Molecular Remission Can Be Attained in Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) and Follicular Lymphomas after Reduced Intensity Conditioning (RIC) and Allogeneic Stem Cell Transplantation (ALLO-SCT).
Authors: Farina Lucia , Carrabba Matteo , Dodero Anna , Rizzo Elena , Zorzan Elisabetta , Ciceri Fabio , Locasciulli Anna , Olivieri Attilio , Rambaldi Alessandro , Tarella Corrado , Santoro Alessandra , Patriarca Francesca , Bacigalupo Andrea , Corradini Paolo 
Published: April 2020

Abstract
RIC followed by allo-SCT is an effective salvage treatment for some relapsed hematologic malignancies due to the postulated graft versus tumour (GVT) effect. In order to evaluate the quality of the clinical response, we have investigated the molecular status of patients receiving allo-SCT for relapsed disease.
Forty-four patients (19 chronic lymphocytic leukemias (CLL), 21 follicular lymphomas (FCL) and 4 small lymphocytic lymphomas (SLL)) were enrolled in a prospective phase II study. The median age was 54 years (range: 32–69 years). The median number of previous chemotherapy regimens was 2 (range: 1–5) and 23% of patients had already failed an auto-SCT. Before transplant 34% of patients were chemorefractory and 34% of the chemosensitive patients were in complete remission (CR). The conditioning regimen consisted of thiotepa 10mg/kg, fludarabine 60mg/ms and cyclophosphamide 60mg/kg; short course of methotrexate and cyclosporin were used as GVHD prophylaxis. Minimal residual disease (MRD) was monitored by nested PCR for IgH or Bcl-2 genes; in PCR-positive patients a TaqMan based quantitative monitoring was also employed.
All patients engrafted. On day +30 after transplant 39% of patients achieved CR. Acute GVHD (aGVHD) was observed in 57% of patients and 52% of 42 evaluable patients developed chronic GVHD; no difference in the incidence of GVHD between FCL and CLL/SLL was observed. In 30 of 44 patients (68%) a PCR marker for MRD monitoring was found. Twenty-five patients (10 CLL, 2 SLL, 13 FCL) of 37 patients in CR after allo-SCT were monitored by nested PCR and 4 PCR-positive patients were monitored by TaqMan PCR. At a median molecular follow up of 15 months (range: 3–62) 15 of 25 patients (60%) were alive and in molecular remission; one CLL patient died of TRM in molecular remission (MR); five of these patients were chemorefractory. Nine patients (3 FCL, 5 CLL, 1 SLL) never achieved PCR negativity and 3 of them relapsed (2 CLL; 1 SLL) after a median time of 270 days. In one of these patients the TaqMan PCR system could detect a continuous increase of tumour genomes in the marrow prior to the clinical relapse. The SLL patient achieved MR after chemotherapy and DLI, developing limited cGVHD; the other two patients never developed GVHD, even after DLI. Eighty percent of PCR-negative patients developed GVHD and it preceded or was concomitant with the achievement of MR. The better molecular outcome of FCL seems to be due to a longer follow up (19 months vs 12 months) if compared to CLL/SLL, in which a slow clearance of MRD has been observed. In conclusion, MR can be achieved in relapsed and chemorefractory patients affected by indolent lymphoproliferative disorders; quantitative PCR monitoring can be used to modulate post-transplant immunotherapy; a longer follow up is warranted to evaluate if the GVT effect can sustain MR in the long-term.