Myeloproliferative Syndromes
Definition And Classification
- Clonal hematopoietic stem cell disorders.
- Characterized by hyperproliferation of mature and immature cells of one or more myeloid lineages.
- World Health Organization (WHO) 2017 classification categorizes myeloproliferative neoplasms (MPN) and overlap myelodysplastic/myeloproliferative (MDS/MPN) diseases.
| Category | Specific Syndromes |
|---|---|
| Myeloproliferative Neoplasms (MPN) | Chronic myeloid leukemia (CML), BCR-ABL1 positive. |
| Polycythemia vera (PV). | |
| Essential thrombocythemia (ET). | |
| Primary myelofibrosis (PMF). | |
| Chronic neutrophilic leukemia. | |
| Chronic eosinophilic leukemia, NOS. | |
| Overlap MDS/MPN Diseases | Juvenile myelomonocytic leukemia (JMML). |
| Chronic myelomonocytic leukemia (CMML). | |
| Down Syndrome Associated | Transient abnormal myelopoiesis (TAM). |
Chronic Myeloid Leukemia
- Pathophysiology: Clonal disorder of pluripotent hematopoietic stem cells. Characterized by Philadelphia (Ph) chromosome t(9;22)(q34;q11) reciprocal translocation resulting in BCR-ABL1 fusion gene.
- Epidemiology: Rare in childhood; accounts for 2-3% of pediatric leukemias.
- Clinical Features: Fatigue, weight loss, anorexia, fever. Massive splenomegaly causing left upper quadrant pain. High leukocyte count (median ~250x10^9/L in children, higher than adults).
- Disease Phases: Triphasic course.
- Chronic Phase (CP): Usual presentation (~85%). Hyperproliferation of mature elements.
- Accelerated Phase (AP): Increasing blasts (10-19%), persistent thrombocytosis/thrombocytopenia unresponsive to therapy, increasing splenomegaly.
- Blast Crisis (BP): Differentiation arrest. >20% blasts. Can be myeloid or lymphoid.
- Diagnosis: Bone marrow cytogenetics (20 metaphases) identifies Ph chromosome in 95%. Fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR) detects BCR-ABL1 fusion gene.
- Treatment:
- Tyrosine kinase inhibitors (TKI) represent standard first-line therapy.
- Imatinib, Dasatinib, and Nilotinib approved for pediatric use.
- TKI selection dictated by specific kinase domain mutations (e.g., T315I mutation requires Ponatinib).
- Allogeneic hematopoietic stem cell transplantation (HSCT) indicated for suboptimal response, failure of two second-generation TKIs, or advanced disease phases.
Juvenile Myelomonocytic Leukemia
- Pathophysiology: Aggressive overlap MDS/MPN. Characterized by hyperproliferation of monocytic and granulocytic cells. Driven by hyperactive RAS signaling pathways. Demonstrates characteristic hypersensitivity of myeloid progenitors to Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF).
- Genetics: Somatic or germline mutations in PTPN11, KRAS, NRAS, CBL, or NF-1 identified in ~90% of cases. Strong association with Neurofibromatosis type 1 (NF-1) and Noonan syndrome.
- Clinical Features: Age typically <2 years (median 1.8 years). Manifests with fever, failure to thrive, maculopapular rash, xanthoma, cafe-au-lait spots, massive hepatosplenomegaly, lymphadenopathy, respiratory distress.
- Laboratory Findings: Leukocytosis (usually <100,000/mm3). Absolute monocytosis (>1000/mm3) mandatory for diagnosis. Elevated fetal hemoglobin (HbF). <20% blasts in blood/marrow.
Diagnostic Criteria For Juvenile Myelomonocytic Leukemia
| Category | Diagnostic Parameters (Must meet specific combinations) |
|---|---|
| Category 1 (Mandatory) | Blood monocyte count >1x10^9/L. Blasts <20%. Splenomegaly. Absence of t(9;22) BCR-ABL1. |
| Category 2 (Molecular) | Somatic mutation in PTPN11, KRAS, or NRAS. Clinical diagnosis/mutation of NF-1. Germline CBL mutation. |
| Category 3 (Supportive) | Monosomy 7 or clonal abnormality. Increased HbF. Circulating myeloid precursors. GM-CSF hypersensitivity. Hyperphosphorylation of STAT5. |
- Treatment: HSCT is sole curative therapy (5-year overall survival 52-64%). Standard chemotherapy yields poor response. Pre-HSCT cytoreduction (6-mercaptopurine, cis-retinoic acid, low-dose cytarabine) utilized selectively for aggressive disease to minimize organomegaly/pulmonary infiltration.
Polycythemia Vera
- Pathophysiology: Acquired primary erythrocytosis. Clonal proliferation of erythrocytes, granulocytes, and platelets. Characterized by erythropoietin (EPO) independence and low serum EPO levels.
