Pathobiology and treatment of Richter's transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma
- Jennifer R Brown, MD, PhD
Jennifer R Brown, MD, PhD
- Associate Professor
- Harvard Medical School
Richter's transformation (RT, Richter's syndrome) was first described in 1928 by Maurice Richter as the development of an aggressive large-cell lymphoma in the setting of underlying chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Although diffuse large B cell lymphoma is the most common histology seen in patients with RT , Hodgkin lymphoma [2,3] and T cell lymphomas  have also been reported less commonly. The clinical features, pathogenesis, and treatment of RT will be discussed here.
Evolution to a component of B cell prolymphocytic leukemia (B-PLL) during the natural history of relapsed CLL/SLL is also common, but is not usually included under the rubric of RT. (See "Staging and prognosis of chronic lymphocytic leukemia", section on 'Prolymphocytoid transformation'.)
INCIDENCE AND CLINICAL FEATURES
Incidence — The incidence of Richter's transformation (RT) from chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) to diffuse large B cell lymphoma has been variously estimated at 2 to 9 percent [1,5-9], making it less common than histologic transformation of other low-grade mature B cell malignancies (picture 1). The median time from the diagnosis of CLL/SLL to transformation has been in the range of two to four years [5,6,10]. For example, a series of 185 consecutive, previously untreated patients with CLL followed for a median of 47 months identified RT in 17 cases (9 percent) at a median of 23 months from diagnosis . This group took an aggressive approach to repeat biopsy, which may explain the high rate of RT. In addition to those transforming to DLBCL, an additional 0.4 percent of patients will transform to Hodgkin lymphoma . (See "Histologic transformation of follicular lymphoma", section on 'Clinical presentation and diagnosis'.)
Clinical features — The onset of RT is heralded by sudden clinical deterioration, characterized by a marked increase in lymphadenopathy at one or more sites (often abdominal), splenomegaly, and worsening "B" symptoms (ie, fever, night sweats, weight loss). The serum level of lactate dehydrogenase (LDH) is elevated in 50 to 80 percent of patients with RT compared with 8 percent of CLL patients [6,10,12]. Anemia with a hemoglobin <11 g/dL is seen in about 50 percent of cases, and thrombocytopenia with a platelet count <100,000/microL in 43 percent . Symptoms are similar in the Hodgkin lymphoma variant. The clinical course of RT is rapidly progressive, with a median survival of 5 to 8 months [1,6,13-15].
Risk factors — Risk factors for the development of RT remain poorly defined.
Subscribers log in hereLiterature review current through: Nov 2017. | This topic last updated: Apr 30, 2015.References
- Tsimberidou AM, Keating MJ. Richter syndrome: biology, incidence, and therapeutic strategies. Cancer 2005; 103:216.
- Brecher M, Banks PM. Hodgkin's disease variant of Richter's syndrome. Report of eight cases. Am J Clin Pathol 1990; 93:333.
- 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.
- 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.
- Morrison VA, Rai K, Peterson BL, et al. Transformation to Richter's Syndrome or Prolymphocytic Leukemia (PLL): an Intergroup Study (CALGB 9011). Blood 1999; 94:539a.
- Robertson LE, Pugh W, O'Brien S, et al. Richter's syndrome: a report on 39 patients. J Clin Oncol 1993; 11:1985.
- Yee KW, O'Brien SM, Giles FJ. Richter's syndrome: biology and therapy. Cancer J 2005; 11:161.
- Rossi D, Cerri M, Capello D, et al. Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndrome. Br J Haematol 2008; 142:202.
- Parikh SA, Rabe KG, Call TG, et al. Diffuse large B-cell lymphoma (Richter syndrome) in patients with chronic lymphocytic leukaemia (CLL): a cohort study of newly diagnosed patients. Br J Haematol 2013; 162:774.
- Harousseau JL, Flandrin G, Tricot G, et al. Malignant lymphoma supervening in chronic lymphocytic leukemia and related disorders. Richter's syndrome: a study of 25 cases. Cancer 1981; 48:1302.
- 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.
- Tsimberidou AM, 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.
- Armitage JO, Dick FR, Corder MP. Diffuse histiocytic lymphoma complicating chronic lymphocytic leukemia. Cancer 1978; 41:422.
- van Dongen JJ, Hooijkaas H, Michiels JJ, et al. Richter's syndrome with different immunoglobulin light chains and different heavy chain gene rearrangements. Blood 1984; 64:571.
- 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.
- 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.
- Tabuteau S, Fernandez J, Garidi R, et al. Richter's Syndrome in B-CLL: report of 37 cases (abstract). Blood 1999; 94:306b.
- 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.
- 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.
- Fabbri G, Rasi S, Rossi D, et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med 2011; 208:1389.
- Rossi D, Rasi S, Fabbri G, et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood 2012; 119:521.
- Aydin S, Rossi D, Bergui L, et al. CD38 gene polymorphism and chronic lymphocytic leukemia: a role in transformation to Richter syndrome? Blood 2008; 111:5646.
- 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.
- Cheson BD, Vena DA, Barrett J, Freidlin B. Second malignancies as a consequence of nucleoside analog therapy for chronic lymphoid leukemias. J Clin Oncol 1999; 17:2454.
- 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.
- Falchi L, Keating MJ, Marom EM, et al. Correlation between FDG/PET, histology, characteristics, and survival in 332 patients with chronic lymphoid leukemia. Blood 2014; 123:2783.
