JAK2 V617 Mutation with Reflex to Jak2 Ex- 12 CALR Ex-9 Mutation & MPL W515, S505 Mutation

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Detects JAK2/CALR/MPL mutations.

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JAK2 V617 Mutation with Reflex to JAK2 Exon-12, CALR Exon-9 & MPL W515/S505 Mutation Testing

Why is it done?
- Detection of Myeloproliferative Neoplasms (MPNs): This test identifies somatic driver mutations that cause Philadelphia chromosome-negative myeloproliferative neoplasms, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF).
- Initial Diagnostic Evaluation: Performed when patients present with elevated blood counts (hemoglobin, hematocrit, platelet count) or clinically suspected MPN based on symptoms such as thrombosis, hemorrhage, splenomegaly, or constitutional symptoms.
- Diagnostic Stratification: Distinguishes between PV, ET, and PMF, and helps differentiate MPNs from reactive causes of thrombocytosis or erythrocytosis.
- Risk Stratification: Helps assess thrombotic and hemorrhagic risk and guides therapeutic decision-making, including treatment intensity.
- Ongoing Monitoring: May be repeated to monitor for transformation to accelerated phase or acute leukemia in established MPN cases.
- Reflex Testing Strategy: Initial testing focuses on JAK2 V617F, which is present in approximately 95% of PV cases and 50-60% of ET and PMF cases. If JAK2 V617F is negative, testing reflexively proceeds to JAK2 exon-12, CALR exon-9, and MPL W515/S505 mutations to identify alternative driver mutations.
Normal Range
- Negative Result (Normal): No detection of JAK2 V617F, JAK2 exon-12, CALR exon-9, or MPL W515/S505 mutations. This is reported as 'Not Detected' or 'Negative.' Normal result indicates no evidence of the common driver mutations associated with Philadelphia chromosome-negative MPNs.
- Positive Result (Abnormal): Detection of one or more mutations. Results are typically reported as 'Detected' with specification of which mutation(s) are present and, when quantifiable, the allele burden (percentage of mutant alleles).
- Interpretation of Allele Burden: Typically expressed as percentage (0-100%). Higher allele burden may correlate with disease burden but clinical significance varies by mutation and individual patient context.
- Units of Measurement: Mutations reported as present/absent (qualitative) or as allele burden percentage (quantitative), depending on laboratory methodology.
- Triple-Negative Status: If all three mutation categories (JAK2, CALR, MPL) are not detected, patient is classified as 'triple-negative,' which may warrant additional testing or suggests alternative diagnoses.
Interpretation
- JAK2 V617F Mutation Detected: Strongly suggests diagnosis of PV, ET, or PMF. Found in ~95% of PV, 50-60% of ET, and 50-60% of PMF cases. Reflex testing to other mutations typically not performed. High allele burden may indicate higher disease burden and increased thrombotic risk.
- JAK2 V617F Not Detected (Triggers Reflex Testing): Testing reflexively proceeds to screen for alternative driver mutations.
- JAK2 Exon-12 Mutation Detected: Found in ~3-5% of PV cases (JAK2 V617F-negative PV). Indicates polycythemia vera without V617F mutation. Usually associated with lower allele burden than V617F. Clinical features and prognosis similar to V617F-positive PV.
- CALR (Calreticulin) Exon-9 Mutation Detected: Found in ~25-30% of ET and ~25-35% of PMF cases. Predominantly present in JAK2 V617F-negative cases. Associated with favorable prognosis in ET and intermediate prognosis in PMF. Two types: Type 1 (52bp deletion, ~70%) and Type 2 (5bp insertion, ~30%). Clinical outcomes differ slightly between types.
- MPL W515 (Thrombopoietin Receptor) Mutation Detected: Most common is W515L, found in ~3-5% of ET and ~5-10% of PMF. W515K is less common. Indicates a myeloproliferative neoplasm, particularly ET or PMF. Associated with intermediate to unfavorable prognosis in PMF.
- MPL S505 Mutation Detected: Rare mutation (S505N) found in very small percentage of MPN cases. Presence indicates myeloproliferative disorder.
- Triple-Negative Results (All Three Mutation Groups Negative): Suggests either: (1) Reactive thrombocytosis or erythrocytosis from secondary causes; (2) MPN with other rare driver mutations not tested (e.g., IDH1/2, ASXL1, TET2, TP53); (3) Masked MPN where mutations are at very low allele burden; (4) Potential variant MPN. Additional testing and clinical correlation essential.
- Factors Affecting Results: Test sensitivity may be affected by low allele burden, sample quality, type of sample (bone marrow vs peripheral blood—bone marrow typically more sensitive), and laboratory methodology. Recent phlebotomy or therapeutic cytoreduction may affect allele burden measurements.
- Clinical Significance of Mutation Patterns: Each MPN patient typically harbors exactly one driver mutation (mutually exclusive pattern). Detection of single specific mutation helps confirm diagnosis and guides risk stratification. Prognosis and treatment response vary by mutation type.
Associated Organs
