Next-generation sequencing for myeloid malignancies: Uncovering clinical gaps in physician knowledge and practice Free

Background Next-generation sequencing (NGS) is integral to the diagnosis, risk stratification, and treatment selection for patients with myeloid malignancies, with recommendations embedded in guidelines from the European LeukemiaNet (ELN) and National Comprehensive Cancer Network (NCCN). Despite its critical role, the extent to which specialist clinicians have uniformly incorporated NGS into practice is unclear. This activity was designed to quantify knowledge, confidence, and practice gaps related to incorporating NGS into practice among a global cohort of hematology/oncologists (hem/oncs) and pathologists.

Methods A 28-question, online, continuing medical education (CME) self-assessment was developed that included a range of demographic, knowledge, confidence and practice-based multiple-choice questions on NGS for myeloid malignancies. The activity was launched for oncologists and pathologists practicing globally in March 2025; data collected through August 2025.

Results At the time of analysis, 67 hem/oncs and 30 pathologists completed the assessment. The assessment revealed educational gaps regarding NGS in both foundational knowledge and its application in complex clinical scenarios, including:

• Foundational knowledge gaps: 33% of pathologists failed to identify that targeted NGS has greater specificity for genomic alterations than whole exome sequencing. In a knowledge-based question, 61% of hem/oncs and 67% of pathologists could not identify the optimal tissue source (cultured skin fibroblasts) to distinguish germline from somatic mutations.

• Diagnostic and guideline gaps: In a polycythemia vera case, 64% of hem/oncs and 63% of pathologists incorrectly believed a JAK2 mutation alone was sufficient for diagnosis, failing to identify the need for a bone marrow biopsy. Similarly, in an AML case, 45% of hem/oncs and 43% of pathologists failed to identify that a peripheral blood sample with 10% blasts was sufficient for NGS testing.

• Complex case interpretation (AML/MDS): In a case of AML with an FLT3 mutation, 43% of pathologists failed to identify the correct combination of biomarkers (FLT3 or IDH1) predictive for benefit from targeted therapy. For a patient with MDS, 31% of hem/oncs and 37% of pathologists could not identify RUNX1 and TP53 as the mutations that would most significantly elevate risk according to the IPSS-M algorithm.

• Complex case interpretation (CML): In a case with suboptimal response to treatment and evidence of progressive disease, 28% of Hem/Oncs and 40% of pathologists failed to identify NGS's primary role in detecting resistance mutations. For a patient with suspected atypical CML, 48% of Hem/Oncs and 40% of pathologists could not identify the diagnostic use of the SETBP1 mutation identified by NGS.

• Complex case interpretation (MPN): When asked to identify the three genes defining “triple-negative” primary myelofibrosis (PMF) in a case scenario, 28% of Hem/Oncs and 37% of pathologists answered incorrectly.

• Logistical and practice barriers: NGS testing pathways are fragmented; 33% of hem/oncs use a core facility in another institution, while pathologists are split between their own institution's lab (27%) and commercial labs (27%). Average turnaround time for NGS results exceeded 5 working days for 84% of hem/oncs and 80% of pathologists. This may contribute to inconsistent adoption, as 42% of hem/oncs but only 20% of pathologists reported that less than half of their patients undergo NGS analysis.

• Impact on confidence: The cumulative effect of these knowledge and clinical application gaps is low physician confidence. Only 43% of hem/oncs and 27% of pathologists were mostly/very confident in their ability to implement NGS findings to inform treatment of myeloid malignancies.

Conclusion The findings reveal critical and widespread educational gaps in the application of NGS for myeloid malignancies. Even among specialists, there are significant inconsistencies in foundational knowledge, confidence, interpretation of guidelines, and application to nuanced clinical cases. These challenges, compounded by logistical hurdles like fragmented testing pathways and prolonged turnaround time, suggest a clear and urgent need for targeted, case-based educational initiatives to standardize the use of NGS, improve adherence to guidelines, and ensure the optimal and equitable application of this technology for all patients with myeloid malignancies.