De-Escalation of the Alemtuzumab Dose Prior to Nonmyeloablative HLA-Identical Sibling Transplantation: Crucial Role of Timing.
Authors: Chakraverty Ronjon , Dimopoulou Maria , Glanville Julie , Thomson Kirsty , Peggs Karl , Milligan Donald , Cook Gordon , Jackson Graham , Parker Anne , Hunter Ann , Russell Nigel , Pearce Rachel , Mackinnon Stephen 
Published: October 2019

Abstract
Nonmyeloablative conditioning with Fludarabine/Melphalan/Alemtuzumab prior to allogeneic stem cell transplantation is associated with low toxicity. In vivo T-cell depletion with Alemtuzumab is highly effective at preventing GVHD, but the antibody persists for several weeks post-transplantation and this contributes to high rates of viral infection. We reasoned that a reduction in the dose of Alemtuzumab (from the initial total dose of 100mg divided over 5 days from d-8 to d-4) would permit improved immune reconstitution post-transplantation. We report here an analysis of two consecutive multi-center trials in which the dose of Alemtuzumab was reduced to a total dose of 60mg or below. Eligibility criteria included patients with hematological malignancies who were aged 18–65yr, who had an HLA-identical sibling, life expectancy >3 months and who were not suitable for standard myeloablative conditioning. Primary endpoints included TRM, incidence of GVHD/infection and chimerism. The studies received IRB approval and all patients gave informed consent. Study 1 evaluated a dose reduction of Alemtuzumab to a total dose of 60mg split between day d-8 and d-7 and was terminated when stopping rules were invoked after accrual of 18 patients (median follow up 23mo). Study 2 evaluated de-escalation of the Alemtuzumab dose in three consecutive cohorts of patients: 60mg split between d-2 and d-1 (n=26, median follow-up 15mo); 40mg split between d-2 and d-1 (n=27, 9mo); 30mg d-1 (n=28, 4mo). 91/99 patients recruited to the 2 studies are evaluable. Median age is 50yr (range 18–64). Diagnoses were AML/ALL n=25, CLL n=12, NHL n=30, Hodgkins n=12, myeloma n=11, MDS n=1. 80.6% of patients had advanced disease at the time of transplantation. No significant differences were identified in patient characteristics between each study/cohort. Study 1 (60mg total, split d-8 and d-7) OS, PFS at 1 year and 100d TRM were 89%, 72% and 0% respectively. Cumulative incidences of acute GVHD II-IV and chronic GVHD were 28% and 17% respectively. All patients engrafted and 77% were full donor chimeras. In study 2, cohort 1 (60mg total, split d-2 and -1), OS, PFS at 1 year and 100d TRM were 84%, 57% and 4% respectively. Cumulative incidences of acute GVHD II-IV and chonic GVHD were 0% (p<0.005 versus study 1) and 14% respectively. All patients engrafted but only 18% of patients in this cohort were full chimeras (p<0.01 versus study 1). No differences in the cumulative incidences of CMV reactivation were observed (33% vs. 43%). Subsequent total dose reductions to 40mg and 30mg Alemtuzumab in cohorts 2 and 3 have shown no significant changes in the 100d TRM (3.7% and 0% respectively) or the incidence of acute GVHD (12% and 5% respectively). We conclude that significant de-escalation of the Alemtuzumab dose following HLA-identical sibling transplantation is feasible without increasing the toxicity of the procedure. However, there is a higher rate of acute GVHD if the antibody is administered 7–8d compared to 24–48h prior to stem cell infusion.