Skip to main content
SpringerLink
Log in

Richter Syndrome

  • Chapter
  • First Online:
Advances in Chronic Lymphocytic Leukemia

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 792))

Abstract

Transformation of chronic lymphocytic leukemia (CLL) to aggressive lymphoma is known as Richter syndrome (RS). In the CLL population considered as a whole, the prevalence of RS development ranges from 2 to 7 %. The most common pathologic phenotype at the time of RS transformation is diffuse large B-cell lymphoma (DLBCL), while, in a small fraction of cases, the transformed phase shows pathologic features mimicking Hodgkin lymphoma. TP53 disruption and MYC activation cooperate as dual hits in driving DLBCL transformation. Two biomarkers (NOTCH1 mutations and usage of the immunoglobulin VH CDR3 subset 8) may help in identifying CLL patients at risk of DLBCL transformation to be considered for close monitoring and a careful biopsy policy. In the presence of clinical features suspicious of RS, diagnosis of transformation and choice of the site of biopsy may take advantage of 18FDG PET/CT. The prognosis of RS transformation is generally highly unfavorable. However, the pattern of survival is not homogeneous and may be predicted on clinical and biological grounds. RS that are clonally unrelated to the paired CLL phase are biologically and clinically different from clonally related cases, and should be considered, and probably managed, as a de novo DLBCL arising in the context of CLL. Rituximab-containing polychemotherapy represents the backbone for induction treatment in patients with clonally related DLBCL transformation. Younger patients who respond to induction therapy should be offered stem cell transplant to prolong survival.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Müller-Hermelink HK, Montserrat E, Catovsky D, Campo E, Harris NL, Stein H. Chronic lymphocytic leukemia/small lymphocytic lymphoma. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, editors. World Health Organization classification of tumours, pathology and genetics of tumours of haematopoietic and lymphoid tissues. Lyon: IARC; 2008. p. 180–2.

    Google Scholar 

  2. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111:5446–56.

    Article  PubMed  CAS  Google Scholar 

  3. Cherepakhin V, Baird SM, Meisenholder GW, Kipps TJ. Common clonal origin of chronic lymphocytic leukemia and high-grade lymphoma of Richter’s syndrome. Blood. 1993;82:3141–7.

    PubMed  CAS  Google Scholar 

  4. 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;83:1363–72.

    PubMed  CAS  Google Scholar 

  5. Aoki H, Takishita M, Kosaka M, Saito S. Frequent somatic mutations in D and/or JH segments of Ig gene in Waldenstrom’s macroglobulinemia and chronic lymphocytic leukemia (CLL) with Richter’s syndrome but not in common CLL. Blood. 1995;85:1913–9.

    PubMed  CAS  Google Scholar 

  6. Timar B, Fulop Z, Csernus B, et al. Relationship between the mutational status of VH genes and pathogenesis of diffuse large B-cell lymphoma in Richter’s syndrome. Leukemia. 2004;18:326–30.

    Article  PubMed  CAS  Google Scholar 

  7. Rossi D, Berra E, Cerri M, et al. Aberrant somatic hypermutation in transformation of follicular lymphoma and chronic lymphocytic leukemia to diffuse large B-cell lymphoma. Haematologica. 2006;91:1405–9.

    PubMed  CAS  Google Scholar 

  8. Smit LA, van Maldegem F, Langerak AW, et al. Antigen receptors and somatic hypermutation in B-cell chronic lymphocytic leukemia with Richter’s transformation. Haematologica. 2006;91:903–11.

    PubMed  CAS  Google Scholar 

  9. Mao Z, Quintanilla-Martinez L, Raffeld M, et al. IgVH mutational status and clonality analysis of Richter’s transformation. Am J Surg Pathol. 2007;31:1605–14.

    Article  PubMed  Google Scholar 

  10. Rossi D, Spina V, Cerri M, et al. Stereotyped B-cell receptor is an independent risk factor of chronic lymphocytic leukemia transformation to Richter syndrome. Clin Cancer Res. 2009;15:4415–22.

    Article  PubMed  CAS  Google Scholar 

  11. Rossi D, Spina V, Deambrogi C, et al. The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. Blood. 2011;117:3391–401.

