Hodgkin’s lymphoma and a “new old” bendamustine

S.S. Shklyaev, and V.V. Pavlov

Medical Radiological Research Center, RF Ministry of Health, Obninsk, Russian Federation


Hodgkin’s lymphoma is a malignant tumor that eventually turned from a fatal incurable to successfully curable disease after primary treatment in the vast majority of cases. However, the prognosis for patients with refractory and relapsed disease is not infrequently dismal and life-threatening, especially if the tumor continues progressing after high-dose chemotherapy with autologous stem cell transplantation or, in some instances, even after allogeneic stem cell grafting. Bendamustine is a “new old” cytostatic agent that can be effectively applied for treating this group of patients. Our literature review highlights a variety of relevant options in treatment of Hodgkin’s lymphoma using bendamustine.

Keywords: Hodgkin’s lymphoma, refractory and relapsed disease, treatment, bendamustine.

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  1. Hodgkin T. On some morbid appearances of the absorbent glands and spleen. Med. Chir. Trans. 1832; 17: 68–114.
  2. Wilks S. Cases of enlargement of the lymphatic glands and spleen (or Hodgkin’s disease), with remarks. Guy’s Hosp. Rep. 1865; 11: 56–67.
  3. Sternberg K. Uber eine eigenartige unter dem Bilde der Pseudoleukamie verlaufende Tuberculose des lymphatischen Apparates. Z. Heilk. 1898; 19: 21–90.
  4. Rosenfield L. Hodgkin’s disease: origin of an eponym — and one that got away. Bull. N. Y. Acad. Med. 1989; 65: 618–32.
  5. Winiwarter A. Arch. Klin. Chir. 1875; 18: 98–102.
  6. Trousseau A. De l’adenie. Clin. Med. De Hotel-Dieu 1877; III: 609.
  7. Pusey W.A. Cases of sarcoma and of Hodgkin’s disease treated by exposure to X-rays: a preliminary report. J. Am. Med. Assoc. 1902; 38: 166–9.
  8. Goodman L.S., Wintrobe M.M., Dameshek W. et al. Nitrogen mustard therapy; use of methyl-bis (beta-chloroethyl) amine hydrochloride and tris (beta-chloroethyl) amine hydrochloride for Hodgkin’s disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. J. Am. Med. Assoc. 1946; 132: 126–32.
  9. De Vita V., Serpick A. Combination chemotherapy in the treatment of advanced Hodgkin’s disease. Proc. Am. Assoc. Cancer Res. 1967; 8: 13.
  10. De Vita V., Serpick A., Carbone P.P. Combination chemotherapy in the treatment of advanced Hodgkin’s disease. Ann. Int. Med. 1970; 73: 891–5.
  11. Fairley G.H., Patterson M.J., Scott R.B. Chemotherapy of Hodgkin’s Disease with Cyclophosphamide, Vinblastine, and Procarbazine. Br. Med J. 1966; 2(5505): 75–8.
  12. Bonadonna G., Zucali R., Monfardini S. et al. Combination chemotherapy of Hodgkin’s disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer 1975; 36(1): 252–9.
  13. Canellos G.P., Anderson J.R., Propert K.J. et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N. Engl. J. Med. 1992; 327(21): 1478–84.
  14. Diehl V. Dose-escalation study for the treatment of Hodgkin’s disease. The German Hodgkin Study Group (GHSG). Ann. Hematol. 1993; 66(3): 139–40.
  15. Connors J.M. State-of-the-art therapeutics: Hodgkin’s lymphoma. J. Clin. Oncol. 2005; 23(26): 6400–8.
  16. Brenner H., Gondos A., Pulte D. Ongoing improvement in long-term survival of patients with Hodgkin disease at all ages and recent catch up of older patients. Blood 2008; 111: 2977–83.
