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Richter syndrome (RS) describes the development of high-grade non-Hodgkin lymphoma (NHL) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). The syndrome was first described in 1928 by Maurice N. Richter, who reported a patient with rapidly fatal generalized lymphadenopathy and hepatosplenomegaly associated with CLL.1 Histologic examination of the lymph nodes, liver, and spleen revealed two types of cells: leukemic and tumor cells. Leukemic cells referred to lymphocytes of small size and tumor cells referred to numerous, polymorphous endothelial cells, several times as large as the lymphocytes, with abundant basophilic cytoplasm, well defined nuclei, and several prominent nucleoli.1
In 1964, Lortholary et al.2 introduced the term “Richter's syndrome” to describe the histologic progression of CLL to a “malignant reticulopathy” in the terminal stages. They described 4 patients and reviewed the cases of 10 previously reported patients with presentations similar to that in Richter's first report.2 Subsequently, RS was expanded to include other lymphoid malignancies that develop in patients with CLL, such as prolymphocytic leukemia (PLL), Hodgkin disease, the so-called Hodgkin variant of Richter's transformation,3 small noncleaved cell lymphoma,4 lymphoblastic lymphoma,5 and hairy cell leukemia.6 In rare cases, patients with B-cell CLL may develop high-grade, T-cell NHL.7, 8
Patients with RS typically present with a history of CLL, fever in the absence of infection, an elevated lactate dehydrogenase (LDH) level, and rapidly enlarging lymph nodes. Diagnosis is confirmed by biopsy of an enlarging lymph node or other involved site. The prognosis is poor, particularly in patients with classic RS. The therapeutic options are limited and include chemotherapeutic regimens that were developed for de novo diffuse large cell lymphoma (DLCL) or acute lymphoblastic leukemia (ALL). Most patients with RS fail to respond to even intensive regimens or novel agents with activity in CLL or NHL, and the median survival duration ranges from 5 months to 8 months.9–13
RS may represent the end stage of CLL, with similarities to accelerated or blastic-phase chronic myeloid leukemia. Better understanding of the mechanisms involved in the pathogenesis of RS may lead to effective therapeutic strategies.
ETIOLOGY AND ONCOGENESIS
The molecular mechanisms involved in the transformation of CLL to RS are poorly understood. The large cell lymphoma clone occurs either by transformation of the original CLL clone (in the majority of patients)9, 13–23 or as a separate and independent neoplasm,21, 24–29 as shown by characterization of immunoglobulin (Ig) heavy-chain gene rearrangements and light-chain isotype analyses. Clonal evolution may be triggered by viral infections, which are common in immunosuppressed patients. In some cases, acquisition of additional chromosomal abnormalities also has been implicated. Genetic abnormalities at both the chromosomal and nucleic acid level have been documented.20, 30–34 Karyotypic changes include chromosome 12 and 13 abnormalities and other structural anomalies that are common in CLL, such as deletions and translocations at chromosomes 13q, 11q, 6q, and 14q.35
Trisomy 12 is an acquired cytogenetic abnormality in CLL that occurs with high frequency in RS.32 Immunophenotyping and interphase fluorescence in situ hybridization (FISH) analyses have shown that trisomy 12 is associated strongly with atypical lymphocyte morphology and is a secondary event in leukemogenesis.36–39 The atypical lymphocytes have some immunophenotypic deviations (i.e., CD5 negativity, FMC7 positivity, and strong surface Ig staining) that are more frequent in patients with trisomy 12 than in patients with CLL with other chromosome anomalies.35–39 Trisomy 12 also has been associated with high rates of proliferation and disease progression. It has an adverse impact on survival35 and has been implicated in the pathogenesis of RS. In particular, a gene dosage effect may play a role in the biologic consequences of trisomy 12. This gene most likely is located in the region between 12q13 and 12q22.35
