Allogeneic Hematopoietic Cell Transplant Recipients Carrying DNMT3A and ASXL1 Mutations More Frequently Develop Severe Graft Versus Host Disease and Arterial Hypertension
Authors: Weiss-Haug Alisha , Haraszti Reka A , Merz Britta , Reuss Kristina , Faul Christoph , Bethge Wolfgang Andreas , Schwartz Frederike , Vogel Wichard , Lengerke Claudia 
Published: December 2023

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is defined as the presence of an expanded blood-cell clone due to acquired somatic mutations in hematopoietic stem cells without evidence of hematologic malignancy, dysplasia or cytopenia. CHIP associates with an increased risk of hematologic malignancies, as well as a pro-inflammatory state and an increased risk for cardiovascular disease. Inflammation furthermore plays crucial roles in the pathogenesis of arterial hypertension (aHTN), which we thus hypothesized may be also induced by CHIP. The epigenetic regulators DNMT3a and ASXL1 count to the most commonly mutated genes in CHIP. While donor CHIP mutations were previously associated with an increased risk for acute Graft versus Host Disease (GVHD), we here report that patients with DNMT3A or ASXL1 mutations in pre-transplant samples also show an enhanced risk for the development of severe (stadium III/IV and systemically treated) GvHD as well as arterial hypertension (aHTN).

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&lt;0.05; severe GvHD: 28/61, 46% vs. 12/47, 25.5%, p&lt;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&lt;0.05). The frequency of severe GvHD was significantly higher in both DNMT3A (17/35, 48.6%, p&lt;0.05) and ASXL1 mutation carriers (16/32, 50%, p&lt;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&lt;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&lt;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.