Diffuse large B-cell lymphoma (DLBCL) arising in the setting of HIV infection remains a complex and heterogeneous disease, both clinically and biologically. Although dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-da-EPOCH) is widely accepted as a standard treatment, variability in patient outcomes highlights the need for more tailored therapeutic approaches. One strategy under investigation is the incorporation of targeted agents based on tumor biology, including the use of ibrutinib, a BTK inhibitor with additional effects on inducible T-cell kinase (ITK). Because HIV utilizes ITK during viral replication, ibrutinib may offer added biologic benefit in this population.
A multicenter study explored the addition of ibrutinib to R-da-EPOCH in patients with HIV-associated DLBCL, with an emphasis on evaluating safety, feasibility, and clinical activity. The trial also aimed to better understand how tumor cell of origin and immune effects, particularly in T-cell subsets, may influence treatment response. The study design included a standard 3+3 dose de-escalation phase followed by expansion at the recommended phase 2 dose.
Eligible participants were adults aged 18 to 64 years with stage II to IV HIV-related DLBCL. Patients could be newly diagnosed or have received a single prior cycle of R-da-EPOCH. Importantly, the study allowed enrollment of patients with CD4 counts <100 cells/µL and those with asymptomatic leptomeningeal disease, reflecting a broader, real-world population. Ibrutinib was administered daily on days 1 through 21 of each cycle, in combination with 6 cycles of R-da-EPOCH. Patients taking moderate or strong CYP3A4 inhibitors were excluded due to potential drug interactions.
In total, 43 patients were evaluable for safety and 38 for efficacy. The mean age was 52 years, and 89.1% of patients were aged <60 years. Baseline CD4 counts varied widely, with 50.0% having a CD4 count of <200 cells/µL. Most participants had advanced-stage disease (65.2%, stage IV), and 40% were classified as having non–germinal center B-cell (GCB) subtype. Despite the intensity of combined therapy, treatment delivery was feasible: 95% of patients completed at least 2 cycles, with a median of 5 cycles administered.
The recommended phase 2 dose of ibrutinib was established at 560 mg daily. Clinical activity was notable, with an overall response rate of 100% among evaluable patients. Complete responses (CRs) were observed in 58% of patients, and partial responses were observed in 42% of patients. At a median follow-up of 4.2 years, disease progression or relapse was reported in 6 patients. The median duration of response was 2.8 years.
Estimated 1-year progression-free survival (PFS) was 89%, and overall survival (OS) was 92%. When examined by subtype, patients with GCB disease had somewhat better outcomes than those with non-GCB disease, although both groups demonstrated meaningful benefit.
The safety profile of the combination was consistent with expectations for R-da-EPOCH. Across 679 treatment-related adverse events (AEs), the most common toxicities were anemia (5 patients), nausea (5 patients), leukopenia (4 patients), neutropenia (4 patients), and diarrhea (4 patients). One case of sepsis was reported. Treatment discontinuation occurred infrequently and was attributed to disease progression, AEs, patient withdrawal, or loss to follow-up.
Overall, the addition of ibrutinib to dose-adjusted R-EPOCH was feasible and associated with manageable toxicity in stage II-IV HIV-DLBCL. Although the CR rate was somewhat lower than anticipated, longer-term outcomes such as PFS and OS were comparable to or better than those previously reported with standard therapy alone. Ongoing analyses are expected to provide further insight into the immunologic effects of treatment and the relationship between response and tumor-specific factors, including genomic features and circulating tumor DNA.
Source: Wong-Sefidan I, et al. Integrating BTK inhibition into R-da-EPOCH for HIV-related DLBCL. Presented at: ASCO Annual Meeting. May 29-June 2, 2026; Chicago, IL. Abstract 7001.