38  Beyond Classical Ph-Negative MPNs

Key Points
  • Rare MPNs beyond PV, ET, PMF: CNL, SM, eosinophilic neoplasms
  • CNL: CSF3R T618I, ↑ mature neutrophils → ruxolitinib ORR 35%
  • SM: KIT D816V >20 ng/mL tryptase → midostaurin/avapritinib
  • Eosinophilic: PDGFRA/PDGFRB/FGFR1 fusions → fusion-specific TKIs

38.1 Scope

  • Rare MPNs: CNL, SM, myeloid/lymphoid neoplasms w/ eosinophilia
  • Criteria: WHO 5th edition, International Consensus Criteria (ICC) 2022

38.2 Chronic Neutrophilic Leukemia (CNL)

38.2.1 Diagnosis

  • WHO 5th edition:
    • BCR::ABL1-negative MPN
    • WBC ≥25×10⁹/L, ≥80% segmented neutrophils/bands
    • Hypercellular BM w/ neutrophilic proliferation
    • ± Hepatosplenomegaly
  • ICC 2022: WBC ≥13×10⁹/L + activating CSF3R mutation
    • Neutrophil precursors, monocytes ≤10% of WBC
  • DDx: aCML (now MDS/MPN w/ neutrophilia) → shared CSF3R, ASXL1, SETBP1 mutations

38.2.2 Management

  • Ruxolitinib (JAK inhibitor for CSF3R-mutant):
    • ORR 35%, median OS 23.1 months
    • Only option if CSF3R-mutated
  • Allo-HCT: Only curative therapy; consider eligible candidates

38.3 Systemic Mastocytosis (SM)

38.3.1 Presentation

  • Spectrum: cutaneous → indolent → advanced → mast cell leukemia (MCL)
  • Symptoms: urticaria pigmentosa, flushing, pruritus, diarrhea, abdominal pain, anaphylaxis
  • Subtypes:
    • Indolent SM: ± associated myeloid neoplasm (SM-AMN)
    • Aggressive SM (ASM), MCL (rare)

38.3.2 Diagnosis

  • Lab: Serum tryptase, KIT D816V mutation, abnormal FC (CD25/CD2/CD30 coexpression)
  • Major criterion: ≥15 mast cells in aggregates (CD117+, tryptase+)
    • Multifocal in BM/other organs
  • Minor criteria (≥3 if major absent):

    • 25% spindle-shaped/atypical mast cells in BM

    • Abnormal immunophenotype (CD25/CD2/CD30)
    • KIT D816V or activating KIT mutation
    • Tryptase persistently >20 ng/mL
  • SM-AMN: SM + aCML/CMML/MDS/MPN/AML

38.3.3 Management

  • Indolent SM: Observation, symptom control
    • H₁/H₂ blockers, cromolyn, leukotriene antagonists
    • Topical glucocorticoids, PPIs as needed
  • Advanced SM (KIT D816V ~90%):
    • Midostaurin: ORR 57%, TTR 2 mo, PR ~50%
    • Avapritinib: Superior in accelerated phase
  • Imatinib: Only if KIT wild-type (D816V-resistant)
SM Subtypes
Feature Indolent SM Advanced SM
KIT D816V ~80% ~90%
Cytopenia Absent/mild ↑ incidence
Blasts <5% BM ≥5% BM or >2% blood
Organomegaly Mild/absent Marked
Treatment Observation/H₁H₂ Midostaurin/avapritinib

38.4 Eosinophilic Myeloid/Lymphoid Neoplasms w/ Tyrosine Kinase Fusions

38.4.1 Overview

  • Rare neoplasms from pluripotent HSCs w/ constitutive TK activation
  • Definition: Eosinophils ≥1.5×10⁹/L (excl. secondary causes)
  • Diagnosis: Molecular confirmation (FISH, RT-PCR) required

38.4.2 PDGFRA/PDGFRB-Rearranged

  • Features: Multisystem involvement, BM eosinophilia, monocytosis
  • Presentation: Eosinophilia, weakness, fatigue, cardiopulmonary sx
  • Most common: PDGFRB rearrangement (>PDGFRA)
  • Tx: PDGFRA/PDGFRB fusion → imatinib-sensitive
    • Responsive, well-tolerated

38.4.3 FGFR1-Rearranged

  • Subtypes: Lymphoproliferative, MDS, eosinophilic (e.g., t(8;13) FOP1::FGFR1)
  • Presentations: MPN-like, B/T-cell lymphoblastic, AML
  • Age: 3-84 years (median 30)
  • Sx: Weight loss, night sweats, lymphadenopathy, anemia, hyperleukocytosis
  • Prognosis: Very poor → rapidly progressive (1-2 years)
  • Tx: Pemigatinib (FGFR1 inhibitor)
    • Variable response, limited options

38.4.4 Rare Fusions

  • ETV6::ABL1:
    • Dasatinib-responsive, high MR
  • DCTN1::JAK2:
    • JAK inhibitor-responsive (ruxolitinib)

38.5 Clinical Pearls

  • CNL: CSF3R-mutated + ruxolitinib → ORR 35%; allo-HCT for eligible
  • SM: Tryptase >20 + BM infiltrate → midostaurin/avapritinib; indolent = observation
  • Eosinophilic: Always screen for TK fusion (FISH/RT-PCR)
    • PDGFRA/B → imatinib
    • FGFR1 → pemigatinib (poor prognosis, urgent tx)
    • Fusion-specific TKI = standard therapy