Efficacy and safety of bendamustine for the treatment of patients with recurring Hodgkin lymphoma
Corresponding Author
Gaetano Corazzelli
Haematology-Oncology and Stem Cell Transplantation Unit, Department of Haematology, Fondazione ‘G. Pascale’, IRCCS, Naples, Italy
Correspondence: Antonio Pinto and Gaetano Corazzelli, Haematology-Oncology and Stem Cell Transplantation Unit, National Cancer Institute, Fondazione ‘G. Pascale’, IRCCS, Naples, Italy.
E-mail: [email protected]; [email protected]
Search for more papers by this authorFrancesco Angrilli
Department of Haematology, Santo Spirito Hospital, Pescara, Italy
Search for more papers by this authorAlfonso D'Arco
Division of Oncology-Haematology, ‘Umberto I’ Hospital, Nocera Inferiore, Italy
Search for more papers by this authorFelicetto Ferrara
Division of Haematology and Stem Cell Transplantation, Cardarelli Hospital, Naples, Italy
Search for more papers by this authorPellegrino Musto
Department of Oncology-Haematology, IRCCS-CROB, Rionero in Vulture, Italy
Search for more papers by this authorAttilio Guarini
Haematology Unit, Institute “Giovanni Paolo II”, IRCCS, Bari, Italy
Search for more papers by this authorMaria Christina Cox
Department of Haematology, University “La Sapienza”, S. Andrea Hospital, Rome, Italy
Search for more papers by this authorCaterina Stelitano
Division of Haematology, Ospedale ‘Bianchi-Melacrino-Morelli’, Reggio Calabria, Italy
Search for more papers by this authorSergio Storti
Haematology Unit, Università Cattolica, Campobasso, Italy
Search for more papers by this authorEmilio Iannitto
Haematology Unit, Ospedale SS Annunziata, Taranto, Italy
Search for more papers by this authorSimona Falorio
Department of Haematology, Santo Spirito Hospital, Pescara, Italy
Search for more papers by this authorCatello Califano
Division of Oncology-Haematology, ‘Umberto I’ Hospital, Nocera Inferiore, Italy
Search for more papers by this authorAlfonso Amore
Abdominal Surgery D, Fondazione ‘G. Pascale’, IRCCS, Naples, Italy
Search for more papers by this authorManuela Arcamone
Haematology-Oncology and Stem Cell Transplantation Unit, Department of Haematology, Fondazione ‘G. Pascale’, IRCCS, Naples, Italy
Search for more papers by this authorRosaria De Filippi
Haematology-Oncology and Stem Cell Transplantation Unit, Department of Haematology, Fondazione ‘G. Pascale’, IRCCS, Naples, Italy
Department of Clinical and Experimental Medicine and Surgery, Federico II University, Naples, Italy
Search for more papers by this authorCorresponding Author
Antonio Pinto
Haematology-Oncology and Stem Cell Transplantation Unit, Department of Haematology, Fondazione ‘G. Pascale’, IRCCS, Naples, Italy
Correspondence: Antonio Pinto and Gaetano Corazzelli, Haematology-Oncology and Stem Cell Transplantation Unit, National Cancer Institute, Fondazione ‘G. Pascale’, IRCCS, Naples, Italy.
E-mail: [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Gaetano Corazzelli
Haematology-Oncology and Stem Cell Transplantation Unit, Department of Haematology, Fondazione ‘G. Pascale’, IRCCS, Naples, Italy
Correspondence: Antonio Pinto and Gaetano Corazzelli, Haematology-Oncology and Stem Cell Transplantation Unit, National Cancer Institute, Fondazione ‘G. Pascale’, IRCCS, Naples, Italy.
