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Richter's transformation, or Richter's syndrome, is an uncommon clinicopathological condition observed in about 5% to 10% of patients with chronic lymphocytic leukemia (CLL). This review summarizes advances in our understanding of the pathobiology and in the management of Richter's transformation in patients with CLL.
Richter's transformation, or Richter's syndrome, is an uncommon clinicopathological condition observed in about 5% to 10% of patients with chronic lymphocytic leukemia (CLL). “Richter's transformation” refers to the development of aggressive lymphoma during the course of CLL. Diffuse large B-cell lymphoma occurs in the majority of cases of Richter's transformation. Clinically, patients with Richter's transformation present with an aggressive disease course with rapidly enlarging lymph nodes, hepatosplenomegaly, and elevated serum lactate dehydrogenase levels. Specific risk factors for the development of Richter's transformation in a patient with CLL have yet to be identified; however, TP53 disruption, c-MYC abnormalities, unmutated immunoglobulin heavy chain (IGHV) < 2%, non-del13q cytogenetics, CD38 gene polymorphisms, stereotypy, and VH4-39 gene usage may predispose to Richter's transformation. The prognosis is generally poor, with a median survival of about 10 months. Development of rituximab (Rituxan)-containing intensive chemotherapy regimens and chemo-immunotherapy regimens (eg, R-HyperCVAD [rituximab plus hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone] or OFAR [oxaliplatin (Eloxatin), fludarabine, and ara-C]) have improved response rates but have not clearly affected long-term outcomes. Allogeneic stem-cell transplantation may offer a chance for prolonged survival.
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation and proliferation of monoclonal B cells with a characteristic immunophenotype (CD5-, CD19-, and CD23-positive; and FMC-7–, sIgG-, and CD20-diminished). CLL is the most common leukemia in adults in the Western world. It is estimated that 16,060 persons (9490 men, 6570 women) will be diagnosed with CLL and 4580 patients will die of CLL in 2012 in the United States. The median age at diagnosis of CLL is about 72 years, and CLL is predominantly a disease affecting older individuals.
Richter's transformation (or Richter's syndrome) is a clinicopathological term used to describe the rapid development of a histologically proven aggressive lymphoma in a patient with CLL. The most common lymphoma seen in patients with Richter's transformation is diffuse large B-cell lymphoma. Other rarer types of Richter's transformation that have been described are Hodgkin's variant of Richter's transformation,[5,6] composite lymphoma, and very rarely, interdigitating dendritic cell sarcoma. The development of lymphoma in CLL was originally reported by Maurice N. Richter in 1928, and the term “Richter's syndrome” was coined in 1964 by Lortholary et al to describe the development of malignant reticulopathy in 14 patients with CLL. Studies have shown that the diffuse large B-cell lymphoma that develops in Richter's transformation can be clonally related to the original CLL (true Richter's transformation; 78% of cases) or can be clonally unrelated diffuse large B-cell lymphoma (20% of cases).[10,11] It is unclear whether the clonally unrelated diffuse large B-cell lymphoma is a sequential lymphoma or a clonally unrelated transformation in patients with CLL. The term “composite lymphoma” is used whenever there is initial discovery of CLL and another lymphoma at the same time in the same tissue; composite lymphoma is different from Richter's transformation. Richter's transformation should also be differentiated from prolymphocytic transformation and accelerated CLL (expanded proliferation centers without histologically proven large-cell lymphoma).
Every year about 500 patients are diagnosed with Richter's transformation in the United States. The incidence rates of Richter's transformation range from 2% to 10% in most major studies. The largest study of Richter's transformation was reported by investigators at the MD Anderson Cancer Center in 2006. Of 3986 patients with CLL, 148 patients (3.7%) had a histologically proven Richter's transformation and 204 patients (5.1%) had possible Richter's transformation. Survival after Richter's transformation was reported to range from a few weeks to up to 15 years. Two other studies, one from Italy, another from China, have reported the percentage of Richter's transformation in CLL patients as 9% (17/185) and 10.7% (16/149), respectively. Richter's transformation can present at any time during the course of CLL. Development of Richter's transformation is dependent on intrinsic biological features of the initial CLL clone. In one study (with a uniform biopsy protocol), the cumulative incidence of Richter's transformation at 5 and 10 years exceeded 5% and 10%, respectively, and the median time to development of Richter's transformation was 23 months from the date of diagnosis of CLL.
