R‐CHOP/R‐HDAC AND RITUXIMAB MAINTENANCE RESULTS IN HIGH COMPLETE REMISSION RATE, MINIMAL RESIDUAL DISEASE NEGATIVITY, AND EXCELLENT SURVIVAL IN ELDERLY MCL PATIENTS

Abstract

Introduction: Mantle cell lymphoma (MCL) is an incurable subtype of B-cell non-Hodgkin lymphoma. Implementation of high-dose cytarabine (HDAC) into induction therapy followed by stem-cell transplantation and rituximab maintenance (RM) became standard of care for the younger patients with newly dg. MCL. Treatment of the transplant-ineligible patients is still largely based on CHOP or alkylating agents and RM. Methods: We conducted a multicenter observational study designed by the Czech lymphoma study group (CLSG-MCL-01, GovTrial #NCT03054883), which prospectively analyzed safety and efficacy of alternating 3 + 3 cycles of R-CHOP and R-HDAC (1 or 2 g / m2, 2 doses over 24 hours) for newly diagnosed transplant-ineligible MCL patients. Pathological review of all samples was performed. MRD assessment was implemented in Euro-MRD member CLIP laboratory Prague. Primary objectives included response after induction by PET-CT, and progression-free survival (PFS). Secondary objectives included safety, overall survival (OS), and prognostic significance of PET imaging and minimal residual disease (MRD) after induction. Results: 73 patients were enrolled with median age 70 years. Most patients had intermediate (39.7%) and high-risk (50.7%) disease according to MCL International Prognostic Index (MIPI). Out of the 56 analyzed biopsies 55.4% revealed high proliferation index by Ki-67 (≥ 30%). The overall response rate in the 68 evaluable patients was 95.6% by PET-CT, including 80.9% complete remissions. MRD was evaluated after induction in 54 patients using paired samples of bone marrow (BM) and peripheral blood (PB). Grade 3-4 hematologic and non-hematologic toxicity was documented in 48% and 20.5% patients, respectively. RM was initiated in 59 patients. At the median follow-up of 43.8 months, median PFS and OS were not reached and were 53.9% and 71.3% at 4 years, respectively. For pts on RM 4-year PFS and OS was 61% and 77.2%, respectively. By univariate analysis MIPI, Ki-67 (≥ 30%), bulky disease (≥5 cm), involvement of the spleen, and MRD in PB after induction correlated with PFS. Interestingly, MRD in BM after induction did not correlate with PFS or OS. Multivariate analysis revealed that MIPI, bulky disease ≥5 cm, achievement of PET-negativity, and MRD in PB after induction independently correlated with PFS. Conclusion: Alternating R-CHOP and R-HDAC represents feasible and very effective regimen for elderly/comorbid MCL patients. The observed loss of predictive value of MRD in BM after induction appears to be impacted by rituximab maintenance. Keywords: Ara-C; mantle cell lymphoma (MCL); minimal residual disease (MRD)