Concordance/Discordance of Paired Sequencing of Bone Marrow Tissue and Myeloid Sarcoma Samples- a Meta-Analysis
Authors: Padmanabhan Dakshin , Aguilar Jeff , Dyson Gregory , Potluri Lakshmi Bhavani , Dhillon Vikram , Nanja Reddy Sushmitha , Maciejewski Jaroslaw P. , Balasubramanian Suresh Kumar 
Published: December 2023

Background:
Myeloid sarcoma (MS) is a rare architecture-effacing tumor comprising myeloid blasts outside the bone marrow. It can present concurrently with acute myeloid leukemia or can present without bone marrow involvement as isolated MS. In the era of next-generational sequencing (NGS), studies have been performed to compare the mutational profiles of MS tumor with paired bone marrow samples. Few studies have reported data pertaining to concordance or discordance between MS and bone marrow NGS somatic mutations. In this study, we analyzed all prior existing data to understand the distribution of mutations, the prevalence of concordance/discordance, and which mutations were commonly discordant; our working hypothesis was that clonal heterogeneity between MS and paired bone marrow samples may exist due to their differing biological niche and features. If differences were found, it would underscore the utility of performing paired NGS examination routinely on MS and bone marrow samples in clinical practice, especially in the context of the emerging realm of targeted therapies to specific mutations.
Methods:
A PubMed literature search using clinically relevant keywords and MeSH terms was performed to obtain articles pertaining to MS, with 1647 results generated. Studies were excluded or included based on the relevance and availability of paired MS-bone marrow NGS mutational profiles. After independent review, 9 studies were deemed relevant to our clinical question, and data were abstracted independently by 2 reviewers. It included clinical and demographic data and mutational distribution between the MS and bone marrow samples. The chi-square test was used for statistical analysis to compare differences in frequencies between bone marrow and MS and other categorical variables. Figures to represent the data were created with GraphPad Prism version 9.5.1 software. The systematic review and meta-analysis were registered in PROSPERO and application is under review with ID # 445255.
Results:
76 patients from nine studies were identified with available paired MS and bone marrow NGS data. 51 patients had complete clinical and demographic data. The mean age of the meta-analytic cohort was 52 ± 17.9 y, male: female ratio from available data was 1.83:1. 27/60 (45%) of patients had skin/soft tissue localization of MS, 22/73 (30.1%) patients had isolated MS, 29/73 (39%) had systemic MS, and 22/73 (30.1%) had secondary/relapse-related MS. Concordance of mutations was found in 41 (53.9%) of patients; discordance was noted in 35 (46.1%) of patients. NPM1 was the most observed mutation in the MS sample in 20 (26.3%) of patients; FLT3 was the most common mutation in the bone marrow sample in 11 (14.5%) of patients. NPM1 was also the most commonly discordant mutation found more in the MS sample than in the bone marrow sample (p=0.02; Figure 1). On further analyzing discordant mutations that occurred two or more times in the MS sample alone, after NPM1 (25.6% of mutations), the next most common discordant mutations were TP53 (16.3%), FLT3 (9.3%) and U2AF1 (9.30%) (Figure 2). Patients with discordant mutations were more likely to have myeloid sarcoma localized to a site other than skin or soft tissue (p=0.04).
Conclusion:
Discordant mutations are commonly seen in myeloid sarcoma when compared with paired bone marrow biopsy samples. NPM1 mutation discordance was the most enriched in the MS sample, followed by TP53. Discordance was associated with non-skin/soft tissue sites. It is apparent that discordance is noted in actionable genes in MS. Hence, paired NGS analysis should be done routinely in clinical practice as MS mutations may not be present in the bone marrow sample. Further studies into molecular discordance between MS and paired bone marrow samples should be conducted to better understand the clonal heterogeneity and the biology of extramedullary homing.