richter s transformation in chronic lymphocytic leukemia

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ONCOLOGY. Vol. 26 No. 12REVIEW ARTICLE

Richter's Transformation in Chronic LymphocyticLeukemia

Challenging Situations in the Management of Leukemias

By Preetesh Jain, MD, DM, PhD , Susan O'Brien, MD |1 1 December 18, 20121Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas

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, disruption, abnormalities, unmutated immunoglobulin heavyTP53 c-MYC

chain < 2%, non-del13q cytogenetics, gene polymorphisms, stereotypy, and gene(IGHV) CD38 VH4-39

usage may predispose to Richter's transformation. The prognosis is generally poor, with a median

survival of about 10 months. Development ofrituximab(Drug information on rituximab)(Rituxan)-containing intensive chemotherapy regimens and chemo-immunotherapy regimens (eg,

R-HyperCVAD [rituximab plus hyperfractionated cyclophosphamide(Drug information on

, , vincristine, andcyclophosphamide) doxorubicin(Drug information on doxorubicin) dexamethasone

] or OFAR [oxaliplatin (Eloxatin), fludarabine, and ara-C]) have(Drug information on dexamethasone)

improved response rates but have not clearly affected long-term outcomes. Allogeneic stem-cell

transplantation may offer a chance for prolonged survival.

Introduction

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-, andCD20-diminished). CLL is the most common leukemia in adults in the Western world.[1] It is estimated that16,060 persons (9490 men, 6570 women) will be diagnosed with CLL and 4580 patients will die of CLL in2012 in the United States.[2] The median age at diagnosis of CLL is about 72 years, and CLL ispredominantly a disease affecting older individuals.

Richter's transformation (or Richter's syndrome) is a clinicopathological term used to describe the rapiddevelopment of a histologically proven aggressive lymphoma in a patient with CLL.[3] The most commonlymphoma seen in patients with Richter's transformation is diffuse large B-cell lymphoma.[4] Other rarertypes of Richter's transformation that have been described are Hodgkin's variant of Richter'stransformation,[5,6] composite lymphoma,[7] and very rarely, interdigitating dendritic cell sarcoma.[8] The

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development of lymphoma in CLL was originally reported by Maurice N. Richter in 1928,[9] and the termRichter's syndrome was coined in 1964 by Lortholary et al to describe the development of malignantreticulopathy in 14 patients with CLL.[3] Studies have shown that the diffuse large B-cell lymphoma thatdevelops in Richter's transformation can be clonally related to the original CLL (true Richter'stransformation; 78% of cases) or can be clonally unrelated diffuse large B-cell lymphoma (20% ofcases).[10,11] It is unclear whether the clonally unrelated diffuse large B-cell lymphoma is a sequentiallymphoma or a clonally unrelated transformation in patients with CLL. The term composite lymphoma isused 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 bedifferentiated from prolymphocytic transformation[12] and accelerated CLL (expanded proliferation centerswithout histologically proven large-cell lymphoma).[13]

Every year about 500 patients are diagnosed with Richter's transformation in the United States. The incidencerates of Richter's transformation range from 2% to 10% in most major studies.[4] The largest study ofRichter's transformation was reported by investigators at the MD Anderson Cancer Center in 2006.[14] Of3986 patients with CLL, 148 patients (3.7%) had a histologically proven Richter's transformation and 204patients (5.1%) had possible Richter's transformation. Survival after Richter's transformation was reported torange from a few weeks to up to 15 years. Two other studies, one from Italy,[15] another from China,[16]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 ofRichter'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 yearsexceeded 5% and 10%, respectively, and the median time to development of Richter's transformation was 23months from the date of diagnosis of CLL.[15]

This review summarizes advances in our understanding of the pathobiology and in the management ofRichter'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 diffuselarge B-cell lymphoma in both clinical behavior and disease biology.

Chromosomal aberrations

Specific cytogenetic abnormalities/translocations are not seen in Richter's transformation. Non-del13q14abnormalities in CLL cells are considered a risk factor for Richter's transformation. Chromosome 14q32translocations, commonly seen in other non-Hodgkin's lymphomas (eg, 14;18 in follicular lymphoma and11;14 in mantle cell lymphoma) are not observed in Richter's transformation.