The clinical significance of trisomy 12 has been evaluated in three studies. In a cytogenetic study of 77 patients with CLL, trisomy 12 was the sole abnormality in 13% of patients and was combined with other chromosome anomalies in 10% of patients.40 Of the four patients with RS for whom an autopsy was performed, three had trisomy 12 and other chromosome abnormalities.40 In another study, seven of eight patients who developed RS had complex karyotypic changes with or without trisomy 12 before the time of transformation.41 In another series, trisomy 12 was identified in all five patients with RS but in only one of the five patients before transformation, using an alpha-satellite DNA probe to the centromere of chromosome 12.32 These findings suggest that trisomy 12 may be the primary change in some patients with CLL undergoing transformation to RS and that patients with complex karyotypes may have a higher probability of transformation to RS than those with a single trisomy or a normal karyotype.40, 41 However, it is unlikely that trisomy 12 plays a direct role in the transformation of B-cell CLL to RS, because only a subpopulation of the neoplastic cells contains an extra copy of chromosome 12.32, 35, 37
Structural Abnormalities of Chromosome 11q
Patients with CLL/SLL with deletion 11q23 appear to be more prone to develop RS, probably because this region is considered to harbor genes,42 such as the nerve cell adhesion molecule gene, that may cause the transformation.43 In particular, FISH analysis in the region represented by YAC755b11 located deletion 11q23 in three of three patients with RS compared with 13 of 62 patients with CLL/SLL (21%).42
In contrast to deletion 11q, which is common in patients with “typical” CLL,44 translocation t(11;14)(q13;q32) is found in patients with atypical CLL.45 Of 72 patients with CLL, t(11;14) was identified in 7 (atypical CLL, n =2; PLL, n = 5).45 Atypical morphology, disease progression, and karyotype evolution occurred more frequently in patients with CLL with t(11;14) than in patients without the translocation. The immunologic profile of the seven patients with t(11;14) was distinct and shared some biologic features with mantle cell lymphoma. For instance, surface Igs were expressed in six of seven patients and CD23 in one of seven patients.45 In addition, overexpression of cyclin-D1 in some patients with RS suggests a possible relation between t(11;14)/cyclin-D1 overexpression and RS development.46 This event may occur alone or in association with other abnormalities, such as p53 mutations.47
The accumulation of multiple, different genetic lesions in the transformed stage of CLL suggests that an acquired genome-wide instability or mutator phenotype of the neoplastic cells predisposes and promotes the development of Richter's transformation.48, 49 DNA mismatch-repair of defect-initiated genetic instability frequently develops during disease progression. Alterations in three of nine microsatellite repeats were detected in one patient with RS, which had evolved from a preexistent B-cell CLL/SLL, but were not detected in any patients with B-cell CLL/SLL.48 In the same RS patient, the CLL tissue sample displayed a germline pattern at the microsatellites examined, indicating that microsatellite instability developed during disease progression.48 In another study, tissue samples from 19 patients with CLL, 9 of whom had disease transformation to RS, were examined for microsatellite instability using 8 microsatellite markers.49 High levels of microsatellite instability were observed in four patients with Richter's transformation but were not observed in any of the patients with nontransformed CLL.49 Microsatellite instability was initiated in transformed patients with a hypermethylated hMLH1 mismatch repair gene promoter. Hypermethylation of this promoter was associated with high levels of microsatellite instability in four patients with RS and with low levels of instability in one patient.49 In contrast, none of the four patients with RS analyzed in another study showed microsatellite alterations.50
In patients with CLL, loss of heterozygosity status occurs at different frequencies in large and small cells.51 Loss of heterozygosity on chromosomes 11 (11q22 at the ATM gene), 17 (11p13), and 20 (20q12) has been found more frequently in large cells than in small cells, suggesting that these differences may be involved in the transformation of small CLL cells to large (Richter) cells.51
Tumor Suppressor Genes
Different genetic defects, such as mutations of the p53 tumor suppressor gene,47, 52, 53p16INK4A,54 and p21, loss of p27 expression, deletion of retinoblastoma,55 increased copy number of C-MYC,56 and decreased expression of the A-MYB gene,57 have been detected in Richter's transformation. Although none of these multiple cell cycle regulator disruptions appears to be a predominant factor responsible for the transformation to RS,49 they may cause CLL cells to proliferate and, by facilitating the acquisition of new genetic abnormalities, transform into RS cells.46
