Bendamustine combined with rituximab for patients with relapsed or refractory diffuse large B cell lymphoma

Jeffrey L Vacirca, Peter I Acs, Imad A Tabbara, Peter J Rosen, Peter Lee, Eric Lynam, Jeffrey L Vacirca, Peter I Acs, Imad A Tabbara, Peter J Rosen, Peter Lee, Eric Lynam

Abstract

Patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) are treated with salvage regimens and may be considered for high-dose chemotherapy and autologous stem cell transplantation if disease is chemosensitive. Bendamustine is active in indolent B cell lymphomas and chronic lymphocytic leukemia but has not been extensively studied in aggressive lymphomas. This trial examines the combination of bendamustine and rituximab in patients with relapsed and refractory DLBCL. Patients received bendamustine at 90 mg/m² (n = 2) or 120 mg/m² (n = 57) on days 1 and 2 and rituximab at 375 mg/m² on day 1 every 28 days for up to 6 cycles. The study evaluated objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and treatment safety. Fifty-nine patients were treated, and 48 were evaluable for response. Median age was 74; 89 % had stage III or IV disease, and 63 % had high revised International Prognostic Index scores; the median number of prior therapies was 1. Based on analysis using the intent-to-treat population, the ORR was 45.8 % (complete response, 15.3 %; partial response, 30.5 %). The median DOR was 17.3 months, and the median PFS was 3.6 months. Grade 3 or 4 hematological toxicities included neutropenia (36 %), leukopenia (29 %), thrombocytopenia (22 %), and anemia (12 %). The combination of bendamustine and rituximab showed modest activity in patients with relapsed and refractory DLBCL and has an acceptable toxicity profile.

Figures

Fig. 1
Fig. 1
Kaplan–Meier time to event curves. Vertical axis represents the percentage of patients. Horizontal axis depicts time in months. a Duration of response (median = 17.3 months). b Progression-free survival (median = 3.6 months)

