Chapter 51: Pediatric Myeloid Neoplasms – Comprehensive Bullet-Point Notes

ACUTE MYELOGENOUS LEUKEMIA (AML)

• Definition: malignant clonal transformation of a hematopoietic stem/progenitor cell resulting in accumulation of myeloid blasts.

Epidemiology & Etiology

• Incidence (U.S.): \approx 5.1/100{,}000 (age <14 y); \approx 4.6/100{,}000 (age 15–19 y). Annual pediatric cases: \approx 500–600.
• Bimodal peaks: infancy (<2 y) & adolescence (15–20 y).
• Risk factors
– Therapy related (alkylators → 5q^{−}/7q^{−}, topoisomerase-II → 11q23/MLL fusions; anthracyclines).
– Radiation (in-utero, atomic blast survivors).
– Environmental: benzene, organic solvents, pesticides, radon, magnetic fields* (data conflicting).
– Prenatal: maternal alcohol (OR \uparrow to 7.6 for FAB M1/M2), dietary topoisomerase-II inhibitors (soy, tea, cocoa).
– Viral: maternal EBV re-activation, Parvovirus B19 (requires HLA-DRB1 predisposition).
– Constitutional syndromes: Down, Noonan, NF1, Fanconi, Bloom, Kostmann, Shwachman-Diamond, Diamond-Blackfan, Klinefelter*, aplastic anemia, PNH.
– Germ-line predisposition: RUNX1, CEBPA, GATA2, NF1, ANKRD26.

Biology

• Clonality: X-inactivation (G6PD) & cytogenetics prove monoclonal origin.
• Leukemia-Initiating Cells (LICs): CD34^+/CD38^− fraction; self-renew, transplantable to NOD/SCID mice.
• Cell of origin:
– HSC transformation (e.g., BCR-ABL, HOXA9/MEIS1 require intrinsic self-renewal).
– Committed progenitor transformation with acquired self-renewal (e.g., MLL-ENL, MOZ-TIF2).
• Integrated model: serial acquisition of \approx 2–3 driver lesions → clonal evolution → frank AML.
• Two-Hit Paradigm (Gilliland):
– Class I (“proliferation/survival”): activating TK/RAS pathway (NRAS/KRAS, PTPN11, NF1 loss, FLT3-ITD, KIT, JAK2).
– Class II (“differentiation/self-renewal”): transcription factor fusions (RUNX1-RUNX1T1 t(8;21), CBFB-MYH11 inv(16), PML-RARA t(15;17), MLL fusions), CEBPA, NPM1, WT1, GATA1 in DS.

Molecular Genetics–Key Frequencies (Children)

• RUNX1-RUNX1T1 15\%; CBFB-MYH11 10\%; MLL fusions 20\%.
• FLT3-ITD 5–16\% (poor prognosis if allelic ratio >0.4).
• NPM1 mut 6–8\% overall (≈27\% of normal karyotype).
• CEBPA \sim 5\%; KIT mut 17–41\% in core-binding factor AML.
• DNMT3A, IDH1/2, TET2 rare (<5\%).

Morphology & Cytochemistry (FAB)

• MPO & Sudan Black B positive in myeloblasts; NSE positive in monoblasts; chloroacetate esterase for granulocytes.
• Recognize M0–M7 subtypes. Auer rods pathognomonic.

Immunophenotype

• Myeloid antigens: CD13, CD33, CD117; stem: CD34, HLA-DR.
• Monocytic: CD14, CD64.
• Megakaryocytic: CD41/CD61/CD42.
• Flow cytometry essential for lineage, MRD.

Cytogenetics & WHO Categories

• Recurrent: t(8;21), inv(16)/t(16;16), t(15;17), 11q23, t(6;9), inv(3).
• WHO (2008) lowers blast cut-off to 20\%, adds “with recurrent genetic abnormalities,” therapy related, myelodysplasia-related.

