Abstract
Bendamustine is a unique cytotoxic agent that has demonstrated efficacy in the treatment of indolent B‐cell non‐Hodgkin lymphomas (B‐NHLs). In this multicenter phase II trial, the efficacy and safety of bendamustine were evaluated in Japanese patients with relapsed or refractory indolent B‐NHL or mantle‐cell lymphoma (MCL). Patients received bendamustine (120 mg/m2) on days 1–2 of a 21‐day cycle, for up to six cycles. The primary endpoint was the overall response rate (ORR) as assessed by an extramural committee according to International Workshop Response Criteria (IWRC). Secondary endpoints included complete response (CR) rate, ORR according to Revised Response Criteria (revised RC), progression‐free survival (PFS), and safety. Fifty‐eight patients with indolent B‐NHL and 11 with MCL were enrolled. By IWRC, bendamustine produced an ORR of 91% (95% confidence interval [CI], 82–97%; 90% and 100% in patients with indolent B‐NHL and MCL, respectively), with a CR rate of 67% (95% CI, 54–78%). ORR and CR rates according to revised RC were 93% (95% CI, 84–98%) and 57% (95% CI, 44–68%), respectively. After a median follow‐up of 12.6 months, median PFS had not been reached. Estimated PFS rates at 1 year were 70% and 90% among indolent B‐NHL and MCL patients, respectively. Bendamustine was generally well tolerated. Reversible myelosuppression, including grade 3/4 leukopenia (65%) and neutropenia (72%), was the most clinically significant toxicity observed. Common non‐hematologic toxicities included mild gastrointestinal events and fatigue. These results demonstrate the high efficacy and tolerability of single‐agent bendamustine in relapsed patients with indolent B‐NHL or MCL histologies. (ClinicalTrials.gov ID: NCT00612183). (Cancer Sci 2010;)
Non‐Hodgkin lymphoma (NHL) is a heterogeneous group of lymphoid malignancies, comprising 3% to 5% of all malignancies in the USA, Japan, and worldwide.( 1 , 2 , 3 ) A total of 65 980 new cases and 19 500 deaths due to NHL are estimated for 2009 in the USA,( 2 ) with similar incidence and mortality rates in Japan.( 3 )
Indolent B‐cell non‐Hodgkin lymphomas (B‐NHLs), including follicular lymphomas, are less aggressive than other NHL subtypes; however, they are generally considered incurable due to their relapsing nature.( 4 , 5 ) Front‐line therapy with a regimen of cyclophosphamide, doxorubicin, vincristine, and prednisolone in combination (CHOP) plus rituximab produces high response rates in these patients and has improved progression‐free survival (PFS) and overall survival compared with chemotherapy alone.( 6 , 7 , 8 , 9 ) These improvements notwithstanding, most patients relapse and many become refractory to chemotherapy and rituximab. Effective second‐line therapies are needed, especially those that do not exhibit cross‐resistance with chemotherapy or rituximab.
Mantle cell lymphoma (MCL) is a relatively aggressive subtype of B‐NHL, associated with poor responsiveness to treatment and shortened survival, that occurs in 3% to 8% of NHL patients.( 10 , 11 , 12 , 13 , 14 ) Limited effective therapies are available for this population, particularly for relapsed patients.
Bendamustine is a unique cytotoxic agent with a multifaceted mechanism of action.( 15 ) Structurally, it includes both a mechlorethamine group and a benzimidazole ring, intended to confer properties of both alkylators and purine analogs.( 16 ) Bendamustine acts by directly damaging DNA as well as inducing apoptosis and mitotic catastrophe.( 15 , 17 , 18 ) Importantly, bendamustine shows a distinct pattern of activity and a lack of cross‐resistance with other alkylating agents.( 15 , 19 )
Single‐agent bendamustine has demonstrated efficacy in patients with relapsed, rituximab‐refractory B‐NHL in two North American trials. In a phase II trial by Friedberg et al. ( 20 ) bendamustine produced a response in 47 (80%) of 59 assessable patients with indolent B‐NHL, with a median response duration of 9.0 months. Results from the subsequent single‐arm pivotal trial indicated a response rate of 75% in rituximab‐refractory indolent B‐NHL patients with a median response duration of 9.2 months.( 21 ) Based on the results of these trials, bendamustine was approved in the USA and Canada for the treatment of indolent B‐NHL that has progressed during or within 6 months of treatment with rituximab or a rituximab‐based regimen. The objective of the present trial was to determine the safety and efficacy of bendamustine in Japanese patients with previously treated indolent B‐NHL or MCL.
