Background Richter transformation (RT) of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a known but uncommon complication with dismal prognosis despite improvements in CLL outcomes with novel agents. Previously published studies are characterized by cohort heterogeneity with respect to CLL treatments (predating the rituximab era and novel agents) and RT histology [diffuse large B-cell lymphoma (DLBCL) and classic Hodgkin lymphoma (cHL)], limiting their generalizability in the modern era. To this end, we examined characteristics and outcomes in 222 DLBCL-RT cases, enriching for patients treated with novel agents. Methods We collected 247 RT cases diagnosed between 1995-2022 across eight academic institutions, excluding 23 with cHL-RT and 2 with "pseudo-transformation" after BTKi withdrawal (final n = 222; 41% of cases post-2010). We analyzed > 65 CLL/RT biologic, pathologic, and clinical parameters. Primary outcomes included complete response (CR) to first line of therapy [in CLL (iwCLL 2008/2018) and RT (Lugano 2014)] and 5-year overall survival (5yr-OS) after RT, estimated using Cox proportional hazards [yielding hazard ratios (HRs) and 95% confidence intervals (CIs)] and flexible parametric survival models (for prediction of standardized survival). Results The antecedent CLL included: 11% cases with atypical CLL, 84% IGHVUM, and 70% ZAP70+ with 46% and 43% of patients harboring del(13q) and del(17p), respectively. CLL/RT was synchronous (CLL diagnosis within 2 months of RT diagnosis) in 13% of cases. Only del(17p) correlated with C/HC (≥ 3 / ≥ 5 chromosome abnormalities) karyotype (p < 0.0001), and ZAP70/CD38 had no association with IGHV status. RT was primarily nodal (47.3%), non-GCB (90.3%), and EBV-negative (95%) with p53 IHC-positive large cells in 60% of cases and MYC translocation in 10%. Preceding CLL was treated with a median of 2 lines of therapy (range: 1-7) with 53% heavily-treated (≥ 2 lines). The most common first lines (LOT1) were chemotherapy (fludarabine-based or bendamustine/CHOP equivalents; 73.6%) and BTKi/novel agents (17%); 37% received BTKi as any LOT, while 44% received any novel agent (BTKi, BCL2i, PI3Ki, or SYKi). CLL CRLOT1 was achieved in 41.2% with overall response of 77%. Median time to RT from CLL diagnosis (sequential group) was 47.6 months pre-2010 (IQR: 87.8) vs. 21.8 months post-2010 (IQR: 34.6, p < 0.0001). During a median follow up of 10.2 months (IQR: 27.1 months) post-RT, 59% of patients died. Median OS was 17.4 months (range: 11.3-24.2) with 28% 5yr-OS. In the pre-rituximab era (i.e. prior to 2010), median OS was significantly shorter compared to the present era (8 vs. 19.9 months). Indicators of inferior 5yr-OS on univariable analysis included: sequential transformation (HR: 2.34 [95% CI: 1.25-4.35]), not achieving CRLOT1 for CLL (HR: 1.62 [95% CI: 1.01-2.58]), heavily-treated CLL (HR: 1.98 [95% CI: 1.36-2.88]), and C/HC karyotype (HR: 1.59 [95% CI: 1.02-2.46]). While trisomy 12 predicted superior outcome (HR: 0.54 [95% CI: 0.32-0.94]), del(13q) and del(17p) had no impact. Adverse baseline covariates at RT diagnosis were low (< 3.5 g/dL) serum albumin (HR: 3.13 [95% CI: 2.09-4.69]), low (< 150x103/uL) platelet count (HR: 2.38 [95% CI: 1.64-3.47]), LDH > 1.5x ULN (HR: 1.63 [95% CI: 1.12-1.38]), and ECOG-PS ≥ 2 (HR: 2.4 [95% CI: 1.51-3.81]). Notably, p53 IHC positivity in RT predicted increased all-cause mortality (HR: 2.13 [95% CI: 1.27-3.5]), retaining significance in both minimally- and heavily-treated CLL subsets. RT was treated using CHOP-R or EPOCH-R in 62%. Not achieving CRLOT1 for RT predicted worse 5yr-OS (HR: 3.90 [95% CI: 2.09-7.29]). A multivariable, main effects Cox model was constructed using five variables (age at transformation, CLL treatment number, LDH > 1.5x ULN, albumin, and p53 IHC). In this age-adjusted model, all variables retained adverse prognostic significance (Figure 1). Marginal OS was predicted by p53 IHC, standardizing over remaining covariates, and with a trend towards inferior 5yr-OS in p53-positive vs. -negative RT (13% vs. 38%; Figure 2). Conclusion This multicenter, international study is the largest cohort of RT in the era of novel therapies with solely DLBCL histology. We confirmed the utility of several traditional predictors. In addition, we identified p53 IHC as a promising predictor of adverse outcome (in univariable and multivariable analyses) based on these preliminary analyses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract Background Transformation of Chronic Lymphocytic Leukaemia (CLL) or Small Lymphocytic Lymphoma (SLL) to high-grade disease (Richter's Transformation; RT) carries a poor prognosis. Despite the advent of novel therapies, published data indicates that chemoimmunotherapy remains the standard