Clinical Presentation

• Symptoms: fever, fatigue, bleeding, bone pain, organomegaly.
• 25\% present with WBC >100{,}000/\mu L (hyperleukocytosis/leukostasis).
• DIC common in APL.
• Extramedullary: chloromas (orbit, epidural), gingival, CNS \sim 15\%.

Treatment Overview

• Induction: “7 + 3” backbone → intensified pediatric regimens.
• Contemporary COG backbone: ADE 10+3+5 → ADE 8+3+5 → AE → MA ± HD Ara-C.
• Risk-adapted HSCT in CR1:
– Low risk (CBF, NPM1mut/FLT3wt, CEBPA) → chemo only.
– High risk (FLT3-ITD high, monosomy 7/–5, MRD >0.1\% after induction) → best-available donor HSCT.
• Targeted add-ons: GMTZ (anti-CD33), bortezomib, sorafenib for FLT3-ITD.
• Support Care: mandatory hospitalization during neutropenia, antibacterial (cipro/vancomycin) & antifungal prophylaxis (fluconazole vs caspofungin trial), PCP prophylaxis (TMP-SMX), transfusion thresholds <10{,}000/\mu L platelets.

Prognosis & Minimal Residual Disease

• Favorable: CBF AML, NPM1mut/FLT3wt, CEBPA biallelic, APL.
• Poor: FLT3-ITD high, monosomy 5/7, complex karyotype, MLL-PTD.
• MRD by flow >0.1\% after induction I → 3-year relapse 60\% (vs 29\%).

Relapsed / Refractory AML

• High-dose cytarabine-based re-induction (FLAG ± IDA, clofarabine + Ara-C).
• Consolidation = allogeneic HSCT.
• Emerging agents: quizartinib, ponatinib (FLT3), DOT1L inhibitors (MLL), HDAC + DNA-methyltransferase inhibitors.

ACUTE PROMYELOCYTIC LEUKEMIA (APL)

• Genetics: >90\% t(15;17)(q22;q11) → PML-RARA. Variants: PLZF-RARA t(11;17), NPM-RARA t(5;17).
• Pathobiology: PML-RARA recruits N-CoR/SMRT/HDAC → transcriptional repression; disrupts PML nuclear bodies; sensitivity to ATRA (differentiation) & As2O3 (degradation/apoptosis).
• Clinical: DIC, hyperleukocytosis in \sim 20\% (higher in children), differentiation syndrome.
• Risk stratification: WBC >10{,}000/\mu L = high risk.
• Therapy:
– Induction: ATRA + anthracycline (idarubicin or daunorubicin); high-risk add cytarabine or GMTZ.
– Consolidation: ATRA + anthracycline ± high-dose Ara-C; As2O3 (5 courses) improves EFS to >90\%.
– Maintenance: ATRA + 6-MP + MTX x 1–2 y (under re-evaluation).
• Complications: ATRA syndrome (fever, edema, effusions; tx dexamethasone), pseudotumor cerebri in \sim 16\% children.
• MRD: RT-PCR for PML-RARA; post-consolidation positivity → pre-emptive As2O3 ± GMTZ.

DOWN SYNDROME (DS)–TMD & AML

Transient Myeloproliferative Disorder (TMD)

• Incidence: \approx 10\% of DS neonates.
• GATA1 exon 2 mutations → GATA1s isoform; pathogenesis requires trisomy 21.
• Spontaneous regression \le 3 mo in \approx 70\%; risk for hepatic fibrosis, hydrops.
• Therapy: observation unless life-threatening (WBC >100\,000/\mu L, organ failure) → low-dose Ara-C 10 mg/m^2 q12h × 7 d.
• 20–30\% evolve to AML (usually AMKL) within 3 y.

