HIGH DOSE SEQUENTIALCHEMOTHERAPY WITH RITUXIMAB AND ASCT AS FIRST LINE THERAPY IN ADULT MCL PATIENTS: CLINICAL AND MOLECULARRESPONSE OF THE MCL0208 TRIAL, A FIL STUDY

Background: In spite of the improvement of the disease control obtained with the intensive chemo-immunotherapy in adult patients with MCL with or without autograft (ASCT) the rate of relapse and death is still high. Recent data showed that a therapeutic strategy including a maintenance in responding patients to chemoimmunotherapy can prolong the response duration and clinical outcome of MCL patients. Aims: In 2008 the Fondazione Italiana Linfomi (FIL) designed the phase III trial MCL0208, to evaluate the efficacy and safety of lenalidomide as maintenance therapy in patients with MCL achieving at least a Partial Response (PR) after an upfront intensive chemotherapy with rituximab (R) and ASCT (NCT02354313). This trial was approved by the Ethical Committee of all partecipating centers. Herein, we present the analysis of clinical and molecular response after the chemotherapy with Rituximab (R) and ASCT, one of the secondary objectives of MCL0208 study. Methods: Adult patients aged<66 years, with advanced stage MCL without clinically significant comorbidities are enrolled. The primary end-point of the study is the 2-year PFS from randomization. Patients receive 3 cycles of R- CHOP-21, followed by R-HDS which includes: R-high-dose cyclophosphamide (R-HD-CTX) (4g/m2), 2 cycles of R-high-dose Ara-C (R-HD-Ara-C) (2g/m2 q12x3 d), followed by BEAM and ASCT. CD34+ cell harvest is performed after the first course of R-HD-Ara-C. A second harvest will be performed after the second course of R-HD-Ara-C, if prior harvest is PCR+. After ASCT, responding patients are randomized between maintenance with lenalidomide (15 mg days 1-21 every 28 days) or observation for 24 months. Minimal Residual Disease (MRD) is examined at diagnosis, after R-HDCT, before and after ASCT, during maintenance/observation and during follow-up every six months. The total number of patients to be enrolled is 300. Results: From May 2010 to November 2014, 260 patients have been enrolled by 48 italian and 1 international (Lisboa, Portugal) cancer centers. The median age was 57 years (IQR 51-61), predominantly male (80%) and the majority of patients presented with adverse features such as: advanced stage (98%), poor ECOG-PS (24%), bulky disease (>5 cm) (33%), elevated LDH (31%), BM infiltration (76%) and intermediate-high MIPI (53%). Nine percent of patients had blastoid variant. Among the 260 enrolled patients, 187 completed R-HDS (72%). Ultimately, 168 patients (65%) proceed to ASCT and 146 (56%) have been randomized between lenalidomide or observation. At the time of the present analysis according to Cheson (JCO 2007) of 202 patients evaluable for final response 137 (68%) reached CR after RHDS and 156 (77%) after ASCT. Regarding MRD a molecular marker was found in 87% of cases. Before ASCT a complete molecular response (CMR) on PB and BM were 72% and 53% by nested PCR and 80% and 67% by RQ-PCR. After ASCT CMR on PB and BM were 79% and 50% by nested PCR and 86% and 73% by RQ-PCR. After a median fol- low-up of 19 months the 2-year PFS and OS were 77% and 88%, respectively. As expected with intensive regimens there was an hematological toxicity, particularly CTC grade 3-4 neutropenia (38% of cycles) and thrombocytopenia (31% of cycles), but the infections were recorded only in 17% of patients and the treatment-related deaths (TRD) were 1.6%. Summary and Conclusions: RHDS with ASCT is a feasible regimen with limited toxicity in a multicenter setting and produces an high rate of durable responses. These promising results are supported by the high rate of molecular responses by RQ-PCR.