Materials and Methods
Study design and objectives. This multicenter, open‐label, single‐arm, phase II clinical study was designed to determine the antitumor effect and safety of bendamustine in patients with relapsed or refractory indolent B‐NHL or MCL. The primary endpoint was the overall response rate (ORR), defined as the proportion of patients achieving a partial remission (PR) or better, according to International Workshop Response Criteria (IWRC) for NHL.( 24 ) Secondary endpoints included the complete response (CR) rate, the ORR according to the Revised Response Criteria for Malignant Lymphoma (revised RC),( 25 ) PFS, and safety. This study was performed in compliance with the ethical principles provided by the Helsinki Declaration and the Japanese Pharmaceutical Affairs Act. The protocol was approved by the institutional review board of each participating institution.
Eligibility. Patients aged 20 to 75 years were eligible if they had previously treated, histopathologically confirmed indolent B‐NHL or MCL( 22 ) that failed to respond to, or relapsed after, prior therapy. There was no maximum number of allowed prior therapies. Patients were required to have a measurable lesion >1.5 cm in one dimension, an Eastern Cooperative Oncology Group performance status( 23 ) of 0 or 1, and a life expectancy ≥3 months. Adequate hematologic (neutrophils ≥1500/μL and platelets ≥100 000/μL), renal (serum creatinine <1.5 × the upper limit of the normal [ULN] at each study institution), hepatic (aspartate aminotransferase [AST] and alanine aminotransferase [ALT] <2.5 × ULN; total bilirubin <1.5 × ULN), and respiratory and cardiovascular (arterial oxygen partial pressure ≥65 mmHg; no abnormal electrocardiogram findings in need of treatment) function were required. Patients could have no carry‐over effect of prior therapy, with a required 4‐week wash‐out period (at least 3 months for antibody therapy). Patients were excluded if they had an apparent infection (including viral infection), other serious medical disorder, infiltration of lymphoma to the central nervous system, or an active malignancy other than lymphoma. Patients were required to provide written informed consent.
Treatment. Bendamustine 120 mg/m2 was administered by intravenous infusion over 60 min on days 1 and 2 every 21 days for up to six treatment cycles. Hospitalization was required during days 1–3 of cycle 1; subsequent treatment was allowed on an outpatient basis at the discretion of the investigator. Computed tomography (CT) examination was performed at enrollment, during the third and last cycles, and 3 months after the last cycle. When available, positron emission tomography (PET) examination was performed at enrollment and during the last cycle. Hematologic and biochemical laboratory tests were performed at study entry and at 1, 2, and 3 weeks after administration of each cycle. Before beginning each treatment cycle, recovery of neutrophil and platelet counts (to ≥1000/μL and ≥75 000/μL, respectively) and the absence of grade ≥3 toxicities was required. Dose reductions to 90 mg/m2 were performed in patients with grade 4 neutropenia persisting for ≥1 week despite treatment with granulocyte colony‐stimulating factor (G‐CSF), febrile neutropenia (grade ≥3 neutropenia, accompanied by a fever of ≥38.5°C) persisting for 3 days or longer, platelet count <10 000/μL or hemorrhagic tendency requiring platelet transfusion, or other grade 3/4 toxicities at the discretion of the investigator. In the case of toxicity recurrence, the dose was reduced to 60 mg/m2. Further recurrence of toxicity at 60 mg/m2 resulted in discontinuation of treatment.
The use of prophylactic antiemetics and antibiotics for prevention of opportunistic infection was recommended. The use of G‐CSF was permitted during cycles 2 through 6, as well as during cycle 1 when grade ≥3 neutropenia was confirmed. Prophylaxis for tumor lysis syndrome (e.g. allopurinol) was recommended in patients with high tumor burden.