Alterations of p53 have a high frequency in the transformation of B-cell CLL/SLL to RS52 and may be related to the development of a new malignant clone rather than to progression of the indolent CLL clone.21 Single-strand conformation polymorphism analysis and direct sequencing of polymerase chain reaction (PCR)-amplified fragments identified p53 mutations in 3 of 7 patients with RS compared with 6 of 40 patients with B-cell CLL.52
In addition to p53, p16INK4A tumor suppressor gene pathways may be involved in Richter's transformation.46, 58p16INK4A exerts a strong inhibitory action on cell cycle progression59 and is frequently inactivated in patients with advanced-stage disease of solid tumors.60–62 INK4a knock-out mice have been shown to spontaneously develop B-cell lymphomas with an aggressive morphology.63 Inactivation of the p16INK4a gene, either by biallelic deletions or by point mutations, is a relatively common phenomenon in patients with progressive NHL.54 Inactivation of the p16INK4A gene has been detected in 33% of transformed cases of CLL, follicular cell lymphoma, and blastic mantle cell lymphoma but in only 5% of their indolent counterparts.54p53 mutations and/or ARF/INK4a homozygous deletions are found in approximately 60% of patients with RS.21, 52, 54
Another gene that allows DNA repair is the p21Waf1 gene, which is induced by wild-type, but not mutant, p53.64 Patients with RS express p53+/p21+ more frequently, as shown by immunohistochemical studies, and have higher p21Waf1 immunoreactivity than patients with CLL. A p53+/p21− pattern of immunohistochemical expression has been found exclusively among p53-mutated CLL and RS tumors,46 suggesting the existence of p53-independent mechanisms of p21Waf1 induction, such as the signal transducer and activator of transcription (STAT) signaling pathway.65
Loss of expression of the p27 gene, which is involved in G1 arrest in response to different extracellular signals,66 has been described in RS.46 Reduced expression of the p27 protein has been associated with disease progression and poor prognosis.67 p27 protein loss in RS may be explained by a posttranslational mechanism, such as enhanced ubiquitin proteasome-mediated degradation.46
Findings regarding the role of Retinoblastoma (Rb) in Richter's transformation are conflicting. Some studies show undetectable Rb mRNA levels in some cases of aggressive CLL68 and inactivation of the Rb gene in a subset of aggressive NHL.69, 70 Other studies show low and high Rb expression in CLL and RS, respectively, and therefore preclude participation of this tumor suppressor gene in CLL transformation and support a direct correlation between the amount of Rb product and the proliferative index of these tumors.46
Studies of A-myb, c-myb, and B-myb in a patient with CLL that progressed to RS showed that disease progression was accompanied by a loss in CD5 expression and a 25-fold decrease in A-myb expression, suggesting a shift in differentiation.57 In this patient, the Richter cells were of the same origin as the original CLL cells (i.e., a similar λ light-chain isotype).57 In contrast, although c-myc rearrangements are involved in the transformation of low-grade lymphomas into aggressive types, to our knowledge they are not involved in Richter's transformation of CLL.21, 47
Epstein–Barr virus (EBV) is a B-lymphotropic human herpesvirus that infects > 90% of the adult population worldwide.71 The majority of carriers are asymptomatic throughout their lives because natural killer cells, T-suppressor cells, and human leukocyte antigen (HLA) and antigen-restricted T-cytotoxic and T-suppressor cells restrict virus-infected B-lymphocyte proliferation at different stages of human EBV infection.72, 73
