Longitudinal analysis of richter syndrome risk and survival in CLL: The role of targeted therapy and molecular markers. experience at the fondazione policlinico gemelli in rome.

Abstract

Abstract Background: Richter Syndrome (RS) is the development of an aggressive lymphoma in patients (pts) with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). It is reported to occur in 5-16% of pts, presenting in 95-99% of the cases as Diffuse Large B-Cell Lymphoma (DLBCL) and in 0.5-5% as Hodgkin Lymphoma (HL) variant. RS can arise from a transformation of CLL clones (clonally related) or as a de novo lymphoma (clonally unrelated), with different prognosis (median overall survival [OS] 14.2 vs 62.5 months, respectively) (Rossi et al., 2011). A key unresolved issue is whether chemo-free CLL treatment regimens might increase RS risk. Aims: The aim of this study is to evaluate the incidence and determinants of evolution to RS in our cohort of CLL patients, with a primary focus on the impact of type of CLL therapy on the risk of RS, and, secondly, on the RS outcome. Methods: We conducted a retrospective analysis of a well-characterized cohort of CLL pts followed at our institution in the last 25 years. Pts were stratified in four categories, according to the therapy received for the CLL phase: naïve (TN), chemo-immunotherapy (CT), chemo-immunotherapy and targeted therapy (CTT), and targeted therapy alone (TT). Survival analyses were conducted to evaluate incidence and risk factors for RS using Cox proportional hazards regression models, applied both uni- and multivariately. Log-rank test was performed to evaluate differences in OS across the four groups in the RS cohort. R 4.3.3 software was used, considering a p-value < 0.05 as statistically significant. Results: We report a total of 53 RS, among 836 CLL pts followed, with 50 DLBCL and 3 HL cases. The median age at RS diagnosis was 68 years, while median time between CLL diagnosis and RS development was 55 months. Clonal relationship was available in 17 pts; 4 cases were unrelated, 13 cases were related; the latter were all part of the CTT or the TT group. The incidence of RS in our cohort was 6.34%. The TN, CT, CTT and TT groups consisted of 23, 6, 14 and 10 RS pts, respectively. Incidence rates per 100 person-years were 0.72 for the TN, 0.83 for the CT, 1.39 for the CTT and 0.61 for the TT groups. In the univariate analyses, unmutated IGHV status was significantly associated with an increased risk of RS (HR≈2.06; 95% CI, p=0.036). The presence of TP53 mutation was also associated with an increased risk (HR ≈ 2.08), although the result was marginally significant (p=0.06). In the multivariate model including therapy type, high-risk FISH characteristics, IGHV, TP53/NOTCH1 mutations, both unmutated IGHV (HR≈2.06; p=0.15) and TP53 mutation (HR ≈ 2.34; p = 0.08) retained a trend toward increased risk of evolution, but did not reach statistical significance. Kaplan-Meier analysis, with RS as the event of interest, revealed a trend driven by the high number of cases in the CTT group relative to its size. The TT group initially exhibited a lower cumulative incidence of RS, but over time its survival curve tended to converge with that of the CTT group. This aligns with the doubling of RS cases witnessed in the last 12 months. However, time-dependent Cox regression did not show a statistically significant change in HR over time. No significant difference in OS among the therapy groups was found in our RS cohort. Discussion: The findings on the impact of TP53 mutation and IGHV status are consistent with literature. Hitherto, available studies have failed to demonstrate an increased incidence or RS risk in patients treated with targeted therapy. The increase of RS cases in the last year is consistent with the visual patterns observed in Kaplan-Meier curves, where the TT group's cumulative risk tended to converge with the CTT group over time. This suggests a potential increase in the RS risk over extended follow-up in patients treated only with targeted therapies. However, the time-dependent Cox model analysis did not provide statistically significant confirmation of a time-varying treatment effect, likely due to limited event numbers and sample size. Conclusion: Our analysis highlights the relevance of markers such as IGHV and TP53 in the risk of RS development. Although no statistically significant difference in the risk of RS was observed among the four treatment groups during the study period, it is reasonable to expect a rise in its incidence in the upcoming years in pts treated exclusively with targeted therapies, as longer follow-up data will be available.