Assessment. Response was assessed after the third and last cycles of treatment by an extramural committee according to the IWRC,( 24 ) as well as by the revised RC.( 25 ) Patients were classified by best tumor response: CR (disappearance of all evidence of disease), unconfirmed CR (CRu; a CR with indeterminate bone marrow histology or a more than 75% decrease from baseline in the sum of the products of the greatest perpendicular diameters [SPD] of all the measurable lesions but with a residual mass; used in IWRC only), partial response (PR; a more than 50% decrease from baseline in the SPD of all the measured lesions, no increase in size of any other lesions, and no new lesions), stable disease (failure to achieve a PR, but without disease progression), or progressive disease (any new lesions or an increase by ≥50% of a previously involved site from nadir). PFS was determined at 3 months after completion of the last cycle, with additional assessments performed every 3 months during the study. PFS was calculated as the time from study enrollment to either disease progression (including relapse and exacerbation) or death from any cause.
Adverse events were reported according to the Common Terminology Criteria for Adverse Events version 3.0.( 26 ) Serious adverse events were also recorded; these were defined as events that led to death or disability, were life‐threatening, required hospitalization, caused congenital anomaly, or resulted in medically significant conditions.
Statistical analyses. The sample size was calculated based on an expected and threshold ORR of 55% and 35% in patients with indolent B‐NHL and 40% and 15% in patients with MCL, respectively. The ORR was calculated as the proportion of treated patients who achieved a PR or better, along with a 95% confidence interval (CI). The CR rate was calculated as the proportion of treated patients who achieved a CR or CRu, along with a 95% CI. PFS was assessed by the Kaplan–Meier method, with a 95% CI based on Greenwood confidence bounds.
Results
Patients. Fifty‐eight patients with indolent B‐NHL and 11 patients with MCL were enrolled. Patient demographics and baseline characteristics are summarized in Table 1. Among patients with indolent B‐NHL, histologies included follicular (n = 52), small lymphocytic (n = 3), and one each lymphoplasmacytic, nodal marginal zone, and mucosa‐associated lymphoid tissue lymphomas. The median number of prior regimens administered was two (range, 1–9) in patients with indolent B‐NHL and four (range, 1–16) in patients with MCL. Thirty‐seven (64%) patients with indolent B‐NHL and six (55%) patients with MCL were known to be responsive to their last prior therapy.
Table 1.
Patient demographics and baseline characteristics
| Indolent B‐NHL (n = 58) | MCL (n = 11) | |
|---|---|---|
| Age, years | ||
| Median | 58.5 | 70 |
| Range | 33–75 | 59–75 |
| Sex, n | ||
| Male | 33 | 7 |
| Female | 25 | 4 |
| ECOG performance status, n | ||
| 0 | 52 | 7 |
| 1 | 6 | 4 |
| Diagnosis (WHO classification), n | ||
| Small lymphocytic lymphoma | 3 | |
| Lymphoplasmacytic lymphoma | 1 | |
| Splenic marginal zone B‐cell lymphoma | 0 | |
| MALT lymphoma | 1 | |
| Nodal marginal zone B‐cell lymphoma | 1 | |
| Follicular lymphoma | 52 | |
| Mantle cell lymphoma | 11 | |
| Stage at diagnosis, n | ||
| Stage I or II | 7 | 4 |
| Stage III | 21 | 1 |
| Stage IV | 29 | 6 |
| Unknown | 1 | 0 |
| Risk category, n† | ||
| Low risk | 30 | 2 |
| Intermediate risk | 13 | 8 |
| High risk | 15 | 1 |
| Prior treatment, n | ||
| Chemotherapy | 56 | 11 |
| Purine analogs | 20 | 4 |
| Rituximab | 55 | 11 |
| Ibritumomab tiuxetan | 2 | 0 |
| Radiotherapy | 7 | 2 |
| Corticosteroids alone | 3 | 0 |
| Other | 8 | 4 |
| Number of prior regimens | ||
| Median | 2 | 4 |
| Range | 1–9 | 1–16 |
| Time since last treatment, months | ||
| Median | 13.4 | 6.6 |
| Range | 1.1–29.5 | 1.1–35.8 |
†Risk categories were determined using the Follicular Lymphoma International Prognostic Index (FLIPI) for patients with indolent B‐cell non‐Hodgkin lymphoma (NHL) and International Prognostic Index (IPI) for patients with mantle cell lymphoma (MCL). ECOG, Eastern Cooperative Oncology Group; MALT, mucosa‐associated lymphoid tissue; WHO, World Health Organization.