EBV infection has been identified in the lymphoma cells in a few patients with RS. It arises from CLL-related or unrelated clones74, 75 and is clearly implicated in the pathogenesis of some other B-cell malignancies, such as endemic Burkitt lymphoma and Hodgkin disease.76 In endemic Burkitt lymphoma, Ig/myc translocation and viral terminal repeats have demonstrated that the cellular and latent episomal EBV genomes are monoclonal.77, 78 EBV infection also is linked to lymphoproliferative disease in patients with congenital or acquired immunodeficiency, such as that resulting from severe combined immunodeficiency, organ or bone marrow transplants, or acquired immunodeficiency syndrome (AIDS). These patients have impaired T-cell immunity and are unable to control the proliferation of EBV-infected B cells.79, 80 Peripheral blood Epstein–Barr viral load increases before the development of the disease and decreases with effective therapy.81 Elevation in serum levels of interleukin-6, which is a B-cell growth factor, may increase the proliferation of EBV-infected B cells.82
The mechanisms via which EBV infection causes lymphomagenesis are complex. To be oncogenic, the virus must maintain its viral genome while in the cell (latent infection in the B cells), not kill the cell, prevent the cell from being destroyed by the immune system, and activate cellular growth-control pathways.83 After infection of a B cell, the EBV genome is transported into the nucleus, in which it is predominantly present as an extrachromosomal circular molecule (episome).84 The cohesive terminal repeats of EBV, which comprise a variable number of tandem repeat (VNTR) sequence, mediate the formation of the circular episomes.84 Because of the heterogeneity of the EBV termini, the precise number of VNTR sequences enclosed in the newly formed episomes varies to a marked degree, thus providing a constant clonal marker of a single infected cell.85
In vitro studies have demonstrated that EBV infection can efficiently transform and immortalize human B cells. After infection, the B cells become activated as a result of the expression of EBV latent antigens, and these latently infected lymphoblastoid cell lines proliferate indefinitely.86 During the latency period of EBV infection in NHL, the virus is not replicated and expresses a limited number of viral genes.84 EBV infection is also able to significantly alter the growth of B cells in vivo.84 EBV-infected NHL cells generally harbor one single form of fused EBV termini, indicating that infection has preceded, and may have contributed to, clonal expansion.77, 85, 87 A percentage of EBV-infected patients with NHL express the EBV encoding proteins latent membrane protein 1 (LMP1) and EBV nuclear antigen 2, which are well known transforming agents for B cells. However, some EBV-infected patients with NHL, such as patients with Burkitt lymphoma, fail to express these proteins.88, 89 The different patterns of expression of the EBV genes in B-cell malignancies suggest distinct roles for the virus in the transformation process or the maintenance of malignant growth,90 and the involvement of EBV infection in the pathogenesis of these different types of lymphoma supports the idea that a B-cell lymphoma is defined, mainly, by the combination of transforming events and the stage of differentiation at which a B cell is a target for transformation.91
LMP1 in EBV-infected cells plays a central role in this process, most likely by mimicking members of the family of tumor necrosis factor (TNF) receptors. LMP1 has a cytoplasmic tail that binds to the intracellular proteins, TNF-receptor–associated factors (TRAFs). These LMP1-bound proteins activate the nuclear factor-kappa B transcription factor, causing the cell to proliferate.92–95 The lymphocyte growth and activation also may be mediated by other members of the TNF-receptor family, such as CD30 and CD40. Evidence of LMP1-mediated signal transduction through TRAFs was shown in tumor tissue specimens from patients with posttransplantation lymphoproliferative disease and NHL associated with AIDS.96 In this setting, the combination of chronic B-cell stimulation and severe T-cell immunodeficiency in patients with previous EBV infection may predispose them to the development of NHL.76
In Richter's transformation, the precise role of EBV infection remains to be established, and a causative relation between EBV and RS has not been proven yet. The prevalence of EBV in patients with RS has been examined in a single retrospective study of 78 patients with available biopsy tissue specimens for EBV studies.97 Four of the 25 patients with RS (16%) had evidence of EBV infection in large cell lymphoma cells as demonstrated by immunoperoxidase staining for expression of LMP and in situ hybridization for expression of EBV RNA and DNA.97 Among these four patients, three patients with a B-cell phenotype were positive for LMP, EBV DNA, and EBV RNA and one patient with a T-cell phenotype had positive EBV RNA in the large cell lymphoma cells.97 The 4 patients with EBV infection had a median survival duration of 3 months, compared with 9 months in patients without EBV infection. However, this difference did not reach statistical significance, most likely because of the few patients in the group of patients with EBV infection.97 In the same study, one patient with EBV-positive RS was treated with intravenous acyclovir followed by oral acyclovir. A lack of response resulted in death 8 weeks after the diagnosis of RS.97