  17. Павлов В.В., Богатырева Т.И., Шахтарина С.В., Даниленко А.А. Оптимизация лучевого компонента в программах комбинированного химио лучевого лечения больных лимфомой Ходжкина. В кн.: Терапевти- ческая радиология. Руководство для врачей. Под ред. А.Ф. Цыба, Ю.С. Мардынского. М.: ООО «МК», 2010: 461–505. Pavlov V.V., [Bogatyreva T.I., Shakhtarina S.V., Danilenko A.A. Optimizatsiya luchevogo komponenta v programmakh kombinirovannogo himioluchevogo lecheniya bolnikh limfomoy Hodzhkina. V kn.: Terapevticheskaya radiologiya. Rukovodstvo dlya vrachey. Pod red. A.F. Tsyba, Yu.S. Mardynskogo [Optimization of radiotherapy component in combined chemoradiotherapy programs for patients with Hodgkin’s lymphoma. In: Therapeutic radiology. Manual for medical practitioners. Ed. by A.F. Tsyba, Yu.S. Mardynsky. M.: OOO “MK”, 2010: 461–505.]
  18. Ansell S.M., Armitage J.O. Management of Hodgkin lymphoma. Mayo Clin. Proc. 2006; 81(3): 419–26.
  19. Richardson S.E., McNamara C. The Management of Classical Hodgkin’s Lymphoma: Past, Present, and Future. Adv. Hematol. 2011; 2011: 865870. doi: 10.1155/2011/865870.
  20. Holmberg L., Maloney D.G. The role of autologous and allogeneic hematopoietic stem cell transplantation for Hodgkin lymphoma. J. Natl. Compr. Canc. Netw. 2011; 9(9): 1060–71.
  21. Богатырева Т.И., Павлов В.В., Шкляев С.С. Рецидивы лимфомы Ход- жкина: возможности продления жизни без высокодозной химиотерапии. Врач 2012; 11: 5–8.  [Bogatyreva T.I., Pavlov V.V., Sklyayev S.S. Retsidivy limfomy Hodzhkina: vozmozhnosti prodleniya zhizni bez vysokodoznoy himioterapii [Hodgkin’s lymphoma relapse: possibilities of life prolongation without high-dose chemotherapy. Vrach 2010; 11: 5–8.]
  1. Павлов В.В. Кроветворение при дистанционной гамма-терапии в условиях ежедневного ритма облучения: Автореф. дис. ¼ канд. мед. наук. М., 1973. Pavlov V.V. [Krovetvoreniye pri distantsionnoy gamma-terapii v usloviyakh ezhednevnogo ritma oblucheniya: Avtoref. dis. … kand. med. nauk [Hemopoiesis during X-ray therapy using daily rhythm irradiation. Author’s summary of dissertation for the degree of Candidate of medical sciences. M., 1973.]
  2. Younes A., Gopal A.K., Smith S.E. et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J. Clin. Oncol. 2012; 30(18): 2183–9.
  3. Goyal S.D., Bartlett N.L. Where does brentuximab vedotin fit into the management of patients with Hodgkin lymphoma? Curr. Hematol. Malig. Rep. 2012; 7(3): 179–85.
  4. de Claro RA, McGinn K, Kwitkowski V et al. U.S. Food and drug administration approval summary: brentuximab vedotin for the treatment of relapsed Hodgkin lymphoma or relapsed systemic anaplastic large-cell lymphoma. Clin. Cancer Res. 2012; 18(21): 5845–9.
  5. Moskowitz A.J. Novel agents in Hodgkin lymphoma. Curr. Oncol. Rep. 2012; 14(5): 419–23. doi: 10.1007/s11912-012-0251-y. Review.
  6. Canellos G.P. Brentuximab vedotin and panobinostat; new drugs for Hodgkin’s lymphoma — can they make one of medical oncology’s chemotherapy success stories more successful? J. Clin. Oncol. 2012; 30(18): 2171–2. doi: 10.1200/JCO.2011.39.6416.
  7. Lemoine M., Derenzini E., Buglio D. et al. The pan-deacetylase inhibitor panobinostat induces cell death and synergizes with everolimus in Hodgkin. Blood 2012; 119(17): 4017–25. doi: 10.1182/blood-2011- 01-331421.
