Outcome of Second Allogeneic Transplants Using Reduced Intensity Conditioning Following Relapse after an Initial Allogeneic Transplant.
Authors: Shaw B.E. , Mufti G.J. , Mackinnon S. , Cavenagh J. , Towlson K. , Pearce R. , Pagliuca A. , Apperley J. , Craddock C. , Kazmi M. , Littlewood T. , Milligan D. , Marks D. , Russell Nigel H. 
Published: October 2019

Abstract
The management of disease relapse following an allogeneic transplant is problematic. For patients with some diseases treatment with DLI alone can be successful. The use of a second allogeneic procedure has been associated with a prohibitively high TRM, especially when using myeloablative conditioning. Here we report the results of a British Society for Blood and Marrow Transplantation (BSBMT) registry retrospective multicentre analysis of 70 patients receiving a second allogeneic transplant using reduced intensity conditioning (RIC) after disease relapse following an initial allogeneic transplant. In 41 cases the first procedure was myeloablative and in 17 this was with RIC (unknown: 12). Over half of the first grafts were T cell depleted (TCD). The donor was an HLA identical sibling (48), unrelated (17) or other family member (2). In 11 cases a different donor was used at second transplant. The median age at first transplant was 39 (range: 8–69). The underlying diseases are as follows: AML 21, MDS 13, ALL 13, Lymphoma 11, CML 7, MPD 3, MM 2. For the second transplant, a variety of RIC regimens were used. Of these, 85% were fludarabine based and less than 20% include TCD. At the time of analysis, 27 patients were alive at a median follow-up of 1.7 years from second allograft (range: 0.3–7.4 years). In the cohort overall, the predicted overall survival and TRM at 2 years post second allograft were 27% and 27% respectively. Disease type was significantly associated with outcome (OS 1yr: lymphoma 82%, AML 32%, MDS 39%, ALL 41%, p=0.049). Age and disease status did not impact on OS or TRM. The median time to relapse after the first transplant was 1 year (range: 0.1–12.2). There was a significant survival advantage to those who relapsed more than a year post first allograft (2yr post second allograft: 33% vs 21%, p=0.038). In addition, patients with later relapses had a TRM of 12% at 2 years compared to 39% in those relapsing within a year (p=0.009). The incidence of acute GvHD was higher following the second procedure (43%) than the first (28%). Although aGvHD at any time did not impact on OS in the whole cohort, in those who relapsed prior to a year the presence of acute GvHD post second allograft was significantly associated with a superior outcome (p=0.001). The median time to relapse from the second transplant was 0.73 years (range = 0.1 – 1.6). The predicted relapse risk post second transplant was 52 % at 2 years. Those under the median age (p=0.029) and with acute leukaemia (1 yr post second transplant risk: AML 57%, MDS 34%, ALL 54%, lymphoma 14%; p=0.056) were at higher risk. Remission status prior to either transplant, acute or chronic GvHD post second allograft, donor type and time to first relapse did not impact significantly on relapse risk. In conclusion, compared to second myeloablative transplants, a second allograft using RIC can be performed with a low TRM in those relapsing more than one year after a first allograft, even when using UD. These patients achieved an encouraging OS of > 30% at 2 years. In those relapsing within a year of first transplant the development of GvHD was strongly associated with a better outcome.