- Ma Y, Mansour A, Bekele BN, et al. The clinical significance of large cells in bone marrow in patients with chronic lymphocytic leukemia. Cancer 2004; 100:2167.
- 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.
- Matolcsy A, Casali P, Knowles DM. Different clonal origin of B-cell populations of chronic lymphocytic leukemia and large-cell lymphoma in Richter's syndrome. Ann N Y Acad Sci 1995; 764:496.
- Bertoli LF, Kubagawa H, Borzillo GV, et al. Analysis with antiidiotype antibody of a patient with chronic lymphocytic leukemia and a large cell lymphoma (Richter's syndrome). Blood 1987; 70:45.
- Foon KA, Thiruvengadam R, Saven A, et al. Genetic relatedness of lymphoid malignancies. Transformation of chronic lymphocytic leukemia as a model. Ann Intern Med 1993; 119:63.
- Beà S, López-Guillermo A, Ribas M, et al. Genetic imbalances in progressed B-cell chronic lymphocytic leukemia and transformed large-cell lymphoma (Richter's syndrome). Am J Pathol 2002; 161:957.
- Mao Z, Quintanilla-Martinez L, Raffeld M, et al. IgVH mutational status and clonality analysis of Richter's transformation: diffuse large B-cell lymphoma and Hodgkin lymphoma in association with B-cell chronic lymphocytic leukemia (B-CLL) represent 2 different pathways of disease evolution. Am J Surg Pathol 2007; 31:1605.
- Fabbri G, Khiabanian H, Holmes AB, et al. Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome. J Exp Med 2013; 210:2273.
- Fitzgerald PH, McEwan CM, Hamer JW, Beard ME. Richter's syndrome with identification of marker chromosomes. Cancer 1980; 46:135.
- Chena C, Cerretini R, Noriega MF, et al. Cytogenetic, FISH, and molecular studies in a case of B-cell chronic lymphocytic leukemia with karyotypic evolution. Eur J Haematol 2002; 69:309.
- Lee JN, Giles F, Huh YO, et al. Molecular differences between small and large cells in patients with chronic lymphocytic leukemia. Eur J Haematol 2003; 71:235.
- Zhu Y, Monni O, Franssila K, et al. Deletions at 11q23 in different lymphoma subtypes. Haematologica 2000; 85:908.
- Brynes RK, McCourty A, Sun NC, Koo CH. Trisomy 12 in Richter's transformation of chronic lymphocytic leukemia. Am J Clin Pathol 1995; 104:199.
- Chigrinova E, Rinaldi A, Kwee I, et al. Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome. Blood 2013; 122:2673.
- Timár B, Fülöp 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.
- 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.
- Tzankov A, Fong D. Hodgkin's disease variant of Richter's syndrome clonally related to chronic lymphocytic leukemia arises in ZAP-70 negative mutated CLL. Med Hypotheses 2006; 66:577.
- Reiniger L, Bödör C, Bognár A, et al. Richter's and prolymphocytic transformation of chronic lymphocytic leukemia are associated with high mRNA expression of activation-induced cytidine deaminase and aberrant somatic hypermutation. Leukemia 2006; 20:1089.
- Fülöp Z, Csernus B, Tímár B, et al. Microsatellite instability and hMLH1 promoter hypermethylation in Richter's transformation of chronic lymphocytic leukemia. Leukemia 2003; 17:411.
- Gaidano G, Ballerini P, Gong JZ, et al. p53 mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 1991; 88:5413.
- Pinyol M, Cobo F, Bea S, et al. p16(INK4a) gene inactivation by deletions, mutations, and hypermethylation is associated with transformed and aggressive variants of non-Hodgkin's lymphomas. Blood 1998; 91:2977.
- Pinyol M, Hernández L, Martínez A, et al. INK4a/ARF locus alterations in human non-Hodgkin's lymphomas mainly occur in tumors with wild-type p53 gene. Am J Pathol 2000; 156:1987.
- Cobo F, Martínez A, Pinyol M, et al. Multiple cell cycle regulator alterations in Richter's transformation of chronic lymphocytic leukemia. Leukemia 2002; 16:1028.
- Ansell SM, Li CY, Lloyd RV, Phyliky RL. Epstein-Barr virus infection in Richter's transformation. Am J Hematol 1999; 60:99.
- 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.
- Dabaja BS, O'Brien SM, Kantarjian HM, et al. Fractionated cyclophosphamide, vincristine, liposomal daunorubicin (daunoXome), and dexamethasone (hyperCVXD) regimen in Richter's syndrome. Leuk Lymphoma 2001; 42:329.
- 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 GM-CSF in patients with Richter syndrome or fludarabine-refractory chronic lymphocytic leukemia. Cancer 2003; 97:1711.
- Tsimberidou AM, Murray JL, O'Brien S, et al. Yttrium-90 ibritumomab tiuxetan radioimmunotherapy in Richter syndrome. Cancer 2004; 100:2195.
- 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.
- Rodriguez J, Keating MJ, O'Brien S, et al. Allogeneic haematopoietic transplantation for Richter's syndrome. Br J Haematol 2000; 110:897.
- 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.
- INCIDENCE AND CLINICAL FEATURES
- Clinical features
- Risk factors
- MAKING THE DIAGNOSIS
- Bone marrow
- TREATMENT AND PROGNOSTIC FEATURES
- - Hodgkin lymphoma variant
- Hematopoietic cell transplantation
- SUMMARY AND RECOMMENDATIONS
- Clinical presentation