Evidence supports EBV infection in the Hodgkin variant of Richter's transformation. Although some of these cases may represent a coincidental occurrence, EBV infection plays an important role in the pathogenesis of some cases via integration of its genome in the absence of active viral replication.98–101
In vitro data suggest that EBV infection may affect the sensitivity of B cells to treatments such as fludarabine. The induction of apoptosis by fludarabine was different in three cell lines that differed in their EBV infection status.102 An EBV-negative Burkitt lymphoma cell line (BL2) was very sensitive to fludarabine, whereas two EBV-positive cell lines (BL2.B95.8 and PRI) were resistant, with the EBV-immortalized lymphoblastoid cell line (PRI) being more sensitive than the EBV-infected Burkitt lymphoma cell line (BL2.B95.8).102 This finding may be explained by the induction of the antiapoptotic protein bcl-2 in B cells by EBV infection.103, 104 However, the mechanisms of inhibition of apoptosis in EBV-infected B cells are not fully understood.102
RS may occur in patients with infections other than EBV. RS outside the central nervous system (CNS) has been reported in a patient with concurrent progressive multifocal leukoencephalopathy, a demyelinating infectious disease caused by a human polyomavirus (JC virus).105
The reported incidence of transformation to RS in patients with CLL ranges from 2.2% to 8% and from 5% to 7% in the 2 largest series.9, 106–111 The 20-year actuarial risk of RS was 19 ± 7% in a single report.112
In a retrospective review of 1374 patients with CLL treated at The University of Texas M. D. Anderson Cancer Center (Houston, TX) during a 20-year period between 1972 and 1992, Robertson et al.9 reported Richter's transformation in 39 patients (2.8%). During the next decade (1992–2002), RS developed in 105 of 2147 patients with CLL (4.9%). The incidence of transformation increases with the number of previous regimens (Fig. 1).
In a U.S. Intergroup prospective study evaluating 544 patients with previously untreated CLL, 6.3% of patients developed Richter's transformation and 1.8% of patients developed PLL after a median time of 21.9 months (range, 1–66 months) and 14.8 months (range, 1–36 months), respectively.110 In an Italian retrospective analysis of 1011 patients with CLL, 2.2% of patients developed RS (classic RS, 1.8%; Hodgkin disease variant, 0.4%).111 In that analysis, patients age ≤ 55 years had a 5-fold higher incidence of RS compared with older patients (5.9% vs. 1.2%; P < 0.00001), most likely because older patients with advanced and unresponsive disease are less likely to undergo tissue biopsies.111
Transformation to RS or PLL is not generally associated with previous purine analog therapy.9, 110 In one study, the incidence of transformation was not higher in patients previously treated with fludarabine or 2-chlorodeoxyadenosine therapy than in patients previously treated with alkylating agents,9 and in another study, it was not reduced by fludarabine-containing regimens.110 However, in a single (preliminary) analysis of the actuarial risk of Richter's transformation in a French study (CLL, n = 620; RS, n = 37), previous fludarabine therapy was an unfavorable factor (P = 0.02).112
SYMPTOMS AND SIGNS: NATURAL HISTORY
Richter's transformation is characterized by the development of systemic symptoms (e.g., fever, weight loss, and/or drenching night sweats), sudden clinical deterioration, and, usually, a rapid increase in the size of a lymphoid mass at one site. Patients may have abdominal symptoms due to increasing splenomegaly and/or hepatomegaly or symptoms related to other sites of disease involvement.9, 13, 106, 113–115 Bulky retroperitoneal adenopathy and massive splenomegaly are common presenting features. The majority of patients have had a previous diagnosis of CLL, but a patient may present occasionally with de novo RS.
