Sodium 2-Mercaptoethanesulfonate (MESNA), Ifosfamide, Mitoxantrone, and Etoposide (MINE) in Transplant-Ineligible Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Is the Old Regimen Still Gold?

Abstract

Introduction: For decades, the rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone (R-CHOP) regimen has been the standard treatment for aggressive B-cell non-Hodgkin lymphoma (NHL), such as diffuse large B-cell lymphoma (DLBCL). However, patients with relapsed or refractory (R/R) disease continue to face a poor prognosis. Those eligible for autologous hematopoietic stem cell transplantation (ASCT) are usually rescued with a platinum-containing regimen. Conversely, milder regimens are preferred for ineligible patients, such as gemcitabine and oxaliplatin (GemOx). At our institution, the standard second-line treatment for patients over 65 years or with comorbidities that make them unsuitable for ASCT is a non-platinum-based regimen composed of sodium 2-mercaptoethanesulfonate (MESNA), ifosfamide, mitoxantrone, and etoposide (MINE). Although newer targeted and immune-based therapies are emerging, there remains a lack of prospective studies on optimal treatment choices for this group of patients, particularly regarding non-platinum-based regimens.

Aim: The study aimed to evaluate in a real-world setting the efficacy and safety profile of MINE, with or without rituximab, in patients with R/R DLBCL.

Methods: This was a retrospective, single-center study conducted from April 2007 to August 2024. It included patients who underwent at least one cycle of MINE. Data were collected from patients' electronic records. The primary endpoints were overall survival (OS), progression-free survival (PFS), and duration of response (DoR). The secondary endpoints included complete response (CR) and overall response rates (ORR), as well as toxicity-related surrogates, such as the total number of required RBC units or platelet concentrates (PC), total number of febrile neutropenia (FN) episodes, ICU admissions, and treatment-emergent adverse events (TEAEs).

Results: A total of 167 patients were included, with a median follow-up time of 10 months (IQR: 4-40), a female-to-male ratio of 1.26, and 127/167 (76.0%) patients over the age of 65 (median age: 70). About 47/167 (28.1%) cases resulted from the transformation of indolent NHL. Disease was localized in 94/151 (62.3%), and 52/166 (31.3%) were refractory to the previous treatment. The protocol was used as second-line therapy in 121/167 (72.4%), with rituximab added in 86/167 (51.5%). Median OS, PFS, and DoR were 11, seven, and 24 months, respectively. In univariate analysis, PFS and OS were significantly higher in patients receiving rituximab with MINE and lower in those who presented with bulky masses, advanced-stage disease, and refractoriness to the prior line. CR was 45.3% and ORR was 63.5%. Myelotoxicity was the primary complication, with 38/124 (30.6%) patients developing FN, and six (4.8%) requiring ICU admission. This was followed by cardiotoxicity in 18/124 (14.5%). Treatment was discontinued in 17/152 (11.2%) patients, and 11/152 (7.2%) died due to toxicity.

Conclusions: This retrospective study demonstrates that the MINE protocol offers favorable outcomes and an acceptable safety profile, with myelotoxicity as the most significant adverse effect. Although inclusion criteria were not strictly limited to ineligible patients, they constituted the majority of this cohort. In conclusion, while additional prospective studies are needed, these findings reinforce MINE as a still viable and cost-efficient alternative, particularly for R/R DLBCL patients who are not eligible for ASCT.

Keywords: autologous hematopoietic stem cell transplantation; diffuse large b-cell lymphoma (dlbcl); etoposide; ifosfamide; mitoxantrone; non-hodgkin lymphoma; systemic chemotherapy.

Figure 1. Bar chart displaying the proportions of CR and PR.

CR: complete response; PR: partial response; ORR: overall response rate

Figure 2. Survival curves regarding (A) OS, (B) PFS, and (C) DoR.

DoR: duration of response; PFS: progression-free survival; OS: overall survival