Results of the Regimen Dime in Diffuse Large B-Cell Lymphoma with MYC over-Expression: A Retrospective Analysis

Introduction:

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with a curative rate of 60% using standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). The presence of MYC +/- BCL2 gene rearrangement and/or MYC and BCL2/BCL6 co-expression confers poor outcome and increased risk of relapse in the central nervous system (CNS). There has been no consensus on the ideal strategy for this subgroup of high-risk patients. The use of systemic high-dose methotrexate to penetrate the blood-brain-barrier may be an effective method to decrease the rate of CNS relapse. Our institution has been using a combination of dexamethasone, ifosfamide, high dose methotrexate, and etoposide (DIME) together with rituximab (R) or obinutuzumab (O) in the frontline setting for this group of high risk DLBCL patients since 2016. Rituximab or obinutuzumab were administered at Day 0 of each cycle, followed by DIME (methotrexate 2 g/m² infusion over 6 hours (day 1), dexamethasone 40 mg/day, ifosfamide 1500 mg/m² infusion concurrent with mesna 900 mg/m², and etoposide 100 mg/m² infusion over 2 hours (days 2-4)).

Methods:

Data of patients with primary DLBCL who received R/O-DIME in the frontline setting from January 2016 up to June 30, 2023 were retrospectively reviewed. All patients underwent a ¹⁸F-fluorodeoxyglucose-positron emission tomography-computed tomography (PET-CT) scan at diagnosis, interim after 2 or 3 cycles of DIME, and end of treatment. Complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD) were defined according to the International Working Group revised response criteria in malignant lymphomas. Patient demographics and tumour characteristics were analyzed. All patient data were censored on June 30, 2024. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Parameters related to the survivals were determined using the Cox proportional hazard regression model. Multivariate analysis was performed for parameters with p values < 0.1 on univariate analysis. Differences with p values < 0.05 (2-tailed) were considered statistically significant.

Results:

In a 7.5-year period, 78 patients (male=34; female=44) at a median age of 62 (range: 24-81) years were treated. The median follow-up time was 49 months. All patients had Eastern Cooperative Oncology Group (ECOG) score of 0 to 1. Forty-three patients (55%) had Ann Arbor stage III/IV disease, 31 (40%) had International Prognostic Index (IPI) score of 3 to 5, and 18 (23%) had CNS-IPI score of 4 to 6. Most patients (N=72; 92%) had MYC over-expression in immunohistochemical staining, while MYC translocation was not commonly found (present: 12%; absent: 36%; not tested: 53%). The overall response rate (ORR) was 98% (CR: 89%; PR: 9%). The 1-year and 5-year PFS were 81% and 61%. The 1-year and 5-year OS were 91% and 65%. CNS relapse occurred in 6 (7%) patients after achieving a response with DIME, including 4 patients who achieved CR, and 2 patients who achieved PR as their best response. Multivariate analysis indicated that failure to achieve CR (p<0.001) was associated with inferior PFS, while the development of CNS disease after achieving a response (p = 0.031) was associated with inferior OS. Most patients (N=58; 74%) did not develop febrile neutropenia, and 11 patients (14%) developed nephrotoxicity.

Conclusions:

This retrospective analysis showed that DIME was an effective frontline chemotherapy regimen in our cohort of high-risk DLBCL patients. The rate of CNS disease relapse and survivals are comparable to figures quoted in literature for this subgroup of high-risk DLBCL patients treated with R-CHOP. Further studies are needed to analyze its effect on lymphomas with MYC translocation and double hit lymphomas.

Chan:Takeda: Other: Travel support; Novartis: Other: Travel support. Gill:Otsuka: Consultancy, Other: Conference Support; Celgene: Research Funding; PharmaEssentia Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Conference Support, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Conference Support, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Conference Support; Lecture fees, Research Funding; MSD: Consultancy, Honoraria, Other: Conference Support; Lecture fees, Research Funding; Jacobson Pharma Corporation: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Research Funding; Astellas: Consultancy, Honoraria, Other: Lecture fees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Conference Support; Lecture fees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Imago Biosciences: Research Funding.