Between 2 percent and 8 percent of chronic lymphocytic leukemia (CLL) patients develop Richter syndrome (RS), a clinico-pathological transformation to aggressive lymphoma. RS is represented in most cases by diffuse large B-cell lymphoma, with less common transformations evolving to Hodgkin disease, and is generally characterized by a poor clinical outcome. The pathogenetic mechanisms underlying this transformation process remain to be clarified.
Since RS is biologically and clinically distinct from CLL, known poor prognosis CLL risk factors such as immunoglobulin (IG) VH gene mutation status, cytogenetic abnormalities including del(17p13), and expression levels of proteins such as CD38 and ZAP70 cannot necessarily be used in predicting RS. Importantly, RS outcome is not uniformly poor, so prompt diagnosis may be clinically useful and may be improved by the availability of new biological predictors.
Several recent studies have identified factors that predict the risk of CLL transformation to RS. These include but are not limited to predominantly nodal disease, shortened telomeres, IGHV4-39 usage, CD38 expression, and absence of del(13q14). Recently, an RS score that includes performance status, lactate dehydrogenase level, platelet count, tumor size, and number of prior therapies has become available to assess RS prognosis. Although the design of this scoring system represents a significant advance in identifying patients who may benefit from a specific treatment approach, it has been built only on clinical factors and does not take into consideration the biological characteristics of the disease. Furthermore, the RS score fails to identify those patients expected to have prolonged survival.
In this paper, Rossi and colleagues from Novara, Italy, report that mutations and deletions in the gene that encodes p53 (TP53) and translocations and amplification in c-MYC are the most common genetic abnormalities in a large cohort of RS patients (n=86). More importantly, the authors showed that TP53 disruption plays an important, independent role as a predictor of RS patient survival. Interestingly, the authors report a median survival for RS patients with TP53 disruption of only 9.4 months (95% CI: 4.6-14.2) versus 47.1 months (95% CI: 6.9-87.3) for patients without TP53 disruption (p<0.001). The authors built an algorithm to stratify RS patients into high, intermediate, and low risk of death using TP53 status, induction treatment response, and ECOG performance status. More than half of the RS patients assigned to the intermediate-risk group using this algorithm would have been assigned to the more favorable risk group using the RS score. The authors also show that their model has a significantly higher probability of predicting survival compared to the RS score. Interestingly, 80 percent of the patients developed
RS that was clonally related to CLL, while the 20 percent of patients with clonally unrelated disease experienced significantly longer survival. Collectively, this study validates the importance of both biological and clinical risk factors in predicting RS patient survival and provides a rationale for a direct personalized approach to RS treatment.
In Brief
This work is valuable for its clarification of the genetics of RS, a disease with substantial molecular, immunologic, and clinical heterogeneity. This is no small feat, considering the relative rarity of RS and the difficulty in obtaining such a large sample set. Furthermore, the authors provide a useful tool to identify specific risk sub-groups of RS patients and provide a rationale for testing alternative p53-independent agents in the sub-group of patients with TP53 disruption.
Competing Interests
Drs. Alinari and Byrd indicated no relevant conflicts of interest.