    Article  PubMed  CAS  Google Scholar 

  12. O’Brien SM, Kantarjian HM, Thomas DA, et al. Alemtuzumab as treatment for residual disease after chemotherapy in patients with chronic lymphocytic leukemia. Cancer. 2003;98:2657–63.

    Article  PubMed  Google Scholar 

  13. Karlsson C, Norin S, Kimby E, et al. Alemtuzumab as first-line therapy for B-cell chronic lymphocytic leukemia: long-term follow-up of clinical effects, infectious complications and risk of Richter transformation. Leukemia. 2006;20:2204–7.

    Article  PubMed  CAS  Google Scholar 

  14. Kluin-Nelemans HC, Coenen JL, Boers JE, van Imhoff GW, Rosati S. EBV-positive immunodeficiency lymphoma after alemtuzumab-CHOP therapy for peripheral T-cell lymphoma. Blood. 2008;112:1039–41.

    Article  PubMed  CAS  Google Scholar 

  15. Lepretre S, Aurran T, Mahé B, et al. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood. 2012;119:5104–10.

    Article  PubMed  CAS  Google Scholar 

  16. Keating MJ, O’Brien S, Lerner S, et al. Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood. 1998;92:1165–71.

    PubMed  CAS  Google Scholar 

  17. Tabuteau S, Fernandez J, Garidi R, Desablens B. Richter’s syndrome in B-CLL: report of 37 cases. Blood. (ASH Annual Meeting Abstracts) 1999;34(Suppl 1):306b.

    Google Scholar 

  18. Mauro FR, Foa R, Giannarelli D, et al. Clinical characteristics and outcome of young chronic lymphocytic leukemia patients: a single institution study of 204 cases. Blood. 1999;94:448–54.

    PubMed  CAS  Google Scholar 

  19. Robak T, Blonski JZ, Gora-Tybor J, et al. Second malignancies and Richter’s syndrome in patients with chronic lymphocytic leukaemia treated with cladribine. Eur J Cancer. 2004;40:383–9.

    Article  PubMed  CAS  Google Scholar 

  20. Thornton PD, Bellas C, Santon A, et al. Richter’s transformation of chronic lymphocytic leukemia. The possible role of fludarabine and the Epstein-Barr virus in its pathogenesis. Leuk Res. 2005;29:389–95.

    Article  PubMed  CAS  Google Scholar 

  21. Maddocks-Christianson K, Slager SL, Zent CS, et al. Risk factors for development of a second malignancy in patients with chronic lymphocytic leukaemia. Br J Haematol. 2007;139:398–404.

    Article  Google Scholar 

  22. Tsimberidou A-M, O’Brien S, Khouri I, 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. 2006;24:2343–51.

    Article  PubMed  CAS  Google Scholar 

  23. Alipour S, Leiitch H, Vickars LM, et al. Richter transformation of chronic lymphocytic leukemia: incidence, risk factors and outcome. Blood. (ASH Annual Meeting Abstracts) 2008;112:3179.

    Google Scholar 

  24. Rossi D, Cerri M, Capello D, Deambrogi C, et al. Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndrome. Br J Haematol. 2008;142:202–15.

    Article  PubMed  CAS  Google Scholar 

  25. Solh M, Rai KR, Peterson BL, et al. The impact of initial fludarabine therapy on transformation to Richter’s syndrome or prolymphocytic leukemia in patients with chronic lymphocytic leukemia: analysis of an intergroup trial (CALGB 9011). Leuk Lymphoma. 2013;54(2):252–4. doi:10.3109/10428194.2012.710327.

    Article  PubMed  CAS  Google Scholar 

  26. Fischer K, Bahlo J, Fink AM, et al. Extended follow up of the CLL8 protocol, a randomized phase-III trial of the German CLL study group (GCLLSG) comparing fludarabine and cyclophosphamide (FC) to FC plus rituximab (FCR) for previously untreated patients with chronic lymphocytic leukemia (CLL): results on survival, progression-free survival, delayed neutropenias and secondary malignancies confirm superiority of the FCR regimen. Blood. (ASH Annual Meeting Abstracts) 2012;120:435.

    Google Scholar 

  27. Parikh SA, Rabe KG, Kay NE, et al. Transformation of chronic lymphocytic leukemia into diffuse large B-cell lymphoma (Richter’s syndrome): large retrospective analysis from a single institution. Blood. (ASH Annual Meeting Abstracts) 2012;120:2902.