Molecular profiling

In one study, a comprehensive molecular profiling of 84 patients with Richter's transformation wasperformed.[11] disruption (47.1%) and c-MYC abnormalities (26.2%) were the most common geneticTP53lesions. Patients with Richter's transformation did not have the common mutations seen in de novo diffuselarge B-cell lymphoma (eg, , , NF-B pathway, and , and ). The medianBCL2 BCL6 CD79a CD79b EZH2survival for patients with mutations was 10 months, compared with 27 months in patients withoutTP53 TP53mutations, while median survival with disruptions (deletion or mutations) was 9.4 months, comparedTP53with 47.1 months in patients without such disruptions. However, the presence of mutations at the timeTP53of diagnosis of CLL did not predict for a higher risk of Richter's transformation.




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FIGURE 1

Pathways of Development of Richters Transformation in Chronic Lymphocytic Leukemia (CLL)

Clonality analysis

Diffuse large B-cell lymphoma that develops in patients with Richter's transformation can be either clonallyrelated or unrelated to the original CLL clone. Clonally related Richter's transformation and clonallyunrelated Richter's transformation differ in many respectsand clonally unrelated Richter's transformation isalso different from de novo diffuse large B-cell lymphoma. depicts the outline of the development ofFigure 1clonally related/unrelated diffuse large B-cell lymphoma in patients with CLL.[17] Immunoglobulin heavychain ( ) gene sequencing by polymerase chain reaction (PCR) is useful in determining the clonality inIGHV

patients with Richter's transformation.[10] Clonally unrelated Richter's transformations have a lowerprevalence of disruption, stereotyped V CDR3, and a higher prevalence of mutated . PatientsTP53 H IGHV

with clonally unrelated Richter's transformation have a longer survival than patients with clonally relateddiffuse large B-cell lymphoma (true Richter's transformation).[11]

EBV infection

Some reports have suggested the presence of Epstein-Barr virus (EBV) in the large cells of Richter'stransformation 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 thecommon diffuse large B-cell lymphoma Richter's transformation.[20]

Activation-induced cytidine deaminase

This enzyme is responsible for somatic hypermutation and class-switch recombination in B cells. Any defectin somatic hypermutation caused by aberrancy in actions of activation-induced cytidine deaminase can lead to lymphomagenesis. In Richter's transformation, the pathologicalrelevance of mutations in activation-induced cytidine deaminase is not clear, whereas in de novo diffuse largeB-cell lymphoma, activation-induced cytidine deaminase is known to cause aberrant somatic hypermutation,thus activating proto-oncogenes such as .c-MYC

Cell-cycle dysregulation

The deletion of the gene, loss of cell-cycle inhibitors CDKN1A and CDKN2A, and increased copyRbnumbers of the gene also contribute to transformations in CLL.MYC

Predisposing Factors for Richter's Transformation

Extensive studies of genomic changes occurring in Richter's transformation were reported by Rossi etal.[11,21] Factors that were seen to predispose to Richter's transformation were different from the risk factorsassociated with CLL progression. Specific guidelines for interventions in patients having risk factors forRichter's transformation are not yet available.




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A pilot study reported by Rossi et al in 2008[15] involving 185 CLL patients and paired samples (CLL andRichter's transformation in the same patient) has shown that the following factors[22] predispose to Richter'stransformation in a patient with CLL. (Detailed discussions of the pathological mechanisms behind thesefactors are beyond the scope of this article.)

1. expression (CD38 30%)CD38

2. Stereotyped B-cell receptor

3. gene usageIGHV4-39

4. Telomere length < 5000 base pairs

5. Lymph node size > 3 cm

6. Absence of del13q14

Other studies have reported on polymorphisms with and genes. GG homozygous patientsCD38 LRP4 CD38 had a 30.6% increased risk compared with the risk in patients having the GC or CC genotype[23] and patients

having the TT genotype (which is related to Wnt signaling pathways in CLL).LRP4

NOTCH1 mutations were recently shown to predict for the development of Richter's transformation, whilemutations did not.[24]SF3B1

Currently, there is no evidence that treatment with purine analogues (fludarabine, cladribine(Drug), alone or in combination with cyclophosphamide and rituximab (Rituxan), caninformation on cladribine)

increase the risk of Richter's transformation in patients with CLL.[25]

