Richter Transformation (RT) in Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL): A Comparison of Two Eras

Background: Transformation of CLL/SLL to aggressive lymphoma, known as Richter transformation (RT), carries a dismal prognosis with survival < 1 year (y) in the chemoimmunotherapy (CIT) era. To date, few studies characterize RT in the modern era with availability of novel agents (NAs). The objective herein was to contrast the clinical presentation and outcomes of RT in a real-world cohort before and after 2016, when NAs were first approved and funded in British Columbia (BC) for CLL/SLL. Methods: CLL/SLL patients (pts) with RT in BC from Jan. 1, 2000 to Dec. 31, 2023 were identified through the BC Provincial CLL, BC Cancer Lymphoma, and Providence Health databases. Transformation to Hodgkin lymphoma was excluded. Outcomes were compared for pts diagnosed with RT before 2016 (CIT era) and after 2016 (NA era). Results: 207 RT pts (165 CLL, 42 SLL) were identified, with histologies including: diffuse large B-cell NOS (72%; n = 150), high-grade B-cell (3%; n=6), and plasmablastic lymphoma (1%; n = 2). 49 (24%) pts had clinical RT without histologic confirmation. Median age at RT was 71 y (range 42 - 94), with median time from CLL/SLL diagnosis of 5.0 y (range 0 - 25.6). Pts had median 1 prior CLL-directed therapy (range 0 - 7), with 33% (n = 69) previously untreated. Prior therapies included: chemotherapy 65%, anti-CD20 antibodies 39%, BTK inhibitors (BTKi) 16%, and BCL2 inhibitors (BCL2i) 3%. At RT, 60% had constitutional symptoms, 61% ECOG 2 - 4, 74% elevated LDH, 27% tumor bulk ≥ 10 cm, and 6 had CNS involvement. 122/161 (76%) had IPI 3-5 and 25/94 pts (27%) had del17p. Most pts (74%; n = 153) received R-CHOP-like regimens, while others received single-agent chemotherapy (4%; n = 8) or other treatment such as GDP, RICE, HD-MTX, FR (n = 1 each) and venetoclax-R (n = 6). 36 pts had no systemic therapy due to frailty (17%). 15 pts had consolidative transplant (12 allo; 3 auto) in first (n = 8) or second (n = 7) remission. With a median follow-up (f/u) of 12 y (range 1-261), median PFS was 5.8 months (m) (95%CI 4.2 - 7.4) and OS 9.8 m (95% CI 7.1 - 12.5). Pts who received systemic therapy had 59% ORR (32% CR), with median PFS and OS of 7.5 m (95% CI 4.6 - 10.4) and 13.0 m (95%CI 8.1 - 17.9), respectively. 2y-OS and PFS were 30.7% (95%CI 23.6 -37.8) and 40.8% (95%CI 33.4 - 48.2), respectively. Baseline characteristics, PFS (p = .43) and OS (p = .37) did not statistically differ between clinical and biopsy-confirmed RT. When comparing CIT (n = 132) and NA (n = 75) eras, median f/u was 15.5 y (95%CI 8.9 - 22) and 3.7 y (95% CI 2.8 - 4.6), respectively. Baseline characteristics differed in terms of median age (69 vs. 73 y, p < .001), ECOG 2-4 (48% vs. 78%, p < .001), and IPI 3-5 (68% vs. 86%, p = .009). Median time from CLL/SLL treatment to RT was significantly longer in the NA era (2.2 vs. 4.9 y, p = .008). There was no difference in median number of prior therapy lines (n = 1; p = .14), previously untreated CLL (p = .19), or prior chemotherapy (65% vs. 64%; p = .87). However, the NA era had significantly more prior use of anti-CD20 antibodies (p < .001), BTKi (p < .001) with 33 pts (44%) in the NA era, mostly for relapsed CLL (88%, n = 29), and BCL2i (p = .004) with 7 pts in the NA era only. For RT treatment, more pts had systemic therapy omission due to frailty in the NA era (23% vs. 14%, p = .07). A trend towards shorter OS was noted in the NA era (median 6.8 vs. 11.3 m, p = .08). In the overall cohort regardless of era, untreated CLL/SLL prior to RT had significantly longer OS than those with prior CLL treatment: median OS 42.7 m (95%CI 0.5 - 84.9) vs 6.1 m (95%CI 4.3 - 7.9), p < .001, with 2-y OS 62% (95%CI 50 - 73) and 21% (95% CI 14 -27), respectively. By univariate Cox-regression, prior CLL treatment (HR 2.6 [95%CI 1.8 - 3.8]), ECOG ≥ 2 (HR 3.0 [95%CI 1.8 - 5.1]), elevated LDH (HR 1.7 [95%CI 1.1 - 2.6]), and IPI 3-5 (HR 2.4 [95%CI 1.6 - 3.8]) were associated with shorter OS among pts treated for RT. Del17p was not significantly associated with OS (HR 1.7 [95%CI 0.95 - 2.9]; p = .08), with increased used of allotransplant in the del17p group (5/21 vs. 3/58; p = .03). Conclusion: Since the introduction of NAs for CLL/SLL, RT outcomes remain dismal with pts presenting at older age with poor performance status and later in their CLL/SLL disease course. However, in this cohort, most pts had prior CIT exposure which may have impacted outcomes. RT after NAs alone should be further explored. Nonetheless, this study reaffirms the significant unmet need for new treatment strategies that are more effective, but also better tolerated in this population.

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