Up-Front ASCT Overcomes the Survival Benefit Provided By HDAC-Based Induction Regimens in Mantle Cell Lymphoma: Data from a Real-Life and Long-Term Cohort
Authors: Lage Luís Alberto de Pádua Covas , do Vale Marcela Elias , Reichert Cadiele Oliana , Culler Hebert Fabrício , de Freitas Fábio Alessandro , Costa Renata de Oliveira , Rocha Vanderson , da Siqueira Sheila Aparecida Coelho , Pereira Juliana 
Published: December 2023

Introduction: Mantle cell lymphoma (MCL) is a rare malignancy with heterogeneous behavior. Despite the therapeutic advances recently achieved, MCL remains incurable. Currently, the standard of care for young and fit patients involves induction immunochemotherapy followed by up-front autologous stem cell transplantation (ASCT). However, the role of more intensive induction regimens, such as those based on high-doses of cytarabine (HDAC) remains controversial in the management of ASCT-eligible patients. Based on this premise, the current study aims to describe clinical and laboratory characteristics, assess outcomes, determine survival predictors, and compare responses between different primary therapeutic strategies, with focus on assessing the impact of HDAC-based regimens on outcomes in ASCT-eligible patients.

Methods: This retrospective, observational, and single-center study involved 165 MCL patients, diagnosed and treated at the Department of Hematology, University of São Paulo, Brazil, from January 2010 to December 2022. Endpoints included overall survival (OS), event-free survival (EFS), and progression of disease within 24 months (POD-24) from up-front treatment. Survival curves were constructed using the Kaplan-Meier method and the Log-Rank test was used to assess the relationship between variables and outcomes. Univariate analysis was performed using the semi-parametric Cox test and multivariate analysis by Cox regression method or proportional ratios model. The results were presented in hazard ratio (HR) and 95% confidence interval (95% CI), and a p-value ≤ 0.05 was considered statistically significant.

Results: The median age at diagnosis was 65 years (38-89) and 73.9% (122/165) were male. More than 90% of cases (150/165) had a classic nodal variant (cnMCL), 76.4% (120/157) had bone marrow infiltration, and 56.4% (93/165) presented splenomegaly. Bulky ≥ 7 cm, B-symptoms, ECOG ≥ 2, and advanced-stage III/IV were observed in 32.7% (54/165), 64.8% (107/165), 32.1% (53/165), and 95.8% (158/165), respectively [ Table 1]. Sixty-four percent of patients (106/165) were categorized as high-risk according to MIPI score. Table 2 summarizes the main therapeutic modalities applied to the whole cohort. With a median follow-up of 71.1 months (95% CI: 61.8-80.4) the estimated 2-year OS and EFS were 64.1% (95% CI: 56.2-71.9%) and 31.8% (95% CI: 23.0-40.6%), respectively. The ORR for the whole cohort was 64.7% (95% CI: 57.1-71.7%), with CR achieved in 41.5% (95% CI: 34.1-49.1%). POD-24 was observed in 46.7% (95% CI: 39.1-54.3%), and the overall mortality rate (OMR) during all follow-up was 58.2% (95% CI: 50.6-65.5%), with disease progression being the main cause of death. Patients treated with R-HDAC-based regimens (43.4%-66/152) had higher ORR (85.9% vs 65.7%, p=0.007) compared to those receiving R-CHOP (46.0%-70/152), as well as lower POD-24 rates (61.9% vs 80.4%, p=0.043) and lower mortality (43.9% vs 68.6%, p=0.004). However, intensified induction regimens using R-HDAC were not associated with a real OS benefit in MCL patients undergoing up-front consolidation with ASCT (N=41) (2-year OS: 88.7% for R-HDAC plus ASCT vs 78.8% for R-CHOP plus ASCT, p=0.289), as summarized in Figure 1. Furthermore, up-front ASCT was independently associated with increased OS (p&lt;0.001), EFS (p=0.005), and lower POD-24 rates (p&lt;0.001) in MCL. Additionally, CNS involvement (HR: 3.12, 95% CI: 1.45-6.73, p=0.004), tumor lysis syndrome (HR: 2.79, 95% CI: 1.13-6.86, p=0.026), albumin &lt; 3.5 g/dL (HR: 2.69, 95% CI: 1.61-4.50, p&lt;0.001), and failure to achieve remission after induction therapy (HR: 3.71, 95% CI: 2.07-6.67, p&lt; 0.001) were predictors of poor OS.

Conclusion: In the largest Latin American cohort of MCL reported to date, we confirmed the OS benefit promoted by up-front consolidation with ASCT in young anf fit patients, regardless of the intensity of the immunochemotherapy regimen used in the pre-ASCT induction. Although HDAC-based regimens were not associated with an unequivocal increase in OS, it was associated with higher ORR and lower rates of early-relapses.