This review summarizes advances in our understanding of the pathobiology and in the management of Richter's transformation in patients with CLL.
As mentioned earlier, the majority of patients with Richter's transformation develop diffuse large B-cell lymphoma. Multiple immune and genetic factors can influence the development of Richter's transformation. The diffuse large B-cell lymphoma that arises from Richter's transformation is different from de novo diffuse large B-cell lymphoma in both clinical behavior and disease biology.
Specific cytogenetic abnormalities/translocations are not seen in Richter's transformation. Non-del13q14 abnormalities in CLL cells are considered a risk factor for Richter's transformation. Chromosome 14q32 translocations, commonly seen in other non-Hodgkin's lymphomas (eg, 14;18 in follicular lymphoma and 11;14 in mantle cell lymphoma) are not observed in Richter's transformation.
In one study, a comprehensive molecular profiling of 84 patients with Richter's transformation was performed. TP53 disruption (47.1%) and c-MYC abnormalities (26.2%) were the most common genetic lesions. Patients with Richter's transformation did not have the common mutations seen in de novo diffuse large B-cell lymphoma (eg, BCL2, BCL6, NF-ÎºB pathway, CD79a and CD79b, and EZH2). The median survival for patients with TP53 mutations was 10 months, compared with 27 months in patients without TP53 mutations, while median survival with TP53 disruptions (deletion or mutations) was 9.4 months, compared with 47.1 months in patients without such disruptions. However, the presence of TP53 mutations at the time of diagnosis of CLL did not predict for a higher risk of Richter's transformation.
Pathways of Development of Richter’s Transformation in Chronic Lymphocytic Leukemia (CLL)
Diffuse large B-cell lymphoma that develops in patients with Richter's transformation can be either clonally related or unrelated to the original CLL clone. Clonally related Richter's transformation and clonally unrelated Richter's transformation differ in many respects-and clonally unrelated Richter's transformation is also different from de novo diffuse large B-cell lymphoma. Figure 1 depicts the outline of the development of clonally related/unrelated diffuse large B-cell lymphoma in patients with CLL. Immunoglobulin heavy chain (IGHV) gene sequencing by polymerase chain reaction (PCR) is useful in determining the clonality in patients with Richter's transformation. Clonally unrelated Richter's transformations have a lower prevalence of TP53 disruption, stereotyped VH CDR3, and a higher prevalence of mutated IGHV. Patients with clonally unrelated Richter's transformation have a longer survival than patients with clonally related diffuse large B-cell lymphoma (true Richter's transformation).
Some reports have suggested the presence of Epstein-Barr virus (EBV) in the large cells of Richter's transformation patients,[18,19] but conclusive evidence demonstrating a cause-effect relationship is lacking. EBV infection was more commonly associated with Hodgkin's variant Richter's transformation than with the common diffuse large B-cell lymphoma Richter's transformation.
This enzyme is responsible for somatic hypermutation and class-switch recombination in B cells. Any defect in somatic hypermutation caused by aberrancy in actions of activation-
induced cytidine deaminase can lead to lymphomagenesis. In Richter's transformation, the pathological relevance of mutations in activation-induced cytidine deaminase is not clear, whereas in de novo diffuse large B-cell lymphoma, activation-induced cytidine deaminase is known to cause aberrant somatic hypermutation, thus activating proto-oncogenes such as c-MYC.
The deletion of the Rb gene, loss of cell-cycle inhibitors CDKN1A and CDKN2A, and increased copy numbers of the MYC gene also contribute to transformations in CLL.
