Investigating Myeloid Neoplasms in the Era of Precision Oncology

PATHCHAT Edition No. 79
Published: June 2022
Please contact your local Ampath pathologist for more information.

Author:

• Dr. Janin Alant

Introduction: The Role of Genomics in Myeloid Neoplasms

✅ Advances in Molecular Diagnostics

• Next-generation sequencing (NGS) has revolutionized the understanding of myeloid neoplasms.
• Genomic profiling reveals significant mutational overlap between myeloid disorders.
• Many myeloid neoplasms may represent different evolutionary phases of the same disease.

✅ Impact on Diagnosis & Prognosis

• The 2016 WHO classification emphasizes genetic testing in myeloid malignancies.
• Prognostic models like the 2017 European Leukaemia Net (ELN) Guidelines incorporate molecular markers.
• Targeted therapies, such as imatinib for chronic myeloid leukaemia (CML), have drastically improved patient outcomes.

📌 Comprehensive genomic profiling is now central to diagnosing, classifying, and risk-stratifying myeloid neoplasms.

Oncomine™ Myeloid Assay GX (OMAGEN) at Ampath

✅ What is OMAGEN?

• A targeted next-generation sequencing (NGS) assay designed to analyze myeloid malignancies.
• Simultaneously detects various clinically relevant mutations and fusions.

📌 The OMAGEN panel provides a streamlined approach to diagnosing and managing myeloid neoplasms.

Myeloid Neoplasms Diagnosed Using the OMAGEN Panel

1. Acute Myeloid Leukaemia (AML)

✅ Molecular Subtypes Detected:

• AML with RUNX1-RUNX1T1 [t(8;21)].
• AML with CBFB-MYH11 [inv(16) or t(16;16)].
• APL with PML-RARA.
• AML with KMT2A-MLLT3 [t(9;11)].
• AML with DEK-NUP214 [t(6;9)].
• AML with GATA2-MECOM [inv(3) or t(3;3)].
• AML (megakaryoblastic) with RBM15-MKL1 [t(1;22)].
• AML with mutated NPM1 or biallelic CEBPA mutation.
• Provisional AML subtypes with BCR-ABL1 and mutated RUNX1.

✅ AML Risk Stratification Based on ELN Guidelines:

• Favourable risk: RUNX1-RUNX1T1, CBFB-MYH11, NPM1 mutations (without FLT3-ITD), biallelic CEBPA mutations.
• Intermediate risk: NPM1 mutations with FLT3-ITD high, wild-type NPM1 with FLT3-ITD low, certain cytogenetic abnormalities.
• Adverse risk: DEK-NUP214, KMT2A rearrangements, BCR-ABL1, MECOM rearrangements, TP53 mutations, complex karyotypes.

📌 AML subtypes and risk stratification guide targeted therapy decisions and prognosis assessment.

2. Chronic Myeloid Leukaemia (CML)

✅ BCR-ABL1 Fusion Detection:

• Detection of 18 different BCR-ABL1 fusion transcripts, including p210, p190, and p230.
• Differentiates between various fusion types to tailor treatment strategies.

✅ Tyrosine Kinase Inhibitor (TKI) Resistance Mutations:

• ABL1 sequencing detects resistance mutations that influence TKI therapy selection.
• Key resistance mutations include T315I (resistant to multiple TKIs), Y253H (resistant to nilotinib), and F317L/V (resistant to dasatinib).

📌 The OMAGEN panel aids in both CML diagnosis and treatment monitoring.

3. Myeloproliferative Neoplasms (MPNs)

✅ Key Driver Mutations in MPNs:

• JAK2 V617F (common in polycythaemia vera, primary myelofibrosis, essential thrombocythaemia).
• MPL and CALR mutations (associated with JAK2-negative MPNs).
• BCR-ABL1 rearrangement exclusion (necessary to differentiate MPNs from CML).

✅ Comprehensive MPN Testing with OMAGEN:

• Simultaneously detects all key driver mutations in a single test.
• Identifies additional mutations that indicate disease clonality in triple-negative MPNs.

📌 OMAGEN improves diagnostic accuracy and speeds up treatment decisions in MPNs.

4. Clonal Eosinophilias

✅ Genetic Abnormalities Linked to Clonal Eosinophilia:

• PDGFRA, PDGFRB, FGFR1, and JAK2 rearrangements.
• AML with CBFB-MYH11 and systemic mastocytosis may also present with eosinophilia.

📌 The OMAGEN panel identifies primary eosinophilic neoplasms and distinguishes them from reactive causes.

5. Clonal Cytopenias & Myelodysplastic Syndromes (MDS)

✅ Genetic Testing for Clonal Cytopenias:

• Identifies clonal cytopenias of uncertain significance (CCUS).
• Detects mutations in >50 genes associated with MDS.
• Excludes CHIP (clonal haematopoiesis of indeterminate potential).

📌 Early detection of MDS-related mutations allows for better patient monitoring and treatment planning.

6. Myeloid Neoplasms with Germline Predisposition

✅ Germline Mutations Detected in Myeloid Neoplasms:

• CEBPA, DDX41, RUNX1, ANKRD26, ETV6, GATA2, TP53.
• Recognition of inherited predisposition syndromes enables genetic counselling for affected families.

📌 Germline mutation screening helps distinguish inherited haematological disorders from sporadic cases.

Conclusion: The Future of Myeloid Genomic Testing

✅ Why Choose OMAGEN?

• Comprehensive NGS-based myeloid genetic testing in a single assay.
• Simultaneous detection of mutations, fusions, and resistance variants.
• Improves diagnostic accuracy, prognostication, and treatment planning.
• Faster turnaround times compared to sequential genetic testing.

📌 The OMAGEN panel represents a major advancement in myeloid neoplasm diagnostics, aligning with modern precision oncology strategies.

Contact Information for Myeloid NGS Testing

✅ For More Information:

• NGS Laboratory: ngs@ampath.co.za
• Genetic Counselling Appointments: geneticsclinic@ampath.co.za
• Phone: 012 678 0645

📌 Ampath provides cutting-edge molecular oncology services to enhance myeloid neoplasm diagnosis and management.