Abstract

Abstract Introduction/Objective Myeloid neoplasms associated with DDX41 germline genetic alterations are becoming increasingly recognized as a unique subset of hematologic cancer predisposition syndromes. As such, we sought to review their clinicopathologic characteristics. Methods/Case Report We searched our next-generation sequencing database for cases with two DDX41 variants; one variant at heterozygous variant allele fraction (VAF) indicating known or putative germline status, and second variant at low VAF consistent with an acquired subclone. We reviewed the clinicopathologic features. Results (if a Case Study enter NA) We identified 18 cases - male:female ratio 2.6:1, average age at presentation, 69 years (range 57-89). The diagnoses included no diagnostic abnormality (3), MDS-MLD (1), MDS-EB1 (1), increased blasts only(5-19%) (7), and AML (6). All had anemia [average hemoglobin (10.2) (range 6.5-12.9 g/dL)], 17/18 with thrombocytopenia [average 87 (range 22-222 K)], 17/18 with neutropenia [average absolute neutrophil count (ANC) (819) (range 90-1800)] and 13/18 with macrocytosis [average (101.5) (range 83.7-114 fL)]. Bone marrow cellularity (corrected for increased blasts >20%) was predominantly hypocellular (11/19) followed by normocellular (5/19). 3/19 cases showed erythroid dysplasia; no cases demonstrated granulocytic dysplasia; 7/19 cases showed megakaryocytic dysplasia. Of non-AML cases, 8/12 cases showed increased blasts [average 10% (range 5-19%)]. Of 4 cases without an increase in blasts, 1 showed MDS, 2 no dysplasia [1 -ANC of 666 and preserved platelets (222); 2- thrombocytopenia with preserved ANC (1800)] and 1 had slight megakaryocytic atypia. 16/17 cases were karyotypically normal. 14/18 of the patients are alive (median follow-up, 48) (8-125 months). Conclusion This cohort finds that myeloid neoplasms arising from DDX41 germline predisposition syndrome tend to present in older individuals, have infrequent dysplasia and are associated with a prolonged clinical course despite elevated blast counts at diagnosis. Recognition of these disorders is challenging and DDX41 testing should be included as part of genetic profiling. The presence of a suspected DDX41 germline variant may prompt confirmatory and familial testing, particularly in the event a hematopoietic transplant is a treatment option.

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