CNL, atypical CML, and MDS/MPN overlap neoplasms
Other MPN/MDS-MPN
Scope note: Systemic mastocytosis, hypereosinophilic syndromes, and rare polycythemias now have their own dedicated notes. CMML is covered in its own note. This note covers chronic neutrophilic leukemia and the remaining MDS/MPN overlap entities.
Chronic Neutrophilic Leukemia (CNL)
- Definition: mature granulocytic (neutrophil) proliferation in blood and marrow with organ infiltration producing hepatosplenomegaly.
- Ph-negative: a key distinguishing feature from CML is that CNL does NOT carry the Philadelphia chromosome (no BCR::ABL1).
- Driver mutation: activating CSF3R mutation (T618I predominant) in ~80 to 90% of WHO-defined CNL (classically CSF3R T618I). One seminal study found CSF3R mutations in 16 of 27 (59%) of CNL or atypical CML patients.
- Signaling and drug sensitivity: CSF3R mutations signal preferentially through SRC family-TNK2 or through JAK kinases, giving differential kinase-inhibitor sensitivity.
- Membrane-proximal / JAK-activating mutations → sensitive to the JAK1/2 inhibitor ruxolitinib (a patient with the JAK-activating CSF3R mutation had marked clinical improvement on ruxolitinib).
- Truncation mutations → biochemical studies show sensitivity to dasatinib.
- Prognosis: guarded, overall survival about 2 years.
- Treatment: no standard therapy; reports of response to interferon and ruxolitinib. Options: hydroxyurea, interferon, ruxolitinib (especially if CSF3R mutation positive), allo-HSCT for aggressive disease or young fit patients.
Chronic neutrophilic leukemia: diagnostic criteriaWHO 2016
| CNL 2016 WHO criteria | Detail |
|---|---|
| Blood | WBC ≥25K with ≥80% neutrophils (ICC 2022: ≥13K if CSF3R-mutated) (<10% immature granulocytes, <1 ×109/L monocytes, and <1% blasts in blood). |
| Bone marrow | Hypercellular marrow, ↑ neutrophilic granulopoiesis with preserved maturation, <5% blasts, no significant dysgranulopoiesis (M:E ratio increased but no fixed value; mild reticulin fibrosis allowed). |
| Exclude other MPNs | No evidence of BCR::ABL1 (Ph negative), and no PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2 rearrangement. |
| Molecular | CSF3R T618I or another activating CSF3R mutation, present in ~80 to 90% of CNL (T618I, a membrane-proximal mutation, signals via JAK and is ruxolitinib-sensitive; truncation mutations signal via SRC family-TNK2, giving kinase-inhibitor sensitivity to dasatinib). If CSF3R negative: persistent neutrophilia (minimum 3 months), splenomegaly, and no identifiable cause of neutrophilia (no plasma cell neoplasm, or if present, demonstration of myeloid clonality by cytogenetic or molecular studies). |
- Classification note: atypical CML (aCML) was renamed MDS/MPN with neutrophilia in WHO 2022 (ICC retains the term aCML).
Atypical CML (aCML, BCR::ABL1-negative)
- Definition: leukocytosis with dysgranulopoiesis, no Ph chromosome, and without eosinophilia or monocytosis sufficient for HES or CMML. Now placed in the MDS/MPN overlap category (WHO 2022: MDS/MPN with neutrophilia).
- Mutations: ETNK1, SETBP1.
- Treatment: ruxolitinib has activity; allo-HSCT if fit.
MDS/MPN overlap category
- Concept: cases with both myelodysplastic and myeloproliferative features (for example leukocytosis or thrombocytosis) are classified in a separate overlap category, MDS/MPN, which is diagnostically useful but has only limited prognostic value (other tools are used for risk stratification).
- Entities in this category:
- CMML: defined by sustained monocytosis ≥0.5 ×109/L and ≥10% of leukocytes (WHO5/ICC 2022); 0.5 to <1.0 ×10^9/L also requires dysplasia plus a clonal cytogenetic or molecular abnormality (covered in its own note; not duplicated here).
- Atypical CML (BCR::ABL1-negative): as above.
- MDS/MPN with SF3B1 mutation and thrombocytosis (WHO5/ICC 2022; formerly MDS/MPN-RS-T, ring sideroblasts not required if SF3B1-mutant): requires a platelet count ≥450 ×109/L. Combines features of refractory anemia with ring sideroblasts (RARS) and thrombocytosis; associated with SF3B1 mutation, frequently co-occurring with JAK2 V617F.
- JMML (juvenile myelomonocytic leukemia): childhood myeloid neoplasm (historically MDS/MPN; reclassified as an MPN in WHO 2022) driven by RAS-pathway lesions (NF1, NRAS, KRAS, PTPN11, CBL).
- MDS/MPN-NOS (unclassifiable): overlap features not meeting criteria for CMML, aCML, MDS/MPN-RS-T, or JMML.
Veli Bakalov MD, Board Review Notes 2026