Disposition. All enrolled patients received treatment with bendamustine and were included in both efficacy and safety analyses (Table 2). Fifty (72%; 41 with B‐cell NHL and nine with MCL) patients completed the planned treatment of three or more cycles of bendamustine. The median number of cycles administered was five (range, 1–6). All 19 early discontinuations were due to adverse events, mainly myelosuppression, including neutropenia (9), neutropenia/leukopenia (3), thrombocytopenia (2), leukopenia (1), pneumonia (1), fatigue/nausea (1), anorexia/nausea/vomiting (1), and fever/vomiting/increased ALT/AST (1).
Table 2.
Objective response to bendamustine treatment, by IWRC
| Disease type | n | Response by IWRC, n (%)† | CR/CRu,% (95% CI) | ORR, % (95% CI) | |||
|---|---|---|---|---|---|---|---|
| CR | CRu | PR | SD | ||||
| All | 69 | 27 (39) | 19 (28) | 17 (25) | 6 (9) | 67 (54–78) | 91 (82–97) |
| Indolent B‐NHL | 58 | 20 (34) | 18 (31) | 14 (24) | 6 (10) | 66 (52–78) | 90 (79–96) |
| Follicular | 52 | 19 (37) | 17 (33) | 11 (21) | 5 (10) | 69 | 90 |
| Small lymphocytic | 3 | 0 | 1 (33) | 1 (33) | 1 (33) | 33 | 67 |
| Lymphoplasmacytic | 1 | 0 | 0 | 1 (100) | 0 | 0 | 100 |
| MALT | 1 | 0 | 0 | 1 (100) | 0 | 0 | 100 |
| Nodal marginal zone | 1 | 1 (100) | 0 | 0 | 0 | 100 | 100 |
| MCL | 11 | 7 (64) | 1 (9) | 3 (27) | 0 | 73 (39–94) | 100 (72–100) |
†International Workshop Response Criteria (IWRC) for NHL.( 24 ) CI, confidence interval; CR, complete response; CRu, unconfirmed CR; MALT, mucosa‐associated lymphoid tissue; MCL, mantle cell lymphoma; NHL, non‐Hodgkin lymphoma; PR, partial response; SD, stable disease.
Efficacy. Bendamustine produced an ORR of 91% according to the IWRC, with a CR rate (CR plus CRu) of 67% (Table 2). Among patients with indolent B‐NHL, the ORR was 90%, including a CR/CRu rate of 66%. All 11 MCL patients responded to bendamustine (100%), with eight patients achieving a CR/CRu (73%). Results were similar using the revised RC, with an ORR of 93% and a CR rate of 57% (Table 3). Among 57 patients who underwent both CT and PET examinations, the evaluation of overall response according to IWRC and the revised RC did not agree in nine patients (seven of 47 with indolent B‐NHL and two of 10 with MCL).
Table 3.
Objective response to bendamustine treatment, by revised RC
| Disease type | n | Response by revised RC, n (%)† | CR, % (95% CI) | ORR, % (95% CI) | |||
|---|---|---|---|---|---|---|---|
| CR | PR | SD | PD | ||||
| All | 69 | 39 (57) | 25 (36) | 4 (6) | 1 (1) | 57 (44–68) | 93 (84–98) |
| Indolent B‐NHL | 58 | 31 (53) | 22 (38) | 4 (7) | 1 (2) | 53 (40–67) | 91 (81–97) |
| MCL | 11 | 8 (73) | 3 (27) | 0 | 0 | 73 (39–94) | 100 (72–100) |
†Revised Response Criteria for Malignant Lymphomas (revised RC).( 25 ) CI, confidence interval; CR, complete response, MCL, mantle cell lymphoma; NHL, non‐Hodgkin lymphoma; PD, progressive disease; PR, partial response; SD, stable disease.
In patients with indolent B‐NHL, ORR by Follicular Lymphoma International Prognostic Index (FLIPI)( 27 ) risk category was 97% (29 of 30) in low‐risk, 92% (12 of 13) in intermediate‐risk, and 73% (11 of 15) in high‐risk patients (P = 0.041). Response rates were similar by disease stage, number of prior therapy regimens, or response to most recent prior therapy. In patients who received fewer than three cycles of bendamustine, the ORR was 74% (95% CI, 49–91%), compared with 98% (95% CI, 89–100%) in patients who received three or more cycles (Table 4).
