Second Allogeneic Hematopoietic Stem Cell Transplantation for Relapse of Malignant Disease: Retrospective Analysis of Outcome and Predictive Factors
Authors: Ruutu Tapani , Brand Ronald , van Biezen Anja , Rocha Vanderson , Sureda Anna , Tichelli André , Einsele Hermann , Dini Giorgio , Bregni Marco , Garderet Laurent , Apperley Jane , Gratwohl Alois , Niederwieser Dietger , de Witte Theo 
Published: April 2020

Abstract
on behalf of the European Group for Blood and Marrow Transplantation (EBMT) and the European LeukemiaNet
A significant proportion of patients treated with allogeneic hematopoietic stem cell transplantation for a malignant disease suffer from a relapse of the disease after the transplantation. The best treatment approach in this situation is often unknown. In a retrospective analysis, all second allogeneic hematopoietic stem cell transplantations carried out for a relapse of malignant disease after the first transplantation at the centers of the European Group for Blood and Marrow Transplantation (EBMT) between 1994 and 2005 and reported to the EBMT registry (n = 1633) were analysed for outcome and predictive factors. The principal aim was to evaluate transplantation-related problems. The age of the patients was 1–71 (median 35) years. Five hundred and fifty-eight patients had primary AML, 366 ALL, 265 CML, 149 MDS, 73 lymphoma, 71 myeloproliferative disorder (including 41 MPS/MDS), 50 myeloma, 47 secondary acute leukemia, 28 CLL, and 26 other diagnosis. At the second transplantation, 23 % of the patients were in complete or partial remission or in chronic phase, 59% were in relapse or had resistant or progressive disease, and in 18% the data is missing. In the second transplantation the donor was HLA-identical sibling in 67 %, other related in 9 % and unrelated in 24 % of the cases. In 81 % the donor was the same as in the first transplantation. The conditioning was reported to be myeloablative (MAC) in 65 % and of reduced intensity (RIC) in 18 % of the transplantations, in 17% this data is missing. The graft was blood stem cells in 75 %, bone marrow in 23 %, a combination of these in 1 %, and cord blood in 1 %. Twenty-two per cent of the patients had had grade II–IV acute GvHD and 15 % chronic GvHD after the first transplantation. The overall survival in the whole group of patients was 39% at one year, 29 % at 2 years and 21 % at 5 years. The respective figures for the cumulative incidence of relapse were 39, 44, and 49%, those for non-relapse death 31, 35 and 37 %, and those for relapse-free survival 30, 21, and 14 %. In multivariate analysis, factors highly significantly associated with better survival were disease (chronic leukemias vs. other diagnoses), longer interval between first and second transplantation (&gt; 1year vs. &lt; 1 year), younger age, and the state of the disease (CR, CP or partial remission vs. others). Factors showing no significant independent association with overall survival were the occurrence of grade II-IV acute GvHD or chronic GvHD after the first transplantation, duration of remission after the first transplantation, conditioning at the second transplantation or any combination of conditioning intensity in the two transplantations (MAC – RIC), the type or donor, and whether the donor was the same as in the first transplantation or not. The main cause of death was relapse or disease progression in 52 %, GvHD in 17 %, infection in 11 %, organ damage or failure in 12 %, and other non-relapse cause in 8 %. There were no differences in non-relapse mortality between acute leukemias (AL), chronic leukemias (CL), myelodysplastic/myeloproliferative syndromes (MDS/MPD), and plasma cell dyscrasias/lymphomas/solid tumours. At 5 years, the cumulative incidence of relapse was 53 % in AL, 44 % in MDS/MPD and 35 % in CL. The relapse-free survivals were 9, 15, and 27 % and overall survivals 15, 18, and 40 %, respectively. As examples, among patients with AL not in CR, transplanted within one year from the first transplantation, the survival at one year was 14 %, whereas 54 % of patients with CL in CR/CP/partial remission transplanted more than one year from the first transplantation survived at 5 years. In conclusion, retransplantation offers a reasonable option especially for younger patients with a time interval of &gt; 1 year from the first transplantation and a disease responsive to reinduction.