    Google Scholar 

  28. Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 trial): a randomised controlled trial. Lancet. 2007;370:230–9.

    Article  PubMed  CAS  Google Scholar 

  29. Rossi D, Rasi S, Spina V, et al. Different impact of NOTCH1and SF3B1 mutations on the risk of chronic lymphocytic leukemia transformation to Richter syndrome. Br J Haematol. 2012;158:426–9.

    Article  PubMed  CAS  Google Scholar 

  30. Lobry C, Oh P, Aifantis I. Oncogenic and tumor suppressor functions of Notch in cancer: it’s NOTCH what you think. J Exp Med. 2011;208:1931–5.

    Article  PubMed  CAS  Google Scholar 

  31. Fabbri G, Rasi S, Rossi D, Trifonov V, Khiabanian H, Ma J, et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med. 2011;208:1389–401.

    Article  PubMed  CAS  Google Scholar 

  32. Puente XS, Pinyol M, Quesada V, Conde L, Ordóñez GR, Villamor N, et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011;475:101–5.

    Article  PubMed  CAS  Google Scholar 

  33. Rossi D, Rasi S, Fabbri G, Spina V, Fangazio M, Forconi F, et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood. 2012;119:521–9.

    Article  PubMed  CAS  Google Scholar 

  34. De Keersmaecker K, Michaux L, Bosly A, et al. Rearrangement of NOTCH1 or BCL3 can independently trigger progression of CLL. Blood. 2012;119:3864–6.

    Article  PubMed  Google Scholar 

  35. Agathangelidis A, Darzentas N, Hadzidimitriou A, et al. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. Blood. 2012;119:4467–75.

    Article  PubMed  CAS  Google Scholar 

  36. Chu CC, Catera R, Zhang L, et al. Many chronic lymphocytic leukemia antibodies recognize apoptotic cells with exposed nonmuscle myosin heavy chain IIA: implications for patient outcome and cell of origin. Blood. 2010;115:3907–15.

    Article  PubMed  CAS  Google Scholar 

  37. Gounari M, Ntoufa S, Chu CC, et al. Promiscuous antigen reactivity may underlie clinical aggressiveness and increased risk for richter’s syndrome in chronic lymphocytic leukemia with stereotyped IGHV4-39/IGKV1(D)-39 B cell receptors. Blood. (ASH Annual Meeting Abstracts) 2012;120:561.

    Google Scholar 

  38. Tsimberidou AM, O’Brien S, Kantarjian HM, et al. Hodgkin transformation of chronic lymphocytic leukemia: the M. D. Anderson Cancer Center experience. Cancer. 2006;107:1294–302.

    Article  PubMed  CAS  Google Scholar 

  39. Bockorny B, Codreanu I, Dasanu CA. Hodgkin lymphoma as Richter transformation in chronic lymphocytic leukaemia: a retrospective analysis of world literature. Br J Haematol. 2012;156:50–66.

    Article  PubMed  Google Scholar 

  40. Ohno T, Smir BN, Weisenburger DD, Gascoyne RD, Hinrichs SD, Chan WC. Origin of the Hodgkin/Reed-Sternberg cells in chronic lymphocytic leukemia with “Hodgkin’s transformation”. Blood. 1998;91:1757–61.

    PubMed  CAS  Google Scholar 

  41. van den Berg A, Maggio E, Rust R, Kooistra K, Diepstra A, Poppema S. Clonal relation in a case of CLL, ALCL, and Hodgkin composite lymphoma. Blood. 2002;100:1425–9.

    PubMed  Google Scholar 

  42. de Leval L, Vivario M, De Prijck B, et al. Distinct clonal origin in two cases of Hodgkin’s lymphoma variant of Richter’s syndrome associated with EBV infection. Am J Surg Pathol. 2004;28:679–86.

    Article  PubMed  Google Scholar 

  43. Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP. Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer. 2009;9:862–73.

    Article  PubMed  CAS  Google Scholar 

  44. de Paoli L, Cerri M, Monti S, et al. MGA, a suppressor of MYC, is recurrently inactivated in high risk chronic lymphocytic leukemia. Leuk Lymphoma. 2013;54(5):1087–90. doi:10.3109/10428194.2012.723706.

