Extended Follow-Up of Reduced Intensity Transplantation with an Alemtuzumab-Containing Regimen for Follicular Lymphoma.
Authors: Thomson Kirsty , Morris Emma , Milligan Donald , Hunter Ann , Cook Gordon , Bloor Adrian , Craddock Charles , Yung Lynny , Parker Anne , Chakraverty Ronjon , Peggs Karl , Mackinnon Stephen 
Published: April 2020

Abstract
Allogeneic transplant with reduced intensity conditioning (RIC) is currently being investigated as potential curative therapy for patients with lymphoma. We report 64 consecutive patients with follicular lymphoma (FL) transplanted at 9 centres with a RIC regimen containing fludarabine 150mg/m2, melphalan 140mg/m2 and alemtuzumab (20–100mg). Cyclosporin A was given at 3mg/kg. Donors were HLA-matched siblings in 34 (53%), and unrelated in 30 (47%), of whom 9 (14%) were HLA-mismatched at up to 2/10 loci. Median age was 44 yrs (26–65), median lines of previous therapy was 3 (1–8) and 17 (27%) had failed a prior autograft. Fifty-five patients (86%) had chemosensitive disease pre-RIC (complete remission 11, partial remission 44), 8 (12%) were chemorefractory and 1 had untreated relapse. Median follow-up was 39 months (1–98). Non-relapse mortality (NRM) at 5 yrs was 12%, with 9% at 5 yrs for sibling donors and 15% for unrelated (p=0.41). There was no significant impact of prior autograft on NRM. Acute graft-versus-host disease (GVHD) grade II occurred in 11 (17%) with no grade III-IV, and extensive chronic GVHD occurred in 9 (16%). Relapse rate (RR) was 18% at 1 year and 32% at 5 years. Those who had failed a prior autograft had an increased RR (53% at 5 yrs) compared to those with no prior autograft (22% at 5 yrs; p=0.01). Median time to relapse from RIC was 8 months (1–43) with 15/17 events occurring within the 1st 2 years. Donor lymphocyte infusions (DLI) were given to 13 patients, at a starting dose of 1–10×106 CD3+/kg. Nine patients remitted, of whom 6 had no GVHD and 7 had received prior rituximab. Median follow-up from last DLI dose was 34 months (3–72). Overall survival (OS) for the whole cohort was 80% at 1 yr and 76% at 5 yrs. On univariate analysis, those with sibling donors had significantly improved OS (88% at 5 yrs), compared to unrelated donors (61% at 5 yrs; p=0.016), as did those with chemosensitive disease pre-RIC (80% at 5 yrs) compared to chemorefractory disease (50% at 5 yrs; p=0.028), and those who had not undergone a prior autograft (86% at 5 yrs) compared to those who had (47% at 5 yrs; p=0.001). Similarly, current progression-free survival (cPFS) for the whole cohort was 79% at 1 yr and 77% at 5 yrs, with significantly superior outcome in those with sibling donors (88% at 5 yrs) compared to unrelated donors (63% at 5 yrs; p=0.018), those with chemosensitive disease (81% at 5 yrs) compared to those with chemorefractory disease (50% at 5 yrs; p=0.0198), and those who had not failed a prior autograft (86% at 5 yrs) compared to those who had (50% at 5 yrs; p=0.001). No factor remained significant for OS or cPFS on multivariate analysis. In conclusion, RIC for FL using an alemtuzumab-containing regimen can be undertaken with relatively low rates of significant acute and chronic GVHD, and low NRM for both HLA-matched and mismatched related and unrelated donors. Responses to DLI occur, often in the absence of clinical GVHD, and appear durable so far, although further follow-up is required.