  8. Guarini A., Minoia C., Giannoccaro M. et al. mTOR as a target of everolimus in refractory/relapsed Hodgkin lymphoma. Curr. Med. Chem. 2012; 19(7): 945–54.
  9. Mandac I., Kolonic S.O. Lenalidomide induced good clinical response in a patient with multiple relapsed and refractory Hodgkin’s lymphoma. J. Hematol. Oncol. 2010; 3: 20. doi: 10.1186/1756-8722-3-20.
  10. Kalaycio M. Bendamustine: a new look at an old drug. Cancer 2009; 115: 473–9.
  11. Ozegowski W., Krebs D. w-[bis-(chlorethyl)-amino-benzimidazolyl-(2)]- propionic or butyric acids as potential cytostatic agents. J. Prakt. Chem. 1963; 20: 178–86.
  12. Ozegowski W., Krebs D. IMET 3393, gamma-(1-methyl-5-bis-(b-chlrathyl)- amino-benzimidazlolyl(2)-buttersaure-hydrochlorid, ein neues Zytostatikum aus der Reihe der Benzimidazol-Loste. Zbl. Pharm. 1971; 110: 1013–9.
  13. Anger G., Hesse P., Kohler P., Baufeld H. Erste klinische Erfahrungen mit einem neuen Zytostatikum. Deutsch Gesundheitswes. 1967; 22: 1079–84.
  14. Anger G., Hesse P., Baufeld H. Behandlung des multiplen Myeloms mit einem neuen Zytostatikum. Dtsch. Med. Wochenschr. 1969; 48: 2495–500.
  15. Anger G., Fink R., Fleischer J. et al. Vergleichsuntersuchungen zwischen Cytostasan und Cyclophosphamid bei der chronischen Lymphadenose, dem Plasmozytom, der Lymphogranulomatose und dem Bronchialkarzinom. Dt. Gesundh. Wesen. 1975; 30: 1280–5.
  16. Schnabel R., Jungstand W., Gutsche W. et al. Comparative studies on the cytostatic activity of the nitrogen mustard derivative IMET 3393 and endoxan in three experimental mouse tumors (Ehrlich-ascites-carcinoma, sarcoma 180 solid, leukaemia LAJ 1). Acta Biol. Med. 1967; 19: 534–58.
  17. Hoche D., Wutke K., Anger G. et al. Vergleichende Untersuchung zur Wirksamkeit des DBVCy-Protocolls mit dem ABVD-Protokoll beim fortgeschrittenen Hodgkin Lymphom. Arch. Geschwulstforsch. 1984; 54(4): 333–42.
  18. Herold M., Anger G., Hoche D., Kastner R. Vorlaufige Ergebnisse einer zyklisch-alternierenden Chemotherapie (CVPP/DBVCy) bei fortgeschrittenem Morbus Hodgkin. Med. Klin. 1987; 82(10): 345–9.
  19. Dennie T.W., Kolesar J.M. Bendamustine for the treatment of chronic lymphocytic leukemia and rituximab-refractory, indolent B-cell non-Hodgkin lymphoma. Clin. Ther. 2009; 31: 2290–311.
  20. Cheson B.D., Wendtner C.M., Pieper A. et al. Optimal use of bendamustine in chronic lymphocytic leukemia, non-Hodgkin lymphomas, and multiple myeloma: treatment recommendations from an international consensus panel. Clin. Lymphoma Myeloma Leuk. 2010; 10(1): 21–7.
  21. Borchmann P., Schnell R., Diehl V., Engert A. New drugs in the treatment of Hodgkin’s disease. Ann. Oncol. 1998; Suppl. 5: S103–8. 43. http://ash.confex.com/ash/2009/webprogram/Paper16834.html.
  22. Moskowitz A.J., Hamlin P.A., Gerecitano J. et al. Bendamustine is highly active in heavily pre-treated relapsed and refractory Hodgin’s lymphoma and serves as a bridge to allogeneic stem cell transplant. Blood 2009; 114: Abstract 720.