Prognostic Factors in Richter's Transformation

In 2006, one of the largest studies in patients with Richter's transformation (n = 148) proposed a prognosticscoring system (Richter's transformation Score).[14] Five factors that significantly predicted for pooroutcome 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 thenumber of risk factors at the time of presentation (identified by scores of 01, 2, 3, and 45, respectively).Median survival of patients in low-, low-intermediate, high-intermediate, and high-risk categories was1.12, 0.9, 0.33, and 0.2 years, respectively ( ).Figure 2

FIGURE 2




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Survival in 130 Assessable Treated Patients in the Study of Richters Transformation From Which a

Prognostic Scoring System Was Developed

Histopathology of Richter's Transformation

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 withcentroblastic/immunoblastic morphology. The majority (about 80%) of diffuse large B-cell lymphoma casesin Richter's transformation displays a postgerminal center (GC) phenotype (MUM1/IRF4 expression) andonly 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 proliferationmarker 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 ofCD15 and CD30 by the R-S cells similar to that seen in de novo Hodgkin's disease.[10]

Approach to a Patient With Suspected Richter's Transformation

Suspect Richter's transformation when a patient with CLL presents with a rapidly deteriorating clinicalprofile and enlargement of lymph nodes, prominent B symptoms (night sweats, weight loss, fever withoutinfection), and extranodal involvement (such as involvement of the central nervous system, skin, stomach,testes, eyes, or lungs).[26] Pancytopenia is common. Elevated LDH levels are common. Hypercalcemia withor without lytic bone lesions and monoclonal gammopathy can also be seen.

Imaging

PET-CT (positron emission tomographycomputed tomography) scanning may be quite helpful in diagnosingRichter's transformation. An abnormal increase in uptake of the tracer 18F-FDG (18-fluorodeoxyglucose, aglucose analogue) on PET-CT with standardized uptake value (SUV) > 5 is highly suggestive of thedevelopment of Richter's transformation. In a study of 37 patients with CLL,[27] 11 patients developedRichter's transformation, and PET-CT scanning detected Richter's transformation with a sensitivity, aspecificity, and positive and negative predictive values of 91%, 80%, 53%, and 97%, respectively. Particularattention to the following factors is needed when examining results from PET-CT scans for evidence ofsuspected 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.[28]

Attention must be paid to the type of chemotherapy administered: one study showed that a negative biopsyfollowing a positive PET-CT scan was fairly common after dose-intense chemotherapy.[29]

Rigorous quality control must be maintained to compensate for variability in data acquisition and image




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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.[28]Nevertheless, PET-CT can indicate a site of Richter's transformation amenable to biopsy, since all nodes maynot be involved. Biopsy with a pathologic diagnosis remains the gold standard for diagnosing Richter'stransformation. Gallium-67 scanning was used in the past to differentiate Richter's transformation from CLL,

but is of limited value in the current era.

FIGURE 3

Survival in Patients With Richters Transformation Who Underwent Stem-Cell Transplantation, According to

Type of Transplant and Disease Status at the Time of Transplant

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 histopathologicalevaluation of the involved nodal or extranodal site. It is important to distinguish such conditions fromRichter'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 proliferationrate (either > 2.4 mitoses/proliferation center or Ki-67 > 40%/proliferation center). Patients usually havehigher LDH levels, and CLL cells express ZAP-70. The median survival of patients with accelerated CLL vsthose with Richter's transformation was 34 months and 4.3 months, respectively.[13] Data regarding thetreatment 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 ofRichter's transformation is associated with EBV positivity. The R-S cells in Hodgkin's variant of Richter'stransformation 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'slymphoma.[30,31]

Prolymphocytic transformation

These patients have increased prolymphocytes (> 55%) with positive CD5, CD23 expression, and weakCD22 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 forB-PLL, incorporating (Campath), rituximab-based purinealemtuzumab(Drug information on alemtuzumab)analogue combinations, and allogeneic stem-cell transplantation (SCT).[12,32]




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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 EBVin lymphoid tissues. Patients with EBV-associated lymphoproliferative disorder may present with rapidlyenlarging lymph nodes and progressive clinical symptoms. Histopathological evaluation mimics that ofage-related diffuse large B-cell lymphoma of the elderly[33] or a classical Hodgkin's lymphoma, but theseentities 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 asimmunoblastic, centroblastic morphology and MUM1/CD10/bcl2/bcl6 expression in monoclonal B cells). InEBV-associated lymphoproliferative disorder, the morphology is polymorphous, with predominantgeographic 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 butyratetherapy with ). Of note, misdiagnosis of this entity may lead tocidofovir(Drug information on cidofovir)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 ofthe chemo-refractoriness of the lymphomatous cells (due to mutations), rapid cell turnover, and poorTP53performance status of the patients.[14]

