FORUM

DCTH - 1•2014 - 22-29

Bendamustine in diffuse large cell lymphomas Michele Spina Division of Medical Oncology A, National Cancer Institute, Aviano (PN), Italy

SUMMARY Elderly patients with diffuse large B cell lymphoma often are no suitable of standard treatment due to comorbidities. Therefore to have the opportunity to use less toxic regimens and of similar efficacy represents a medical need. The combination of rituximab and bendamustine has shown a significant reduction in terms of both hematological and extra-hematological toxicity and a surprising activity both in front line and in relapsing/ refractory setting.

◗◗◗ INTRODUCTION Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin’s lymphoma (NHL), accounting for approximately 30% of all lymphoma diagnoses. It is a heterogeneous disorder with subtypes distinguished by various clinical, pathologic, and molecular characteristics (1). Since the 1970s, the combination of cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) has been the standard therapy for DLBCL (2), producing long-term 5-year survival in 30-35% of patients with other more intensive drug combinations producKey words: non-Hodgkin’s lymphoma; therapy; bendamustine. Correspondence: Michele Spina Division of Medical Oncology A National Cancer Institute Aviano (PN), Italy E-mail: [email protected]” [email protected]

ing no additional benefit (3). In 2002, the addition of the chimeric anti-CD20 monoclonal antibody rituximab to CHOP (R-CHOP) was shown to significantly improve both the complete response (CR) rate and overall survival (OS) of patients with DLBCL, with 5-year OS of 58% for R-CHOP versus 45% for CHOP alone (4). The combination of R-CHOP has since become the most broadly accepted treatment regimen for DLBCL. Despite the proven efficacy of this firstline regimen for DLBCL, approximately one third of patients develop relapsed or refractory disease, which remains a major cause of morbidity and mortality (5). Salvage strategies generally include the use of chemotherapy (with or without rituximab) followed by high dose chemotherapy with autologous stem-cell transplantation (ASCT) with a 3-year OS of less than 50% (6). However, a large proportion of elderly or frail patients are not suitable for standard treatments both in frontline and salvage settings due to the presence

Bendamustine in diffuse large cell lymphomas

of severe comorbidities. Therefore alternative regimens should be tested in these patients. Bendamustine has shown a broad clinical activity in the treatment of numerous hematological and solid malignancies (7). Based on the findings of several phase I and II trials in NHL and chronic lymphocytic leukemia, several randomized trials were initiated to compare bendamustine plus rituximab with standard therapies showing (specially in low grade NHL) to be highly active with low toxicity (8,9). Moreover, the efficacy of bendamustine in aggressive B-cell lymphomas has been evaluated in a few studies in both the relapsed-refractory and upfront settings. ◗◗◗ FIRST LINE (PROSPECTIVE STUDIES) Regarding the first line setting only few prospective studies have been conducted. Weidmann conducted a prospective phase II study with rituximab (375 mg/m2 day 1) plus bendamustine (120 mg/m2 days 2-3) (R-B) every 3 weeks as first-line treatment in 14 patients aged 80 years or older with newly diagnosed DLBCL. All patients were considered not eligible to R-CHOP or not suitable for aggressive chemotherapy. The median age was 85 years (range 80-95 years) and 43% of patients had advanced stage of disease. The CR rate was 54% with a good safety profile: neutropenia in 23% of patients (17% grade 3 and 6% grade 4). All other grade 3 and 4 hematotoxicities and non-hematological toxic effects ranged between 2% and 11%. The median OS was 7.7 months,