  23. Moskowitz A., Perales M., Kewalramani T. et al. Outcomes for patients who fail high dose chemoradiotherapy and autologous stem cell rescue for relapsed and primary refractory Hodgkin lymphoma. Br. J. Haematol. 2009; 146: 158–63.
  24. http://clinicaltrials.gov/ct2/show/NCT00705250?term=Bendamustine+in+ Relapsed+and+Primary+Refractory+Hodgkin%27s+Lymphoma&rank=2
  25. De Flippi R., Aldinucci D., Galati D. et al. Effect of bendamustine on apoptosis and colony-initiating precursors in Hodgkin lymphoma cells. J. Clin. Oncol. 2011; 29(Suppl.): Abstract e18559.
  26. Leoni L.M., Bailey B., Reifert J. et al. Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clin. Cancer Res. 2008; 14(1): 309–17.
  27. Leoni L.M., Niemeyer C.C., Kerfoot C. et al. In vitro and ex vivo activity of SDX-105 (bendamustine) in drug-resistant lymphoma cells [abstract 1215]. Proc. Am. Assoc. Cancer Res. 2004; 45: 278.
  28. Friedberg J.W., Cohen P., Chen L. et al. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin’s lymphoma: results from a phase II multicentere, single-agent study. J. Clin. Oncol. 2008; 26(2): 204–10.
  29. Konstantinov S.M., Kostovski A., Topashka-Ancheva M. et al. Cytotoxic efficacy of bendamustine in human leukemia and breast cancer cell lines. J. Cancer Res. Clin. Oncol. 2002; 128(5): 271–8.
  30. Leoni L.M., Hartley J.A. Mechanism of action: the unique pattern of bendamustine-induced cytotoxicity. Semin. Hematol. 2011; 48(Suppl. 1): S12–23.
  31. Furukawa Y., Hiraoka N., Wada T. et al. Mechanisms of action and clinical effectiveness of the newly approved anti-cancer drug bendamustine. Nihon Yakurigaku Zasshi (Folia Pharmacol. Jpn.). 2011; 138(1): 26–32.
  32. Beeharry N., Rattner J.B., Belacosa A. et al. Dose dependent effects on cell cycle checkpoints and DNA repair by bendamustine. PLoS One. 2012; 7(6): e40342.
  33. Стругов В.В., Стадник Е.А., Зарицкий А.Ю. Механизм действия и кли- ническая эффективность нового алкилирующего препарата бендамустин при хроническом лимфолейкозе. Клин. онкогематол. 2011; 4(3): 217–27. [Strugov V.V., Stadnik E.A., Zaritskiy A.Yu. Mekhanizm deystviya i klinicheskaya effectivnost novogo alkiliruyushchego preparata bendamustin pri khronicheskom limfoleykoze [Mechanism of action and clinical efficacy of bendamustine, a new alkylating agent, in chronic lymphocytic leukemia]. Klin. onkogematol. 2011; 4(3): 217–27.]
  1. D’Elia G.M., De Anelis F., Breccia M. et al. Efficacy of bendamustine as salvage treatment in an heavily pre-treated Hodgkin lymphoma. Leuk. Res. 2010; 34(11): e300–1.
  2. Magyari F., Simon Z., Barna S. et al. Successful administration of rituximab-bendamustine regimen in the relapse of Hodgkin lymphoma after autologous hemopoietic stem cell transplantation. Hematol. Oncol. 2012; 30(2): 98–100.
  3. Jones R.J., Gocke C.D., Kasamon Y.L. et al. Circulating clonotypic B cells in classic Hodgkin lymphoma. Blood 2009; 113(23): 5920–6.
  4. Younes A., Oki Y., McLaughlin P. et al. Phase 2 study of rituximab plus ABVD in patients with newly diagnosed classical Hodgkin lymphoma. Blood 2012; 119(18): 4123–8.
  5. Kasamon Y.L., Jacene H.A., Gocke C.D. et al. Phase 2 study of rituximabABVD in classical Hodgkin lymphoma. Blood 2012; 119(18): 4129–32.
