Myeloid NGS Analyses of Paired Samples from Bone Marrow and Peripheral Blood Yield Concordant Results: A Prospective Cohort Analysis of the AGMT Study Group

Abstract

Background: Next generation sequencing (NGS) has become indispensable for diagnosis, risk stratification, prognostication, and monitoring of response in patients with myeloid neoplasias. Guidelines require bone marrow evaluations for the above, which are often not performed outside of clinical trials, indicating a need for surrogate samples. Methods: Myeloid NGS analyses (40 genes and 29 fusion drivers) of 240 consecutive, non-selected, prospectively collected, paired bone marrow/peripheral blood samples were compared. Findings: Very strong correlation (r = 0.91, p < 0.0001), high concordance (99.6%), sensitivity (98.8%), specificity (99.9%), positive predictive value (99.8%), and negative predictive value (99.6%) between NGS analyses of paired samples was observed. A total of 9/1321 (0.68%) detected mutations were discordant, 8 of which had a variant allele frequency (VAF) ≤ 3.7%. VAFs between peripheral blood and bone marrow samples were very strongly correlated in the total cohort (r = 0.93, p = 0.0001) and in subgroups without circulating blasts (r = 0.92, p < 0.0001) or with neutropenia (r = 0.88, p < 0.0001). There was a weak correlation between the VAF of a detected mutation and the blast count in either the peripheral blood (r = 0.19) or the bone marrow (r = 0.11). Interpretation: Peripheral blood samples can be used to molecularly classify and monitor myeloid neoplasms via NGS without loss of sensitivity/specificity, even in the absence of circulating blasts or in neutropenic patients.

Can O-GIcNAc Transferase (OGT) Complex Be Used as a Target for the Treatment of Hematological Malignancies?

“…OGT improves ASXL1 stability by inducing O -GlcNAcylation at the ASXL1 Ser199 site [ 127 ], while ASXL1 interacts with and activates BAP1 [ 66 ]. It is reported that ASXL1 is mutated in numerous myeloid malignancies, including MDS, AML, and CMML [ 128 , 129 ], and ASXL1 mutations have been shown to be positively associated with poor prognosis in patients with MDS and AML [ 130 , 131 ]. The ASXL1 mutation occurs at the C-terminus, generating a C-terminally truncated ASXL1 mutant [ 132 , 133 ], which retains the DEUBAD binding domain and facilitated the catalytic activity of BAP1 and promotes H2AK119ub1 deubiquitination, which in turn drives myeloid leukemogenesis [ 134 ].…”

Molecular responses in decitabine- and decitabine/venetoclax-treated patients with acute myeloid leukemia and myelodysplastic syndromes

“…Like others, we note high concordance between PB and BM mutation VAF. 5 , 18 , 19 In principle, PB collections can occur more often, allowing for a more granular analysis of response kinetics than BM. Also, PB avoids complications with hemodilute aspirates and collections are less likely to be declined or missed.…”