Allogeneic Stem Cell Transplantation for MDS Patients More Than 70 Years of Age: a Retrospective Study of the MDS Subcommittee of the Chronic Malignancies Working Party (CMWP) of the EBMT
Authors: Heidenreich Silke , Ziagkos Dimitris , van Biezen Anja , Finke Jürgen , Platzbecker Uwe , Niederwieser Dietger , Einsele Hermann , Bethge Wolfgang A , Schleuning Michael , Beelen Dietrich W. , Tischer Johanna , Nagler Arnon , Glass Bertram , Maertens Johan , Richard Carlos , Beguin Yves , Sill Heinz , de Witte Theo , Robin Marie , Kroeger Nicolaus 
Published: October 2019

Abstract
Introduction
Myelodysplastic syndromes (MDS) are diagnosed at median age of 70 years. Allogeneic stem cell transplantation (HSCT) is the only curative treatment option, but with an increasing age, morbidity escalates. Treatment guidelines suggest HSCT for intermediate-II and high risk constellations up to the age of 65, and reduced intensity conditioning (RIC) regimens are commonly used up to 70 years of age. However, increasing life expectancy, availability of RIC regimens and good Karnofsky performance status (KPS) of MDS patients more than 70 years of age, has led to an increased use of HSCT. We performed a retrospective analysis to investigate results after HSCT for those patients and influence of KPS on outcome.
Patients and methods
We analyzed data of 345 patients in the EMBT database older than 70 years with MDS/sAML. The disease status at transplantation was available in 233 patients and most of the them were in more advanced stage of the disease: RA/RARS,RCMD (n=25) , RAEB (n=68) and RAEB-T/secondary acute leukemia (sAL, n=140). Donor were: related (n=88) and unrelated (n=257). Cytogenetic data were available only in 73 patients and classified as good (58), intermediate (6), poor (5) and very poor (4). Median follow up was 29.7 months. Median age at transplantation was 72 years (70-79 years) with 249 male and 96 female patients. KPS was defined in 300 cases, being 90-100% in 61% and 80% or less in 39%. Stem cell source was peripheral blood (94%) or bone marrow (6%). The intensity of the conditioning regimen was mainly reduced intensity (78%) rather than myeloablative (22%). Negative or positive CMV sero-status of the patient were seen in 35% and 65%, respectively.
Results
The number of HSCT for MDS patients of 70 years or more has increased over time. While 2000-2004 only 19 patients received transplantation, the following 3-year periods included 28 (2005-2007), 97 (2008-2010) and 200 (2011-2013) patients, respectively. The estimated 3-year OS was 33% (27-39%). A significant better 3 year OS in the univariate analysis was seen for Karnofsky (90-100%) vs 80% or less (41 vs 23%, p=0.008) and for CMV negative sero-status (46% vs 27%, p> <0.001) while disease status, remission status, intensity of the conditioning regimen, and donor source did not influence OS significantly. The cumulative incidence of relapse at 3 years was 40% (95% CI: 32-48) and significantly lower with unrelated than related donors (24% vs 43%, p =0.004). There was only a trend for a lower incidence of relapse after myeloablative conditioning in comparison to RIC (22% vs 31%, p=0.09), while remission status, T-cell depletion or disease stage did not influence the risk of relapse. The cumulative incidence of non-relapse mortality at 1 year was 36% (95% CI: 30-42) and significantly influenced by CMV sero-negativity of the recipient (22% vs 38%, p=0.02) and by Karnofsky index 90-100% (29% vs 34% and at 2 years: 32% vs 46%, p=0.01). A trend for lower NRM was seen for related donors (24% vs 35%, p=0.07) and after reduced intensity conditioning (29% vs 41%, p=0.09). No impact on NRM was seen for disease and remission status.
In a multivariate analysis (MVA) significant factor for improved OS was Karnofsky index of 90-100% (HR 0.65: 95% CI: 0.48-0.88, p=0.001) and for worse survival CMV sero-positivity (HR 1.61; 95% CI: 1.15-2.21, p<0.001). For relapse the only significant factor was the use of unrelated donors (HR 0.50; 95% CI: 0.32-0.80, p=0.004). Significant factors for NRM in the MVA were Karnofsky index 90-100% (HR 0.63; 95% CI: 0.42-0.96, p=0.03), CMV sero-positivity of the recipient (HR 1.76; 95% CI: 1.12-2.76, p=0.001) and unrelated donors (HR 1.67; 95% CI: 0.16-2.76, p=0.04).
Conclusion
HSCT from related or unrelated donor after myeloablative or dose reduced intensity conditioning for advanced MDS patients 70-years and more is a curative treatment option with a 3-year OS of 33%. Good performance, determined by KPS, and sero-negativity for CMV in the patient increase the 3 year estimated overall survival to 41 and 46%, respectively.

Disclosures
Platzbecker: Boehringer: Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Einsele:Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Tischer:Sanofi-Aventis: Other: advisory board. Nagler:Novaratis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. Glass:Roche, MSD, Takeda, Riemser, Ctilifesciences: Honoraria, Research Funding. Sill:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. de Witte:Novartis: Research Funding.