E-mail: [email protected]; [email protected]
Search for more papers by this authorFrancesco Angrilli
Department of Haematology, Santo Spirito Hospital, Pescara, Italy
Search for more papers by this authorAlfonso D'Arco
Division of Oncology-Haematology, ‘Umberto I’ Hospital, Nocera Inferiore, Italy
Search for more papers by this authorFelicetto Ferrara
Division of Haematology and Stem Cell Transplantation, Cardarelli Hospital, Naples, Italy
Search for more papers by this authorPellegrino Musto
Department of Oncology-Haematology, IRCCS-CROB, Rionero in Vulture, Italy
Search for more papers by this authorAttilio Guarini
Haematology Unit, Institute “Giovanni Paolo II”, IRCCS, Bari, Italy
Search for more papers by this authorMaria Christina Cox
Department of Haematology, University “La Sapienza”, S. Andrea Hospital, Rome, Italy
Search for more papers by this authorCaterina Stelitano
Division of Haematology, Ospedale ‘Bianchi-Melacrino-Morelli’, Reggio Calabria, Italy
Search for more papers by this authorSergio Storti
Haematology Unit, Università Cattolica, Campobasso, Italy
Search for more papers by this authorEmilio Iannitto
Haematology Unit, Ospedale SS Annunziata, Taranto, Italy
Search for more papers by this authorSimona Falorio
Department of Haematology, Santo Spirito Hospital, Pescara, Italy
Search for more papers by this authorCatello Califano
Division of Oncology-Haematology, ‘Umberto I’ Hospital, Nocera Inferiore, Italy
Search for more papers by this authorAlfonso Amore
Abdominal Surgery D, Fondazione ‘G. Pascale’, IRCCS, Naples, Italy
Search for more papers by this authorManuela Arcamone
Haematology-Oncology and Stem Cell Transplantation Unit, Department of Haematology, Fondazione ‘G. Pascale’, IRCCS, Naples, Italy
Search for more papers by this authorRosaria De Filippi
Haematology-Oncology and Stem Cell Transplantation Unit, Department of Haematology, Fondazione ‘G. Pascale’, IRCCS, Naples, Italy
Department of Clinical and Experimental Medicine and Surgery, Federico II University, Naples, Italy
Search for more papers by this authorCorresponding Author
Antonio Pinto
Haematology-Oncology and Stem Cell Transplantation Unit, Department of Haematology, Fondazione ‘G. Pascale’, IRCCS, Naples, Italy
Correspondence: Antonio Pinto and Gaetano Corazzelli, Haematology-Oncology and Stem Cell Transplantation Unit, National Cancer Institute, Fondazione ‘G. Pascale’, IRCCS, Naples, Italy.
E-mail: [email protected]; [email protected]
Search for more papers by this authorSummary
The management of patients with Hodgkin lymphoma (HL) recurring after stem cell transplantation (SCT) and multiply relapsed disease remains challenging. We report on 41 such patients who received bendamustine hydrochloride, a bifunctional mechlorethamine derivative mechanistically unrelated to traditional alkylators, after a median of four prior chemotherapy lines, including SCT in 85% of cases. Bendamustine was given at doses of 90–120 mg/m2 every 21 or 28 d. At first assessment (2–4 cycles), the overall response rate (ORR) was 78% with 12 (29%) complete (CR) and 20 (49%) partial responses (PR). Upon treatment prolongation to 6–8 courses, 40% of PRs progressed, yielding a final ORR of 58% with 31% of CRs. Eight patients (two CRs, six PRs) were subsequently allotransplanted. Median progression-free and overall survival exceeded 11 and 21 months respectively; complete responders displayed a median disease-free survival above 9 months with a relapse rate of only 30%. Outcomes were independent of disease chemosensitivity, previous transplant and bendamustine dose-intensity. No life-threatening or unexpected adverse events occurred. Within the limits of a retrospective analysis and schedule heterogeneity, these results appear very encouraging and prompt prospective trials to confirm bendamustine as a valuable option in the palliative setting and in cytoreductive strategies before allotransplantation.
References
- Aldinucci, D., Gloghini, A., Pinto, A., De Filippi, R. & Carbone, A. (2010) The classical Hodgkin's lymphoma microenvironment and its role in promoting tumour growth and immune escape. Journal of Pathology, 221, 248–263.
- Apostolopoulos, C., Castellano, L., Stebbing, J. & Giamas, G. (2008) Bendamustine as a model for the activity of alkylating agents. Future Oncology, 4, 323–332.
- Bauer, K., Skoetz, N., Monsef, I., Engert, A. & Brillant, C. (2011) Comparison of chemotherapy including escalated BEACOPP versus chemotherapy including ABVD for patients with early unfavourable or advanced stage Hodgkin lymphoma. The Cochrane Database of Systematic Reviews, CD007941.
- Brice, P. (2008) Managing relapsed and refractory Hodgkin lymphoma. British Journal of Haematology, 141, 3–13.
- Buglio, D., Georgakis, G. & Younes, A. (2007) Novel small-molecule therapy of Hodgkin lymphoma. Expert Review of Anticancer Therapy, 7, 735–740.
- Byrne, B.J. & Gockerman, J.P. (2007) Salvage therapy in Hodgkin's lymphoma. Oncologist, 12, 156–167.
- Canellos, G. & Josting, A. (2007) Management of recurrent Hodgkin Lymphoma. In: Hodgkin Lymphoma (ed. by R. Hoppe, P. Mauch, J. Armitage, V. Dielh & L. Weiss), pp. 271–280. Lippincott Williams & Wilkins, Philadelphia, PA.
