Introduction: Current treatment strategy for HIV-associated Burkitt lymphoma (BL) typically rely on intensive chemotherapy regimens modeled on anti-leukemia protocols such as GMALL, LMB, and their regional derivatives. These are often resource-intensive, prolonged, and associated with dose-limiting toxicities, frequent interruptions, and high treatment-related mortality. The “CARMEN” protocol is a dose-dense regimen developed to improve tolerability while maintaining efficacy [Ferreri, Blood Adv 2022]. It includes a 36-day, single-course induction with weekly sequential doses of six anticancer drugs, plus intrathecal chemo, followed by high-dose cytarabine–based consolidation. Favorable safety and efficacy profiles with CARMEN and similar regimens have helped narrow the outcome gap between HIV-pos and HIV-neg patients (pts) with BL. However, systematic comparisons of efficacy across chemo regimens—particularly when stratified by prognostic scores—remain limited. In the absence of feasible prospective comparative trials, the HIV Lymphoma Network of the European Hematology Association launched an international study to assess feasibility and efficacy of GMALL (and its derivatives), CARMEN, and other regimens in HIV-pos pts with BL treated at 19 centers across Germany, Italy, Spain, France, and Croatia.

Methods: HIV-pos adults with BL treated between 2005–2024 were included. All pts were eligible regardless of ECOG PS, stage, IPI, BLIPI [Olszewski, JCO 2021], or treatment. Pts with HBV/HCV infection were included; those lost to follow-up within 6 months of diagnosis were excluded. The primary endpoint was overall survival (OS), analyzed by treatment regimen and stratified by IPI (low: 0–1; intermediate: 2–3; high: 4–5) and BLIPI (low: 0; intermediate: 1; high: 2–4). Feasibility and tolerability were assessed by the incidence of treatment-related deaths, dose reductions or interruptions, grade ≥3 non-hematologic toxicities, and grade ≥3 infections. Variables significantly associated with OS were further evaluated using Cox proportional hazards models.

Results: Of 247 consecutive HIV-pos pts with BL (median age 43; range 25–68; 227 males), 16 were excluded for early loss to follow-up, leaving 231 for analysis. Of these, 145 received GMALL or derivatives (BFM, BURKIMAB), 41 received CARMEN, 16 received LMB, and 20 received R-CHOP. Nine pts treated with other regimens were excluded from analyses. Baseline characteristics were comparable across groups, except for B symptoms, which were not recorded in the LMB cohort.

At a median follow-up of 65 months (range 7–164), 73 pts experienced a PFS event, and 61 died: 41 from lymphoma, 17 from infections, and 2 from second cancers. The 5-yr PFS and OS were 70% (95%CI:69–71) and 71% (95%CI:70–72), respectively. Stratified by treatment regimen, 5-yr OS was 74% (95%CI:73–75) for GMALL and derivatives, 68% (95%CI:66–70) for CARMEN, 79% (95%CI:78–80) for LMB, and 45% (95%CI:25–62) for R-CHOP.

IPI data were available for 212 pts (95%). Among 49 with IPI 0–1, only two events occurred, with a 5-yr OS of 95% (95%CI:94–96) and no significant differences across regimens. Among 163 pts with IPI 2–5, the 5-yr OS was 65% (95%CI:64–66), with comparable efficacy among GMALL and derivatives, CARMEN, and LMB, but significantly worse outcomes for R-CHOP. Similar findings were observed using BLIPI stratification. Multivariable analysis identified bulky disease, HIV-RNA levels, gender, and IPI as independent OS predictors. Notably, it confirmed equivalent efficacy among intensified regimens and their superiority over R-CHOP.

In terms of feasibility, CARMEN had the most favorable profile: only 5 pts (12%) required dose reductions and 2 (5%) discontinued treatment due to toxicity. In comparison, dose reductions and discontinuations occurred in 30% and 16% of pts on GMALL, and 38% and 16% with LMB.

Conclusions: OS rates are encouraging in HIV-pos pts with BL; however, nearly one-third of deaths are still attributable to iatrogenic toxicity. Despite the limitations of a retrospective design, our findings suggest that CARMEN regimen provides outcomes comparable to those of standard intensive protocols (GMALL, its derivatives, and LMB). Efficacy was consistent across all risk subgroups defined by IPI and BLIPI. In addition to its short duration and favorable tolerability, CARMEN may reduce the risk of chronic toxicity and secondary malignancies, owing to its use of single doses of chemotherapeutic agents.

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2025
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