Rituximab Given after High Dose Therapy and Autologous Stem Cell Transplantation Induces Durable Clearance of Minimal Residual Disease in about Half of the Patients with Follicular Non Hodgkin’s Lymphoma : 36 Months Results of a Multicenter Open Label Phase II Trial (M39012 Trial).
Authors: Morschhauser Franck , Recher Christian , Milpied Noel , Gressin Remi , Salles Gilles , Brice Pauline , Vey Norbert , Haioun Corinne , Colombat Philippe , Bourhis Jean-Henri , Rossi Jean-Francois , Berriot-Varoqueaux Nathalie , Bergougnoux Loic , Bosly Andre , Delsol Georges , Attal Michel 
Published: October 2019

Abstract
In patients with follicular non hodgkin’s lymphoma (FL), high dose therapy and autologous stem cell transplantation (ASCT) can improve disease free survival. However, patients with minimal residual disease (MRD) after ASCT relapse in most cases. The use of immunotherapy in patient with a MRD state after ASCT is an attractive strategy. Rituximab is an anti-CD20 monoclonal antibody that has demonstrated efficacy alone or in combination with chemotherapy in FLNH. The purpose of the present study is to evaluate the efficacy of rituximab on MRD after ASCT. Methods : Three months after ASCT, 39 patients (median age: 48 years) including 14 patients with clinical MRD (group A: nodal or extra-nodal mass > 1 cm but < to 3 cm; bone marrow infiltration less than 30% allowed) and 25 patients with molecular MRD (group B: complete clinical response but bcl-2 gene rearrangement detectable by clonospecific PCR in blood and/or marrow) were eligible to receive Rituximab (375 mg/m2 IV, once a week for 4 weeks). Clinical examination, imaging and blood and bone marrow sampling for centralized molecular MRD studies by clonospecific PCR (sensitivity of the PCR assay : 10-6) were performed at day 50 and every 6 months post treatment.
Results: In group A, overall clinical response rate was 36 % (5/14) at day 50 and 71 % (10/14) at 12, 24 and 36 months post treatment, respectively. Median time to response was 183 days. Median Progression free survival (PFS) was not reached and PFS was 62 % at M36. In responders, no relapse was observed. In group B, molecular response (conversion from PCR positive to PCR negative status) was achieved in 12/23 (52 %), 11/22 (50 %), 10/22 (45 %) and 11/24 (46 %) assessable patients at day 50, 12, 24 and 36 months post treatment, respectively. Median time to response was 185 days. Four molecular responders became persistently PCR positive and had a clinical relapse. Median clinical PFS was not reached. Treatment was well tolerated. Only one serious adverse event (AE) was reported as related during the study (grade 3 NCI granulocytopenia). No patient was withdrawn for AE.
Conclusion: Rituximab is effective in 71 % of the patients with clinical MRD after ASCT with a response maintained at 3 years. The molecular response induced by rituximab persisted after 3 years of follow-up in 46 % of the patients. These results demonstrate that in FL patients with MRD after ASCT, Rituximab is well tolerated and effective completing the effect of intensive chemotherapy and inducing durable response. Further studies are required to identify the most effective program in combination with rituximab which may result in a chance of cure.