P651: VENETOCLAX-BASED TREATMENT OF PATIENTS WITH RICHTER SYNDROME: OUTCOMES FROM A MULTICENTER RETROSPECTIVE STUDY

Abstract

Background: Patients (pts) with chronic lymphocytic leukemia (CLL) who develop Richter Syndrome (RS) have a poor prognosis with median overall survival (OS) often reported as less than 12 months (Tsimberidou JCO 2006; Rogers BJH 2018), using chemoimmunotherapy (CIT) regimens typically administered to de novo large cell lymphoma. Venetoclax (ven) has demonstrated single-agent activity in RS with an overall response rate of 43% (Davids JCO 2017). Ven combined with DA-EPOCH-R achieved a median OS of 19.6 months and the highest complete response (CR) rate (50%) reported in pts with RS (Davids Blood 2022). These results support a synergistic effect when compared to CR rates of 20% and 0% with EPOCH-R and ven monotherapy, respectively. Aims: To evaluate the outcomes of pts with RS treated with ven-based treatment, outside clinical trials, including novel-novel combinations and CIT combinations. Methods: We analyzed pts with RS treated with a ven-based regimen at MDACC (n=37) or Mayo Clinic (n=18) between 12/2013 and 8/2021. Patient and disease characteristics from the time of ven-based treatment start were ascertained. Retrospective response assessment was as per Lugano 2014 guidelines. Toxicity was recorded per iwCLL 2018 guidelines (hematologic toxicity) or CTCAE v5.0 (non-hematologic toxicity). OS and progression-free survival (PFS) were analyzed using the Kaplan-Meier method, with and without censoring for allogeneic hematopoietic stem cell transplantation (alloSCT). No formal statistical comparisons were made between different treatment groups. Results: Fifty-five pts were identified with a median age of 66 years (range 43-83 years); 31% were female. High-risk CLL disease characteristics were frequently identified: 92% unmutated IGHV, 42% del(17p), 57% TP53 mutation, and 62% complex karyotype. The median number of prior CLL-directed therapies was 2 (range 0-7), including prior chemotherapy (42%), prior Bruton tyrosine kinase inhibitor (BTKi; 38%), and prior ven (22%); 62% of pts were previously untreated for RS. Median follow-up from the start of ven-based RS treatment was 9 months (mo). The most common ven-based combination regimens achieved overall response and CR rates as follows: 50%/40% with intensive CIT + ven (n=20), 40%/30% with BTKi + ven +/- CD20 antibody (n=20), 60%/50% with R-CHOP + ven (n=10). Among the remaining 5 patients, 2 received ven monotherapy and 3 received varied ven-based combination regimens. Nine pts proceeded to subsequent alloSCT. The median PFS for the total cohort when censored at alloSCT was 4.0 mo; PFS uncensored for alloSCT was 4.4 mo (Figure 1A). Median PFS by treatment group (Figure 1B) was as follows: 3.7 mo for intensive CIT + ven, 3.9 mo with BTKi + ven +/- CD20 antibody, not reached with R-CHOP + ven. The median OS for the total cohort was 9 mo. The estimated median OS by treatment group (Figure 1C) was 8.4 mo with intensive CIT + ven, 10.6 mo with BTKi + ven +/- CD20 antibody and not reached with R-CHOP + ven. Grade 3-4 neutropenia and thrombocytopenia were more common with intensive CIT + ven (71%; 69%) and R-CHOP + ven (77%; 67%) compared to BTKi + ven +/- CD20 antibody (35%; 25%). Febrile neutropenia occurred in 42%, 33%, and 25% of pts in these three groups, respectively, with 37%, 33%, and 30% experiencing a grade 3-4 infection. Image:Summary/Conclusion: In the notoriously difficult-to-treat RS patient population, ven-based combination regimens achieve high response rates, including some with prolonged duration, particularly with the use of R-CHOP + ven. A prospective clinical trial evaluating this combination is ongoing (NCT03054896).