphocytopenia, leukocytopenia, neutropenia (nine of nine patients each), and thrombocytopenia (two of nine patients). No Grade 3/4 gastrointestinal events or fatigue were reported.

Table 2.   Dose-limiting toxicity and Grade 3/4 toxicity associated with bendamustine plus rituximab in patients with aggressive B cell non-Hodgkin’s lymphoma
 No. events
90 mg/m2 bendamustine (= 3)120 mg/m2 bendamustine (= 6)
  1. †Dose-limiting toxicity (DLT) was assessed during Cycle 1 only. ‡Grade 4 neutropenia lasting >1 week and accompanied by fever (38°C or higher). §Grade 4 thrombocytopenia or hemorrhage requiring platelet transfusion. ¶Any other Grade 4 hematologic toxicity excluding lymphocytopenia and differential white blood cell count (%). LDH, lactate dehydrogenase.

DLT (Cycle 1†)
 Grade 4 neutropenia‡00
 Platelets <10 000 cells/mm3§00
 Other Grade 4 hematologic toxicity¶00
 Grade ≥3 non-hematologic toxicity00
Grade 3/4 events in all cycles
 Lymphocytopenia, Grade 436
 Leukocytopenia, Grade 3/43/05/1
 Neutropenia, Grade 3/42/13/3
 Decrease in CD4, Grade 3/42/12/3
 Thrombocytopenia, Grade 302
 Febrile neutropenia, Grade 310
 Decreased IgA, Grade 310
 Decreased IgG, Grade 310
 Increased LDH, Grade 310
 Hypokalemia, Grade 301
 Hyperuricemia, Grade 301
 Lower back pain, Grade 301

One case of Grade 1 oral candidiasis was recorded in Cohort 2. Incidences of nausea and vomiting were low with granisetron and dexamethasone prophylaxis (in Cohort 1, one case of Grade 2 nausea; in Cohort 2, three cases of Grade 1 nausea and one case of Grade 1 vomiting). Two serious AE were reported in a 65-year-old male patient with MCL in Cohort 2, consisting of Grade 1 fatigue and Grade 2 fever without neutropenia. These events were thought to be caused by incidental infection and were considered serious because the patient required hospitalization for i.v. hydration and antibiotic therapy. Both events resolved with treatment and were considered by the investigator to be unrelated to the study drugs.

Efficacy.  Efficacy analyses were conducted on the FAS. The ORR, as determined by central review, were 33% and 100% in Cohorts 1 and 2, respectively (Table 3). A CR was achieved in five patients in Cohort 2 (two DLBCL, two MCL, one transformed lymphoma) and a PR was achieved in one patient with DLBCL in Cohort 1 and in one patient with transformed lymphoma in Cohort 2. Of the four patients with pathologically confirmed de novo DLBCL, 3 (75%) achieved an objective response, including two CR and one PR.

Table 3.   Treatment response according to bendamustine dose and histology in patients (= 9; full analysis set) treated with bendamustine plus rituximab for aggressive B cell non-Hodgkin’s lymphoma
Dose (mg/m2)HistologyBest response† (n)ORR (%)CR (%)
NCRPRSDPD
  1. †As determined by an extramural central review committee. ‡This patient was determined to be pathologically ineligible after completing the study. Among the eight patients with pathologically eligible disease, the overall response rate (ORR) and complete response (CR) rate were 88% and 63%, respectively. DLBCL, diffuse large B cell lymphoma; MCL, mantle cell lymphoma; PD, progressive disease; PR, partial response; SD, stable disease; TL, transformed lymphoma.

90DLBCL3011‡1330
120DLBCL22000100100
MCL22000100100
TL2110010050
Cohort total6510010083
All patients952117856

Pharmacokinetics.  Pharmacokinetic analyses were conducted on the FAS (Table 4). Plasma levels of bendamustine peaked upon completion of infusion (tmax = 1 h; Fig. 2). The Cmax and AUC increased in a dose-dependent manner. Unchanged bendamustine was rapidly eliminated from the circulation, and the mean elimination t½ was similar in Cohorts 1 and 2 (0.36 and 0.32 h, respectively).

Table 4.   Pharmacokinetic parameters of unchanged bendamustine in patients treated with bendamustine plus rituximab for aggressive B cell non-Hodgkin’s lymphoma
Bendamustine doseNPatient no.ResponseCmax (μg/mL)tmax (h)t½ (h)AUC (μg h/mL)
  1. AUC, area under the curve; B-NHL, B cell non-Hodgkin lymphoma; Cmax, maximum concentration; CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease; tmax, time to maximum concentration; t½, half-life.

90 mg/m231-1SD4.91.00.425.9
1-2PD4.11.00.324.9
1-3PR2.41.00.332.8
Mean ± SD3.8 ± 1.31 ± 00.36 ± 0.064.5 ± 1.6
120 mg/m262-1CR4.81.00.345.7
2-2CR7.81.00.298.5
2-3PR5.71.00.397.6
2-4CR6.21.00.266.5
2-5CR3.91.00.424.4
2-6CR4.11.00.234.2
Mean ± SD5.4 ± 1.51 ± 00.32 ± 0.076.1 ± 1.7
image

Figure 2.  Mean (±SD) plasma bendamustine concentrations following administration of either 90 (○) or 120 mg/m2 (•) bendamustine (= 3 and 6, respectively) to patients with aggressive B cell non-Hodgkin’s lymphoma. Each i.v. infusion was administered over 1 h. Peak plasma concentrations were 3.8 ± 1.3 μg/mL following infusion of 90 mg/m2 bendamustine and 5.4 ± 1.5 μg/mL following infusion of 120 mg/m2 bendamustine. Concentrations <0.0005 μg/mL were recorded as 0 μg/mL.

