Session: 722. Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Poster II
Hematology Disease Topics & Pathways:
MDS, Biological therapies, Acute Myeloid Malignancies, AML, adult, MPN, CHIP, CML, CMML, Chronic Myeloid Malignancies, Diseases, immunology, Therapies, Biological Processes, Myeloid Malignancies, molecular biology, Study Population, Human, Transplantation
Methods: We retrospectively analyzed a cohort of 129 patients with myeloid malignancies (74 AML, 25 MDS, 5 CMML, 25 MPN) treated with allo-HCT at our University Hospital between January 2020 and April 2023. Next generation sequencing data performed on bone marrow samples collected maximum one month prior to allo-HCT were analyzed and correlated with the prevalence of pre-transplant diagnosed aHTN (n=129 analyzed patients) and the development of post-transplant GvHD at 3 months post-allo-HCT (n=108 analyzed patients).
Results: DNMT3A and/or ASXL1 mutations were surprisingly common and detected in 78/129 patients (61%), (DNMT3A-mutations: 42/129, 33%; ASXL1-mutations: 44/129 (34%); double mutations: 8/129, 6%). Patients with pre-transplant detectable DNMT3A/ASXL1 mutations in the bone marrow showed an increased risk to develop GvHD within 3 months post-transplant and more frequently showed severe GvHD (28/61, 46%) vs. patients with no detectable DNMT3A or ASXL1 mutations (overall GvHD: 34/61, 56% vs. 16/47, 34%, p<0.05; severe GvHD: 28/61, 46% vs. 12/47, 25.5%, p<0.05). Broken down to single mutations: DNMT3A mutation carriers showed a tendency for increased overall GvHD incidence when compared to patients with no detectable DNMT3A or ASXL1 mutations (19/35, 54,3%, versus 12/47, 25.5%, p=0.07), whereas ASXL1 mutation carriers showed significantly higher overall GvHD incidence compared to patients with no detectable DNMT3A or ASXL1 mutations (19/32, 59,4%, vs. 16/47, 34% , p<0.05). The frequency of severe GvHD was significantly higher in both DNMT3A (17/35, 48.6%, p<0.05) and ASXL1 mutation carriers (16/32, 50%, p<0.05) when compared to patients with no detectable DNMT3A or ASXL1 mutations(12/47, 25.5%).
DNMT3A/ASXL1-mutation carriers had more frequently arterial hypertension compared to patients with no detectable DNMT3A or ASXL1 mutations(54/78, 69% vs. 22/51, 43%, p<0.05). DNMT3A mutation carriers showed in 28/42 (66.7%) of cases aHTN, whereas ASXL1 mutation carriers showed in 32/44 (72.7%) of cases aHTN, and thus in both categories significantly (p<0.05) higher aHTN rates compared to patients with no detectable DNMT3A or ASXL1 mutations (22/51, 43% with aHT).
The presence of DNMT3A/ASXL1 mutations did not delay the time to the engraftment of neutrophils (25.1 vs. 20.5 days in DNMT3A/ASXL1 carriers compared to patients with no detectable DNMT3A or ASXL1 mutations, p=0.64) or thrombocytes (25.6 days vs. 22.6 days, p=0.89). Interestingly, the relapse rates were by trend lower in DNMT3A/ASXL1 carriers when compared to patients with no detectable DNMT3A or ASXL1 mutations in the pre-transplant bone marrow sample (19,1% vs. 28%, p=0.33), although higher numbers of patients need to be analyzed to ensure whether these effects are significant.
Conclusion: ASXL1 and DNMT3A mutations are commonly documented in patients with myeloid malignancies undergoing allo-HCT, and associate with increased rates of severe acute GvHD and pre-transplant arterial hypertension, but perhaps with lower relapse probability in the post-transplant setting. The biologic mechanisms underlying these observations are under further investigation. An extended follow-up of these patients shall be presented at the meeting.
Disclosures: No relevant conflicts of interest to declare.