Implications of Genetic, Biological and Clinical Parameters in Patients With Richter Syndrome: A Monocentric Experience

This is the authors' abstract. We don't add key points for this paper.

The development of a high-grade lymphoma from previous or concurrent chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) is known as Richter Syndrome (RS) [1]. Its annual incidence rate in patients with CLL is estimated to be between 0.5% and 1%, with an overall incidence of 5%–16% [2]. The most common form is diffuse large B-cell lymphoma (DLBCL-RS), while 0.5%–5% of cases resemble Hodgkin lymphoma (HV-RS) [2, 3]. If the IGHV rearrangement is concordant between the two disease phases, RS is clonally related (80% of DLBCL-RS cases) and reflects a direct transformation of CLL clones. Conversely, clonally unrelated RS is analogous to a de novo DLBCL [4]. Targeted therapies with BTK, BCL2 and PI3K inhibitors have shown limited success in RS, compared to non-transformed CLL [5]. Chemo-immunotherapy remains the standard initial treatment, followed by post-remission consolidation with allogenic hematopoietic stem cell transplantation. Outcomes in clonally related RS are still poor, with complete response (CR) rates below 20% and OS near 1 year, highlighting an urgent unmet clinical need [6]. A key unresolved issue regarding RS incidence is whether the new chemo-free treatment regimens available for CLL phase might increase the risk of RS. This retrospective, monocentric study evaluates the impact of CLL therapies on RS incidence, with secondary aims to explore biological and clinical factors affecting time to Richter transformation (TTR), progression-free survival (PFS), and overall survival (OS). Naïve (watch-and-wait), CIT (chemo-immunotherapy with fludarabine or bendamustine), CIT + TT (chemo-based and targeted therapies), TT (targeted therapies: BTK, BCL2, or PI3K inhibitors). The incidence and incidence rate for each group are reported in Table 1. Biological characteristics are reported in Table 2. IGHV sequencing was performed in 30/38 (77%) cases. FISH analysis was available for 33 (84%) patients. High-risk TP53 and NOTCH1 mutations, were assessed in 22 patients. Median prior therapy lines for CLL were 1 (range 0–6). The predominant RS histology was DLBCL-RS in 35/38 cases (92%), with 3 HV-RS cases (8%), consistently with literature. Clonal relationship was studied in 11 (30%) patients; RS was clonally related to CLL in 9/11 (82%), 8 treated with CIT + TT, 1 with TT, and unrelated in 2/11, both naïve. Median age at RS diagnosis was 66.5 years (41–86). Median TTR was 29, 73.5, 99.5, and 68 months for Naïve, CIT, CIT + TT, and TT groups, respectively. Median PFS across the four groups was 17, 9, 4, and 9 months, while median OS was 17, 13.5, 5, and 30 months, respectively. CIT + TT showed significantly superior TTR compared to Naïve (p = 0.00193). Overall, median PFS was 6.5 months, and OS was 12.5 months (Figures 1 and 2.). Progression-free survival (PFS) in months of RS patients from diagnosis. Overall survival (OS) in months of RS patients from diagnosis. Age of CLL diagnosis, age of RS diagnosis, and TTR, did not seem to impact on PFS and OS. IGHV-unmutated and TP53-mutated patients showed trends toward lower PFS and OS, without statistical significance. HV-RS cases, all with mutated IGHV, lacked high-risk features. TTR ranged from 112 to 221 months, with two cases previously treated with BTKi or oral fludarabine/cyclophosphamide. We reported an overall incidence rate of RS of 0.72% person-years, consistently with literature. The Mayo Clinic experience documented a rate of RS of approximately 0.5%/year, out of a series of 37 RS [7]. While epidemiological findings vary across studies, recent analyses of treatment-naïve CLL patients receiving novel therapies indicated no RS rate increase [8]. In our study, the RS incidence was comparable between Naïve and TT groups (3.9% vs. 3.2%; 6.4 vs. 4.3 per 1000 person-years). However, for relapsed/refractory CLL patients, RS incidence rose to 2%–15% post-targeted therapy, with notably higher rates in the CIT + TT group, reflecting their exposure to multiple treatment lines. In our cohort, all the clonally related cases had undergone at least two CLL treatment lines, and at least one targeted therapy treatment. Conversely, all the clonally unrelated patients were untreated (p = 0.01818), indicating that clonally unrelated RS represents a de novo lymphoma, unconnected to prior therapies and favored by CLL patients' susceptibility to secondary malignancies. Naïve patients showed a significantly shorter TTR than the CIT + TT group (29 vs. 99.5 months; p = 0.00193), emphasizing the unpredictability of clonally unrelated RS, which may occur early in the CLL course. Similar short TTRs for untreated and previously treated CLL patients have been reported in a series of 7664 CLL patients [9], dating to prior to the implementation of targeted therapies. The paucity of our cohort and the late implementation of targeted therapy into clinical practice prevent us from speculating about the impact of targeted therapy on RS. Indeed, the comparison between the incidence rates in the CIT and the TT lacked statistical significance. Clonal relationship, consistently cited as a critical prognostic factor [4], aligns with our findings, as multi-treated patients exhibited shorter PFS and OS. This supports the hypothesis that multiple chemo-immunotherapy and targeted therapy lines increase RS risk. In literature, RS developing from CLL treated with targeted agents is associated with a dismal prognosis [10]. In our cohort, TT patients show median OS and PFS of 9 and 4 months, respectively, likely due to high rates of TP53 mutation and unmutated IGHV in this subgroup. HV-RS, affecting 0.4% of our CLL population, was excluded from this analysis as a distinct entity, responding well to standard chemotherapy regimens. Previous treatment with chemotherapy and/or targeted therapy is associated with development of clonally related RS. Conversely, HV-RS development is not linked to previous treatments and represents a separate entity. A longer time of observation is needed to fully elucidate the effect of targeted drugs on the incidence of RS and its features. Sincerely, the study team, Fondazione Policlinico Gemelli The authors declare no conflicts of interest. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1002/hon.70028. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.