References

    1. Jaffe ES, Harris NL, Stein H, et al. Classification of lymphoid neoplasms: the microscope as a tool for disease discovery. Blood. 2008;112:4384–4399. doi: 10.1182/blood-2008-07-077982.
    1. 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;3:1318–1324.
    1. 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;328:1002–1006. doi: 10.1056/NEJM199304083281404.
    1. 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;23:4117–4126. doi: 10.1200/JCO.2005.09.131.
    1. Mey UJ, Orlopp KS, Flieger D, et al. Dexamethasone, high-dose cytarabine, and cisplatin in combination with rituximab as salvage treatment for patients with relapsed or refractory aggressive non-Hodgkin’s lymphoma. Cancer Invest. 2006;24:593–600. doi: 10.1080/07357900600814490.
    1. Harting R, Venugopal P, Gregory SA, et al. Efficacy and safety of rituximab combined with ESHAP chemotherapy for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Clin Lymphoma Myeloma. 2007;7:406–412. doi: 10.3816/CLM.2007.n.019.
    1. López A, Gutierrez A, Palacios A, et al. GEMOX-R regimen is a highly effective salvage regimen in patients with refractory/relapsing diffuse large-cell lymphoma: a phase II study. Eur J Haematol. 2008;80:127–132. doi: 10.1111/j.1600-0609.2007.00996.x.
    1. 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;28:4184–4190. doi: 10.1200/JCO.2010.28.1618.
    1. Cheson BD, Rummel MJ. Bendamustine: rebirth of an old drug. J Clin Oncol. 2009;27:1492–1501. doi: 10.1200/JCO.2008.18.7252.
    1. Ujjani C, Cheson B. Efficacy of bendamustine in rituximab-refractory indolent B-cell non-Hodgkin lymphoma: review of a pivotal trial. Future Oncol. 2011;1:9–14. doi: 10.2217/fon.10.169.
    1. Rummel MJ, Niederle N, Maschmeyer G et al (2009) Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus rituximab as first-line treatment of patients with advanced follicular, indolent, mantle cell lymphomas: final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). Blood 114, Abstract 405
    1. Rummel MJ, Niederle N, Maschmeyer G et al (2012) 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 30, Abstract 3
    1. Moskowitz AJ, Hamlin PA, Gerecitano J et al (2009) Bendamustine is highly active in heavily pre-treated relapsed and refractory Hodgkin lymphoma and serves as a bridge to allogeneic stem cell transplant. Blood 114, Abstract 720
    1. D’Elia GM, De Angelis F, Breccia M, et al. Efficacy of bendamustine as salvage treatment in an heavily pre-treated Hodgkin lymphoma. Leuk Res. 2010;34(11):300–301. doi: 10.1016/j.leukres.2010.06.011.
    1. DCTD, NCI, NIH, DHHS (2006) Cancer Therapy Evaluation Program: common terminology criteria for adverse events, version 3.0. . Accessed 6 June 2012
    1. MedDRA (2008) Medical dictionary for regulatory activities. Version 10.0. Northrop Grumman Corporation, Los Angeles. . Accessed 6 June 2012. Available by subscription
    1. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;26:579–86. doi: 10.1200/JCO.2006.09.2403.
    1. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10:1–10. doi: 10.1016/0197-2456(89)90015-9.
    1. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–481. doi: 10.1080/01621459.1958.10501452.
    1. Aukema SM, Siebert R, Schuuring E, et al. Double-hit B-cell lymphomas. Blood. 2011;117:2319–2331. doi: 10.1182/blood-2010-09-297879.
    1. Friedberg JW. Diffuse large B-cell lymphoma. Hematol Oncol Clin North Am. 2008;22(5):941–952. doi: 10.1016/j.hoc.2008.07.002.
    1. Lee PP, Rosen PJ. Radioimmunotherapy for CD20-positive B-cell non-Hodgkin’s lymphoma. Commun Oncol. 2011;8:24–31. doi: 10.1016/S1548-5315(12)70004-9.
    1. Cheng S, Coffey G, Zhang XH, et al. SYK inhibition and response prediction in diffuse large B-cell lymphoma. Blood. 2011;118:6342–6352. doi: 10.1182/blood-2011-02-333773.
    1. Lannutti BJ, Meadows SA, Herman SE, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling ad cellular viability. Blood. 2011;117:591–594. doi: 10.1182/blood-2010-03-275305.
    1. Habermann TM. New developments in the management of diffuse large B-cell lymphoma. Hematol Suppl. 2012;1:S93–7.
    1. Choi MY, Kipps TJ. Inhibitors of B-cell receptor signaling for patients with B-cell malignancies. Cancer J. 2012;18(5):404–410. doi: 10.1097/PPO.0b013e31826c5810.
    1. Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL, et al. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype. Cancer. 2011;117:5058–5066. doi: 10.1002/cncr.26135.
    1. Weidmann E, Kim SZ, Rost A, et al. Bendamustine is effective in relapsed or refractory aggressive non-Hodgkin’s lymphoma. Ann Oncol. 2002;13(8):1285–1289. doi: 10.1093/annonc/mdf189.
    1. Rigacci L, Puccini B, Cortelazzo S, et al. Bendamustine with or without rituximab for the treatment of heavily pretreated non-Hodgkin’s lymphoma patients. Ann Hematol. 2012;91:1013–1022. doi: 10.1007/s00277-012-1422-5.
    1. Walter E, Schmitt T, Dietrich S, 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 Lymphoma. 2012;53(11):2290–2292. doi: 10.3109/10428194.2012.682311.
    1. 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(10):1579–1586. doi: 10.1007/s00277-012-1503-5.
    1. 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(17):2103–2109. doi: 10.1200/JCO.2012.46.5203.
    1. Corazzeli G, Capobianco G, Arcamone M, et al. Long-term results of gemcitabine plus oxaliplatin with and without rituximab as salvage treatment for transplant-ineligible patients with refractory/relapsing B-cell lymphoma. Cancer Chemother Pharmacol. 2009;64(5):907–916. doi: 10.1007/s00280-009-0941-9.

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