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7559 Background: Chronic myelomonocytic leukemia (CMML) has features of both a myeloproliferative neoplasm and a myelodysplastic syndrome. The median overall survival (OS) in most series is 20-40 months. CMML is a relatively rare entity, and there is limited understanding of prognostic molecular markers. CMML associated with bone marrow fibrosis grade 1, appear to have shorter progression free survival. In this study we investigated the correlation of mutations with bone marrow reticulin fibrosis in patients with CMML. Methods: We investigated a cohort of 41 consecutive patients diagnosed with CMML 0, 1, 2, and CMML-AML from 2014 to 2019 at our institute. The median age of 41 patients was 68 years (range, 34-82). 27% were females and 73% were males. This cohort consists of 8 (20%) patients with CMML0, 19 (46%) with CMML1, 8 (20%) with CMML2 and 6 (15%) with CMML-AML. Genomic DNA was extracted from the bone marrow aspirates and targeted mutation NGS libraries were prepared from 200 ng of genomic DNA using the SureSelect target enrichment system (Agilent Technologies Inc.). The gene panel consists of 73 genes focused on myeloid neoplasms. The data were curated on the basis of our molecular pathology and national databases. Additionally, clinical data and bone marrow (BM) reticulin fibrosis grades (n = 27 available) were retrieved from the patient’s medical record. Results: The mutational profile frequency in our cohort showed that the most common mutations were TET2 (31%), ASXL1 (31%), and SRSF2 (23%), with frequencies very similar to those reported in the literature. Of the 27 cases with an available reticulin stain, only low grade fibrosis (MF-0, n = 18. MF-1, n = 9) were identified in our cohort. The frequencies of mutations in ASXL1, U2AF1, TP53, JAK2 and RUNX1, positively correlated with low grade fibrosis (MF-1). Additionally, patients with higher frequencies of SRSF2, TET2, and SETBP1 mutations showed no fibrosis (MF-0). Conclusions: This study is the first to correlate the degree of fibrosis with the frequency of mutations in CMML. We found similar mutations spectrum reported in the literature in patients with CMML. The mutational profile associated with CMML cases appears to affect the degree of the bone marrow fibrosis at the time of diagnosis.

1509 Background: Clonal hematopoiesis (CH) in myeloid related-genes is associated with development of primary and secondary leukemia and atherosclerotic disease, as well as, decreased overall survival. Identification of factors beyond age and cytotoxic exposures that predispose to CH may be useful to both recognize individuals at increased risk for CH and to better understand how CH develops. We have previously shown that germline mutations in the DNA repair gene ATM may predispose to CH. We hypothesized here that heterozygous ATM germline mutation carriers would have higher rates of CH in myeloid genes compared to controls. Methods: Germline DNA samples from 34 heterozygous ATM germline mutation carriers (cases) and 22 controls without ATM germline mutations were sequenced on an Illumina 2500 using a custom 79-gene-myeloid-CH-coding-exon-amplicon-based Qiaseq panel. Read depth averaged 130x. Pathogenic and likely pathogenic CH variants (PV) above an allele fraction of 2% were used for analyses. Cases and controls were compared using a rank-sum test. Results: Cases had a higher median age (56 years, range 30-82) than controls (48 years, range 5-72). Cases and controls were similar in solid tumor cancer history and known exposure to cancer cytotoxic therapy; 73.5% vs 86.4%, and 18.1 vs 20.6%, respectively. The number of CH PV was similarly associated with age in both cases and controls (cor = 0.31, p = 0.01). Cases displayed more CH PVs than controls (total 62 vs 3 PVs, median 2 PVs vs 0, p = 10-6). Of note, cases frequently had a concomitant second (n = 10; 29% of cases) or third (n = 4; 11.8% of cases) unique ATM CH PV, whereas no ATM CH PVs were seen in controls. Even after excluding ATM CH PVs, CH PVs were more frequent in cases (p = 0.00003). After ATM CH PVs, the most frequent CH PVs in cases were in NF1 (5 PVs), BCORL1 (4 PVs), and DMNT3A (4 PVs). Conclusions: Our study supports ATM as a strong predisposition locus for myeloid gene CH. CH in ATM germline mutation carriers frequently involved unique low allele fraction PVs in ATM, suggesting ATM germline PVs are driving production of likely bi-allelic ATM inactivation in white blood cells, or complete ATM loss. Complete ATM loss may be a nidus particularly for lymphocytic leukemia, as bi-allelic ATM inactivation is a frequent somatic finding.

e23131Background: The O6-methylguanine methyltransferase (MGMT) is a DNA repair enzyme that is responsible for de-alkylation of naturally occurring O6-methylguanines in DNA and aids in the preventi...