Second Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome
Authors: Hartwig Maite , Ocheni Sunday , Kröger Nikolaus , Zabelina Tatjana , Klyuchnikov Evgeny , Asenova Svetlana , Kabisch Hartmut , Erttmann Rudolf , Zander Axel R. , Bacher Ulrike 
Published: April 2020

Abstract
Introduction: In acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), relapse after allogeneic stem cell transplantation (SCT) occurs with frequencies of 30–80% in dependence on risk profiles. Selected patients are offered a 2. allo-SCT. As the number of studies is limited, we here performed retrospective analysis of 20 consecutive MDS and AML pts who received at least 2 allografts from related/unrelated donors from 2000–2007. Patients: There were 4 children and 16 adults who received ≥2 allo-SCTs (10 males, 10 females; 2–63 years, median 38 yy). 14 pts had de novo AML, 3 pts s-AML, 2 MDS RAEB-1; one child had juvenile myelomonocytic leukemia (JMML). 19 pts received two allo-SCTs-18 due to another relapse after the 1. allo-SCT, one due to secondary graft failure after 1. SCT. One pt with MDS had 3 allo-SCTs due to relapses. 13/20 pts received treatment before the 2. allo-SCT, but only 6/20 achieved complete remission (CR). 10/20 pts had unfavorable cytogenetics. The median interval between the 1. and 2. allo-SCTs was 20 months (range 2–47 mo). Median disease free survival (DFS) after the 1. SCT was 16 months (range 3–45 mo). Characterization of 2. allo-SCTs: 4/20 second allo-SCTs were performed from related donors (3 HLA-identical, one haploidentical). 16 SCTs were performed from unrelated donors (HLA matched: n= 8, -mismatched: n=8). In 10 cases, the 2. allo-SCTs was performed from different, in 10 cases from the same donor. Reduced intensity conditioning was applied to 16 pts, myeloablative to 4 pts. Antithymocyte globuline was administered to 12/20 pts. One pt received bone marrow, 19 pts peripheral blood stem cells. Immunosuppression was performed in most pts by cyclosporine A plus short-course MTX or mycophenolate mofetil. Outcomes: Leukocyte engraftment was achieved in 16/20 cases with a median interval of 13 days (r. 10–24 d). 3 pts died prior to engraftment. One pt had secondary graft failure being followed by a 2. allo-SCT. CR was achieved by 16/20 pts. At the time of this report, 5/20 pts are still alive after a median follow-up of 15 months (r. 2–36 mo), three of those in CR with follow-ups of 7, 22, and 36 months. 9/20 pts developed relapse (45%), of whom 2 received donor lymphocytes. Median DFS after the 2. SCT was 7 months (range &lt;1–38 mo). One patient received a 3. allo-SCT after another relapse of AML, but died 8 months after 3rd SCT due to treatment related mortality (TRM). The TRM rate was 7/20 pts (35%) either due to sepsis and multiorgan failure, fungal pneumonia, or acute GvHD. AGvHD (II–IV) was described in 11/20 pts (55%). Chronic GvHD developed in 5/20 pts. Two of those 3 pts, who remained in stable CR, had unfavorable karyotypes. They had developed relapse after 3, 28, and 45 months following the 1. SCT. Two achieved CR before the 2. allo-SCT. In two cases, HLA-mismatched SCTs were performed being followed by extensive cGVHD. All had reduced conditioning before SCT. One of those, a male pt aged 16 years, primarily received no immunosuppression. Following severe intestinal aGvHD after 3 weeks tacrolimus and steroids were started. Discussion: Despite a high rate of reduced intensity conditioning, TRM (35%) and relapse rate were high (45%). However, single pts seemed to benefit from a 2. SCT, even in case of unfavourable karyotypes or when no complete remission was achieved before the 2. SCT, and here also in one case with an early relapse after the 1. SCT. Thus, it seems difficult to predict which patients might have a benefit from this approach. Research should focus on the optimization of conditioning regimens especially for recipients of a 2. SCT and try to provide concepts for immunosuppression in this specific situation due to the high relapse risk.