of care for RT. This project evaluated real-world outcomes in patients with RT across eight Australian centres to validate known prognostic factors, as well as identify new predictors of survival in this cohort of patients. Our aims were also to determine if prior BTK inhibitors (BTKi), BCL 2 inhibitors (BCL2i), or escalation of treatment regimen impacted these patients' outcome. Methods This was a retrospective multicentre study conducted by members of the Australasian Lymphoma Alliance in 8 centres across 4 Australian states. Consecutive patients with biopsy proven Diffuse Large B-Cell Lymphoma (DLBCL) or Hodgkin Lymphoma (HL) type RT between 2010 and 2019 were identified using institutional databases. Patients' diagnoses were confirmed by review of local pathology reports. Patients' characteristics, treatment received, and outcomes were recorded and analysed. Univariate comparisons were made using Cox regression analysis. Kaplan Meier curves were used for analysis of overall survival (OS) measured from diagnosis of high-grade disease. Results Seventy-eight patients (55 with CLL and 23 with SLL) were included in the analysis. The majority had low Rai stage at diagnosis (stage 0 in 41% of patients, 1 in 39%, 2 in 16%, 3 in 3%, and 4 in 1%). 25% had prior treatment of low-grade disease with a BTKi and 18% with a BCL2i. At the time of low-grade diagnosis, 54/78 (69%) of patients (pts) had had mutational analysis: 24% (13/54) had a 17p deletion, 78% (17/22) were IgHv unmutated, and 33% (6/18) had a TP53 mutation. Median time to transformation from CLL diagnosis was 4.8 years (range 0-24). 42% had received 2 prior lines of treatment for CLL/SLL at the time of transformation (range 0-5). The predominant histology was DLBCL (71 pts with DLBCL; 6 pts with HL, 1 pt had HL and DLBCL concurrently). Majority of the pts had ECOG<2 (0-1, 76%; 2, 23%). 50% had transformed disease in extra-nodal sites, 27% with bone marrow involvement, and 6% had CNS involvement. 15/18 pts (83%) had clonally related disease proven by IgHv testing. 71 pts (91%) received curative intent treatment, with the rest receiving palliative radiotherapy and/or steroids. 54 patients were treated with standard therapy (R-CHOP or similar), 13 pts were treated with an intensive regimen (R-HyperCVAD, OFAR, R-EPOCH14, or R-ICE), and 4 were treated with novel therapies (BTKi + PD1 combination, and BiTEs). There was no significant difference seen between the standard and intensive therapy groups in terms of treatment completion (61% in standard vs 62% in intensive, p=0.82) or CR rates (50% in standard vs 62% in intensive; p=0.80). Overall, 48/76 (64%) of patients died with a median OS of 15 months (median OS 11 months in DLBCL; median OS not reached in HL). Surviving pts had a median follow up of 33 months. There was no difference in OS between pts that received standard or intensive regimens (HR 1.49 CI 0.75-2.94). Patients with prior lines of treatment for CLL (HR 3.71; CI 1.73-7.98), elevated LDH (>1.5x ULN) (HR 3.0; CI 1.6-5.8), 17p deletion (HR 2.34; CI 1.12-4.91), or bone marrow involvement by high grade disease (HR 2.99; CI 1.5-5.9) had an inferior OS. Prior low-grade treatment with a BTKi (HR 1.67; CI 0.88-3.18) or a BCL2i (HR 1.79; CI 0.92-3.45) did not impact outcome following transformation. Conclusions This is the largest Australian report on patient outcome following RT. Whilst prior CLL treatment was associated with worse outcome after transformation, prior BTKi or BCL2i use did not seem to have an impact on survival. Furthermore, elevated LDH >1.5 ULN and bone marrow involvement with RT were also predictors of poor patient outcome, with the latter not previously described. Finally, intensive chemotherapy regimens were found not to be superior to R-CHOP chemotherapy, suggesting that RCHOP remains the treatment of choice in this population. The OS for patients with RT is poor, and research into more effective therapies is needed. Figure 1 Figure 1. Disclosures Lewis: Roche: Consultancy, Honoraria; Janssen: Honoraria, Patents & Royalties: Conference attendance; Novartis: Patents & Royalties: Conference attendance; AstraZeneca: Consultancy, Honoraria. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tam: Beigene: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Loxo: Honoraria; Beigene: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Opat: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Sandoz: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; Monash Health: Current Employment; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cheah: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Ascentage Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ku: Roche: Consultancy; Antegene: Consultancy; Genor Biopharma: Consultancy.