- Genetics: JAK2 V617F mutation (exon 14) causes constitutive kinase activation. Present in >98% adults but only 25-40% of pediatric cases.
- Clinical Features: Elevated hemoglobin and hematocrit. Thrombosis risk (Budd-Chiari syndrome, mesenteric thrombosis) significantly lower in children (~5%) than adults. Transformation to myelofibrosis or acute leukemia exceedingly rare in pediatrics.
Diagnostic Criteria For Polycythemia Vera
| Criteria Type | Requirements |
|---|---|
| Major | 1. Hemoglobin >16.5 g/dL (males) / >16.0 g/dL (females) or elevated red cell mass. |
| 2. Bone marrow biopsy showing hypercellularity, panmyelosis, pleomorphic megakaryocytes. | |
| 3. Presence of JAK2 V617F or JAK2 exon 12 mutation. | |
| Minor | 1. Subnormal serum erythropoietin level. |
| Diagnosis | Requires all 3 Major OR first 2 Major + Minor. |
- Treatment: Phlebotomy and low-dose aspirin remain first-line therapy. Cytoreductive therapies (Hydroxyurea, Pegylated-interferon-alpha, Anagrelide) reserved for progressive organomegaly, extreme thrombocytosis, or high-risk features. Ruxolitinib (JAK2 inhibitor) utilized for resistant cases.
Essential Thrombocythemia
- Pathophysiology: MPN characterized by sustained extreme thrombocytosis and megakaryocytic hyperplasia without excessive erythropoiesis.
- Genetics: Mutations in JAK2 (V617F), CALR, or MPL genes. Rare in childhood (~1 per million). Pediatric cases demonstrate lower rates of JAK2 mutations and higher rates of CALR/MPL mutations compared to adults.
- Clinical Features: Highly benign clinical course in pediatrics compared to adults. Decreased risk of thromboembolic events.
- Diagnostic Criteria (WHO): Persistent thrombocytosis (>450,000/uL). Bone marrow megakaryocyte proliferation. Exclusion of PV, PMF, CML, MDS. Presence of clonal marker (JAK2, MPL, CALR). Absence of reactive thrombocytosis causes.
- Treatment: Observation indicated for asymptomatic patients. Antiplatelet agents (aspirin) utilized for low-risk patients with additional thrombophilia risk factors. Cytoreductive therapy (Hydroxyurea, Pegylated-interferon, Anagrelide) escalated for high-risk patients with extreme thrombocytosis or symptomatic bleeding/thrombosis.
Primary Myelofibrosis
- Pathophysiology: Clonal MPN characterized by leukoerythroblastosis, megakaryocyte/granulocyte proliferation, reactive bone marrow fibrosis, and extramedullary hematopoiesis.
- Genetics: Calreticulin (CALR) gene mutations present in ~50% of pediatric cases. JAK2 mutations virtually absent in young children. Rare infantile forms associated with mutations in VPS45, G6b-B, and CDC42.
- Clinical Features: Prefibrotic proliferative phase followed by fibrotic cytopenic phase. Malaise, night sweats, weight loss, massive splenomegaly (hypersplenism).
- Laboratory Findings: Peripheral smear demonstrates teardrop cells, leukoerythroblastosis, initial thrombocytosis followed by progressive pancytopenia. Bone marrow difficult to aspirate (dry tap); biopsy reveals fibrosis and hyperchromatic megakaryocytes.
- Treatment: HSCT is sole curative therapy; indicated for majority of pediatric patients. Supportive care with transfusions. JAK2 inhibitors (ruxolitinib) utilized in adults; pediatric data limited.
Transient Abnormal Myelopoiesis In Down Syndrome
- Pathophysiology: Unique myeloproliferative disorder exclusively affecting neonates with Down syndrome (Trisomy 21).
- Genetics: Driven by acquired somatic mutations in GATA1 (hematopoietic transcription factor).
- Epidemiology: Occurs in approximately 10% of neonates with Down syndrome.
- Clinical Features: High leukocyte counts, circulating immature megakaryoblasts in peripheral blood and liver, hepatosplenomegaly, jaundice, pleural/pericardial effusions.
- Course And Complications: Majority experience spontaneous remission within 3 months. 20-30% subsequently develop Acute Megakaryoblastic Leukemia (AMKL) by 3 years of age. Rare severe cases complicated by hydrops fetalis, disseminated intravascular coagulation, hepatic fibrosis, and multiorgan failure.
- Treatment: Observation for asymptomatic cases. Exchange transfusion, leukapheresis, or low-dose cytarabine utilized for hyperleukocytosis and life-threatening organ dysfunction. Close long-term monitoring required due to leukemic transformation risk.