Extensive studies of genomic changes occurring in Richter's transformation were reported by Rossi et al.[11,21] Factors that were seen to predispose to Richter's transformation were different from the risk factors associated with CLL progression. Specific guidelines for interventions in patients having risk factors for Richter's transformation are not yet available.
A pilot study reported by Rossi et al in 2008 involving 185 CLL patients and paired samples (CLL and Richter's transformation in the same patient) has shown that the following factors predispose to Richter's transformation in a patient with CLL. (Detailed discussions of the pathological mechanisms behind these factors are beyond the scope of this article.)
1.CD38 expression (CD38 ≥ 30%)
2. Stereotyped B-cell receptor
3.IGHV4-39 gene usage
4. Telomere length < 5000 base pairs
5. Lymph node size > 3 cm
6. Absence of del13q14
Other studies have reported on polymorphisms with CD38 and LRP4 genes. CD38 GG homozygous patients had a 30.6% increased risk compared with the risk in patients having the GC or CC genotype and patients having the LRP4 TT genotype (which is related to Wnt signaling pathways in CLL).
NOTCH1 mutations were recently shown to predict for the development of Richter's transformation, while SF3B1 mutations did not.
Currently, there is no evidence that treatment with purine analogues (fludarabine, cladribine), alone or in combination with cyclophosphamide and rituximab (Rituxan), can increase the risk of Richter's transformation in patients with CLL.
In 2006, one of the largest studies in patients with Richter's transformation (n = 148) proposed a prognostic scoring system (Richter's transformation Score). Five factors that significantly predicted for poor outcome in patients with Richter's transformation were:
• Zubrod performance status > 1
• Elevated lactate dehydrogenase (LDH) levels (> 1.5 times normal)
• Platelet count < 100 × 109/L
• Tumor size > 5 cm
• Prior therapies > 1
Patients were divided into low-, low-intermediate–, high-intermediate–, and high-risk categories based on the number of risk factors at the time of presentation (identified by scores of 0–1, 2, 3, and 4–5, respectively). Median survival of patients in low-, low-intermediate–, high-intermediate–, and high-risk categories was 1.12, 0.9, 0.33, and 0.2 years, respectively (Figure 2).
Survival in 130 Assessable Treated Patients in the Study of Richter’s Transformation From Which a Prognostic Scoring System Was Developed
Biopsy of the involved site (core needle/excisional) is necessary to confirm the diagnosis of RT. Morphologically, specimens from Richter's transformation show large atypical cells with centroblastic/immunoblastic morphology. The majority (about 80%) of diffuse large B-cell lymphoma cases in Richter's transformation displays a post–germinal center (GC) phenotype (MUM1/IRF4 expression) and only a few cases will show a GC variety (CD10 and BCL6 expression). CD20 expression is generally bright, while CD5 and CD23 expression may be dim to negative in Richter's transformation. The proliferation marker Ki-67 can be highly expressed in large cells of Richter's transformation. Rarely, Richter's transformation can also present with a Hodgkin's variant with Reed Sternberg (R-S) cells, with expression of CD15 and CD30 by the R-S cells similar to that seen in de novo Hodgkin's disease.
Suspect Richter's transformation when a patient with CLL presents with a rapidly deteriorating clinical profile and enlargement of lymph nodes, prominent B symptoms (night sweats, weight loss, fever without infection), and extranodal involvement (such as involvement of the central nervous system, skin, stomach, testes, eyes, or lungs). Pancytopenia is common. Elevated LDH levels are common. Hypercalcemia with or without lytic bone lesions and monoclonal gammopathy can also be seen.