Table 4.
Objective response to bendamustine treatment, by number of treatment cycles
| Cycles of bendamustine | n | Response by IWRC, n (%)† | CR/CRu, % (95% CI) | ORR, % (95% CI) | |||
|---|---|---|---|---|---|---|---|
| CR | CRu | PR | SD | ||||
| ≥3 cycles | |||||||
| All | 50 | 25 (50) | 13 (26) | 11 (22) | 1 (2) | 76 (62–87) | 98 (89–100) |
| Indolent B‐NHL | 41 | 19 (46) | 12 (29) | 9 (22) | 1 (2) | 76 (60–88) | 98 (87–100) |
| MCL | 9 | 6 (67) | 1 (11) | 2 (22) | 0 | 78 (40–97) | 100 (66–100) |
| <3 cycles | |||||||
| All | 19 | 2 (11) | 6 (32) | 6 (32) | 5 (26) | 42 (20–67) | 74 (49–91) |
| Indolent B‐NHL | 17 | 1 (6) | 6 (35) | 5 (29) | 5 (29) | 41 (18–67) | 71 (44–90) |
| MCL | 2 | 1 (50) | 0 | 1 (50) | 0 | 50 (1–99) | 100 (16–100) |
†International Workshop Response Criteria (IWRC) for NHL.( 24 ) CI, confidence interval; CR, complete response, CRu, unconfirmed CR; MCL, mantle cell lymphoma; NHL, non‐Hodgkin lymphoma; ORR, overall response rate; PR, partial response; SD, stable disease.
After a median follow‐up of 12.6 months (range, 1.3–17.9 months), disease progression was observed in 21 patients, 19 with indolent B‐NHL, and two with MCL; median PFS had not yet been reached (Fig. 1). Estimated PFS rates at 1 year were 74% in the overall population, 70% in patients with indolent B‐NHL, and 90% in patients with MCL.
Figure 1.
Kaplan–Meier analysis of progression‐free survival (PFS) in patients with relapsed indolent B‐cell non‐Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL) who were treated with bendamustine.
Safety. The main toxicity observed with bendamustine treatment was reversible myelosuppression, including grade 3/4 neutropenia (72%), leukopenia (65%), and thrombocytopenia (16%) (Table 5). Twenty‐seven (39%) patients received growth factor support, two patients received platelet transfusions, and one patient received a transfusion of packed red blood cells.
Table 5.
Hematologic toxicity in bendamustine‐treated patients, by grade† (n = 69)
| Event | Patients affected, n | |||||
|---|---|---|---|---|---|---|
| Grade, n | All grades n (%) | Grade 3/4 n (%) | ||||
| 1 | 2 | 3 | 4 | |||
| Leukopenia | 5 | 17 | 37 | 8 | 67 (97) | 45 (65) |
| Neutropenia | 2 | 10 | 17 | 33 | 62 (90) | 50 (72) |
| Thrombocytopenia | 31 | 10 | 7 | 4 | 52 (75) | 11 (16) |
| Anemia | 25 | 17 | 2 | 2 | 46 (67) | 4 (6) |
†As graded by Common Terminology Criteria for Adverse Events, version 3.0.( 26 )
Common non‐hematologic adverse events included nausea (86%), fatigue (62%), and anorexia (61%), and were mainly grade 1/2 in severity (Table 6). Seventeen infections of any grade were observed in 11 patients (16%); grade 3 infection was observed in five patients (7%; one each febrile neutropenia, pneumonia, upper airway infection, varicella/herpes zoster, and viral pharyngitis), and no grade 4 infection was observed. Twenty adverse events in 11 patients were considered serious and required hospitalization. All serious adverse events were resolved with or without treatment. There were no deaths attributed to bendamustine treatment.
Table 6.
