Richter syndrome and fludarabine: a controversial relationship

Over time, a fraction (˜10%) of patients with chronic lymphocytic leukemia (CLL) develop Richter syndrome (RS), representing the clinico-pathologic transformation of CLL to an aggressive lymphoma, most commonly (˜95% of cases) diffuse large B-cell lymphoma (DLBCL) [1,2]. Historically, the definition of Richter syndrome also applies to cases of CLL who have developed classical Hodgkin lymphoma, although this event is very rare (˜5% of cases) [1].

In the classic type of RS, the DLBCL is usually (˜80%) clonally related to the CLL clone, thus representing a true transformation of the indolent disease to an aggressive phase. In the remaining ˜20% of cases, the DLBCL is unrelated to the CLL clone, and should be considered as a de novo DLBCL arising in a patient with CLL [3]. The Hodgkin variant of RS is almost always unrelated to the CLL phase [4].

Within the spectrum of the various disease stages of CLL, clonally related RS is the most aggressive clinical phenotype because of the combined effect of chemoresistance and rapid disease kinetics [3]. On the other hand, patients with CLL developing a clonally unrelated RS display a more favorable outcome, with a survival probability in the range of de novo DLBCL [3].

The poor clinical behavior of clonally related RS mostly relies on its genetics. The high rate of TP53 abnormalities, which occur in ˜60% of cases and represent the most frequent genetic lesion at the time of transformation, accounts for the chemoresistance that is very common in clonally related RS [3]. NOTCH1 mutations and MYC abnormalities, including MYC translocations and amplifications, are the second most frequent genetic lesion in clonally related RS, where they occur in ˜30% of cases, respectively [3,5]. NOTCH1 mutations are largely mutually exclusive with MYC oncogenic activation in RS. This finding is consistent with the observation that NOTCH1 directly stimulates MYC transcription, and suggests that activation of oncogenic MYC may be one common final pathway selected for tumorigenesis in ˜60% of clonally related RS. As for other MYC-associated lymphomas [1], MYC activation may account for the rapid disease kinetics observed in this aggressive disease [5].

Early recognition of RS transformation may be clinically useful in order to avoid the exposure of patients to multiple lines of therapy that, being targeted to CLL progression, are of little efficacy on the transformed clone. This concept prompts the need for a close monitoring of patients with CLL harboring risk factors of RS development. Advancements in the field have unraveled a number of intrinsic characteristics of the tumor clone that predispose CLL to subsequently transform into an aggressive lymphoma, including the disease genetics, namely the presence of NOTCH1 mutations and unfavorable cytogenetics, as well as expression of specific molecules facilitating the interaction between the CLL clone and the microenvironment, as exemplified by CD38 expression and usage of the immunoglobulin heavy variable gene (IGHV) 4-39, especially if rearranged in a stereotyped fashion (so-called VH CDR3 “subset 8”) [6,7].

The development of an aggressive lymphoma may also be the consequence and complication of previous CLL treatments. In this respect, after the introduction of the anti-CD52 antibody alemtuzumab, occasional patients with CLL have been reported to develop clinically aggressive lymphomas, usually clonally unrelated to the CLL phase, mostly characterized by Epstein–Barr virus (EBV) infection, and displaying several similarities to lymphomas arising in immunodeficient hosts. These cases of alemtuzumab-associated aggressive lymphomas represent a novel type of immunodeficiency-related lymphoma developing after T-cell depleting therapies in patients already immunocompromised because of the underlying disease and/or because of previous chemotherapy [8]. The increased risk of aggressive lymphomas and EBV-related lymphoproliferations in patients treated with alemtuzumab-based regimens has been confirmed within a recent randomized trial comparing FCR fludarabine, cyclophosphamide, rituximab) versus FC-alemtuzumab [9].

Fludarabine is a mainstay drug for the treatment of CLL, either alone or in combination with alkylators and monoclonal antibodies. Though concerns have been raised about the carcinogenic effects of fludarabine, analysis of large CLL cohorts have consistently shown that the risk of second primary cancers after fludarabine exposure is not higher than the overall rate expected in these patients [10,11]. However, by limiting the analysis to lymphoproliferative disorders, retrospective studies of case series have postulated a potential relationship between fludarabine exposure and development of aggressive lymphoma, although the results are somehow conflicting [12]. On these bases, a systematic assessment of randomized trials comparing fludarabine monotherapy to alkylating agent-based regimens as first-line therapy for CLL is warranted in order to clarify the impact of fludarabine on this harmful complication.

In this issue, Solh etal. [13] examined a large series of 521 previously untreated patients with CLL enrolled on the CALGB 9011 trial that aimed at comparing the efficacy of fludarabine versus chlorambucil versus fludarabine plus chlorambucil. The study population was provided with a remarkably long follow-up of at least 15 years, and was subjected to long-term evaluation for the assessment of second primary tumors, including lymphomas [13]. Since RS diagnosis requires a pathological assessment, heterogeneity in biopsy policies represents a major factor influencing the incidence of RS observed in different CLL series. Overall, biopsy proven RS developed in 7% of cases from the CALGB 9011 trial [13], a rate of RS transformation that is consistent with other published cohorts [2,6], thus confirming that most, if not all, progressing patients underwent a specific evaluation for transformation in this series. Solh etal. [13] found no impact of initial therapy with fludarabine compared to chlorambucil on the risk of transformation to RS. Consistent with these results, in the LRF CLL4 trial comparing first-line fludarabine versus chlorambucil versus fludarabine plus cyclophosphamide, the frequency of RS was no different across the three treatment arms, although the follow-up is significantly shorter than that of the CALGB 9011 trial [14].

As recognized by Solh etal. [13], two potential limitations affect their study: (i) the off protocol cross-over of patients initially treated with chlorambucil to purine analogs, which may have jeopardized the transformation rates across the treatment arms of the trial; and (ii) the lack of inclusion in the analysis of recently identified biological markers of RS risk due to the fact that the trial was conducted in an earlier era [6,7].

CLL transformation to a DLBCL is conceivably sustained by complex interplay between molecular lesions of the clone, microenvironmental interactions of leukemic cells, immune function of the host, and treatments delivered during the disease course [2]. In order to dissect the independent contribution of each of these factors in RS development, including fludarabine treatment, a time-dependent modeling of the risk of CLL transformation would be required that takes into account all the abovementioned covariates repeatedly assessed during the disease course and treated as time-varying factors.

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