PET-CT (positron emission tomography–computed tomography) scanning may be quite helpful in diagnosing Richter's transformation. An abnormal increase in uptake of the tracer 18F-FDG (18-fluorodeoxyglucose, a glucose analogue) on PET-CT with standardized uptake value (SUV) > 5 is highly suggestive of the development of Richter's transformation. In a study of 37 patients with CLL, 11 patients developed Richter's transformation, and PET-CT scanning detected Richter's transformation with a sensitivity, a specificity, and positive and negative predictive values of 91%, 80%, 53%, and 97%, respectively. Particular attention to the following factors is needed when examining results from PET-CT scans for evidence of suspected Richter's transformation:
• False-positive results can be caused by granulomas, additional malignancies, or infections.
• A uniform method of calculating SUV from the same instrument must be used.
• Poor scanner quality control can result in false-positives.
• Chemotherapy and other immunotherapies increase the likelihood of false-positive PET results.
• Attention must be paid to the type of chemotherapy administered: one study showed that a negative biopsy following a positive PET-CT scan was fairly common after dose-intense chemotherapy.
• Rigorous quality control must be maintained to compensate for variability in data acquisition and image reconstruction.
• Newer biologic agents may inhibit glucose uptake and thus may reduce SUV.
Routine use of PET-CT in clinical practice to detect Richter's transformation in CLL is not necessary. Nevertheless, PET-CT can indicate a site of Richter's transformation amenable to biopsy, since all nodes may not be involved. Biopsy with a pathologic diagnosis remains the gold standard for diagnosing Richter's transformation. Gallium-67 scanning was used in the past to differentiate Richter's transformation from CLL, but is of limited value in the current era.
Survival in Patients With Richter’s Transformation Who Underwent Stem-Cell Transplantation, According to Type of Transplant and Disease Status at the Time of Transplant
The clinical presentation of Richter's transformation can easily mimic the conditions listed below. Differentiation of these conditions from Richter's transformation is dependent on proper histopathological evaluation of the involved nodal or extranodal site. It is important to distinguish such conditions from Richter's transformation, since the management and outcomes are different.
Proliferation centers are the hallmark of lymphoid tissues involved in CLL. Accelerated CLL is diagnosed when patients exhibit expanded proliferation centers (PC) broader than a 20× field and a high proliferation rate (either > 2.4 mitoses/proliferation center or Ki-67 > 40%/proliferation center). Patients usually have higher LDH levels, and CLL cells express ZAP-70. The median survival of patients with accelerated CLL vs those with Richter's transformation was 34 months and 4.3 months, respectively. Data regarding the treatment options appropriate for accelerated CLL are lacking.
This is a rare entity. Most patients have the mixed cellularity variant on biopsy. Hodgkin's variant of Richter's transformation is associated with EBV positivity. The R-S cells in Hodgkin's variant of Richter's transformation have higher CD20 expression. Chemotherapy regimens used in treating Hodgkin's lymphoma are associated with poorer outcomes as compared to the outcomes seen in primary Hodgkin's lymphoma.[30,31]
These patients have increased prolymphocytes (> 55%) with positive CD5, CD23 expression, and weak CD22 and CD79b (a feature differentiating this entity from de novo B-cell prolymphocytic leukemia [B-PLL]). The prognosis of prolymphocytic transformation is poor. Therapy usually is similar to that for B-PLL, incorporating alemtuzumab (Campath), rituximab-based purine analogue combinations, and allogeneic stem-cell transplantation (SCT).[12,32]
Patients with CLL have inherent immune defects that are compounded by the effects of chemotherapy. Purine analogues and monoclonal antibodies such as alemtuzumab can predispose to the reactivation of EBV in lymphoid tissues. Patients with EBV-associated lymphoproliferative disorder may present with rapidly enlarging lymph nodes and progressive clinical symptoms. Histopathological evaluation mimics that of age-related diffuse large B-cell lymphoma of the elderly or a classical Hodgkin's lymphoma, but these entities can be distinguished from EBV-associated lymphoproliferative disorder by expert hematopathologists (by means of the presence of other markers of diffuse large B-cell lymphoma, such as immunoblastic, centroblastic morphology and MUM1/CD10/bcl2/bcl6 expression in monoclonal B cells). In EBV-associated lymphoproliferative disorder, the morphology is polymorphous, with predominant geographic necrosis. The disease course of EBV-associated lymphoproliferative disorder is highly variable, ranging from spontaneous regression to the need for therapy (eg, single-agent rituximab or arginine butyrate therapy with cidofovir). Of note, misdiagnosis of this entity may lead to unnecessary administration of intensive chemotherapy for diffuse large B-cell lymphoma.[34,35]
Richter's transformation in CLL has a rapidly progressive clinical course with extensive tumor burden and widespread or localized extranodal and nodal involvement. Treatment options are usually limited, because of the chemo-refractoriness of the lymphomatous cells (due to TP53 mutations), rapid cell turnover, and poor performance status of the patients.
