Differential Diagnosis
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.
Accelerated CLL
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.[13] Data regarding the treatment options appropriate for accelerated CLL are lacking.
Hodgkin's variant of Richter's transformation
This is a rare entity.[6] 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]
Prolymphocytic transformation
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(Drug information on alemtuzumab) (Campath), rituximab(Drug information on rituximab)-based purine analogue combinations, and allogeneic stem-cell transplantation (SCT).[12,32]
EBV-associated lymphoproliferative disorder
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[33] 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(Drug information on cidofovir)). Of note, misdiagnosis of this entity may lead to unnecessary administration of intensive chemotherapy for diffuse large B-cell lymphoma.[34,35]
Therapeutic Options
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.[14]
Chemotherapy and chemo-immunotherapy
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(Drug information on methylprednisolone), cytarabine, and cisplatin(Drug information on cisplatin)), FACPGM (fludarabine, cytarabine, cyclophosphamide(Drug information on cyclophosphamide), cisplatin, and granulocyte macrophage colony-stimulating factor [GM-CSF]),[36] etc. About one-third of patients respond to the foregoing regimens. With the addition of rituximab to HyperCVXD (hyperfractionated cyclophosphamide, vincristine, liposomal daunorubicin(Drug information on daunorubicin), and dexamethasone(Drug information on dexamethasone)), alternating with methotrexate(Drug information on methotrexate) and ara-C, the response rates were similar to the rates achieved with CHOP, other earlier regimens, and HyperCVXD.[37] The complete remission (CR) rate was 38% with HyperCVXD. Similarly, with HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin(Drug information on doxorubicin), and dexamethasone) plus rituximab (R-HyperCVAD) alternating with methotrexate and ara-C, the response rate was 43%, with a CR rate of 27%.[38] 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 β2 microglobulin < 6 mg/L.[14] In 2008, a phase II study reported responses with the OFAR regimen (oxaliplatin, fludarabine, cytarabine(Drug information on cytarabine), and rituximab) in 20 patients with RT.[39] This combination was developed after preclinical studies showed synergism between oxaliplatin(Drug information on 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.[40] 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.[41] A smaller series of seven patients with Richter's transformation were given 90Y ibritumomab tiuxetan; no patients responded.[42] Treatment regimens in Richter's transformation are similar to each other in their response rates and have not improved outcomes.
Stem-cell transplantation
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.[14]
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.[43] Thus, stem-cell transplantation can be considered as a consolidation strategy in chemo-sensitive and physically fit patients with Richter's transformation.
Clinical trials
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.
Summary
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 δ 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.
The Approach to a Patient With Suspected Richter's Transformation That We Recommend
1. Keep in mind that rapidly progressive B symptoms; bulky lymphadenopathy; organomegaly; anemia; a low platelet count; and elevated serum LDH, calcium, and β2 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.
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