The dose modified (dm)CODOX-M / IVAC protocol for Burkitt Lymphoma (BL) is an iteration of the original treatment regimen described by Magrath et al. in 1996.r The intention was to provide a dose-intensive, compact, non-cross-resistant regimen with effective central nervous system (CNS) targeting. The promising results of this study were confirmed in the LY06 study, a larger, multicentre, international phase 2 trial.rThis regimen was refined in the LY10 trial, wheremethotrexate was dose modifiedto 3 g/m2 (from 6.7 g/m2)to reduce toxicity.r LY10 forms the basis of the current eviQ protocol.
LY10 was a prospective, international, non-randomised phase 2 study that included 53 patients (median age 37 years; range 17 to 76 years) with newly diagnosed BL. Patients with documented CNS involvement received additional intrathecal therapy. The LY10 trial included 11 low-risk and 42 high-risk patients.Patients were considered 'Low Risk' if they had at least 3 of the 4 following international prognostic index (IPI) factors: normal LDH, Ann Arbor stage I to II, WHO performance status 0 to 1 and number of extranodal sites less than or equal to 1. These patients were treated with three cycles of dm CODOX-M.All other patients were considered 'High Risk' and received alternating cycles of dm CODOX-M / IVAC twice. Two year progression-free survival (PFS) and overall survival (OS) rates were 64% and 67%, respectively.r
In recent years, it has been common practice to add rituximab to the dm CODOX-M / IVAC regimen, as its use in combination with standard chemotherapy has demonstrated improved patient outcomes without additional toxicity in several prospective studies.
A French phase 3 multicenter, open-label trial of 260 patients with newly-diagnosed BL, randomised patients to receive dose-dense chemotherapy with or without additional rituximab.rAfter a median follow-up of 38 months, patients receiving rituximab had a superior three year event-free survival (EFS) (hazard ratio [HR], 0.59; 95% CI, 0.38-0.94; P=.025) and OS (HR, 0.51; 95% CI, 0.30-0.86; P=.012) compared with the no-rituximab group.rAdverse events and toxicity were comparable across the two groups across each risk category. A phase 2 prospective multicentertrial for adult BL patients examined the efficacy and tolerability of rituximab in addition to dose-dense chemotherapy in 363 patients across 98 European centres.rRituximab was given before each cycle, with two additional maintenance doses, for a total of 8 doses. Five year PFSand OS rates were 71% and 80%, respectivelywith a complete remission (CR) rate of 88%.
The largest prospective study (n=27) specifically evaluatingdm R-CODOX-M / R-IVAC in BL utilised rituximab (375 mg/m2) on day 1 of eachcycle, with additional doses on day 11 of CODOX-M and on days 21 and 42 after the final IVAC cycle.rAfter a median follow-up of 56.9 months (range 2.2-77.5), 2-year PFS was 77.2% and 2-year OS was 80.7%. Six deaths occurred in total, due to progressive lymphoma (n = 3), treatment-effect (n = 2) or salvage chemotherapy (n = 1). Overall, this regimen was associated with acceptable toxicity and outcomes commensurate with historical dm CODOX-M / IVAC patients who were not exposed to rituximab. Comparable results were seen in another prospective study which added rituximab 375 mg/m2 on day 1 of each dm CODOX-M and IVAC cycle.r15 patients with BL were evaluated with four-year PFS of 92% and OS of 82%.
Another prospective study incorporated high-dose rituximab (500 mg/m2) twice a cycle in addition to the dm CODOX-M / IVAC regimen in 25 newly diagnosed BL patients.rTwo-year PFS and OS rates of 80% and 84%, respectively across all risk categories, and toxicity profile was comparable to prior reports.
Several other groups have reported retrospective data on CODOX-M / IVAC based regimens combined with rituximab.rrrrA recent Canadian study examined survival outcomes of 81 patients with BL treated with dm CODOX-M / IVAC combined with rituximab 375 mg/m2 (added on day 8 of each dm CODOX-M and day 4 of each IVAC cycle).They obtained a five year PFS and OS of 75% and 77%, respectively, with no treatment-related deaths. Treatment modifications due to toxicity were common in this cohort, however those who completed the regimen per protocol (n = 38) had significantly improved PFS 86% (P = 0.04) and OS 92% (P = 0.012).r
| Source | Study & Year Published | Supports Use | Is the dose and regimen consistent with theprotocol? | Comments |
|---|---|---|---|---|
| Phase III trials | Ribraget al.r | Yes | No | Alternate chemotherapy backbone |
| Mead et al. (LY06 trial)r | Yes | No | Higher methotrexate dose of 6.7 g/m2 | |
| Mead et al. (LY10 trial)r | Yes | No | Rituximab not included in the treatment regimen Chemotherapy backbone identical | |
| Hoelzer et al.r | Yes | No | Alternate chemotherapy backbone | |
| Phase II trials | McMillan et al.r | Yes | No | Rituximab 375 mg/m2 concurrently on day 1 of each cycle, with additional doses on day 11 of CODOX-M and days 21 and 42 after the final IVAC cycle (8 doses of rituximab in total) |
| Corazzelli et al.r | Yes | No | Higher doxorubicin dose of 50 mg/m2 | |
| Evens et al.r | Yes | No | Higher rituximab dose of 500 mg/m2 | |
| Zhu et al.r | Yes | Yes | Rituximab administered on day 8 ofdm CODOX-M and day 4 of IVAC, for each cycle |
| Guidelines | Date published / revised | Supports Use | Is the dose and regimen consistent with theprotocol? | Comments |
|---|---|---|---|---|
| NCCN | v.5 2021 | Yes | Yes | - |
| BCCA | April 2022 | Yes | Yes | Doses and scheduling of some drugs are different, but overall regimen is the same |
| CCO | August 2020 | Yes | Yes | High-dose methotrexate (day 10) and leucovorin (start day 11) are given as inpatient |
Efficacy
Progression-free survival and overall survival in the LY10randLY06r and studies, with risk group defined as in LY10:
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Toxicity
In the LY10 study,r there were 9 deaths (1 low-risk, 8 high-risk) reported to be treatment-related, of which 5 (all high-risk patients) died within 12 weeks of starting treatment; 2 of the 9 patients were aged over 65 (66 and 67, respectively).Seventy-six percent of the patients were able to complete the planned therapy. Severe (grade 3/4) toxicities included neutropenia (99%), neutropenic fever (80%), thrombocytopenia (86%), mucositis (47%), and neuropathy (8%). The treatment related death rate was 8%.
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