Real-World Outcomes of Patients with High-Grade B-Cell Lymphoma with <i>MYC</i> and <i>BCL2</i> rearrangements Treated in the Contemporary Era

Introduction: High-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBL-MYC/BCL2-R) has worse prognosis compared to diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) when treated with R-CHOP. Given this and historically poor outcomes with salvage therapy in HGBL-MYC/BCL2-R, intensification of front-line induction and consolidation with autologous stem cell transplant (ASCT) in first complete remission (CR1) have emerged as popular treatment strategies despite a lack of prospective randomized studies indicating superior outcomes. CAR-T and novel antibody-based therapies have shown promise in patients with relapsed/refractory (R/R) DLBCL, but data in the “double-hit lymphoma” setting remain limited. We aimed to assess the impact of initial treatment intensification and salvage with CAR-T for HGBL-MYC/BCL2-R in the contemporary era. Methods: We performed a retrospective analysis of 79 consecutive patients newly diagnosed with HGBL-MYC/BCL2-R, as detected by fluorescence in situ hybridization (FISH), at our center from 06/2013 to 03/2023. MYC, BCL2, and BCL6 disruptions were identified by Vysis break apart probes. Baseline clinicopathologic variables, treatment, response, and outcome data were collected from electronic records. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS) with data cut-off date of 26/07/2024. Results: Median age at diagnosis was 62 (33-93) years. At baseline, 76% patients had advanced stage (Ann Arbor 3-4) disease, 56% had elevated LDH, 52% had bulky disease (largest tumor diameter ≥10 cm), and 3% had CNS involvement. Forty-nine cases arose de novo and 30 cases were transformed from follicular lymphoma. Regarding rearrangement status, 66 cases had MYC/BCL2-R and 13 had MYC/BCL2/BCL6-R. Front-line induction therapy included R-CHOP (n=29), DA-R-EPOCH (n=29), R-CODOX-M/IVAC (n=4), Pola-R-CHP + glofitamab (n=2), R-ICE (n=2), R-HyperCVAD/MA (n=1), obinutuzumab (G)-CHOP (n=1), R-CHOP + glofitamab (n=1), R-CHOP + tafasitamab (n=1), R-CHOP + lenalidomide (n=1), DA-G-EPOCH (n=1), and R-ESHAC (n=1), as well as palliative regimens including R-mini-CHOP (n=2), PEP-C (n=1), and rituximab + prednisolone (n=1). Patients with age &amp;gt;60 years at diagnosis were more likely to receive standard R-CHOP compared with an intensified induction regimen (DA-R-EPOCH, R-CODOX-M/IVAC, R-HyperCVAD/MA) (χ2, p=0.011). Forty received CNS prophylaxis with high-dose methotrexate (MTX) (n=15), intrathecal MTX (n=11), or both (n=14). A total of 17 patients received consolidative ASCT at any time (15 in CR1, 2 in CR2); conditioning regimens were CBV (n=15), BEAM (n=1), and unknown (n=1). After a median follow-up of 42 (2-91) months, median PFS and OS for the entire cohort were 9 and 88 months, respectively, and 7-year PFS and OS rates were 31% and 52%, respectively. Compared to standard R-CHOP, an intensified induction regimen (DA-R-EPOCH, R-CODOX-M/IVAC, R-HyperCVAD/MA) was associated with higher CR rate (44% vs 66%) and improved PFS (p=0.045), but no significant difference in OS (p=0.182). Of the 40 patients who achieved CR to frontline therapy, no significant difference in PFS or OS were observed between those who received consolidation with ASCT and those who did not (7-year PFS rate 83% vs 30%, p=0.178; 7-year OS rate 92% vs 55%, p=0.113). Among patients without CNS involvement identified at diagnosis who received curative-intent induction, use of MTX-containing CNS prophylaxis was associated with a lower rate of CNS relapse and improved OS compared to those who did not (CNS relapse rate 3% vs 6%; median OS 88 months vs 29 months, p=0.044). For the 42 patients with R/R disease, the median OS was 16 months from date of initial diagnosis. Nineteen patients received CAR-T therapy (8 at first relapse, 11 at subsequent relapse), including axicabtagene ciloleucel (n=10), tisagenlecleucel (n=5), rapcabtagene autoleucel (n=2), and CTX110 (n=2); the 4-year PFS and OS rates from date of CAR-T infusion were 62% and 55%, respectively. Conclusions: Our series indicates that intensification of front-line induction in patients with HGBL-MYC/BCL2-R maximizes first response and PFS, and incorporation of CNS prophylaxis into initial therapy minimizes risk of CNS relapse and improves OS. CAR-T represents a promising salvage option for patients with R/R disease.