Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Chronic lymphocytic leukemia

Effect of first-line treatment on second primary malignancies and Richter’s transformation in patients with CLL

Leukemia volume 30, pages 2019–2025 (2016)Cite this article

Subjects

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. 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.

    Article  Google Scholar 

  2. 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.

    Article  Google Scholar 

  3. Travis LB, Curtis RE, Hankey BF, Fraumeni JFJ . Second cancers in patients with chronic lymphocytic leukemia. J Natl Cancer Inst 1992; 84: 1422–1427.

    Article  CAS  PubMed  Google Scholar 

  4. 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.

    Article  CAS  Google Scholar 

  5. Hisada M, Biggar RJ, Greene MH, Fraumeni JFJ, Travis LB . Solid tumors after chronic lymphocytic leukemia. Blood 2001; 98: 1979–1981.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 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.

    Article  CAS  PubMed  Google Scholar 

  9. 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.

    Article  CAS  Google Scholar 

  10. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Penn I, Starzl TE . Immunosuppression and cancer. Transplant Proc 1973; 5: 943–947.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Hallek M . Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies. Hematol Am Soc Hematol Educ Prog 2013; 2013: 138–150.

    Article  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. Dedrick RL, Morrison PF . Carcinogenic potency of alkylating agents in rodents and humans. Cancer Res 1992; 52: 2464–2467.

    CAS  PubMed  Google Scholar 

  15. Palmer RG, Denman AM . Malignancies induced by chlorambucil. Cancer Treat Rev 1984; 11: 121–129.

    Article  CAS  PubMed  Google Scholar 

  16. 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.

    Article  CAS  PubMed  Google Scholar 

  17. Han T, Ezdinli EZ, Shimaoka K, Desai DV . Chlorambucil vs. combined chlorambucil-corticosteroid therapy in chronic lymphocytic leukemia. Cancer 1973; 31: 502–508.

    Article  CAS  PubMed  Google Scholar 

  18. Knospe WH, Loeb VJ . Biweekly chlorambucil treatment of lymphocytic lymphoma. Cancer Clin Trials 1980; 3: 329–336.

    CAS  PubMed  Google Scholar 

  19. 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.

    PubMed  Google Scholar 

  20. 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.

    CAS  PubMed  Google Scholar 

  21. 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.

    Article  CAS  Google Scholar 

  22. 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.

    Article  CAS  PubMed  Google Scholar 

  23. 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.

    Article  Google Scholar 

  24. Richter MN . Generalized reticular cell sarcoma of lymph nodes associated with lymphatic leukemia. Am J Pathol 1928; 4: 285–292, 7.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Brecher M, Banks PM . Hodgkin’s disease variant of Richter’s syndrome. Report of eight cases. Am J Clin Pathol 1990; 93: 333–339.

    Article  CAS  PubMed  Google Scholar 

  26. 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.

    CAS  PubMed  Google Scholar 

  27. 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.

    CAS  PubMed  Google Scholar 

  28. 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.

    CAS  PubMed  Google Scholar 

  29. Strickler JG, Amsden TW, Kurtin PJ . Small B-cell lymphoid neoplasms with coexisting T-cell lymphomas. Am J Clin Pathol 1992; 98: 424–429.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    Article  CAS  PubMed  Google Scholar 

  31. Tsimberidou A-M, Keating MJ . Richter syndrome: biology, incidence, and therapeutic strategies. Cancer 2005; 103: 216–228.

    Article  CAS  PubMed  Google Scholar 

  32. 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.

    Article  CAS  Google Scholar 

  33. 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.

    Article  CAS  PubMed  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

  35. 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.

    Article  CAS  Google Scholar 

  36. 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.

    Article  CAS  Google Scholar 

  37. 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.

    Article  CAS  PubMed  Google Scholar 

  38. 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.

    CAS  PubMed  Google Scholar 

  39. Hamblin TJ . Richter’s syndrome—the downside of fludarabine? Leuk Res 2005; 29: 1103–1104.

    Article  PubMed  Google Scholar 

  40. 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.

    Article  CAS  Google Scholar 

  41. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  42. 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.

    CAS  PubMed  Google Scholar 

  43. 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.

    Article  CAS  PubMed  Google Scholar 

  44. 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.

    CAS  PubMed  Google Scholar 

  45. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  46. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University of Cologne, Cologne, Germany

    C Maurer, P Langerbeins, J Bahlo, P Cramer, A M Fink, N Pflug, A Engelke, J von Tresckow, G Kovacs, K Fischer, M Hallek & B Eichhorst

  2. Department of Internal Medicine III, University of Ulm, Ulm, Germany

    S Stilgenbauer

  3. Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine, Klinikum Schwabing, Munich, Germany

    C-M Wendtner

  4. Oncology Leer, Practice for Hematology and Oncology, Leer, Germany

    L Müller

  5. Second Department of Medicine, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany

    M Ritgen

  6. Department of Medicine III, University Hospital Großhadern/LMU München, Munich, Germany

    T Seiler

  7. Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases, Univeristy of Cologne, Cologne, Germany

    M Hallek

Authors
  1. C Maurer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P Langerbeins
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Bahlo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P Cramer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A M Fink
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N Pflug
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A Engelke
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J von Tresckow
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G Kovacs
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Stilgenbauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. C-M Wendtner
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. L Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. M Ritgen
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. T Seiler
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. K Fischer
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. M Hallek
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. B Eichhorst
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

for the German CLL Study Group

Corresponding author

Correspondence to B Eichhorst.

Ethics declarations

Competing interests

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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). https://doi.org/10.1038/leu.2016.113

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2016.113

This article is cited by

Search

Advanced search

Quick links