In the pre-rituximab era, Richter's transformation was treated similarly to high-grade lymphomas-with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-based regimens, ESHAP (etoposide [Vepesid], methylprednisolone, cytarabine, and cisplatin), FACPGM (fludarabine, cytarabine, cyclophosphamide, cisplatin, and granulocyte macrophage colony-stimulating factor [GM-CSF]), etc. About one-third of patients respond to the foregoing regimens. With the addition of rituximab to HyperCVXD (hyperfractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone), alternating with methotrexate and ara-C, the response rates were similar to the rates achieved with CHOP, other earlier regimens, and HyperCVXD. The complete remission (CR) rate was 38% with HyperCVXD. Similarly, with HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plus rituximab (R-HyperCVAD) alternating with methotrexate and ara-C, the response rate was 43%, with a CR rate of 27%. In a retrospective single-center study, the response rates seen with chemotherapy and chemo-immunotherapy were not significantly different. Median survival with both chemotherapy and chemo-immunotherapy was less than 10 months. Of note, higher response rates were observed in patients who had a platelet count >100 ×109/L, performance status of 0 or 1, a hemoglobin level > 11 g/dL, and Î²2 microglobulin < 6 mg/L. In 2008, a phase II study reported responses with the OFAR regimen (oxaliplatin, fludarabine, cytarabine, and rituximab) in 20 patients with RT. This combination was developed after preclinical studies showed synergism between oxaliplatin, fludarabine, and cytarabine. The overall response rate (ORR) was 46%. Fifty percent of patients aged > 70 years responded, and grade 3/4 toxicities were minimal. The median duration of response was 10 months. Another study from the same group reported on the OFAR2 regimen in 15 patients with Richter's transformation. In OFAR2, the oxaliplatin dose was increased and the cytarabine dose was decreased. The responses seen with OFAR2 were not superior to the rate achieved with the OFAR regimen. In a small trial of 15 patients with Richter's transformation, R-CHOP (rituximab plus CHOP) produced an ORR of 67% and progression-free survival of 15 months. A smaller series of seven patients with Richter's transformation were given 90Y ibritumomab tiuxetan; no patients responded. Treatment regimens in Richter's transformation are similar to each other in their response rates and have not improved outcomes.
Two studies have reported improved outcomes with stem-cell transplantation in patients with Richter's transformation who achieved remission with chemotherapy. In one study of 20 patients who underwent transplantation, the estimated 3-year cumulative survival was 75% for responding patients with Richter's transformation and 21% for patients who received stem-cell transplantation as salvage therapy after failing chemotherapy.
Recently, another study from the European Group for Blood and Marrow Transplantation (EBMT) in 59 patients with Richter's transformation showed that 3-year probabilities of overall survival and relapse-free survival, and the cumulative incidences of relapse and non-relapse mortality were 36%, 27%, 47%, and 26% for allogeneic SCT, and 59%, 45%, 43%, and 12% for autologous SCT, respectively. Thus, stem-cell transplantation can be considered as a consolidation strategy in chemo-sensitive and physically fit patients with Richter's transformation.
