Rituximab Added to CODOX-M/IVAC Is Highly Effective in HIV-Negative and hiv-Positive Burkitt Lymphoma
Authors: Abramson Jeremy S. , Barnes Jeffrey A. , Toomey Christiana E. , Jacobsen Eric D. , Armand Philippe , Takvorian Tak , Fisher David C. , Reynolds Hazel , Hochberg Ephraim P. , LaCasce Ann S. 
Published: October 2019

Abstract
Burkitt lymphoma (BL) is a highly aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for nearly 3% of all newly diagnosed NHLs. Treatment of adult non-HIV-related BL with the intensive CODOX-M/IVAC regimen (modified Magrath regimen) produces complete responses (CR) in 75 to 86% of patients, with lower CR rates reported in HIV-related BL. The CD20-directed monoclonal antibody rituximab has never been reported in combination with CODOX-M/IVAC, and here we report the first series in BL patients, with or without HIV infection. A total of 24 patients were identified at our institutions who received rituximab plus CODOX-M/IVAC with curative intent. Rituximab was administered at 375mg/m2 on day 3 of cycle 1, and then on day 1 of subsequent cycles. Twenty-three patients received 4 alternating cycles of R-CODOX-M/R-IVAC for high risk disease, while 1 patient received 3 cycles of R-CODOX-M alone for low risk disease, defined as a single focus less than 10cm with a normal LDH. All patients received white cell growth factor support, and pneumocystis prophylaxis was included for all HIV+ patients. The median age was 45 years (17–67), advanced Ann Arbor stage 80%, LDH > upper limit of normal 80%, extra nodal involvement 80% and ECOG PS <2 in 96% of patients. Eight patients (33%) were HIV positive, all of whom received concurrent HAART therapy. Mean CD4 count in HIV positive patients was 266. Five patients (21%) had CNS involvement at diagnosis. Twenty-three of 24 patients achieved a complete response (CR rate 96%), and one patient developed progressive disease prior to completion of therapy. At a median follow up of 19 months (range 1–32), the event-free (EFS) and overall survival (OS) were 67% and 75%, respectively. All events occurred in high risk patients. Patients older than the age of 45 had both inferior OS (p=0.03, log rank test) and EFS (p=0.041, log rank test), compared to younger patients. Neither HIV status nor CNS involvement had prognostic value in this series. There were two relapses. One patient relapsed at 3 months post therapy and died of infectious complication during salvage treatment with rituximab, gemcitabine, and cisplatin. The other relapse occurred 11 months post therapy and was alive 22 months after salvage with autologous stem cell transplantation. One patient developed progressive disease in the testes during treatment and is currently undergoing salvage treatment with high dose cytarabine followed by gemcitabine, cisplatin and dexamethasone. Neutropenic fever occurred in 71% of patients, and in 33% of treatment cycles overall. Twenty-three of 24 (96%) patients experienced grade 4 neutropenia and 80% experienced grade 4 thrombocytopenia, with one patient developing grade IV bleeding (subdural hematoma while on therapeutic anticoagulation). The average interval between treatment cycles was 22 days, which is similar to results previously reported for this regimen without the addition of rituximab. There were 6 deaths, 2 of which occurred during treatment. The 2 deaths during treatment were both infection-related and occurred in the 2 patients greater than 60 in this series; both were HIV negative. Of the 4 deaths following the end of therapy, 3 occurred within 3 months of completing treatment, 1 from recurrent BL and 2 from infectious complications (1 of whom was HIV-positive). One patient died in CR of treatment-related myelodysplastic syndrome 22 months after diagnosis. Of the 6 deaths in this series, 2 were in HIV-infected patients.
CODOX-M/IVAC with rituximab results in high efficacy with a CR rate of 96% and favorable progression-free and overall survivals, but should be used with caution in older patients due largely to infection-related toxicity.