The lymphomatous clone in Richter's transformation frequently arises in lymph nodes or bone marrow and disseminates to other organs.114 Rarely, RS may present with extranodal involvement.23, 25, 106, 116–123 Extranodal sites of involvement include the gastrointestinal (GI) tract,23, 25, 106, 114, 116–120, 124 CNS,9, 105, 122, 123, 125 skin,121, 123, 126 eye,127 testis,128 and lung or kidney.114 Most patients with extranodal RS in the GI tract represent a true secondary neoplasm, but less frequently, a clonal relation between CLL and GI RS has been shown by clonality studies.25, 116
In rare cases, CNS involvement may be the only initial manifestation of RS,125 and neurologic symptoms usually develop abruptly. The precise incidence of CNS involvement is unknown. Robertson et al.9 reported that 5 of 39 patients (13%) had CNS involvement at presentation, including 3 patients with isolated leptomeningeal disease.
The natural history of the Hodgkin variant of RS is difficult to determine because of limited reports.3, 99, 101, 129–133 Patients with this variant generally present with a more advanced stage of disease than do patients with true Hodgkin disease.134
The most common feature in Richter's transformation is an elevated LDH level, a marker of tumor growth.9 In a study by Robertson et al.,9 82% of patients with RS had an LDH level at least twice as high as the upper limit of normal, compared with 8% of patients with CLL. Paraproteinemia was observed in 44% of patients with RS.9 Less frequently, lytic bone lesions or hypercalcemia may be present, probably because of increased bone resorption.113, 119, 135, 136 In some patients, the first indication of Richter's transformation may be the presence of circulating immunoblasts in the peripheral blood. Anemia, neutropenia, and thrombocytopenia may occur, but these usually are attributed to the underlying CLL.
The diagnosis of Richter's transformation requires a lymph node biopsy. Gallium-67 (Ga-67) single-photon emission computed tomography (Ga-67 SPECT) scans have been used to detect Richter's transformation. This test was proposed initially as an alternative to invasive methods and is based on histologic findings of DLCL in seven of nine patients with a positive scan.137 However, another study of 13 patients with CLL with suspicion of disease progression to RS or DLCL suggested that the use of Ga-67 SPECT is limited, most likely because Ga-67 uptake is not necessarily related to the rate of proliferation.138 In the latter study, a total of 6 patients had positive Ga-67 SPECT scans and 10 patients (5 patients with a positive Ga-67 SPECT scan and 5 patients with a negative Ga-67 SPECT scan) underwent biopsies. Histologic examination showed DLCL in only one patient, with a negative Ga-67 SPECT scan.138
CNS lymphoma usually presents as mass lesions that involve deep gray structures or periventricular regions that can be either isodense or hyperdense on CT scans.139 The magnetic resonance imaging scan appearance may be variable, with T1-weighted precontrast images generally being hypointense or isointense and T2-weighted images varying from hypointense to hyperintense. After contrast administration, these lesions typically enhance in a homogenous fashion.139 In patients with suspected CNS involvement, cerebrospinal fluid examination, including immunophenotypic studies, is needed.105
Currently, there are no established risk factors for the development of Richter's transformation in patients with CLL. In a univariate analysis of 620 patients with B-cell CLL in a French study, younger age (P = 0.03), the presence of a peripheral tumoral syndrome (P = 0.01), diffuse involvement as demonstrated in tissue specimens from bone marrow biopsies (P = 0.006), initial hemoglobin level < 12 g/dL (P = 0.00001), advanced Rai stage140 (P = 0.00001), LDH level greater than 1.25-fold the upper limit of normal (P = 0.03), and high β-2-microglobulin levels (> 3 mg/L; P = 0.008) predicted the occurrence of RS.112
In the Intergroup Study Cancer and Leukemia Group B 9011, pretreatment characteristics of 521 patients with previously untreated CLL were analyzed with regard to prediction of Richter's transformation. Age, gender, Rai stage of CLL, and the type of therapy (fludarabine, chlorambucil, or fludarabine plus chlorambucil) were analyzed.110 Patients with PLL presented more frequently with Rai Stage III/IV disease than did patients with RS and other patients (80%, 44%, and 38%, respectively; P = 0.02), but no other factors were found to be predictive of Richter transformation.110
With regard to histology, patients with the Hodgkin disease variant of Richter's transformation have a worse prognosis than patients with true Hodgkin disease but a better outcome than those with classic RS.129, 134
In classic RS, the large NHL cells are separate and distinct from the CLL/SLL cells.1 The large cells are moderately irregular or round, with vesicular nuclei, prominent nucleoli, and a moderate amount of cytoplasm.1 In some tissue specimens, the large lymphoma cells may also be intimately admixed with the small lymphocytes, the so-called paraimmunoblastic variant of CLL/SLL.141 The lymph node may be effaced by large cell lymphoma, or CLL and DLCL may coexist as a composite lymphoma in the same specimen.