None of the current regimens have improved response rates in Richter's transformation. One ongoing clinical trial in Richter's transformation is testing ofatumumab (Arzerra) in combination with CHOP (O-CHOP) as induction, and ofatumumab as maintenance treatment.
Richter's transformation is a biologically heterogeneous condition. The clinical course is aggressive, with low response rates and poor outcomes with the currently available chemotherapeutic regimens. Thus, there is no standard of care in the treatment of Richter's transformation. Identification of predictive markers, such as CD38 GG genotype, IGHV mutational status, VH4-39 gene usage, non-del13q chromosomal abnormalities, and bulky disease at the time of diagnosis may help in early identification of patients who are at risk for developing Richter's transformation. Intensive chemo-immunotherapy is used to treat patients after confirming the diagnosis of Richter's transformation. Stem-cell transplantation for responding patients is warranted. The relevance of maintenance therapy in Richter's transformation is unknown. Other directions for future research would be to explore combinations of B-cell receptor inhibitor agents such as ibrutinib (Bruton tyrosine kinase inhibitor) or GS-1101 (phosphoinositol-3 kinase Î´ inhibitor) with intensive chemotherapy, or to use lenalidomide (Revlimid) and/or rituximab maintenance. The identification of newer and targetable mechanisms of CLL transformation may pave the way for improving responses in Richter's transformation.
1. Keep in mind that rapidly progressive B symptoms; bulky lymphadenopathy; organomegaly; anemia; a low platelet count; and elevated serum LDH, calcium, and Î²2 microglobulin levels in a patient with CLL can suggest Richter's transformation.
2. Obtain imaging by whole-body PET-CT scan to pinpoint the area for diagnostic biopsy (SUV > 5).
3. Confirm the diagnosis of Richter's transformation by biopsy of lymph nodes, bone marrow, or involved organs.
4. Initiate treatment with chemo-immunotherapy. Although there is no specific evidence to support any specific regimen, we generally recommend rituximab with HyperCVAD.
5. Evaluate for a possible stem-cell transplantation.
Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. 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.
2. SEER cancer statistics review (1975-2009). Available from: http://seer.cancer.gov/csr/1975_2009_pops09/index.html.
3. Lortholary P, Boiron M, Ripault P, et al. [chronic lymphoid leukemia secondarily associated with a malignant reticulopathy: Richter's syndrome]. Nouv Rev Fr Hematol. 1964;4:621-44.
4. Molica S. A systematic review on Richter syndrome: what is the published evidence? Leuk Lymphoma. 2010;51:415-21.
5. 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.
6. 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.
7. Michelis FV, Kourti G, Skertsou M, et al. Richter transformation of chronic lymphocytic leukemia into composite diffuse large B-cell and Hodgkin lymphoma. Leuk Lymphoma. 2012;
8. Fraser CR, Wang W, Gomez M, et al. Transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma to interdigitating dendritic cell sarcoma: evidence for transdifferentiation of the lymphoma clone. Am J Clin Pathol. 2009;132:928-39.
9. Richter MN. Generalized reticular cell sarcoma of lymph nodes associated with lymphatic leukemia. Am J Pathol. 1928;4:285-92 7.
10. 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;31:1605-14.
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.
12. Melo JV, Catovsky D, Galton DA. The relationship between chronic lymphocytic leukaemia and prolymphocytic leukaemia. II. Patterns of evolution of ‘prolymphocytoid' transformation. Br J Haematol. 1986;
13. Gine E, Martinez A, Villamor N, et al. Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia (“accelerated” chronic lymphocytic leukemia) with aggressive clinical behavior. Haematologica. 2010;95:1526-33.
14. 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;24:2343-51.
15. 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;142:202-15.
16. Fan L, Wang L, Zhang R, et al. Richter transformation in 16 of 149 Chinese patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2012;53:1749-56.
17. 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.
