R‐codox‐m/r‐ivac versus da‐epoch‐r in patients with newly diagnosed high‐risk burkitt lymphoma: final results of a multi‐center randomized hovon/sakk trial

Background: Optimal first-line treatment for patients with high-risk Burkitt lymphoma (BL) remains to be defined. Treatment with high-dose multi-agent regimens such as R-CODOX-M/R-IVAC is effective at the cost of significant toxicity. In single arm phase II studies, DA-EPOCH-R has demonstrated favorable progression free survival (PFS) and overall survival (OS) and less toxicity. Until now, no formal comparison between the regimens has been performed. Methods: This investigator initiated study (EudraCT2013-004394-27) is an international randomized phase III trial designed to demonstrate 2 year PFS (primary endpoint) improvement from 70% with R-CODOX-M/R-IVAC to 85% with DA-EPOCH-R in patients with (sporadic and HIV-associated) BL. Patients (18–75 year) with newly diagnosed high-risk BL (defined as any of: elevated LDH, WHO PS ≥2, stage III/IV, mass ≥10 cm) were eligible. Patients with central nervous system (CNS) involvement were excluded. Patients were randomly assigned to treatment with 2 cycles of R-CODOX-M/R-IVAC or 6 cycles of DA-EPOCH-R. All patients received intrathecal CNS prophylaxis. Due to slow accrual rate, the trial was closed prematurely. Results: From 2014 to 2021, 89 patients were enrolled. Five patients were excluded, 84 patients were randomized (43 to R-CODOX-M/R-IVAC, 41 to DA-EPOCH-R). In the R-CODOX-M/R-IVAC arm, 23% discontinued treatment versus 10% in the DA-EPOCH-R arm. In the R-CODOX-M/R-IVAC arm 65% achieved complete metabolic remission (CMR) versus 66% in the DA-EPOCH-R arm. With a median FU of 28.5 (0.03–88) months and at least 12 months for all patients that completed treatment, survival rates were comparable. Two year PFS in the R-CODOX-M/R-IVAC arm was 76% (95% CI: 60%–86%) versus 70% (95% CI: 54%–82%) in the DA-EPOCH-R arm. Two year OS rates were 76% (95% CI 60%–86%) in the R-CODOX-M/R-IVAC arm versus 75% (95% CI 59%–86%) in the DA-EPOCH-R arm. Patients treated with R-CODOX-M/R-IVAC experienced significantly more infectious adverse events (AE): 56% had ≥one infectious grade 3–5 AE versus 34% of patients treated with DA-EPOCH-R (p = 0.047). Patients treated with R-CODOX-M/R-IVAC arm received significantly more transfusions (platelets and red blood cells, p < 0.01 both), and were significantly more hospitalized (46 (mean, 1–99) versus 25 (4–78) days (p < 0.01)) then DA-EPOCH-R treated patients. Hospitalization days for AE did not differ between the arms. Conclusion: This is the first multi-center randomized trial comparing two different chemotherapy regimens in BL. The trial was closed after enrollment of 89 patients. Treatment with DA-EPOCH-R did not result in superior CMR and survival rates compared to R-CODOX-M/R-IVAC, but was associated with significantly less infectious complications, transfusions and hospitalization days. Besides R-CODOX-M/R-IVAC, treatment with DA-EPOCH-R is a valid and less toxic therapeutic option for high-risk BL patients without CNS localization. The research was funded by: Dutch Cancer Foundation, Schumacher-Kramer Foundation Keywords: aggressive B-cell non-Hodgkin lymphoma, chemotherapy No conflicts of interests pertinent to the abstract.