- Cheson, B.D. (2007) The International harmonization project for response criteria in lymphoma clinical trials. Hematology/Oncology Clinics of North America, 21, 841–854.
- Cheson, B.D. & Rummel, M.J. (2009) Bendamustine: rebirth of an old drug. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 27, 1492–1501.
- Cheson, B.D., Wendtner, C.M., Pieper, A., Dreyling, M., Friedberg, J., Hoelzer, D., Moreau, P., Gribben, J., Knop, S., Montillo, M. & Rummel, M. (2010) Optimal use of bendamustine in chronic lymphocytic leukemia, non-Hodgkin lymphomas, and multiple myeloma: treatment recommendations from an international consensus panel. Clinical Lymphoma, Myeloma & Leukemia, 10, 21–27.
- Connors, J.M. (2005) State-of-the-art therapeutics: Hodgkin's lymphoma. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 23, 6400–6408.
- D'Elia, G.M., De Angelis, F., Breccia, M., Annechini, G., Panfilio, S., Danieli, R., Cavalieri, E. & Pulsoni, A. (2010) Efficacy of bendamustine as salvage treatment in an heavily pre-treated Hodgkin lymphoma. Leukemia Research, 34, e300–e301.
- Eichbaum, M., Bischofs, E., Nehls, K., Schneeweiss, A. & Sohn, C. (2009) Bendamustine hydrochloride – a renaissance of alkylating strategies in anticancer medicine. Drugs of Today, 45, 431–444.
- Gandhi, V. & Burger, J.A. (2009) Bendamustine in B-cell malignancies: the new 46-year-old kid on the block. Clinical Cancer Research: an Official Journal of the American Association for Cancer Research, 15, 7456–7461.
- Garcia, J.F., Camacho, F.I., Morente, M., Fraga, M., Montalban, C., Alvaro, T., Bellas, C., Castano, A., Diez, A., Flores, T., Martin, C., Martinez, M.A., Mazorra, F., Menarguez, J., Mestre, M.J., Mollejo, M., Saez, A.I., Sanchez, L., Piris, M.A. & Spanish Hodgkin Lymphoma Study, G. (2003) Hodgkin and Reed-Sternberg cells harbor alterations in the major tumor suppressor pathways and cell-cycle checkpoints: analyses using tissue microarrays. Blood, 101, 681–689.
- Holmberg, L. & Maloney, D.G. (2011) The role of autologous and allogeneic hematopoietic stem cell transplantation for Hodgkin lymphoma. Journal of the National Comprehensive Cancer Network, 9, 1060–1071.
- Horning, S.J., Fanale, S., de Vos, S., Borchmann, P., Illidge, T., Engert, A., Arai, S. & Younes, A. (2008) Defining a population of Hodgkin lymphoma patients for novel therapeutics: an international effort [Abstract]. Annals of Oncology: Official Journal of the European Society for Medical Oncology, 19(Suppl. 4), iv120–iv121.
- Hryniuk, W. (1998) The importance of dose intensity in outcome of chemotherapy. In: Important Advances in Oncology (ed. by S. Hellman, V. DeVita & S. Rosenberg), pp. 121–141. Lippincott, Philadelphia, PA.
- Jona, A. & Younes, A. (2010) Novel treatment strategies for patients with relapsed classical Hodgkin lymphoma. Blood Reviews, 24, 233–238.
- Juweid, M.E., Stroobants, S., Hoekstra, O.S., Mottaghy, F.M., Dietlein, M., Guermazi, A., Wiseman, G.A., Kostakoglu, L., Scheidhauer, K., Buck, A., Naumann, R., Spaepen, K., Hicks, R.J., Weber, W.A., Reske, S.N., Schwaiger, M., Schwartz, L.H., Zijlstra, J.M., Siegel, B.A. & Cheson, B.D. (2007) Use of positron emission tomography for response assessment of lymphoma: consensus of the imaging subcommittee of international harmonization project in lymphoma. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 25, 571–578.
- Kahl, B.S., Bartlett, N.L., Leonard, J.P., Chen, L., Ganjoo, K., Williams, M.E., Czuczman, M.S., Robinson, K.S., Joyce, R., van der Jagt, R.H. & Cheson, B.D. (2010) Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a multicenter study. Cancer, 116, 106–114.
- Kuruvilla, J., Keating, A. & Crump, M. (2011) How I treat relapsed and refractory Hodgkin lymphoma. Blood, 117, 4208–4217.
- Leoni, L.M. & Hartley, J.A. (2011) Mechanism of action: the unique pattern of bendamustine-induced cytotoxicity. Seminars in Hematology, 48(Suppl. 1), S12–S23.