18. Tsimberidou AM, Keating MJ, Bueso-Ramos CE, Kurzrock R. Epstein-Barr virus in patients with chronic lymphocytic leukemia: a pilot study. Leuk Lymphoma. 2006;47:827-36.
19. 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.
20. 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;66:577-9.
21. Fangazio M, De Paoli L, Rossi D, Gaidano G. Predictive markers and driving factors behind Richter syndrome development. Expert Rev Anticancer Ther. 2011;11:433-42.
22. Rossi D, Gaidano G. Richter syndrome: molecular insights and clinical perspectives. Hematol Oncol. 2009;27:1-10.
23. Aydin S, Rossi D, Bergui L, et al. CD38 gene polymorphism and chronic lymphocytic leukemia: a role in transformation to Richter syndrome? Blood. 2008;111:5646-53.
24. Rossi D, Rasi S, Spina V, et al. Different impact of NOTCH1 and SF3B1 mutations on the risk of chronic lymphocytic leukemia transformation to Richter syndrome. Br J Haematol. 2012;158:426-9.
25. Solh M, Rai KR, Peterson BL, et al. The impact of initial fludarabine therapy on transformation to Richter syndrome or prolymphocytic leukemia in patients with chronic lymphocytic leukemia: analysis of an intergroup trial (CALGB 9011). Leuk Lymphoma. 2012 Sep 8. [Epub ahead of print]
26.Omoti CE, Omoti AE. Richter syndrome: a review of clinical, ocular, neurological and other manifestations. Br J Haematol. 2008;142:709-16.
27. 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.
28. Ansell SM, Armitage JO. Positron emission tomographic scans in lymphoma: convention and controversy. Mayo Clin Proc. 2012;87:571-80.
29. Moskowitz CH, Schoder H, Teruyua-Feldstein J, et al. Risk-adapted dose-dense immune chemotherapy determined by interim FDG-PET in advanced-stage diffuse large B-cell lymphoma. J Clin Oncol. 2010;
30. Abruzzo LV, Rosales CM, Medeiros LJ, et al. Epstein-Barr virus-positive B-cell lymphoproliferative disorders arising in immunodeficient patients previously treated with fludarabine for low-grade B-cell neoplasms. Am J Surg Pathol. 2002;26:630-6.
31. Ansell SM, Li CY, Lloyd RV, Phyliky RL. Epstein-Barr virus infection in Richter's transformation. Am J Hematol. 1999;60:99-104.
32. Dungarwalla M, Matutes E, Dearden CE. Prolymphocytic leukaemia of B- and T-cell subtype: a state-of-the-art paper. Eur J Haematol. 2008;80:469-76.
33. Asano N, Yamamoto K, Tamaru J, et al. Age-related Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorders: comparison with EBV-positive classic Hodgkin lymphoma in elderly patients. Blood. 2009;113:2629-36.
34. Louissaint A, Jr., Ferry JA, Soupir CP, et al. Infectious mononucleosis mimicking lymphoma: distinguishing morphological and immunophenotypic features. Mod Pathol. 2012;25:1149-59.
35. Roschewski M Wilson WH. EBV-associated lymphomas in adults. Best Pract Res Clin Haematol. 2012;25:75-89.
36. 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.
37. 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;42:329-37.
38. 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: 1711-20.
39. 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.
40. Tsimberidou AM, Wierda WG, Wen S, et al. Results of a phase I-II clinical trial of oxaliplatin, fludarabine, cytarabine, and rituximab (OFAR) combination therapy in patients with aggressive, relapsed/refractory chronic lymphocytic leukemia (CLL) and Richter syndrome (RS). ASH Annual Meeting Abstracts. 2010;116:923.
41. 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. ASH Annual Meeting Abstracts. 2011;118:2860.
42. Tsimberidou AM, Murray JL, O'Brien S, et al. Yttrium-90 ibritumomab tiuxetan radioimmunotherapy in Richter syndrome. Cancer. 2004;100:2195-200.
43. 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;30:3322-7.