Non‐hematologic toxicity in bendamustine‐treated patients, by grade† (n = 69)
| Event‡ | Patients affected, n | |||||
|---|---|---|---|---|---|---|
| Grade, n | All grades n (%) | Grade 3/4 n (%) | ||||
| 1 | 2 | 3 | 4 | |||
| Nausea | 37 | 22 | 0 | 0 | 59 (86) | 0 |
| Fatigue | 35 | 8 | 0 | 0 | 43 (62) | 0 |
| Anorexia | 27 | 13 | 2 | 0 | 42 (61) | 2 (3) |
| Constipation | 26 | 6 | 0 | 0 | 32 (46) | 0 |
| Rash | 10 | 21 | 1 | 0 | 32 (46) | 1 (1) |
| Vomiting | 14 | 12 | 3 | 0 | 29 (42) | 3 (4) |
| Weight loss | 17 | 6 | 1 | 0 | 24 (35) | 1 (1) |
| Fever | 15 | 6 | 0 | 0 | 21 (30) | 0 |
| Phlebitis | 12 | 7 | 2 | 0 | 21 (30) | 2 (3) |
| Vascular pain | 20 | 0 | 0 | 0 | 20 (29) | 0 |
| Injection site reaction | 15 | 3 | 0 | 0 | 18 (26) | 0 |
| Dysgeusia | 14 | 3 | 0 | 0 | 17 (25) | 0 |
| Diarrhea | 11 | 5 | 0 | 0 | 16 (23) | 0 |
| Headache | 14 | 2 | 0 | 0 | 16 (23) | 0 |
| Other skin reaction (redness) | 12 | 1 | 0 | 0 | 13 (19) | 0 |
| Oral mucositis | 10 | 2 | 0 | 0 | 12 (17) | 0 |
| Gastric discomfort | 8 | 3 | 0 | 0 | 11 (16) | 0 |
| Infection§ | 5 | 1 | 5 | 0 | 11 (16) | 5 (7) |
| Candida stomatitis | 1 | 1 | 0 | 0 | 2 (3) | 0 |
| Febrile neutropenia | 0 | 0 | 1 | 0 | 1 (1) | 1 (1) |
| Herpes | 3 | 1 | 0 | 0 | 4 (6) | 0 |
| Pneumonia | 0 | 0 | 1 | 0 | 1 (1) | 1 (1) |
| Upper airway infection | 0 | 0 | 1 | 0 | 1 (1) | 1 (1) |
| Varicella/herpes zoster | 1 | 1 | 1 | 0 | 3 (4) | 1 (1) |
| Viral pharyngitis | 0 | 0 | 1 | 0 | 1 (1) | 1 (1) |
| Other infection | 1 | 0 | 0 | 0 | 1 (1) | 0 |
†As graded by Common Terminology Criteria for Adverse Events, version 3.0.( 26) ‡Events occurring in ≥15% of patients. §Indicates the number of patients developing any infection, at the greatest severity; totals do not sum because more than one type of infection could occur per patient.
Dose reductions or delays were not necessary for most patients. In 11 patients (19%), the bendamustine dose was reduced from 120 mg/m2 to 90 mg/m2; in two additional patients (3%), the dose was reduced from 120 mg/m2 to 90 mg/m2 and then reduced again to 60 mg/m2. The mean dose intensity administered was 70.14 ± 8.78 mg/m2/week, which is equivalent to a mean relative dose intensity of 88% ± 11%. During cycles 2 through 5, treatment was delayed in 47 (21%) of 219 cycles administered. No increase in the length of treatment delays was observed at later cycles; mean intervals between the start of treatment cycles ranged from 22.8 ± 3.9 days (between the first and second cycles) and 25.0 ± 5.3 days (between the fifth and sixth cycles).
Discussion
Bendamustine produced high response rates and durable responses in both indolent B‐NHL and MCL patients. Our results in patients with indolent B‐NHL complement previous studies of bendamustine in relapsed indolent B‐NHL. The 91% ORR (by IWRC) observed in this study compares favorably with the 75–80% ORR observed in the two North American trials.( 20 , 21 ) Differences in patient population may account for the higher response rates observed in our study because patients were required to be rituximab refractory or intolerant in the North American studies. In patients with MCL, the observed response rate of 100% in our trial was particularly encouraging. A high response rate in MCL patients was also observed with bendamustine plus rituximab in a North American phase II trial.( 28 ) Although the number of MCL patients treated in both trials was small, bendamustine appears to be at least as effective in these patients as in those with indolent B‐NHL, providing a valuable treatment option in a population that typically demonstrates poor response rates.
The responses were durable in both subtypes, and the median PFS was not reached after a median follow‐up of 12.6 months. The proportion of MCL patients estimated to be progression free at 1 year was similar to that in patients with indolent B‐NHL, even though the MCL population was more heavily pretreated.