- Primary Organ System - Bone Marrow and Hematopoietic System: Mutations affect hematopoietic stem cells in bone marrow, leading to clonal proliferation and overproduction of blood cells.
- Cardiovascular System: Elevated blood counts increase blood viscosity and thrombotic risk, potentially leading to stroke, myocardial infarction, deep vein thrombosis, and pulmonary embolism.
- Splenic System: Extramedullary hematopoiesis causes splenomegaly; splenic infarction and rupture possible; portal vein thrombosis may develop.
- Hepatic System: Hepatomegaly from extramedullary hematopoiesis; increased risk of portal vein and hepatic vein thrombosis (Budd-Chiari syndrome).
- Vascular System: Microvascular and macrovascular thrombosis; increased arterial and venous thrombotic events; bleeding complications from platelet dysfunction despite elevated counts.
- Neurological System: Increased risk of stroke, transient ischemic attacks (TIA), and cognitive dysfunction from thrombotic events; erythromelalgia (burning sensations in extremities) common in PV.
- Diseases Associated with Positive Results: Polycythemia Vera (PV) - typically JAK2 V617F or exon-12 positive; Essential Thrombocythemia (ET) - can be JAK2 V617F, CALR, or MPL positive; Primary Myelofibrosis (PMF) - can be JAK2 V617F, CALR, or MPL positive; Post-PV myelofibrosis, post-ET myelofibrosis, and acute leukemic transformation.
- Potential Complications Associated with Abnormal Results: Thrombotic events (stroke, MI, DVT, PE, mesenteric thrombosis, Budd-Chiari syndrome); hemorrhagic events (GI bleeding, intracranial hemorrhage); transformation to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML); fibrotic transformation; secondary malignancies (from cytotoxic therapy); constitutional symptoms; fatigue and decreased quality of life.
Follow-up Tests
- Bone Marrow Aspiration and Biopsy: Recommended to confirm MPN diagnosis and assess bone marrow cellularity, morphology, and degree of fibrosis. Important for distinguishing between PV, ET, and PMF.
- Complete Blood Count (CBC): Monitor hemoglobin, hematocrit, platelet count, and WBC count at baseline and regularly during follow-up to assess response to treatment and disease progression.
- Additional Mutation Testing: In triple-negative cases or for prognostic refinement, consider testing for other mutations: IDH1/2, ASXL1, TET2, TP53, SRSF2, EZH2. These are associated with worse prognosis, particularly in PMF.
- Metabolic Panel and Liver Function Tests: Assess baseline organ function and monitor for cytopenias or hepatic complications. Elevated uric acid and LDH may indicate higher disease burden.
- JAK2 Allele Burden Quantification: Repeated measurements may be useful to monitor disease burden and treatment response. Some laboratories perform serial quantification, though clinical significance remains debated.
- Cytogenetic Analysis and Molecular Karyotyping: To detect abnormalities associated with unfavorable prognosis, particularly in PMF (del(5q), del(13q), del(20q), complex karyotype).
- JAK Inhibitor Testing (if applicable): In patients treated with ruxolitinib or other JAK inhibitors, mutation testing may help assess treatment response, though allele burden typically does not decrease significantly with JAK inhibitor therapy.
- Reticulocyte Count: Assess erythropoiesis and response to phlebotomy or cytoreductive therapy in PV.
- Phosphorus and Uric Acid Levels: Elevated values suggest high cell turnover; important for detecting tumor lysis risk and managing cytoreduction.
- Monitoring Frequency: At diagnosis: mutation testing + bone marrow biopsy, CBC. During treatment: CBC every 4-12 weeks depending on therapy; mutation testing may be repeated annually or as clinically indicated. At progression: comprehensive reassessment including mutation analysis for alternative mutations.
- Related Complementary Tests: BCR-ABL1 testing (to exclude chronic myeloid leukemia); Flow cytometry (to assess dysplasia and exclude acute leukemia); Serum thrombopoietin level; Erythropoietin level (useful in PV).
Fasting Required?
- Fasting: No
- Reason: Mutation testing is performed on blood or bone marrow samples and is not affected by food intake or fasting status. Genetic testing for somatic mutations does not require fasting.
- Sample Collection Requirements: EDTA (lavender-top) tube for peripheral blood specimens; bone marrow aspirate or biopsy specimen in EDTA tube. Samples should be collected and transported according to laboratory specifications.
- Patient Preparation: No special preparation needed. Patient may eat and drink normally before blood draw. Wear loose, comfortable clothing for venipuncture.
- Medications: No medications need to be held. Current medications do not affect the accuracy of JAK2, CALR, or MPL mutation testing. Continue all prescribed medications unless instructed otherwise by physician.
- Special Considerations: Timing of blood draw not critical for mutation testing. If bone marrow biopsy is required, standard pre-procedure preparation applies. Samples should be processed promptly per laboratory guidelines to maintain sample integrity.

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