    Article  PubMed  Google Scholar 

  45. Cascón A, Robledo M. MAX and MYC: a heritable breakup. Cancer Res. 2012;72:3119–24.

    Article  PubMed  Google Scholar 

  46. Cohen Y, Da’as N, Libster D, Amir G, Berrebi A, Polliack A. Large-cell transformation of chronic lymphocytic leukemia and follicular lymphoma during or soon after treatment with fludarabine-rituximab containing regimens: natural history or related therapy complication. Eur J Hematol. 2002;68:80–3.

    Article  CAS  Google Scholar 

  47. Bruzzi JF, Macapinlac H, Tsimberidou AM, et al. Detection of Richter’s transformation of chronic lymphocytic leukemia by PET/CT. J Nucl Med. 2006;47:1267–73.

    PubMed  Google Scholar 

  48. Dabaja BS, O’Brien SM, Kantarjian HM, et al. Fractionated cyclophosphamide, vincristine, liposomal daunorubicin (daunoXome), and dexamethasone (hyper-CVXD) regimen in Richter’s syndrome. Leuk Lymphoma. 2001;42:329–37.

    Article  PubMed  CAS  Google Scholar 

  49. Tsimberidou AM, Kantarjian HM, Cortes J, et al. Fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone plus rituximab and granulocyte-macrophage-colony stimulating factor (GM-CSF) alternating with methotrexate and cytarabine plus rituximab and GMCSF in patients with Richter syndrome or fludarabine refractory chronic lymphocytic leukemia. Cancer. 2003;97:1711–20.

    Article  PubMed  CAS  Google Scholar 

  50. Tsimberidou AM, O’Brien SM, Cortes JE, et al. Phase II study of fludarabine, cytarabine (Ara-C), cyclophosphamide, cisplatin and GM-CSF (FACPGM) in patients with Richter’s syndrome or refractory lymphoproliferative disorders. Leuk Lymphoma. 2002;43:767–72.

    Article  PubMed  CAS  Google Scholar 

  51. Tsimberidou AM, Murray JL, O’Brien S, Wierda WG, Keating MJ. Yttrium-90 ibritumomab tiuxetan radioimmunotherapy in Richter syndrome. Cancer. 2004;100:2195–200.

    Article  PubMed  CAS  Google Scholar 

  52. Jenke P, Eichhorst B, Busch R, et al. Cyclophosphamide, adriamycin, vincristine and prednisone plus rituximab (CHOP-R) in fludarabine (F) refractory chronic lymphocytic leukemia (CLL) or CLL with autoimmune cytopenia (AIC) or Richter’s transformation (RT): final analysis of a phase II study of the German CLL study group. Blood. (ASH Annual Meeting Abstracts) 2011;118:2860.

    Google Scholar 

  53. Tsimberidou AM, Wierda WG, Plunkett W, et al. Phase I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy in patients with Richter’s syndrome or fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2008;26:196–203.

    Article  PubMed  CAS  Google Scholar 

  54. Cwynarski K, van Biezen A, de Wreede L, et al. Autologous and allogeneic stem-cell transplantation for transformed chronic lymphocytic leukemia(Richter’s syndrome): a retrospective analysis from the chronic lymphocytic leukemia subcommittee of the chronic leukemia working party and lymphoma working party of the European group for blood and marrow transplantation. J Clin Oncol. 2012;30:2211–7.

    Article  PubMed  Google Scholar 

  55. Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146:904–17.

    Article  PubMed  CAS  Google Scholar 

  56. Wiestner A. Emerging role of kinase targeted strategies in chronic lymphocytic leukemia. Blood. 2012;120:4684–91.

    Article  PubMed  CAS  Google Scholar 

  57. Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31:88–94.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Via Solaroli 17, 28100, Novara, Italy

    Davide Rossi M.D., Ph.D. & Gianluca Gaidano M.D., Ph.D.

Authors
  1. Davide Rossi M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gianluca Gaidano M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Davide Rossi M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA

    Sami Malek

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Rossi, D., Gaidano, G. (2013). Richter Syndrome. In: Malek, S. (eds) Advances in Chronic Lymphocytic Leukemia. Advances in Experimental Medicine and Biology, vol 792. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8051-8_8

Download citation

Publish with us

Policies and ethics

Search

Navigation