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Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References
  9. Appendix

The present study is the first clinical trial to evaluate the combination of bendamustine and rituximab in patients with relapsed/refractory aggressive B-NHL including DLBCL. Our results support the safety and tolerability of both bendamustine doses tested in combination with rituximab. All nine patients experienced AE; however, no DLT was observed and the two serious AE (Grade 1 fatigue and Grade 2 fever without neutropenia) were considered unrelated to study treatment.

Our earlier Phase I dose-escalation and pharmacokinetic study(9) of bendamustine monotherapy using the same doses (90 and 120 mg/m2) in refractory/relapsed indolent B-NHL and MCL also did not identify a maximum tolerated dose. Based on the findings from this earlier Phase I study and other studies,(9–12) the 120 mg/m2 dose of bendamustine was selected for further evaluation in Phase II trials. A multicenter Phase II study using this dose of bendamustine showed that it was effective with an acceptable safety profile.(10)

The safety and tolerability of bendamustine plus rituximab observed in the present study were consistent with observations reported in larger Phase II trials evaluating this drug combination in patients with MCL and indolent B-NHL.(8,14) Most common non-hematologic AE were gastrointestinal in nature and were generally mild in both cohorts. The use of granisetron and dexamethasone minimized the incidence of nausea and vomiting in the present study.

The pharmacokinetic profile of unchanged bendamustine was comparable to that reported previously in Japanese patients with indolent B-NHL and MCL.(9) In that study, 120 mg/m2 bendamustine produced a mean Cmax of 8.6 ± 4.5 μg/mL, compared with a mean value of 5.4 ± 1.5 μg/mL in the present study. In both studies, there was considerable variation in Cmax between patients; although mean Cmax values differed slightly, the ranges observed overlapped. Furthermore, the pharmacokinetic profile observed in Japanese patients is similar to that reported for patients in studies conducted in Europe and the US, suggesting little or no effect of ethnicity on the pharmacokinetics of bendamustine.(21–24)

In an in vitro study in lymphoma cell lines, the IC50 of bendamustine was identified as 20 μM or 7.2 μg/mL.(25) In the present clinical study, the maximum plasma concentration ranged from 54% to 108% of this inhibitory concentration in Cohort 2; the observed ORR of 100% in this group suggests that such plasma concentrations are associated with antitumor activity in combination with rituximab.

Although no definitive conclusions can be drawn from the findings of the present study owing to the limitations of a small sample size and a variety of histologic subtypes, the preliminary efficacy findings are promising. Bendamustine plus rituximab elicited objective responses in both cohorts, with 100% of patients responding at the higher (120 mg/m2) dose level. In addition, a CR was observed in 83% of patients and occurred across all disease histologies included.

Among patients with pathologically confirmed de novo DLBCL, the ORR was 75% (3/4), including a CR rate of 50%. In patients with relapsed DLBCL, autologous stem cell transplant (ASCT) following high-dose chemotherapy is the standard of care for patients responding to salvage therapy; however, no chemotherapy regimen has emerged as a preferred salvage regimen.(26,27) The identification of salvage regimens with increased response rates is of significant clinical interest, particularly in patients who have received prior rituximab, among whom response rates are approximately 50%.(27) Furthermore, patients >65 years or those with major organ dysfunction are considered ineligible for ASCT and no standard of care exists for these patients. Among the five patients with de novo DLBCL enrolled in the present study, four were considered ineligible for and one declined ASCT. The response rate observed with bendamustine plus rituximab in these patients supports continued investigation of this combination therapy in this patient group.

Bendamustine plus rituximab appeared safe and well tolerated at both dose levels evaluated. Furthermore, although no conclusions can be drawn about efficacy, this combination demonstrated preliminary activity warranting further exploration in patients with aggressive disease. In consideration of the tolerability of this regimen, administration of the highest dose level evaluated (i.e. 120 mg/m2 bendamustine plus 375 mg/m2 rituximab) appears feasible in this patient population and should be evaluated further in subsequent Phase II trials. Based on the results of the present study, a multicenter, international Phase II study of bendamustine plus rituximab in patients with relapsed or refractory DLBCL is currently underway (clinicaltrials.gov ID no. NCT01118845).

Acknowledgments

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References
  9. Appendix

The authors thank the patients, doctors, nurses, and staff members who participated in this trial. Assistance with the writing of this manuscript was provided by ApotheCom and was funded by SymBio Pharmaceuticals and Eisai Co. The authors were responsible for all content and editorial decisions.

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References
  9. Appendix
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Appendix

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References
  9. Appendix

Institutions participating in the Japanese Bendamustine Lymphoma Study Group: National Cancer Center Hospital, Tokai University School of Medicine, Nagoya Daini Red Cross Hospital, and Kyoto Prefectural University of Medicine; protocol committee members: Drs Kenichi Ishizawa (Tohoku University Hospital), Kensei Tobinai, Takashi Watanabe, Kiyoshi Ando, Michinori Ogura, and Masafumi Taniwaki; independent data and safety monitoring committee members: Drs Toshiyuki Takagi (Kimitsu Chuo Hospital), Hirokazu Murakami (Gunma University), and Noriko Usui (Jikei University School of Medicine Dai-san Hospital); and CT/PET central review committee members: Drs Takashi Terauchi (National Cancer Center Hospital), Ukihide Tateishi (Yokohama City University), and Mitsuaki Tatsumi (Osaka University).