The limited available immunophenotypic data indicate that the RS immunophenotype resembles the original CLL immunophenotype in some tissue specimens.17, 26, 141 However, in other tissue specimens, the antigen expression is different than that of the original immunophenotype.123, 142, 143 In addition, the large cells of RS may express Ki-67.58
Less commonly, patients with CLL/SLL may develop neoplasms that morphologically and immunophenotypically resemble Hodgkin disease and are defined as the Hodgkin variant of Richter's transformation.3 Two types of the Hodgkin variant of RS have been described. Type 1 is characterized by Hodgkin and Reed–Sternberg (H-RS) cells scattered in a background of CLL cells.98, 144–146 In type 2, H-RS cells present in a typical polymorphous inflammatory background separate from the CLL cells.3, 132, 133, 147–150 Histologic and immunophenotypical findings suggest that H-RS cells in patients with type 1 disease represent histologic progression of the underlying CLL cells, especially when the H-RS cells express B-cell markers. Although in type 2, two different disease types are considered to be present, these two lesions may be related. It is unknown whether the two types of Hodgkin variant of RS are associated with distinct clinical and prognostic features. A clonal relation between CLL and H-RS cells has been shown in three of four patients with the Hodgkin variant of RS by single-cell PCR analysis and DNA sequencing.152 Hodgkin variant of RS may share common genetic alterations with classic Hodgkin disease, which result in the morphologic and immunophenotypic features, cytokine production profile, and stromal reactions that are recognized as Hodgkin disease.152
Isolated cases of CLL transformation into small noncleaved cell lymphoma,4 lymphoblastic lymphoma,5 and hairy cell leukemia6 have been reported. In rare cases, patients with B-cell CLL may develop high-grade T-cell NHL.7, 8 Although these cases are examples of RS, the T-cell lymphomas are most likely a coincidence.8
The therapeutic options in classic RS or prolymphocytic transformation of CLL were developed initially for NHL or ALL and range from cytotoxic regimens to more arduous therapies, such as stem cell transplantation. The response rates to the various reported therapies range from 5% to 43% (complete response [CR], 5–38%), and the median survival duration ranges from 5 to 8 months.9–13
In the 1970s and 1980s, these regimens included, but were not limited to, CHOP-Bleo (cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin), MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin), ASHAP (doxorubicin, methylprednisolone, high-dose cytosine arabinoside [ara-C], and cisplatin), PFA (cisplatin, fludarabine, and ara-C), and VAD (vincristine, doxorubicin, and dexamethasone), with or without radiotherapy.9 In more recent years, variants of the hyper-CVXD regimen (fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone) have been used, but without significant improvement in the response rate or survival duration.10, 11
In particular, the hyper-CVXD regimen induced a response in 41% of patients with RS (CR rate of 38%), and the median overall survival duration was 10 months.10 The reported response rate to hyper-CVXD plus rituximab and granulocte-macrophage—colony-stimulating factor (GM-CSF) alternating with methotrexate and ara-C plus rituximab and GM-CSF was 43% (CR rate of 27%).11 Among patients with RS (n = 30), the median survival duration was 8 months and the 12-month survival rate was 28%. In a 2-month landmark analysis, patients with RS had a shorter survival duration than patients with fludarabine-refractory CLL (P = 0.007).153 When compared with hyper-CVXD alone, hyper-CVXD plus rituximab and GM-CSF alternating with methotrexate and ara-C plus rituximab and GM-CSF did not appear to improve the rates of response, disease recurrence-free survival, or overall survival. Both regimens had comparable toxicity, which included neutropenia, thrombocytopenia, and infectious complications.11
The combination of fludarabine, ara-C, cyclophosphamide, cisplatin, and GM-CSF (FACPGM) has been reported to have limited activity and significant toxicity in RS.12 In a Phase II study, FACPGM was administered to 22 patients with RS or refractory PLL or NHL. FACPGM induced a CR in 1 of 16 patients (6%) with RS.12
