This study aimed to assess the frequency of and the contributing factors for second primary malignancies (SPMs) and Richter’s transformations (RTs) following first-line treatment of chronic lymphocytic leukemia within four phase II/III trials of the GCLLSG evaluating fludarabine (F) vs F+cyclophosphamide (FC), chlorambucil vs F, FC without or with rituximab, and bendamustine+R (BR). Among 1458 patients, 239 (16.4%) experienced either an SPM (N=191) or a RT (N=75). Solid tumors (N=115; 43.2% of all second neoplasias) appeared most frequently, followed by RTs (N=75; 28.2%). Patients showed a 1.23-fold increased risk of solid tumors in comparison to the age-matched general population from the German cancer registry. Age>65 (hazard ratio (HR) 2.1; P<0.001), male sex (HR 1.7; P=0.01), co-morbidities (HR 1.6; P=0.01) and number of subsequent treatments⩾1 (HR 12.1; P<0.001) showed an independent adverse prognostic impact on SPM-free survival. Serum thymidine kinase>10 U/l at trial enrollment (HR 3.9; P=0.02), non-response to first-line treatment (HR 3.6; P<0.001) and number of subsequent treatments⩾1 (HR 30.2; P<0.001) were independently associated with increased risk for RT.
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Tsimberidou A-M, Wen S, McLaughlin P, O’Brien S, Wierda WG, Lerner S et al. Other malignancies in chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol Off J Am Soc Clin Oncol 2009; 27: 904–910.
Schöllkopf C, Rosendahl D, Rostgaard K, Pipper C, Hjalgrim H . Risk of second cancer after chronic lymphocytic leukemia. Int J Cancer J Int Cancer 2007; 121: 151–156.
Travis LB, Curtis RE, Hankey BF, Fraumeni JFJ . Second cancers in patients with chronic lymphocytic leukemia. J Natl Cancer Inst 1992; 84: 1422–1427.
Cheson BD, Vena DA, Barrett J, Freidlin B . Second malignancies as a consequence of nucleoside analog therapy for chronic lymphoid leukemias. J Clin Oncol Off J Am Soc Clin Oncol 1999; 17: 2454–2460.
Hisada M, Biggar RJ, Greene MH, Fraumeni JFJ, Travis LB . Solid tumors after chronic lymphocytic leukemia. Blood 2001; 98: 1979–1981.
DiLillo DJ, Weinberg JB, Yoshizaki A, Horikawa M, Bryant JM, Iwata Y et al. Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function. Leukemia 2013; 27: 170–182.
Görgün G, Holderried TAW, Zahrieh D, Neuberg D, Gribben JG . Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells. J Clin Invest 2005; 115: 1797–1805.
Krackhardt AM, Harig S, Witzens M, Broderick R, Barrett P, Gribben JG . T-cell responses against chronic lymphocytic leukemia cells: implications for immunotherapy. Blood 2002; 100: 167–173.
Frisch M, Biggar RJ, Engels EA, Goedert JJ, AIDS-Cancer Match Registry Study Group. Association of cancer with AIDS-related immunosuppression in adults. JAMA J Am Med Assoc 2001; 285: 1736–1745.
Gallagher MP, Kelly PJ, Jardine M, Perkovic V, Cass A, Craig JC et al. Long-term cancer risk of immunosuppressive regimens after kidney transplantation. J Am Soc Nephrol 2010; 21: 852–858.
Penn I, Starzl TE . Immunosuppression and cancer. Transplant Proc 1973; 5: 943–947.
Hallek M . Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies. Hematol Am Soc Hematol Educ Prog 2013; 2013: 138–150.
Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010; 376: 1164–1174.
Dedrick RL, Morrison PF . Carcinogenic potency of alkylating agents in rodents and humans. Cancer Res 1992; 52: 2464–2467.
Palmer RG, Denman AM . Malignancies induced by chlorambucil. Cancer Treat Rev 1984; 11: 121–129.
Rosenberg JD, Burian C, Waalen J, Saven A . Clinical characteristics and long-term outcome of young hairy cell leukemia patients treated with cladribine: a single-institution series. Blood 2014; 123: 177–183.