and the median progression-free survival (PFS) 7.7 months and 6 patients are alive and disease-free at 54.5 months (10). The preliminary results of two ongoing studies have recently reported. Park et al. presented the interim analysis of a multicenter phase II study of R-B in older patients with previously untreated DLBCL. In this study, 23 patients with ≥65 years of age who were deemed poor candidates for R-CHOP therapy at the discretion of the treating physician were enrolled and treated with rituximab (375 mg/m2 day 1) plus bendamustine (120 mg/m2 days 2-3) every 3 weeks for 8 cycles. The median age was 80 years (range 65-89 years) and 83% of patients had stage III-IV of disease and 78% of patients had international prognostic index (IPI) score of ≥3. The overall response rate was 93% with a complete response rate of 60% for 15 evaluable patients. The median time to progression was 7.4 months. The median survival was 9.9 months (95% CI of 3.6-10.9) for all patients, but for patients with Eastern Cooperative Oncology Group (ECOG) score of ≥2, the median survival was 3.6 months (1.4-6.0). Grade 3/4 toxicity observed in >10% of patients were anemia (27%), neutropenia (18%), lymphopenia (68%), thrombocytopenia (18%), and fatigue (14%). Four grade 5 treatment-related toxicities, including two cases of pneumonia and two cases of anorexia, were reported. Four deaths were directly related to disease progression during or after treatment. Six patients died of other causes, including cerebral vascular accidents, congestive heart failure, and hip fracture, which were felt to be related to the patients’ underlying comorbidities. OS at 12 months was 25% (11). Recently, within the Fondazione Italiana Lin-

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fomi (FIL; Italian Lymphomas Foundation), we presented the results of the interim analysis of a phase II multicenter prospective study aiming to evaluate the feasibility and activity of rituximab (375 mg/m2 day 1) plus bendamustine (90 mg/m2 days 2-3) every 4 weeks for 6 cycles in frail patients with DLBCL. The median age of the whole group was 81 years (range 76-89 years), 70% of patients had stage III-IV of disease and 45% an ECOG score ≥2. Five out of 14 evaluable patients achieved a CR (36%) with an acceptable both hematological and extra- hematological toxicity (Spina M, et al. Results of the Interim analysis of R-BENDA Frail. Annual meeting of the Fondazione Italiana Linfomi. Modena, 3-5 October 2014, personal communication). The study recently completed the accrual and the final results will be available for the end of September 2014.

◗◗◗ FIRST LINE (RETROSPECTIVE STUDIES) Several retrospective series have shown the efficacy and low toxicity profile of R-B. Walter et al. evaluated 15 patients treated between 1/2004 and 6/2009. The dose of bendamustine was administered on two consecutive days and differed between 60 and 120 mg/ m2 (mean 90 mg/m2). Cycles were repeated at 21- or 29-days. The median age was 79 years (range 68-88 years) and 60% of patients had advanced stage of disease. The CR rate was 38% with an acceptable toxicity: infection in 26% and neutropenia in 17% of patients, respectively with a premature discontinuation rate of 8%. The median OS was 9 months, and the median PFS 6 months (12). Recently, Hammersen et al. reported the results of a

TABLE 1 • Efficacy of rituximab plus bendamustine upfront. Regimen

No. of patients

Median age (years)

ORR

CR rate

Median survival (months)

R-Benda 90 mg every 21 days Retrospective

15

79

61%

38%

9

Walter et al. (12)

R-Benda 90 mg every 21 days Retrospective

14

82

73%

18%

11.5

Hammersen et al. (13)

R-Benda 120 mg every 21 days Prospective

13

81

69%

54%

7.7

Weidmann et al. (14)

R-Benda 120 mg every 21 days Prospective

15

80

93%

60%

10

Park et al. (11)

R-Benda 90 mg every 28 days Prospective

21

81

67%

36%

Not reported

ORR, overall response rate; CR, complete response.