Allogeneic stem cell transplantation is a promising therapeutic strategy for patients with RS.154 Eight patients were treated with high-dose chemotherapy followed by an allogeneic stem cell transplant. Five patients were in “resistant” relapse and three others were in “sensitive” or untreated relapse of RS. The median number of previous therapies was 4 (range, 2–5 therapies). Preparative regimens varied and included triethylenethiophosphoramide, busulfan, and cyclophosphamide; carmustine, and ara-C; etoposide and melphalan; fludarabine and melphalan; and a nonablative regimen comprised of cisplatin, fludarabine, and ara-C. Six patients received the transplant from an HLA-identical sibling and two patients received the transplant from an unrelated donor. Three patients (38%) achieved durable disease remissions and were free of disease at 14 months, 47 months, and 67 months, including 2 patients who received nonmyeloablative preparative regimens. Five patients died of treatment-related toxicities (3 patients within 30 days of transplantation).154
RS has been reported in a patient 4 months after allogeneic stem cell transplantation for CLL. The patient was treated successfully with withdrawal of immunosuppressive therapy and donor lymphocyte infusion and remained disease free for ≥ 18 months.155 Another patient with RS was treated with bcl-2 antisense monotherapy and achieved a partial response.156 We have previously reported that Yttrium-90 ibritumomab tiuxetan radioimmunotherapy had no activity and had severe hematologic toxicity in seven patients with RS.157
The management of patients with CNS involvement includes systemic chemotherapy, intrathecal chemotherapy, and radiotherapy. Two cases with isolated CNS disease responded to radiotherapy with and without chemotherapy and remained alive at 13 months and 17 months, respectively.125 Another patient treated with radiotherapy and intrathecal methotrexate survived for 3 months.158
The role of radiotherapy is palliative because RS usually is disseminated at the time of diagnosis and radiotherapy is unlikely to control the disease. Local radiotherapy may control pain and symptoms associated with bulky lymphadenopathy or extranodal disease. Although the role of radiotherapy in CNS prophylaxis has not been determined, it may be useful in patients who present with risk factors for CNS involvement (i.e., the involvement of more than one extranodal site and increased LDH levels).159
Data on the optimal treatment of the Hodgkin variant of Richter's transformation are limited.129–132 Most patients respond to standard therapies for Hodgkin disease (i.e., variants of doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD] or mechlorethamine, vincristine, procarbazine, and prednisone [MOPP]), with or without radiotherapy. Patients with the Hodgkin variant of RS are more resistant to therapy than patients with Hodgkin disease but are more sensitive than patients with classic RS.129, 134 Currently, to our knowledge it is unknown whether the two types of the Hodgkin variant of RS respond differently to therapy.
Richter's transformation is a process that may be triggered by viral infections, such as EBV infection, which are common in immunosuppressed patients. The large cells of RS either arise through a transformation of the original CLL clone or, less frequently, represent a new or secondary neoplasm. Karyotypic changes, including trisomy 12, chromosome 11 abnormalities, and multiple cell cycle regulator disruptions, have been found in patients with RS. Although these genetic defects are believed to cause CLL cells to proliferate and, by facilitating the acquisition of new genetic abnormalities, transform into RS cells, none appears predominantly responsible for the transformation. The therapeutic strategies in RS include aggressive lymphoma or ALL-type chemotherapy with or without monoclonal antibodies, stem cell transplantation and, rarely, radiotherapy. The prognosis for patients is generally poor, and most patients do not respond to therapy. Curative treatment strategies are needed.