DS–Acute Megakaryoblastic Leukemia (AMKL)

• Median age

MYELODYSPLASTIC SYNDROMES (MDS)

• Ineffective hematopoiesis + dysplasia + risk of AML.
• Cytogenetics in 59\% kids: deletions 5q^{−}, 7q^{−}, 20q^{−}, trisomy 8.
• Pathogenesis: excess apoptosis early (TNFα, Fas), then anti-apoptotic shift → AML; epigenetic lesions (TET2, DNMT3A, ASXL1) rare in children.
• Classification:
– FAB: RA, RARS, RAEB, RAEB-T, CMML.
– WHO 2008: blast \ge20\% = AML; adds RC with multilineage dysplasia, therapy related, childhood refractory cytopenia.
– IPSS of limited pediatric value.
• Inherited predisposition: Fanconi, Shwachman-Diamond, DC, GATA2, RUNX1, ANKRD26.
• Treatment:
– Low-risk: supportive ± hypomethylating agents (5-azacytidine, decitabine).
– Only curative = allogeneic HSCT; superior when performed early without pre-HSCT chemo.

MYELOPROLIFERATIVE DISORDERS (MPD)

Juvenile Myelomonocytic Leukemia (JMML)

• Diagnostic criteria (must meet category 1 + genetic/clinical): splenomegaly, monocytosis >1\,000, blasts <20\%, Ph^{−}.
• Genetics (mutually exclusive): PTPN11 35\%, NRAS/KRAS 25\%, NF1 10\%, CBL 15\%. All activate RAS-MAPK.
• Clinical: age <4 y, hepatosplenomegaly, skin rash, ↑HbF.
• Therapy: allogeneic HSCT (DFS \sim 50\%); experimental RAS/MEK/mTOR inhibitors.

Chronic Myelogenous Leukemia (CML)

• t(9;22) → BCR-ABL p210 tyrosine kinase; rare in children (1–3\% of childhood leukemias).
• Phases: chronic → accelerated (blasts 10–19\%) → blast crisis (\ge20\%).
• Therapy:
– 1st line imatinib 340\,mg/m^2 daily (CHR >95\%, CCyR >80\%).
– Resistance: dasatinib, nilotinib, ponatinib.
– HSCT reserved for TKI failure or T315I mutation.

Polycythemia Vera (PV)

• JAK2-V617F in >90\% adults; rare pediatric.
• WHO pediatric criteria: elevated Hct, JAK2 mut, low EPO, endogenous erythroid colonies.
• Management: phlebotomy, low-dose acetylsalicylic acid, hydroxyurea or peg-IFN if high-risk.

Essential Thrombocythemia (ET)

• Sustained platelets >450{,}000/\mu L; JAK2-V617F \sim 50\%, MPL W515L 10\%.
• Treat if platelets >1\times10^{6}/\mu L or symptoms: hydroxyurea > anagrelide; avoid aspirin if acquired vWD.

Primary Myelofibrosis (PM)

• Marrow fibrosis + extramedullary hematopoiesis; JAK2-V617F 50\%, MPL mut 10\%.
• Ruxolitinib (JAK1/2 inhibitor) alleviates splenomegaly/symptoms; only curative = allogeneic HSCT.

Mastocytosis

• Clonal mast cell proliferations; systemic forms harbor KIT D816V.
• Subtypes: indolent SM, ASM, SM-AHNMD, mast cell leukemia.
• Therapy: IFN-α + steroids, cladribine; TKIs—imatinib effective only in KIT-WT; midostaurin active in D816V.

KEY TAKE-AWAYS

• Pediatric AML cure \approx 60\%; outcomes hinge on cytogenetics/molecular lesions and MRD.
• CBF-AML, NPM1mut/FLT3wt, CEBPA biallelic, APL (with ATRA + As2O3) = favorable.
• FLT3-ITD high allelic ratio, monosomy 5/7, complex karyotype, MRD >0.1\% after induction I = high-risk → HSCT.
• Imatinib and next-generation TKIs revolutionized CML; HSCT now salvage/curative option after TKI failure.
• DS-AMKL: exploit inherent chemo-sensitivity; drastically reduced-intensity protocols yield >80\% survival.
• Early inclusion of hypomethylating agents & targeted inhibitors (DOT1L, FLT3, JAK2) heralds precision medicine in pediatric myeloid malignancies.