Chemotherapy and chemo-immunotherapy

In the pre-rituximab era, Richter's transformation was treated similarly to high-grade lymphomaswithCHOP (cyclophosphamide, doxorubicin, vincristine, and )-basedprednisone(Drug information on prednisone)regimens, ESHAP (etoposide [Vepesid], ,methylprednisolone(Drug information on methylprednisolone)cytarabine, and ), FACPGM (fludarabine,cisplatin(Drug information on cisplatin) cytarabine(Drug

, cyclophosphamide, cisplatin, and granulocyte macrophage colony-stimulatinginformation on cytarabine)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, and dexamethasone), alternating with(Drug information on daunorubicin) methotrexate(Drug information

and ara-C, the response rates were similar to the rates achieved with CHOP, other earlieron methotrexate)regimens, and HyperCVXD.[37] The complete remission (CR) rate was 38% with HyperCVXD. Similarly,with HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plusrituximab (R-HyperCVAD) alternating with methotrexate and ara-C, the response rate was 43%, with a CRrate of 27%.[38] In a retrospective single-center study, the response rates seen with chemotherapy andchemo-immunotherapy were not significantly different. Median survival with both chemotherapy andchemo-immunotherapy was less than 10 months. Of note, higher response rates were observed in patients

who had a platelet count >100 10 /L, performance status of 0 or 1, a hemoglobin level > 11 g/dL, and 29

microglobulin < 6 mg/L.[14] In 2008, a phase II study reported responses with the OFAR regimen

(oxaliplatin, fludarabine, cytarabine, and rituximab) in 20 patients with RT.[39] This combination wasdeveloped 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 > 70years 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'stransformation.[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 smalltrial 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'stransformation were given 90Y ibritumomab tiuxetan; no patients responded.[42] Treatment regimens inRichter's transformation are similar to each other in their response rates and have not improved outcomes.




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Stem-cell transplantation

Two studies have reported improved outcomes with stem-cell transplantation in patients with Richter'stransformation who achieved remission with chemotherapy. In one study of 20 patients who underwenttransplantation, the estimated 3-year cumulative survival was 75% for responding patients with Richter'stransformation and 21% for patients who received stem-cell transplantation as salvage therapy after failingchemotherapy.[14]

Recently, another study from the European Group for Blood and Marrow Transplantation (EBMT) in 59patients with Richter's transformation showed that 3-year probabilities of overall survival and relapse-freesurvival, 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-celltransplantation can be considered as a consolidation strategy in chemo-sensitive and physically fit patientswith Richter's transformation.

Clinical trials

None of the current regimens have improved response rates in Richter's transformation. One ongoing clinicaltrial 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 lowresponse rates and poor outcomes with the currently available chemotherapeutic regimens. Thus, there is nostandard of care in the treatment of Richter's transformation. Identification of predictive markers, such as

GG genotype, mutational status, gene usage, non-del13q chromosomal abnormalities,CD38 IGHV V 4-39H

and bulky disease at the time of diagnosis may help in early identification of patients who are at risk fordeveloping Richter's transformation. Intensive chemo-immunotherapy is used to treat patients afterconfirming 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 forfuture research would be to explore combinations of B-cell receptor inhibitor agents such as ibrutinib (Brutontyrosine kinase inhibitor) or GS-1101 (phosphoinositol-3 kinase inhibitor) with intensive chemotherapy, orto use lenalidomide (Revlimid) and/or rituximab maintenance. The identification of newer and targetablemechanisms 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; alow platelet count; and elevated serum LDH, calcium, and 2 microglobulin levels in a patient with CLL cansuggest 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 involvedorgans.

4. Initiate treatment with chemo-immunotherapy. Although there is no specific evidence to support anyspecific regimen, we generally recommend rituximab with HyperCVAD.




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5. Evaluate for a possible stem-cell transplantation.

Financial Disclosure:The authors have no significant financial interest or other relationship with themanufacturers of any products or providers of any service mentioned in this article.

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richter s transformation in chronic lymphocytic leukemia

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