Patients with a sole del(20q) chromosomal abnormality and without morphologic features of a myeloid neoplasm (MN) have shown variable clinical outcomes. To explore the potential risk stratification markers in this group of patients, we evaluated their genetic mutational landscape by a 35-gene MN-focused next-generation sequencing (NGS) panel and examined the association of mutations to progression of MNs. Our study included 56 patients over a 10-year period with isolated del(20q), of whom 23 (41.1%) harbored at least one mutation. With a median follow-up of 32.6 months (range: 0.1−159.1), 9 of 23 patients with mutation(s) progressed to MNs, while all 33 patients without mutations did not progress to MN. Kaplan−Meier survival analysis demonstrated the presence of mutation(s) as a significant risk factor for progression to MN (P < 0.0001). MN progression was strongly associated with the presence of non-DNMT3A/TET2/ASXL1 epigenetic modifiers and nonspliceosome mutations (P = 0.003). There was no significant difference among patients with and without MN progression with respect to the number of mutations, variant allele frequency, percentage of del(20q), and other clinical/laboratory variables. This study illustrates the underlying genetic heterogeneity and complexity of isolated del(20q), and underscores the prognostic value of NGS mutational analysis in these cases.

DNMT3A mutations play a prominent role in clonal hematopoiesis and myeloid neoplasms with arginine (R)882 as a hotspot, however the clinical implications of R882 vs. non-R882 mutations in myeloid neoplasms like myelodysplastic syndrome (MDS) is unclear. By data mining with publicly accessible cancer genomics databases and a clinical genomic database from a tertiary medical institution, DNMT3A R882 mutations were found to be enriched in AML (53% of all DNMT3A mutations) but decreased in frequency in clonal hematopoiesis of indeterminate potential (CHIP) (10.6%) or other myeloid neoplasms including MDS (27%) (p&lt;.001). Next with the largest cohort of patients with DNMT3A R882 mutant MDS known to date from multiple institutions, DNMT3A R882 mutant MDS cases were shown to have more severe leukopenia, enriched SRSF2 and IDH2 mutations, increased cases with excess blasts (47% vs 22.5%, p=.004), markedly increased risk of AML transformation (25.8%, vs. 1.7%, p=.0001) and a worse progression-free survival (PFS) (median 20.3, vs. &gt;50 months, p=.009) than non-R882 mutant MDS cases. DNMT3A R882 mutation is an independent risk factor for worse PFS, and importantly the differences in the risk of AML transformation between R882 vs. non-R882 mutant patients cannot be explained by different treatment approaches. Interestingly the higher risk of AML transformation and the worse PFS in DNMT3A R882 mutant MDS cases are mitigated by coexisting SF3B1 or SRSF2 mutations. The unique clinicopathologic features of DNMT3A R882 mutant MDS shed light on the prognostic and therapeutic implications of DNMT3A R882 mutations.

Multinucleated megakaryocytes (≥25%) as an isolated finding in the bone marrow are a rare phenomenon. These patients do not appear to be at increased risk of developing progressive cytopenia(s) or MDS. Caution should be taken to not overdiagnose these cases as MDS.

Deletion of the long arm of chromosome 20 (20q-) is a frequent finding in bone marrow karyotypes, mainly associated with myeloid neoplasms (MNs). Its clinical significance in the setting of normal bone marrow morphology is unclear. We described the clinical characteristics, cytogenetic findings, and outcome of 102 such patients seen at our institution from 2000-2014. Their median age was 66 years. The indication for bone marrow biopsy was either unexplained cytopenias (48%) or hematologic cancer staging/reevaluation (52%). In 88 (86%) patients, 20q-was an isolated finding. Thirty-nine (38%) patients previously received chemotherapy and 88 (86%) had cytopenias at the time of 20q-finding. After a median of 35 months, 12 (13%) patients developed MNs: 10 myelodysplastic syndromes, one acute myeloid leukemia and one myeloproliferative neoplasm. None of 14 patients with normal blood counts, but 7 of 35 (20%) with mild cytopenias, and 5 of 53 (9%) with moderate/ severe cytopenias developed MNs. We did not find an association between the number of metaphases with 20q-and the development of MN. The incidental finding of 20q-in the bone marrow generally does not portend an early stage MN. Particularly, those without cytopenias at the time of diagnosis may have a good prognosis.