Integrating BTK inhibition into R-da-EPOCH for HIV-related DLBCL.

Abstract

7001 Background: Human immunodeficiency virus (HIV)-related diffuse large B-cell lymphomas (DLBCL) are heterogeneous in nature, clinically, & molecularly. R-da-EPOCH is accepted as a standard of care in HIV+DLBCL. Classifying tumors with respect to immunophenotype & genomic features may facilitate personalized therapy to improve outcomes in this diverse disease. The Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (ibr), also inhibits inducible T cell kinase (ITK). As HIV hijacks host ITK during replication, ibr may have additional clinical benefits in HIV+DLBCL. This trial added ibr to R-da-EPOCH in HIV+DLBCL, with an attempt to enrich for non-germinal center B-cell (non-GCB) subtype, to evaluate safety, feasibility & activity, impact on T cells, & correlate lymphoma cell of origin (COO) with response. Methods: This multi-center study included a 3+3 dose de-escalation cohort followed by dose-expansion at recommended phase 2 dose (RP2D). Participants (pts) age 18-64 years (y) with stage II-IV HIV-DLBCL were untreated or received 1 cycle (cy) R-da-EPOCH/CHOP off-study. CD4 <100 & asymptomatic leptomeningeal disease were allowed. Ibr was dosed daily days 1-21 & R-da-EPOCH administered as previously published (PMID 32430507) for 6 total cy. Moderate/strong CYP3A4 inhibitors were excluded, due to effects on ibr and chemotherapy. Results: 43 pts were evaluable for toxicity & 37 evaluable for response. 41/43 (95%) pts tolerated ≥2 cy; median cy of study therapy (tx) received = 5. At baseline median age was 52y (24-64) & CD4 count 204 (21-757); 9 pts had CD4 <100. 81% were male, 42% White & 49% Black. 86% were stage III/IV, 40% non-GCB, & 88% had ECOG 0-1. Ibr RP2D was 560mg daily. Noting PET was optional, overall response rate was 100% with 57% (21/37) complete (CR) & 43% (16/37) partial responses (PR). Relapse/progression occurred in 16% (6/37; 1CR, 5PR) during a median follow-up of 4.2y (95%CI = 2.3 to 4.87); median duration of response = 2.8y. 3y event-free (EFS) & overall survival (OS) were 83 & 81% respectively (GCB: 88 & 87%, non-GCB: 76 & 63%). Among 679 treatment-related adverse events (TRAE), the most frequent were (total, % grade (gr) 3+) anemia (105, 50%), thrombocytopenia (81, 41%), neutropenia (60, 88%) & lymphopenia (60, 68%). Non-hematologic AEs (total TRAE, # max gr) included diarrhea (22, 2 gr3), nausea (21, 1 g3), hypokalemia (20, 4 gr3), fatigue (17, 17 gr1), & sepsis (1 gr4). Reasons for tx discontinuation: 1 progression, 4 withdrawal, 4 TRAE, 1 lost to follow up. Conclusions: Incorporating ibrutinib 560mg daily with R-da-EPOCH in HIV-related DLBCL treatment resulted in manageable toxicities typical of R-da-EPOCH. Although lower confirmed CR, 3y EFS & OS are comparable or higher than prior studies of HIV+DLBCL R-da-EPOCH. Ongoing studies to be updated at the meeting include impact on T cell subsets, & correlations of response & survival with circulating tumor DNA & lymphoma features (EBV, MYC, BCL2, BCL6 & genomic determinations of COO). Clinical trial information: NCI-2017-01240 .