Han T, Ezdinli EZ, Shimaoka K, Desai DV . Chlorambucil vs. combined chlorambucil-corticosteroid therapy in chronic lymphocytic leukemia. Cancer 1973; 31: 502–508.
Knospe WH, Loeb VJ . Biweekly chlorambucil treatment of lymphocytic lymphoma. Cancer Clin Trials 1980; 3: 329–336.
O’Brien S, Kantarjian H, Beran M, Smith T, Koller C, Estey E et al. Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood 1993; 82: 1695–1700.
Urba WJ, Baseler MW, Kopp WC, Steis RG, Clark JW, Smith JW 2nd et al. Deoxycoformycin-induced immunosuppression in patients with hairy cell leukemia. Blood 1989; 73: 38–46.
Kraut EH, Neff JC, Bouroncle BA, Gochnour D, Grever MR . Immunosuppressive effects of pentostatin. J Clin Oncol Off J Am Soc Clin Oncol 1990; 8: 848–855.
Robak T, Blonski JZ, Gora-Tybor J, Kasznicki M, Konopka L, Ceglarek B et al. Second malignancies and Richter’s syndrome in patients with chronic lymphocytic leukaemia treated with cladribine. Eur J Cancer 2004; 40: 383–389.
Morrison VA, Rai KR, Peterson BL, Kolitz JE, Elias L, Appelbaum FR et al. Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil: results of an intergroup study, cancer and leukemia group B 9011. J Clin Oncol Off J Am Soc Clin Oncol 2002; 20: 3878–3884.
Richter MN . Generalized reticular cell sarcoma of lymph nodes associated with lymphatic leukemia. Am J Pathol 1928; 4: 285–292, 7.
Brecher M, Banks PM . Hodgkin’s disease variant of Richter’s syndrome. Report of eight cases. Am J Clin Pathol 1990; 93: 333–339.
Litz CE, Arthur DC, Gajl-Peczalska KJ, Rausch D, Copenhaver C, Coad JE et al. Transformation of chronic lymphocytic leukemia to small non-cleaved cell lymphoma: a cytogenetic, immunological, and molecular study. Leukemia 1991; 5: 972–978.
Pistoia V, Roncella S, Di Celle PF, Sessarego M, Cutrona G, Cerruti G et al. Emergence of a B-cell lymphoblastic lymphoma in a patient with B-cell chronic lymphocytic leukemia: evidence for the single-cell origin of the two tumors. Blood 1991; 78: 797–804.
Duchayne E, Delsol G, Kuhlein E, Klein B, Zhang XG, Attal M et al. Hairy cell transformation of a B-cell chronic lymphocytic leukemia: a morphological, cytochemical, phenotypic and molecular study. Leukemia 1991; 5: 150–155.
Strickler JG, Amsden TW, Kurtin PJ . Small B-cell lymphoid neoplasms with coexisting T-cell lymphomas. Am J Clin Pathol 1992; 98: 424–429.
Lee A, Skelly ME, Kingma DW, Medeiros LJ . B-cell chronic lymphocytic leukemia followed by high grade T-cell lymphoma. An unusual variant of Richter’s syndrome. Am J Clin Pathol 1995; 103: 348–352.
Tsimberidou A-M, Keating MJ . Richter syndrome: biology, incidence, and therapeutic strategies. Cancer 2005; 103: 216–228.
Tsimberidou A-M, O’Brien S, Khouri I, Giles FJ, Kantarjian HM, Champlin R et al. Clinical outcomes and prognostic factors in patients with Richter’s syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J Clin Oncol Off J Am Soc Clin Oncol 2006; 24: 2343–2351.
Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann MA, Ritgen M et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 2009; 114: 3382–3391.
Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 2006; 107: 885–891.
Extermann M, Overcash J, Lyman GH, Parr J, Balducci L . Comorbidity and functional status are independent in older cancer patients. J Clin Oncol Off J Am Soc Clin Oncol 1998; 16: 1582–1587.
Fischer K, Cramer P, Busch R, Böttcher S, Bahlo J, Schubert J et al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol Off J Am Soc Clin Oncol 2012; 30: 3209–3216.
Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 1981; 48: 198–206.
Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O’Brien S et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87: 4990–4997.