We assessed patient response using both the IWRC and the revised RC in order to incorporate PET findings into our assessment while allowing for accurate comparison of our data with historical data. The ORRs assessed using the two sets of criteria were very similar, although the CR rate tended to be lower with the revised RC, possibly due to the elimination of the CRu category in the revised criteria. Overall, the results from either method were in general agreement, and the discrepancies did not affect efficacy conclusions.
In subgroup analyses, we found that patients who completed three or more cycles of treatment had higher response rates than patients who received fewer than three treatment cycles. Conversely, dose reductions did not appear to adversely affect treatment outcome because all 11 patients who underwent dose reductions responded to treatment. Based on these results, it might be reasonable that dose reductions be performed when necessary to allow continuation of treatment. Neither the extent of previous therapy (<3 or ≥3 prior therapies, or 1, 2, or 3 + prior therapies) nor the refractoriness of patients to prior therapy affected response rates. The distinct mechanism of action of bendamustine may partly explain its low cross‐resistance in heavily pretreated or refractory patients.
Reversible myelosuppression was the primary adverse event associated with bendamustine and was the reason given most frequently for discontinuation of treatment. Tumor lysis syndrome was not observed in this study. Few serious adverse events occurred, and all were resolved with or without treatment. No secondary malignancies were observed during the study period (median follow‐up of 12.6 months). Gastrointestinal events were common, but were typically mild in severity. The majority of adverse events that occurred were manageable with supportive care and dose reductions, and most patients were able to continue to receive bendamustine without delays or dose reductions. The toxicity of bendamustine did not appear to be additive, with no increase in treatment delays noted with subsequent treatment cycles.
In conclusion, the results of this study support the use of bendamustine in relapsed indolent B‐NHL and show promising results for single‐agent bendamustine in relapsed MCL. Ongoing studies of bendamustine in combination with rituximab will further clarify the role of this distinct alkylator in both relapsed and newly diagnosed patients.
Abbreviations
- CHOP
cyclophosphamide, doxorubicin, vincristine, and prednisolone
- CI
confidence interval
- CR
complete response
- CRu
unconfirmed CR
- CT
Computed tomography
- ECOG
Eastern Cooperative Oncology Group
- FLIPI
Follicular Lymphoma International Prognostic Index
- G‐CSF
granulocyte colony‐stimulating factor
- IPI
International Prognostic Index
- IWRC
International Workshop Response Criteria
- MALT
mucosa‐associated lymphoid tissue
- MCL
mantle cell lymphoma
- NHL
non‐Hodgkin lymphoma
- ORR
overall response rate
- PD
progressive disease
- PET
positron emission tomography
- PFS
progression‐free survival
- PR
partial response
- SD
stable disease
- SPD
sum of the products of the greatest perpendicular diameters
- ULN
upper limit of the normal
- WHO
World Health Organization
Disclosure Statement
The authors have no conflict of interest.
Acknowledgments
The authors thank the patients, doctors, nurses, and staff members who participated in this multicenter trial for their excellent cooperation. Participating institutions of the Japanese Bendamustine Lymphoma Study Group: National Hospital Organization (NHO) Hokkaido Cancer Center, Tohoku University, National Cancer Center Hospital East, National Cancer Center Hospital, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Japanese Red Cross Medical Center, NTT Medical Center Tokyo, Tokai University, Hamamatsu University School of Medicine, Nagoya Daini Red Cross Hospital, NHO Nagoya Medical Center, Aichi Cancer Center, Kyoto Prefectural University of Medicine, Matsushita Memorial Hospital, National Kyushu Cancer Center, NHO Kumamoto Medical Center, and Imamura Bun‐in Hospital. Central CT/PET Review Committee members: Drs Takashi Terauchi (National Cancer Center), Ukihide Tateishi (Yokohama City University) and Mitsuaki Tatsumi (Osaka University). Data and Safety Monitoring Committee members: Drs Keisuke Toyama (Tokyo Medical University), Mayumi Mori (Tokyo Medical University), and Tomohiro Kinoshita (Nagoya University). Medical writing assistance was provided by Jill Luer, PharmD, and Janis Leonoudakis, PhD, of ApotheCom, with support from Symbio Pharmaceuticals and Eisai Co. The authors, however, were fully responsible for content and editorial decisions for this manuscript.
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