Tag Archives: genetic testing

Genetic Testing Breakthroughs in Blood and Lymph Cancers

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February 28, 2025

Hematopoietic and lymphocytic neoplasms (HLNs) are a diverse group of malignancies affecting blood and lymphatic systems, with outcomes varying from manageable conditions to fatal diseases. Traditional classifications rely on morphology, karyotyping, and fluorescence in situ hybridization (FISH). However, recent advancements in next-generation sequencing (NGS) allow simultaneous genetic profiling of multiple genes, enhancing diagnostic precision and therapeutic strategies. This review examines key molecular applications in diagnosing and managing HLNs, addressing current challenges and proposing solutions to optimize clinical utility.

Chronic Myeloid Leukemia (CML)

CML, historically identified by leukocytosis, is characterized by the BCR::ABL1 fusion gene resulting from the Philadelphia chromosome translocation. This oncogenic fusion drives aberrant tyrosine kinase activity, promoting unchecked proliferation. The introduction of imatinib, a targeted tyrosine kinase inhibitor (TKI), revolutionized CML treatment, leading to normalized white blood cell (WBC) counts within months. However, resistance mutations necessitate molecular monitoring via quantitative PCR, FISH, and karyotyping, ensuring optimal therapeutic adjustments.

Molecular Applications in BCR::ABL1-Negative Myeloid Neoplasms

Certain myeloid neoplasms, such as chronic neutrophilic leukemia (CNL) and chronic eosinophilic leukemia (CEL), lack the BCR::ABL1 fusion gene but exhibit distinct genetic markers like CSF3R mutations in CNL. Classical myeloproliferative neoplasms (MPNs) include polycythemia vera, essential thrombocythemia, and primary myelofibrosis, driven by JAK2, MPL, or CALR mutations. The application of NGS enables comprehensive mutational profiling, aiding accurate diagnosis and prognostication.

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Genetics and Genetic Testing to Inform Myelofibrosis Clinical Management

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by Charles Bankhead, Senior Editor, MedPage Today May 1, 2024

The history of primary myelofibrosis dates back to 1951 and the description of four distinct clinicopathologic entitiesopens in a new tab or window that came to be known as myeloproliferative neoplasms (MPNs): chronic myeloid leukemia (CML), polycythemia vera, essential thrombocythemia, and myelofibrosis.

Discovery of the Philadelphia (Ph) chromosome in 1960opens in a new tab or window paved the way to identification of BCR/ABL as the principal genetic driver of CML. Another 45 years passed before the discovery of a first genetic driver of non-Ph MPNs, a mutation in the Janus kinase 2 (JAK2) gene,opens in a new tab or window which occurs in 50-60% of myelofibrosis cases.

“The identification of that particular pathway was foundational, and it has changed the face of how we treat patients,” said James Rossetti, DO, of the University of Pittsburgh. “The JAK2 mutation is not present in everyone with myelofibrosis, and there are other mutations as well.”

Researchers identified a third key driver in 2013opens in a new tab or window: calreticulin gene (CALR). The mutation is associated with about 25% of myelofibrosis cases.

Most studies have shown that JAK2, MPL, and CALR are mutually exclusiveopens in a new tab or window and do not occur together. However, a few studies have shown co-occurrence of the three key mutations. Even though JAK2, MPL, and CALR usually do not occur together, numerous other mutations have been identified in association with the three primary mutations. As many as 80% of patients with myelofibrosisopens in a new tab or window have one or more other mutations.

Historically, myelofibrosis treatment was palliative in nature, aimed at relieving specific symptoms. The discovery of the JAK2 driver mutation has transformed treatment. Since 2011 four JAK2 inhibitors have received FDA approval: ruxolitinib (Jakafi)opens in a new tab or window, fedratinibopens in a new tab or window (Inrebic), pacritinibopens in a new tab or window (Vonjo), and momelotinibopens in a new tab or window (Ojjaara). All four drugs demonstrated ability to reduce splenomegaly, a major clinical manifestation of myelofibrosis, as well as symptoms.

Some of the co-occurring mutations are targetable, creating interest in combination therapies that simultaneously target different signaling pathways, said Aaron Gerds, MD, of the Cleveland Clinic. One such combination was evaluated in a clinical trial that paired a JAK2 inhibitor with an IDH2 inhibitor.

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