R-DA-Edoch/R-DHAP Alteration Could Overcome High Risk Factors in Younger Mantle Cell Lymphoma

Background: Mantle-cell lymphoma (MCL) is a rare subtype of non-Hodgkin's lymphoma, with a median overall survival of only 3~5 years in the era of immunochemotherapy. Although first-line intensive chemotherapy with rituximab (R) and high dose cytarabine combined with autologous transplantation (ASCT) has significantly prolonged the survival of patients with MCL, some patients still die within few years. Our published data show that Chinese patients with MCL are younger and have a higher proportion of TP53 deletion and MYC abnormality [Oncotarget, 2015 Dec 8;6(39):42362-71]. Considering the efficacy and tolerability of the dose-enhanced immunochemotherapy R-DA-EDOCH regimen in patients with multiple high-risk aggressive B-cell lymphomas and the potential higher proliferative activity of tumor cells in Chinese patients, we conducted a prospective clinical study of alternate R-DA-EDOCH/R-DHAP induction therapy for young patients with newly-diagnosed MCL (NCT02858804). Here, we analyzed the efficacy and safety of this regimen.

Methods: The main inclusion criteria for patients with newly-diagnosed MCL included age ≤ 65 years, Ann Arbor stage II~IV and ECOG ≤ 1. During induction, patients received alternate R-DA-EDOCH/R-DHAP for two cycles. Patients who achieved less than partial remission would quit the trial, while the other patients would continue another one cycle of treatment. After finishing the 3 cycles of inductive treatment, patients would decide whether to continue ASCT consolidation therapy or another cycle of consolidation. R maintenance therapy was recommended to all patients. The primary endpoint of this study was the progression-free survival (PFS). Key secondary endpoints were complete response rate (CRR) and objective response rate (ORR) at the end of induction (EOI), overall survival (OS), minimal residual disease (MRD) status and the incidence of adverse events (AEs).

Results: In this study, we recruited 55 patients with a median age of 53 years (range, 37~65 years) and a male/female ratio of 2.2:1. Totally, 61.8% of patients were of at least one risk factor (HR) according to risk stratification, pathological classification and molecular genetic abnormalities.

All patients received at least two cycles of alternate R-DA-EDOCH/R-DHAP immunochemotherapy, and one patient dropped out due to the poor response. The ORR of the alternate R-DA-EDOCH/R-DHAP inductive treatment was 98% (95% CI 90-100), and the CRR was 89% (95%CI 78-96). There was no significant difference in CRR and ORR among patients with different prognostic characteristics. Moreover, patients rapidly achieved MRD-negative and the rate of MRD-negative after 2 cycles of treatment, the end of the inductive therapy and the end of the overall treatment was 79.2%, 88.7% and 90.6%, respectively.

The median follow-up of the cohort was 31 months (range 4-86). The 3-year PFS and OS rates were 66.3% and 85.4%, respectively. Sequential ASCT consolidation and/or R maintenance slightly increased CRR but significantly prolonged PFS of patients (3-year PFS rate: ASCT+R 90.4% versus R 64.6% versus without ASCT/R 33.3%, P<0.001).

There was no significance difference in PFS and OS between patients with (n=34) and without (n=9) HR (PFS P=0.537, OS P=0.408). For patients receiving ASCT and R maintenance, OS was even longer in patients with HR (mOS not reach versus 47m, P=0.007). Univariate analysis showed that age≥60 years, blastoid/pleomorphic pathologic morphology and TP53 double-allele events were still the risk factors for PFS in this therapeutic pattern. However, high tumor proliferative activity (such as Ki-67≥30% and MYC abnormality) and specific genetic abnormalities (such as 17p deletion, 9p deletion, etc) showed no significant adverse prognostic influence. In particular, patients who achieved MRD-negative by treatment had longer PFS (P<0.001).

The alternate R-DA-EDOCH/R-DHAP regimen was well tolerated, and no patients were discontinued due to intolerance of treatment-related AEs. AEs were mainly hematologic and at least one hematologic AEs occurred in 85.5% of the patients. Grade 3-4 leukopenia and neutropenia were found in 49.1% and 58.2% of the patients, respectively.

Conclusion: The alternate R-DA-EDOCH/R-DHAP induction therapy showed great efficacy and tolerability in young patients with newly diagnosed MCL and could overcome the adverse prognostic impact of some high-risk factors.

Wang:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy.