Session: 637. Myelodysplastic Syndromes: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Acute Myeloid Malignancies, AML, MDS, Adult, Research, APL, Clinical Research, Genomics, Chronic Myeloid Malignancies, Diseases, Therapy sequence, Patient-reported outcomes, Treatment Considerations, Myeloid Malignancies, Biological Processes, Molecular biology, Study Population, Human
Method: This multi-institution study assessed the prevalence of PGVs in 341 patients with HM. Genomic DNA was extracted from germline samples, including hair-root DNA, mesenchymal stromal cells, skin fibroblasts, or peripheral blood T lymphocytes.
Results: PGVs were identified in 23.5% (n=80) of 341 HM patients compared to 4% and 3% of patients with single non-hematological cancer and age-matched controls, respectively (P <0.0001). The median age at diagnosis was not different in HM patients with or without PGVs (65.5 vs. 61 years; P=0.05), and PGV frequencies were 26.9%, 27.6%, 24.4%, and 16.5% in patients aged ≤50, 51–59, 60–69, and ≥70 years (P=0.22), respectively.
Of the 83 PGVs identified, DDX41 (n=13, 15.7%), CHEK2 (n=9, 10.8%), BRCA1 (n=6, 7.2%) and GATA2 (n=5, 6%) were the most frequent. Half of all PGVs were in genes involved in DNA damage repair (DDR) pathways (n=43, 51.8%), followed by PGVs in DDX41 (n=13, 15.7%), and transcription factors (n=11, 13.3%). Interestingly, there were no DDX41 variants in patients diagnosed ≤50 years of age (n=85), however, this population had the highest frequency of PGVs in transcription factors (n=7, 30.4%; P=0.053). Patients ≥70 years of age had PGVs primarily in DDR pathways (n=7, 43.8%) and DDX41 (n=4, 25%). Although the majority of PGVs were distributed evenly across genders, the frequency of DDX41 PGVs was higher in men than women (25% vs. 3.1%; P=0.008).
We further analyzed the distribution of PGVs across different HM subtypes, including primary MN (P-MN; n=92), multiple cancers including at least one HM (n=236), and bone marrow failure (BMF; n=13). Among the patients with ≥2 cancers, with at least one HM, 55 (23.3%) did not receive cytotoxic therapy (CT) prior to HM (MC-HM), while 181 patients (19%) did receive CT prior to HM diagnosis (CT-HM).
The frequency of PGVs did not differ between patients with P-MN and those with MC-HM or CT-HM (30% vs. 19.9%, P=0.056). The relatively high frequency of P-MN in our cohort is probably due to ascertainment bias, as P-MN patients were screened if they had family history, phenotypic features, or a younger age at presentation than expected, whereas patients with ≥2 cancers including HM were screened regardless of other features.
The PGV frequency was comparable between MC-HM and CT-HM (24% vs. 19%; P=0.43). However, the PGV pattern differed between the two groups. We observed striking enrichment of PGV in the DDR pathway of patients with CT-HM compared to those with MC-HM (70.6% vs. 38.5%; P=0.04). PGV in DDX41 (84.6% vs. 41.9%; P=0.002) and transcription factors (72.2% vs. 41.9%; P=0.43) were more prevalent in MC-HM compared to cases without PGV.
PGVs in the DDR pathway were associated with enrichment of complex karyotype (44.4% vs. 19%; P=0.003) and monosomal karyotype (37.0% vs. 13.9%; P=0.002), in addition to lower frequency of somatic ASXL1 somatic mutations (3.8% vs. 20.5%; P=0.04) compared to patients without PGV. DDX41 PGVs were associated with somatic DDX41 mutations (66.7% vs. 0.9%; P <0.001), and these cases were less likely to harbor complex karyotype (0.0% vs. 19.0%; P=0.08) compared to those without PGV.
Conclusion: The frequency of PGVs was higher in MN patients compared to other cancer patients and age-matched healthy controls. PGVs in the DDR pathway were highly prevalent in HM patients with prior exposure to cytotoxic therapies and were associated with poor-risk cytogenetic features. Our observation of a high frequency of PGVs in older MN patients warrants standardization of germline testing at diagnosis to guide optimal management of patients and their families.
Disclosures: Hiwase: Abbvie: Honoraria; Astella Pharma: Honoraria; Otsuka: Honoraria. Shanmuganathan: Novartis: Honoraria, Other: travel support, Research Funding; Janssen: Honoraria, Other: travel support; Takeda: Honoraria; Enliven: Other: travel support. Ross: Takeda: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Keros: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yeung: Ascentage: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; BMS: Research Funding; Amgen: Honoraria; Novartis: Honoraria, Research Funding.
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