Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Children and Adolescents with GATA2-Related Myelodysplastic Syndrome
Authors: Bortnick Rachel , Wlodarski Marcin , de Haas Valerie , De Moerloose Barbara , Dworzak Michael , Hasle Henrik , Masetti Riccardo , Stary Jan , Turkiewicz Dominik , Ussowicz Marek , Albert Michael H. , Bader Peter , Bordon Victoria , Claviez Alexander , Kremens Bernhard , Kühl Jörn Sven , Lankester Arjan C. , Müller Ingo , Pichler Herbert , Sedlacek Petr , Sykora Karl-Walter , Zecca Marco , Göhring Gudrun , Locatelli Franco , Noellke Peter , Niemeyer Charlotte M. , Strahm Brigitte 
Published: November 2019

Background
GATA2 deficiency is an inherited immunodeficiency and predisposition syndrome with a high risk of developing myelodysplastic syndrome (MDS) early in life. Allogeneic hematopoietic stem cell transplantation (HSCT) is presently the only curative therapy for affected patients (pts), but to date there has been no larger study examining in detail outcomes after HSCT for GATA2-related pediatric MDS. Here we report the results of an analysis of pts with a germline GATA2 mutation undergoing HSCT for a diagnosis of MDS enrolled in the registry of the European Working Group of MDS in Childhood (EWOG-MDS).
Patients and transplantation procedure
Of the 87 pts with GATA2 deficiency registered before the age of 18 years, 66 underwent HSCT between 01/1997 and 11/2018. One pt had to be excluded from the analysis due to lack of data. The 65 remaining pts (34 males/31 females) were transplanted at a median age of 13.5 (4.6-19.9) years. Twenty-seven pts were transplanted for refractory cytopenia of childhood (RCC), while 38 pts had advanced disease. The highest bone marrow (BM) blast percentage prior to HSCT was 5-19% (n=23), 20-29% (n= 9) or >30% blasts (n=5); in one pt with myelofibrotic MDS a blast count was not attainable. Karyotypes included monosomy 7 (n=44), der (1;7) (n=4), trisomy 8 (n=4), random aberration (n=1) or a normal karyotype (n=12). Five of the 38 pts with an increased blast percentage had received intensive AML-type therapy prior to HSCT. Pts were grafted from a matched sibling donor (MSD; n=17), unrelated donor (UD; n=40) or a mismatched family donor (MMFD; n=8). The stem cell source was BM (n=37), peripheral blood (n=27) or cord blood (n=1). Pts were prepared with a busulfan-based (n=35), treosulfan-based (n=21), total body irradiation-based (n=5) or an alternative conditioning regimen (n=4).
Results
At 5 years the probability of overall survival (pOS) and disease-free survival (DFS) was 0.74 [0.62-0.86] and 0.69 [0.57-0.81], respectively, non-relapse mortality was 0.15 [0.08-0.27] and the cumulative incidence of relapse was 0.16 [0.09-0.29]. All pts engrafted initially. The cumulative incidence of acute graft versus host disease (GVHD) grade II-IV and III-IV was 0.34 [0.24-0.48] and 0.12 [0.06-0.24], respectively, and of overall and extensive chronic GVHD 0.25 [0.16-0.39] and 0.08 [0.03-0.20]. The most common post-transplant infections were viral (39 of the 43 pts with infections) with one pt each with EBV-related post-transplant lymphoproliferative disease and primary CMV disease. There were no mycobacterial infections. The most common non-infectious complications were hepatobiliary (13 pts, including 3 with veno-occlusive disease) and pulmonary (10 pts, 5 of whom had been prepared with a busulfan-based conditioning regimen).
Pts with >20% BM blasts showed a trend towards a poorer DFS (0.52 [0.24-0.80]) compared to pts with 5-19% blasts (0.72 [0.53-0.91]) or pts with RCC (0.80 [0.64-0.96]; p=0.15). Examining the influence of karyotype in pts with RCC, there were a total of 2 relapses and 3 deaths (1 after relapse) among the 12 pts with monosomy 7, while there was one event among the 15 RCC pts with a normal karyotype (n=10, 1 death), trisomy 8 (n=3), der (1;7) (n=1) or random aberration (n=1).
Limiting the analysis to 9/10 or 10/10 HLA matched-donors, DFS was comparable for pts transplanted from an UD (0.73 [0.55-0.91]) versus a MSD (0.82 [0.64-1.00]). Of the 8 pts transplanted from a MMFD, one patient died after secondary graft failure. No major difference in outcome was seen according to age at HSCT, gender, time from diagnosis to HSCT or stem cell source. Of the five pts who had received AML-type therapy prior to HSCT, three died of a transplant-related cause or relapse.
Conclusions and perspectives
In summary, HSCT resulted in a pOS of 0.74 in this cohort of children and adolescents with GATA2 deficiency and MDS. Pts with increased blasts had a tendency towards poorer outcomes. The high risk of developing advanced MDS and the better outcome in early stages of the disease indicates that HSCT should be performed early in the clinical course of children diagnosed with GATA2 deficiency and MDS. Of note, there was no indication of excessive toxicity, disease-associated comorbidities or an increased risk of GVHD. The HSCT outcomes of children and adolescents with MDS and GATA2 deficiency are similar to what has been previously published for pts transplanted for MDS in the absence of GATA2 germline disease.

Disclosures
Bader: Amgen (Brasil), Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy; Medac: Patents & Royalties, Research Funding; Riemser, Neovii: Research Funding. Locatelli:Miltenyi: Honoraria; bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees. Niemeyer:Celgene: Consultancy.