Reference

R-Benda FRAIL FIL study (Spina et al., 2014, personal communication)

Bendamustine in diffuse large cell lymphomas

TABLE 2 • Hematological toxicity (grade >2) of rituximab plus bendamustine upfront. Regimen

No. of patients

Neutropenia

Anemia

R-Benda 90 mg every 21 days Retrospective

15

11%

9%

12%

Walter et al. (12)

R-Benda 90 mg every 21 days Retrospective

14

15%

5%

11%

Hammersen et al. (13)

R-Benda 120 mg every 21 days Prospective

13

13%

10%

12%

Weidmann et al. (14)

R-Benda 120 mg every 21 days Prospective

15

18%

27%

18%

Park et al. (11)

R-Benda 90 mg every 28 days Prospective

21

43%

22%

9%

R-Benda FRAIL FIL study (Spina et al., 2014, personal communication)

retrospective analysis on 14 patients with newly diagnosed DLBCL treated with rituximab at the standard dose and bendamustine 90 mg/m2 for two consecutive days every 3 weeks. The median age was 82 years (range 7089 years) and 38% of patients had an ECOG score ≥2. The overall response rate (ORR) was 91% with a CR rate of 50% and 7 patients in CR lasting more than 5 years. Moreover, the median PFS was 6 months and the median OS was 15 months. The analysis of cell of origin showed 5 cases of germinal B-cell (GBC) and 6 activated B-cell (ABC) lymphomas. GCB-patients showed an ORR of 80% (2 CR and 2 partial remission, PR), a median PFS of 8 months and an OS of 15 months, respectively. ABC-patients had an ORR 67% (no CR, 4 PR, 2 stable disease), a median PFS of 6 months and OS an of 8 months, respectively (P=n.s.) (13).

Thrombocytopenia Reference

Tables 1, 2 and 3 summarize the efficacy and toxicity of rituximab plus bendamustine upfront (11,12-14; Spina et al., 2014, personal communication). ◗◗◗ RELAPSED OR REFRACTORY SETTING The first study on the use of bendamustine in pretreated patients was published by Weidmann et al. on 18 patients with an ORR of 44% and a CR rate of 17% and no severe toxicity (14). Walter et al. reported with the use of R-B a CR rate of 29% in 12 relapsed/refractory patients with a median PFS of 5 months and a median OS of 12 months (12). In a retrospective evaluation of the FIL 12% of patients with refractory DLBCL achieved a CR (15). Similar data were reported by Horn at al. on 15 patients with a median age of 72

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TABLE 3 • Extra-hematological toxicity (grade >2) of rituximab plus bendamustine upfront. No. of patients

Nausea

Fever

Infection

Alopecia

R-Benda 90 mg every 21 days Retrospective

15

2%

2%

18%

0%

Walter et al. (12)

R-Benda 90 mg every 21 days Retrospective

14

2%

4%

3%

0%

Hammersen et al. (13)

R-Benda 120 mg every 21 days Prospective

13

6%

5%

10%

0%

Weidmann et al. (14)

R-Benda 120 mg every 21 days Prospective

15

1%

7%

13%

0%

Park et al. (11)

0%

R-Benda FRAIL FIL study (Spina et al., 2014, personal communication)

Regimen

R-Benda 90 mg every 28 days Prospective

21

0%

1%

years (range 51-86 years). The authors found a CR rate of 20% without any significant toxicity (16). In a multicenter large clinical phase II study, Ohmachi et al. treated 63 patients with relapsed or refractory DLBCL with R-B (B 120 mg/ m2 on days 2 and 3 of each 21-day cycle for up to six cycles). The median age was 67 years (range, 36 to 75 years), and 62.7% of patients were 65 years of age or older. Fifty-seven patients (96.6%) were previously treated with rituximab-containing chemotherapy. The ORR was 62.7% (95% CI, 49.1% to 75%), with a CR rate of 37.3% (95% CI, 25% to 50.9%). The ORRs were comparable between patients >65 years of age and less than 65 years (62.2% and 63.6%, respectively). The median PFS was 6.7 months (95% CI, 3.6 to 13.7 months). The most frequently observed grade 3 or 4 adverse events were hematologic: lymphopenia (78%), neutropenia (76%), leucopenia (73%), CD4 lymphopenia (66%), and thrombocy-

