R-CODOX-M/R-IVAC Fails to Establish Superior Efficacy Over DA-EPOCH-R in High-Risk Burkitt Lymphoma

Treatment with the R-CODOX-M and R-IVAC regimens elicited similar efficacy to dose-adjusted infused DA-EPOCH-R in patients with newly diagnosed, high-risk Burkitt lymphoma.

Treatment with the R-CODOX-M and R-IVAC regimens elicited similar efficacy to dose-adjusted infused DA-EPOCH-R in patients with newly diagnosed, high-risk Burkitt lymphoma, according to results from a phase 3 trial (EUDRACT 2013-004394-27).1 Study authors concluded that DA-EPOCH-R appears to be the preferred regimen for patients with high-risk Burkitt lymphoma without central nervous system (CNS) localization.

Data presented at the 2022 EHA Congress also showed DA-EPOCH-R (etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab [Ritxuan]) was associated with significantly fewer infectious complications, transfusions, and hospitalization nights.

At a median follow-up of 19.1 months (range, 0.03-88.4), the estimated 2-year progression-free survival (PFS) for R-CODOX-M (rituximab [Rituxen] plus cyclophosphamide, doxorubicin, vincristine, and methotrexate) with R-IVAC (rituximab, ifosfamide, etoposide, and high-dose cytarabine) was 76%, compared with 70% for DA-EPOCH-R (P = 0.38). Additionally, the estimated 2-year overall survival (OS) rates were 75% and 76% in the R-CODOX-M/R-IVAC and DA-EPOCH-R arms, respectively (P = .85).

The complete metabolic remission (CMR) rate at the end of treatment was 65% in the R-CODOX-M/R-IVAC compared with 66% in the DA-EPOCH-R arm.

“Due to the slow accrual of the study and the [failure] of another European group to participate, we had to close the trial prematurely, and the data cutoff was April 16, 2022,” lead study author Martine Chamuleau, MD, PhD, an internist-hematologist at Amsterdam University Medical Centers, said in a presentation of the data.

The optimal first-line treatment for Burkitt lymphoma has yet to be defined. Prior data showed R-CODOX-M/R-IVAC elicited a 3-year PFS rate of 74%, compared with 95% for DA-EPOCH-R in a single-center study, and 85% in a multicenter study.

This phase 3 trial aimed to further evaluate the efficacy and safety of the 2 regimens. The study enrolled patients aged from 18 to 75 years old with newly diagnosed Burkitt lymphoma (sporadic and HIV associated). Patients were also required to have high-risk disease defined by lactate dehydrogenase (LDH) greater than or equal to the upper limit of normal (ULN); a World Health Organization (WHO) performance status of at least 2; Ann Arbor stage II or IV disease; or a tumor mass of at least 10 cm.

Key exclusion criteria included endemic or Burkitt lymphoma and CNS involvement.

Investigators randomly assigned patients 1:1 to R-CODOX-M/R-IVAC in arm A or DA-EPOCH-R in arm B. In arm A, patients received R-CODOX-M at 800 mg/m2 of cyclophosphamide on day 1, then 200 mg/m2 on days 2 through 5, 40 mg/m2 of doxorubicin on day 1, 1 mg/m2 of vincristine on day 1 and 5 mg/m2 on day 8, and 375 mg/m2 of rituximab on days 1 and 9.

Methotrexate was given at 3000 mg/m2 for patients 65 years or younger and 1000 mg/m2 for patients older than 65 years.

R-IVAC administration included 60 mg/m2 of etoposide on days 1 through 5 and 375 mg/m2 of rituximab on days 3 and 7. Patients 65 years or younger received 1500 mg/m2 of ifosfamide on days 1 through 5, and 2000 mg/m2 of cytarabine on days 1 and 2. Patients over 65 years were given 1000 mg/m2 of ifosfamide and 1000 mg/m2 of cytarabine on the same schedule.

Hospitalization was required for all therapeutic administrations. Treatment lasted at least 16 weeks when there were no delays.

In arm B, DA-EPOCH-R was given at 375 mg/m2 of rituximab on days 1 and 5, 50 mg/m2 to 124 mg/m2 of continuous etoposide on days 1 through 4, 10 mg/m2 to 25 mg/m2 doxorubicin on days 1 through 4, 0.5 mg/m2 of continuous vincristine on days 1 through 4, and 480 mg/m2 to 1866 mg/m2 of cyclophosphamide on day 5. Dose adjustments depended on neutropenia and thrombocytopenia. Out-patient administration was permitted and treatment duration was at least 18 weeks when there were no delays.

The primary objective of the trial was to demonstrate an improvement in 2-year PFS from 70% with R-CODOX-M/R-IVAC to 85% with DA-EPOCH-R. Secondary end points included overall response rate and OS at 2 years, grade 3 or higher toxicities per Common Terminology Criteria for Adverse Events, and number of hospitalization nights.

The median age of enrolled patients in arm A (n = 43) was 50 years (range, 18-75) vs 56 years (range, 22-74) in arm B (n = 41). The majority of patients were male (86% and 88% in arms A and B, respectively), had Burkitt lymphoma (84% and 85%), had Ann Arbor stage III/IV disease (88% and 93%), had a WHO performance status of 0 to 2 (93% and 88%), had LDH greater than the ULN (71% and 70%), were HIV negative (88% and 90%), and had peripheral blasts lower than 25% (98% and 95%).

Additional data showed that 33 of 43 patients in arm A completed treatment compared with 37 of 41 in arm B. R-CODOX-M/R-IVAC was fully dosed in 92% of cycles. In arm B, the maximum dose levels of 1, 2, 3, and 4 were given in 35%, 19%, 24%, and 22% of patients, respectively.

Regarding safety, investigators recorded 129 adverse effects (AEs) of any grade in arm A compared with 84 AEs of any grade in arm B. Chamuleau said more grade 3 AEs occurred in arm A vs arm B.

Additionally, investigators recorded 30 serious AEs in arm A compared with 28 in arm B. The most common serious AEs in both arms were infections and febrile neutropenia, which were more common with R-CODOX-M/R-IVAC (P = .04).

Patients in arm A received more red blood cell transfusions (P < .01) and platelet transfusions (P < .01). Hospitalizations planned per protocol were higher in the arm A (P < .01), though hospitalizations for AEs were also higher in arm A (P = .01).


  1. Chamuleau MED, Stenner F, Chitu D, et al. R-CODOX-M/R-IVAC versus DA-EPOCH-R in patients with newly diagnosed high-risk Burkitt lymphoma: first results of a multi-center randomized HOVON/SAKK trial. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract LB2370