Outcome after Allogeneic Stem Cell Transplant in Adults with Inherited Myeloid Malignancies - a Multicenter Retrospective Analysis on Behalf of the German Cooperative Transplant Study Group
Authors: Lohmann Tim , Stelljes Matthias , Pabst Caroline , Klein Stefan , Tischer Johanna , Fraccaroli Alessia , Ruhnke Leo , Groneck Laura , Denk Alexander , Stölzel Friedrich , Wolff Daniel , Schaffrath Judith , Beier Fabian , Hanoun Maher , Schetelig Johannes , Bornhäuser Martin , Schneider Artur , Reinhardt Hans Christian , Rautenberg Christina , Schroeder Thomas 
Published: December 2024

Background: The application of novel sequencing techniques has facilitated the recognition that pathogenic germ line variants drive the development of myeloid neoplasms also in a relevant proportion of adult patients. These patients with hereditary myeloid malignancies (HMMs) receive similar standard therapies including allogeneic stem cell transplantation (allo-SCT) as those with sporadic disease. Still, the evidence from the literature about the management of such adult patients with HMMs in the context of allo-SCT and their post-transplant outcome is restricted to one multicenter analysis (Saygin et al. Blood Advances, 2022) and smaller case series often focusing on germline variants in a specific gene. To expand this evidence, we ask centers participating in the German Cooperative Transplant Study Group to report their transplant experience in adult patients with HMMs.
Methods: We performed a retrospective analysis of adult patients with confirmed HMMs, who received a first allo-SCT at 11 German transplant centers. Patients', disease- and transplant-related data including information on the specific germline variant, method and tissue source of detection as well as family history were collected together with post-transplant outcome data.
Results: Overall, we identified 38 patients with HMMs, who received an allo-SCT from a matched (n=24, 63%) or mismatched unrelated (n=8, 21%), related (n=3, 8%) or haploidentical (n=3, 8%) donor following standard-dose (n=6, 16 %) or reduced-intensity conditioning (n=32, 84%) between 2005 and 2024. The majority of patients suffered from an AML (n=26, 68%), while 11 (29%) and 1 (3%) patients suffered from MDS or MPN, respectively. Among AML and MDS patients, 74% were stratified as adverse or high/very high risk according to ELN 2022 or IPSS-R. Overall, in 9 patients the disease (24%) was classified as therapy-related myeloid neoplasm and 42% had a first degree relative with a cancer history. In 19 patients (50%) a deleterious DDX41 germline variant was present, while in the other 19 patients (50%) germline variants in several other genes known to be associated with HMMs (GATA-2 n=4, RUNX1 n=3, NF1 n=2, TP53 n=2, BRCA1 n=2, BRCA2n=2, TET2 n=1, SBDS n=1, TERC n=1, PALB2 n=1) were found. In those with available information (n=31, 82%), the germline origin of these variants was confirmed by investigation of buccal swabs (n=13, 42%), nails (n=8, 26%), saliva (n=4,13%), hematopoietic tissue (n=4, 13%) or hair follicles (n=2, 6%) and 70% of patients received genetic counselling. With a median follow-up of 14 months, the estimated 2-year overall survival (OS), non-relapse mortality (NRM) and cumulative incidence of relapse (CIR) rate of the entire cohort were 59%, 19% and 23% respectively. Engraftment of neutrophils and platelets was observed in 100% and 97% both in median after 14 days, while incidences of acute and chronic GvHD were 42% and 28%, respectively. As expected, patients carrying DDX41 mutations were significantly older than patients with other HMMs (64 vs. 44 years, p&lt;0.0001), but did not differ with regard to other patient-, disease- and transplant-related characteristics. Despite these similiarities, the 2-year OS rate of DDX41 mutated patients was substantially higher than of those patients with other HMMs (87% vs. 44%, p=.057). This survival advantage was not related to differences in NRM (DDX41 14% vs. others 18% at 2 years, p=.997), but to a significantly lower CIR (0% vs. 42% at 2 years, p=.047). Only one patient with DDX1 mutation ‘relapsed’ as donor cell leukemia at month 27 after transplant.
Conclusion: These data advocate for further standardization of peri-transplant management and reporting of patients with HMMs undergoing allo-SCT in the future. Furthermore, our analysis suggests that among patients with HMMs those with DDX41 mutations seem to have low relapse rates and excellent outcome after allo-SCT, but this requires confirmation in larger data sets.