Long-Term Follow-up of Therapy-Related MDS and AML Patients Treated with Allogeneic Hematopoietic Cell Transplantation Reveals Substantial 10 Year Survival and Comparably Low Treatment-Related Mortality
Authors: Hackanson Björn , Schmoor Claudia , Bertz Hartmut , Marks Reinhard , Wäsch Ralph , Zeiser Robert , Finke Jürgen 
Published: October 2019

Abstract
Introduction: Cytotoxic agents and ionizing radiotherapy in the treatment concept of most cancer types and non-malignant diseases bear a significant risk to develop therapy-related malignancies such as myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML). The outcome of patients treated with low- or high-dose chemotherapy alone for t-MDS/AML remains poor. The only curative treatment option implements allogeneic hematopoietic stem cell transplantation (aHSCT). However, long-term follow-up data beyond 5 years of t-MDS/AML patients having received aHSCT is scarce.
Study cohort: Here we report on 79 patients (12 t-MDS, 67 t-AML) who received aHSCT between 1995 and 2014 at our institution. The median age was 58 years (range (r): 20-76) and time from primary disease (43 hematologic diseases, 29 solid tumors, 7 non-malignant) to t-MDS/AML was 6.6 years (r: 1.0-41.6). 19 (24.1%) patients were in complete remission (CR) prior to aHSCT. A busulfan/cyclophosphamide based myeloablative conditioning regimen was used in 21 (26.6%) patients while 58 (73.4%) patients received reduced-intensity conditioning (RIC; fludarabine/carmustine/melphalane or fludarabine/thiotepa). 71 (89.9%) patients received peripheral blood stem cells and 8 (10.1%) patients received bone marrow; a matched related donor (MRD) was available in 21 (26.6%), a matched unrelated donor (MUD) in 37 (46.8%) and a mismatched unrelated donor (MMUD) in 21 (26.6%) patients.
Results: 71 (89.9%) patients achieved a CR after transplantation. After a median follow-up of 7.5 years (r: 0.07-19.0), 26 (32.9%) patients were alive at the time of analysis (median follow-up: 5.8 years, 23 without relapse, 3 with relapse), 30 patients had died after relapse, and 23 patients had died without previous relapse. Treatment related mortality (TRM) and relapse rate were 16% (95% confidence interval (CI), 9-26%) and 33% (24-46%) at 1 year, 23% (15-35%) and 42% (32-55%) at 5 years, and 32% (22-46%) and 44% (34-57%) at 10 years, respectively. The causes of death were relapse (42.3%), infections (21.2%), organ failure (13.5%), primary malignancy (5.8%), tertiary malignancy (5.8%), chronic graft-versus-host disease (3.8%), central nervous system complications (3.8%) and two unknown. Disease-free survival (DFS) and overall survival (OS) were 51% (39-62%) and 67% (55-77%) at 1 year, 35% (24-46%) and 38% (27-49%) at 5 years and 24% (14-36%) and 24% (13-36%) at 10 years, respectively. In exploratory univariate analyses, no negative impact of patient age, status of remission prior to aHSCT or donor (MRD versus MUD and MMUD), on DFS or OS with p<0.1 could be detected. However, reduced performance status (≤80%) measured by Karnofsky-Index and serum lactate dehydrogenase (LDH) levels above 300 U/l prior to aHSCT were associated with a reduced (p<0.1) DFS (p=0.059 and p=0.029, respectively) and OS (p=0.099 and 0.066, respectively).
Conclusion: Our data show that long-term survival after aHSCT is possible, even for refractory patients that are not in CR. The major reason of treatment failure was relapse while the TRM rate appeared comparably low with infections being the main obstacle. Thus, early donor search and rapid transplantation after diagnosis of t-MDS/AML are warranted, also to decrease the risk of disease-related deterioration of patients´ performance status.

Disclosures
No relevant conflicts of interest to declare.