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.

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

• 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

• 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.