Hamblin TJ . Richter’s syndrome—the downside of fludarabine? Leuk Res 2005; 29: 1103–1104.
Robertson LE, Pugh W, O’Brien S, Kantarjian H, Hirsch-Ginsberg C, Cork A et al. Richter’s syndrome: a report on 39 patients. J Clin Oncol Off J Am Soc Clin Oncol 1993; 11: 1985–1989.
Parikh SA, Rabe KG, Call TG, Zent CS, Habermann TM, Ding W et al. Diffuse large B-cell lymphoma (Richter syndrome) in patients with chronic lymphocytic leukaemia: a cohort study of newly diagnosed patients. Br J Haematol 2013; 162: 774–782.
Mauro FR, Foa R, Giannarelli D, Cordone I, Crescenzi S, Pescarmona E et al. Clinical characteristics and outcome of young chronic lymphocytic leukemia patients: a single institution study of 204 cases. Blood 1999; 94: 448–454.
Gaidano G, Ballerini P, Gong JZ, Inghirami G, Neri A, Newcomb EW et al. p53 mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukemia. Proc Natl Acad Sci USA 1991; 88: 5413–5417.
Matolcsy A, Inghirami G, Knowles DM . Molecular genetic demonstration of the diverse evolution of Richter’s syndrome (chronic lymphocytic leukemia and subsequent large cell lymphoma). Blood 1994; 83: 1363–1372.
Byrd JC, Brown JR, O’Brien S, Barrientos JC, Kay NE, Reddy NM et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014; 371: 213–223.
Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014; 370: 997–1007.
We wish to thank the patients and their treating physicians who participated in the trials. This work was presented in part at the 12th International Conference on Malignant Lymphoma (Palazzo dei Congressi, Lugano, Switzerland, 19–22 June 2013), at the 15th International Workshop on CLL (Maritim Hotel, Cologne, Germany, 9–11 September 2013) and at the Annual Meeting of the German, Austrian and Swiss Society of Hematology and Oncology (DGHO, ÖGHO, SGMO, SGH; Austria Center Vienna, Vienna, Austria, 18–22 October 2013). The CLL4, CLL5 and CLL2M trial were planned and conducted as investigator–initiated trials by the German Chronic Lymphocytic Leukemia Study Group (GCLLSG). They were supported by research grants from German Cancer Aid, Medac Schering Onkologie, F. Hoffmann-La Roche and Mundipharma. The CLL8 study was conducted as an investigator–initiated trial by the German Chronic Lymphocytic Leukemia Study Group (GCLLSG) from 2003 to 2004 and afterwards sponsored by F. Hoffmann-La Roche.
BE received honoraria from Roche and Mudipharma for educational presentations. BE declared advisory board membership for Roche and Mundipharma. BE received research grants form Roche and Mundipharma and travel grants from Mundipharma. CM received travel grants from Mundipharma. PL received travel grants from Janssen, Roche and Mundipharma. PC received travel grants from Roche, Mundipharma and Janssen. NP received honoraria from Novartis and travel grants from JazzPharma and Celgene. AE received travel grants from Roche. JvT received travel grants from Celgene and Roche, research funding by Roche and Janssen and honoraria by Janssen. GK received travel grants from Celgene. SS received honoraria from Roche for educational presentations. SS declared advisory board membership of Roche. SS received research grants from Roche. SS received travel grants from Roche. C-MW received honoraria from Roche and Mundipharma. C-MW declared advisory board membership of Roche and Mundipharma. C-MW received research grants from Roche and Mundipharma and travel grants from Roche and Mundipharma. LM declared advisory board membership of Roche. MR received honoraria from Roche for educational presentations. MR received travel grants from Roche. KF received travel grants from Roche. MH declared advisory board membership of Roche and Celgene. MH declared participation in speakers’ bureau from Roche, Celgene, Mundipharma and Janssen. MH received research grants from Roche, Celgene and Janssen. JB, AMF and TS declare no conflict of interest.
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Maurer, C., Langerbeins, P., Bahlo, J. et al. Effect of first-line treatment on second primary malignancies and Richter’s transformation in patients with CLL. Leukemia 30, 2019–2025 (2016) doi:10.1038/leu.2016.113
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