- Leoni, L.M., Bailey, B., Reifert, J., Bendall, H.H., Zeller, R.W., Corbeil, J., Elliott, G. & Niemeyer, C.C. (2008) Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clinical Cancer Research: an Official Journal of the American Association for Cancer Research, 14, 309–317.
- Linch, D.C., Winfield, D., Goldstone, A.H., Moir, D., Hancock, B., McMillan, A., Chopra, R., Milligan, D. & Hudson, G.V. (1993) Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial. Lancet, 341, 1051–1054.
- Magyari, F., Simon, Z., Barna, S., Udvardy, M., Varoczy, L. & Illes, A. (2011) Successful administration of rituximab-bendamustine regimen in the relapse of Hodgkin lymphoma after autologous hemopoietic stem cell transplantation. Hematological Oncology, 30, 98–100.
- Moskowitz, A.J., Hamlin, P., Gerecitano, J., Horwitz, S., Matasar, M., Noy, A., Palomba, M. L., Portlock, C., Straus, D., Graustein, T., Zelenetz, A. & Moskowitz, C. (2011) Updated results of a phase II trial of bendamustine in relapsed and refractory Hodgkin lymphoma. Annals of Oncology: Official Journal of the European Society for Medical Oncology, 22(Suppl. 4), iv180–iv181.
- Roue, G., Lopez-Guerra, M., Milpied, P., Perez-Galan, P., Villamor, N., Montserrat, E., Campo, E. & Colomer, D. (2008) Bendamustine is effective in p53-deficient B-cell neoplasms and requires oxidative stress and caspase-independent signaling. Clinical Cancer Research: an Official Journal of the American Association for Cancer Research, 14, 6907–6915.
- Steidl, C., Connors, J.M. & Gascoyne, R.D. (2011) Molecular pathogenesis of Hodgkin's lymphoma: increasing evidence of the importance of the microenvironment. Journal of Clinical Oncology, 29, 1812–1826.
- Strumberg, D., Harstrick, A., Doll, K., Hoffmann, B. & Seeber, S. (1996) Bendamustine hydrochloride activity against doxorubicin-resistant human breast carcinoma cell lines. Anti-Cancer Drugs, 7, 415–421.
- Swerdlow, S.H., Campo, E., Harris, N.L., Jaffe, E.S., Pileri, S.A., Stein, H., Thiele, J. & Vardiman, J.W. (2008) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edn. IARC, Lyon, France.
- Tageja, N. & Nagi, J. (2010) Bendamustine: something old, something new. Cancer Chemotherapy and Pharmacology, 66, 413–423.
- Uhm, J. & Kuruvilla, J. (2012) Treatment of newly diagnosed advanced stage Hodgkin lymphoma. Blood Review, 26, 167–174.
- Ujjani, C. & Cheson, B.D. (2010) Bendamustine in chronic lymphocytic leukemia and non-Hodgkin's lymphoma. Expert Review of Anticancer Therapy, 10, 1353–1365.
- Visani, G., Malerba, L., Stefani, P.M., Capria, S., Galieni, P., Gaudio, F., Specchia, G., Meloni, G., Gherlinzoni, F., Giardini, C., Falcioni, S., Cuberli, F., Gobbi, M., Sarina, B., Santoro, A., Ferrara, F., Rocchi, M., Ocio, E.M., Caballero, M.D. & Isidori, A. (2011) BeEAM (bendamustine, etoposide, cytarabine, melphalan) before autologous stem cell transplantation is safe and effective for resistant/relapsed lymphoma patients. Blood, 118, 3419–3425.
- Younes, A. (2009) Novel treatment strategies for patients with relapsed classical Hodgkin lymphoma. Hematology/The Education Program of the American Society of Hematology, 1, 507–519.
10.1182/asheducation-2009.1.507 Google Scholar
- Younes, A., Gopal, A.K., Smith, S.E., Ansell, S.M., Rosenblatt, J.D., Savage, K.J., Ramchandren, R., Bartlett, N.L., Cheson, B.D., de Vos, S., Forero-Torres, A., Moskowitz, C.H., Connors, J.M., Engert, A., Larsen, E.K., Kennedy, D.A., Sievers, E.L. & Chen, R. (2012a) Results of a pivotal phase II study of brentuximab vedotin for patients With relapsed or refractory Hodgkin's lymphoma. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 30, 2183–2189.
- Younes, A., Yasothan, U. & Kirkpatrick, P. (2012b) Brentuximab vedotin. Nature Reviews. Drug Discovery, 11, 19–20.
Citing Literature