  6. Rummel M.J., Chow K.U., Hoelzer D. et al. In vitro studies with bendamustine: enhanced activity in combination with rituximab. Semin. Oncol. 2002; 29(4 Suppl. 13): 12–4.
  7. Currin E.S., Gopal A.K. Treatment strategies for Hodgkin lymphoma recurring following autologous hematopoietic stem cell transplantation. Korean J. Hematol. 2012; 47(1): 8–16.
  8. Mian M., Farsad M., Pescosta N. et al. Bendamustine salvage for the treatment of relapsed Hodgkin’s lymphoma after allogeneic bone marrow transplantation. Ann. Hematol. 2012; published online 22.07.2012.
  9. Corazzelli G., Angrilli F., D’Arco A. et al. Efficacy and safety of bendamustine for the treatment of patients with recurring Hodgkin lymphoma. Br. J. Haematol. 2013; 160(2): 207–15. doi: 10.1111/bjh.12120. [Epub ahead of print 2012 Nov. 20].
  10. Visani G., Malerba L., Stefani P.M. et al. BeEAM (bendamustine, etoposide, cytarabine, melphalan) before autologous stem cell transplantation is safe and effective for resistant/relapsed lymphoma patients. Blood 2011; 118(12): 3419–25.
  11. Регистрация клинического исследования в Европейском медицинском агентстве (European Medicines Agency): EudraCT #2008-002736-15. [Registratsiya klinicheskogo issledovaniya v Evropeyskom meditsinskom agentstve (European Medicines Agency) [Registration of a clinical study in European Medicines Agency]. EudraCT #2008-002736-15.]
  1. Kath R., Blumenstengel K., Fricke H.J. et al. Bendamustine, vincristine; prednisolone (BOP) in therapy of advanced low-grade non-Hodgkin lymphoma. Dtsch. Med. Wochenschr. 2001; 126(8): 198–202.
  2. Friedberg J.W., Vose J.M., Kelly J.L. et al. The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. Blood 2011; 117(10): 2807–12.
  3. Visco C., Castegnaro S., Chieregato K. et al. The cytotoxic effects of bendamustine in combination with cytarabine in mantle cell lymphoma cell lines. Blood Cells. Mol. Dis. 2012; 48(1): 68–75.
  4. Yong H.X., Linn Y.C., Ong K.H. et al. Chemoimmunotherapy with bendamustine hydrochloride and alemtuzumab demonstrates synergism in T-prolymphocytic leukemia. Leuk. Res. 2012; 36(8): e163–5.
  5. Alaikov T., Konstantinov S.M., Tzanova T. et al. Antineoplastic and anticlastogenic properties of curcumin. Ann. N. Y. Acad. Sci. 2007; 1095: 355–70.
  6. Lentzsch S., O’Sullivan A., Kennedy R.C. et al. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood 2012; 119(20): 4608–13.
  7. Loibl S., Doering G., Muller L. et al. Phase II Study with Weekly Bendamustine and Paclitaxel as First- or Later-Line Therapy in Patients with Metastatic Breast Cancer: RiTa II Trial. Breast Care (Basel). 2011; 6(6): 457–61.
  8. Rahn A.N., Schilcher R.B., Adamietz I.A. et al. Palliative radiochemotherapy with Bendamustine for advanced recurrent head and neck tumors. Strahlenther. Onkol. 2001; 177(4): 189–94.
  9. Bottke D., Bathe K., Wiegel T., Hinkelbein W. Phase I trial of radiochemotherapy with bendamustine in patients with recurrent squamous cell carcinoma of the head and neck. Strahlenther. Onkol. 2007; 183(3): 128–32.
  10. Moskowitz A.J., Hamlin P.A. Jr., Perales M.A. et al. Phase II Study of Bendamustine in Relapsed and Refractory Hodgkin Lymphoma. J. Clin. Oncol. 2012 Dec 17 [Epub ahead of print].