0%

Reference

topenia (22%) (17). Recently, two additional studies have confirmed the activity of R-B in relapsed or refractory patients. Hammersen et al. reported the data on 30 patients treated with R-B achieving an ORR of 66% with a median PFS of 8 month and OS of 24 month (13). Vacirca et al. treated 61 patients with R-B (B 120 mg/m2 on two consecutive days every 28 days up to six cycles). Study patients had a median age of 74, evenly distributed for gender, and 94% had ECOG 0 or 1. Eighty-nine percent of patients had Ann Arbor stage III or IV disease, and 63% had a poor revised IPI risk score. Bone marrow involvement was positive in 11% of patients. Fifty-one percent of patients had received one prior line of therapy, 21% had received two, 13% had received three, and 15% had received more than three prior lines of therapy. Almost all patients had received prior rituximab (95%). Five patients (8%) had

Bendamustine in diffuse large cell lymphomas

TABLE 4 • Efficacy of rituximab plus bendamustine in relapsed/refractory patients. Regimen

Dosage (mg/mq)

No. of patients

ORR

CR

PR

Reference

Bendamustine

120

18

44%

17%

27%

Weidmann et al. (14)

Rituximab Bendamustine

375 90/120

48

46%

15%

31%

Vacirca et al. (18)

Rituximab Bendamustine

375 120

63

63%

37%

26%

Ohmachi et al. (17)

Rituximab Bendamustine

375 90

11

54%

20%

34%

Horn et al. (16)

375 90/120

34

32%

12%

20%

Rigacci et al. (15)

Rituximab Bendamustine

375 90

12

58%

29%

29%

Walter et al. (12)

Rituximab Bendamustine +/-

375 120

30

66%

30%

36%

Hammersen et al. (13)

Rituximab Bendamustine +/-

ORR, overall response rate; CR, complete response; PR, partial remission.

TABLE 5 •Hematological toxicity (grade >2) of rituximab plus bendamustine in relapsed/refractory patients. Regimen

No. of patients

Neutropenia

Anemia

Thrombocytopenia

Reference

Benda (120)

18

10%

8%

13%

Weidmann et al. (14)

R-Benda (120)

48

36%

12%

22%

Vacirca et al. (18)

R-Benda (120)

63

76%

17%

22%

Ohmachi et al. (17)

R-Benda (90)

11

22%

12%

18%

Horn et al. (16)

Benda (90) +/- R

34

Not reported

Not reported

Not reported

Rigacci et al. (15)

R-Benda 90

12

17%

Not reported

Not reported

Walter et al. (12)

Benda (120)+/- R

30

15%

12%

20%

Hammersen et al. (13)

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TABLE 6 • Extra-hematological toxicity (grade >2) of rituximab plus bendamustine in relapsed/ refractory patients. Regimen

No. of patients

Nausea

Fever

Infection

Alopecia

Reference

Benda (120)

18

2%

2%

3%

7%

Weidmann et al. (14)

R-Benda (120)

48

4%

4%

3%

0%

Vacirca et al. (18)

R-Benda (120)

63

0%

2%

12%

0%

Ohmachi et al. (17)

R-Benda (90)

11

1%

2%

2%

0%

Horn et al. (16)

Benda (90) +/- R

34

Not reported

Not reported

Not reported

Not reported

Rigacci et al. (15)

R-Benda 90

12

Not reported

Not reported

30%

0%

Walter et al. (12)

