ABSTRACT: 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(Drug information on rituximab) (Rituxan)-containing intensive chemotherapy regimens and chemo-immunotherapy regimens (eg, R-HyperCVAD [rituximab plus hyperfractionated cyclophosphamide(Drug information on cyclophosphamide), doxorubicin(Drug information on doxorubicin), vincristine, and dexamethasone(Drug information on 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.
Pathogenesis of Richter's Transformation
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-κB 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.
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.
Activation-induced cytidine deaminase
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.