Benda (120)+/- R

30

1%

2%

1%

0%

Hammersen et al. (13)

undergone prior ASCT. The ORR was 46% with a 15% of CR and a 30% of PR. As far as toxicity, 36% of patients experienced grade 3-4 neutropenia, 22% thrombocytopenia and 12% anemia. No significant severe extra-hematological toxicity was reported. The median duration of response was 17.3 months and the median PFS was 3.6 months and eighteen patients remained progression free (18). Tables 4, 5 and 6 summarize the efficacy and toxicity of rituximab plus bendamustine in relapsed/refractory patients (12-18). ◗◗◗ CONCLUSIONS Bendamustine showed high efficacy in a variety of lymphoma subtypes and is now widely used as standard therapy

in relapsed follicular, indolent non-follicular non-Hodgkin lymphoma and mantle cell lymphoma. All published studies in DLBCL confirm this activity and low toxicity profile both in first line and subsequent lines. It represents a good choice for those patients not suitable for standard treatment. ◗◗◗ REFERENCES 1. KJaffe ES, Harris NL, Stein H, et al. Classification of lymphoid neoplasms: the microscope as a tool for disease discovery. Blood 2008; 12: 4384-99. 2. Jones SE, Grozea PN, Miller TP, et al. Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone alone or with levamisole or with levamisole plus BCG for malignant lymphoma: a Southwest Oncology Group study. J Clin Oncol 1985; 3: 131824.

Bendamustine in diffuse large cell lymphomas

3. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 1993; 328: 1002-6. 4. Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005; 23: 4117-26. 5. Friedberg JW. Relapsed/refractory diffuse large B-cell lymphoma. Hematology Am Soc Hematol Educ Program 2011; 498-505. 6. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010; 28: 4184-90. 7. Balfour JAB, Goa KL. Bendamustine. Drugs 2001; 61: 631-40. 8. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as firstline treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 2013; 381: 1203-10. 9. Robinson KS, Williams ME, van der Jagt RH, et al. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin’s lymphoma. J Clin Oncol 2008; 26: 4473-9. 10. Weidmann E, Neumann A, Fauth F, et al. Phase II study of bendamustine in combination with rituximab as first-line treatment in patients 80 years or older with aggressive B-cell lymphomas. Ann Oncol 2011; 22: 1839-44. 11. Park SI, Richards KL, Asch AS, et al. A multicenter phase II study of bendamustine in combination with rituximab in older patients with previously untreated diffuse large B-cell lymphoma.

Proceedings of the 54th ASH meeting, Waterloo, ON, Canada, July 18-23, 2010. Abstract 1791. 12. Walter E, Schmitt T, Dietrich T, et al. Rituximab and bendamustine in patients with CD20 diffuse large B-cell lymphoma not eligible for cyclophosphamide, doxorubicin, vincristine and prednisone-like chemotherapy. Leuk Lymph 2012; 53: 2290-2. 13. Hammersen J, Sommer M, Gössel C, et al. A Multicenter Phase II study of bendamustine in combination with rituximab in older patients with previously untreated diffuse large B-cell lymphoma. Proceedings of the 54th ASH meeting, Waterloo, ON, Canada, July 18-23, 2010. Abstract 4371. 14. Weidmann E, Kim SZ, Rost A, et al. Bendamustine is effective in relapsed or refractory aggressive non-Hodgkin’s lymphoma. Ann Oncol 2002; 13: 12859. 15. Rigacci L, Puccini B, Cortelazzo S, et al. Bendamustine with or without rituximab for the treatment of heavily pretreated non-Hodgkin’s lymphoma patients: A multicenter retrospective study on behalf of the Italian Lymphoma Foundation (FIL). Ann Hematol 2012; 91: 1013-22. 16. Horn J, Kleber M, Hieke S, et al. Treatment option of bendamustine in combination with rituximab in elderly and frail patients with aggressive B-non-Hodgkin lymphoma: rational, efficacy, and tolerance. Ann Hematol 2012; 91: 1579-86. 17. Ohmachi K, Niitsu N, Uchida T, et al. Multicenter phase II study of bendamustine plus rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 2013; 31: 2103-10. 18. Vacirca JL, Acs PI, Tabbara IA, et al. Bendamustine combined with rituximab for patients with relapsed or refractory diffuse large B cell lymphoma. Ann Hematol 2014; 93: 403-9.

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