Study aid only. Verify against current guidelines before clinical use.

MPN and MDS summary

Malignant Hematology·MPN·2026
MPNs SUMMARY

Classic Ph-negative MPN comparison (PV / ET / PMF)

Classic Ph-negative MPNs: PV, ET, PMF
EntityDiagnostic criteriaRisk stratificationTreatment
PVPolycythemia vera mOS 10 to 25 yr JAK2 95% to 97% (JAK2 exon 12 ~3%) CALR 0%, MPL 0% Major
  1. Hb >16.5/16.0 (M/F) OR HCT >49%/>48%
  2. Hypercellular BM with panmyelosis and mature pleomorphic megakaryocytes
  3. JAK2 V617F+ or similar (e.g., JAK2 exon 12)
Minor
  1. Low EPO (85%)
Diagnosis: all 3 major, OR first 2 major plus minor Check EPO and rule out secondary erythrocytosis (androgens, low O2 from COPD/OSA, high altitude, Chuvash: VHL mutant with normal/high EPO). Suspect post-PV-MF: ↓phlebotomy requirement (↓Hb), ↑BM fibrosis, ↑splenomegaly, ↑symptoms. 		Low riskNo history of thrombosis AND age ≤60 → no cytoreduction

Goal HCT <45%.

All PV: phlebotomy + low-dose ASA (BID if refractory symptoms); add anticoagulation if active thrombosis.
High riskHistory of thrombosis OR age >60

Cytoreduction:

  • Hydroxyurea: 1st line
  • Interferon: better in younger and pregnant
  • Ruxolitinib: if HU intolerant/​resistant, especially with splenomegaly (RESPONSE)
  • Ropeginterferon alfa-2b: long half-life, decreases JAK2 allele burden unlike hydroxyurea, longer duration of response
  • Rusfertide: a hepcidin mimetic
Indications for cytoreduction: new thrombosis, acquired VWD and/or major bleeding, frequent/​persistent phlebotomy with poor tolerance, symptomatic/​progressive splenomegaly, symptomatic thrombocytosis, progressive leukocytosis, progressive symptoms (night sweats, fatigue, pruritus), vasomotor/​microvascular symptoms despite ASA.
ETEssential thrombocythemia mOS ~20 yr 10% → MF; <5% → AML JAK2 50% to 60% CALR 25%, MPL 3% to 5% Triple-negative ~20% Major
  1. PLT ≥450K
  2. Megakaryocytic hyperplasia (enlarged and mature) in BM
  3. JAK2+, CALR+, or MPL+
  4. Not meeting WHO criteria for another myeloid neoplasm (PV, PMF, CML, MDS)
Minor
  1. Presence of a clonal marker or absence of evidence for reactive thrombocytosis
Major: (1) PLT ≥450K, (2) BM megakaryocytic proliferation, (3) not meeting WHO criteria for another myeloid neoplasm, (4) JAK2/CALR/MPL mutation. Diagnosis: all 4 major, OR first 3 major plus the minor criterion (for triple-negative ET) Rule out secondary thrombocytosis. Watch for bleeding with PLT >1M due to acquired vWD (especially in CALR+). CALR+ has better prognosis. Suspect post-ET-MF: worsening cytopenias, ↑BM fibrosis, ↑splenomegaly, ↑symptoms, ↑LDH. 		IPSET-thrombosis (age, prior thrombosis, JAK2)Very lowAge ≤60, no JAK2, no thrombosis

Observation, low-dose ASA if needed.
LowAge ≤60, JAK2+, no thrombosis

No cytoreduction, consider ASA 81 mg/day (or BID if no bleeding).
IntermediateAge >60, no JAK2, no thrombosis

Consider cytoreduction if PLT >1,000,000/uL, acquired vWD, or ↑symptoms; ASA 81 mg/day if no bleeding.
HighAge >60 AND JAK2+, OR history of thrombosis at any age

Cytoreduction with HU or interferon; Antiplatelet (ASA) for prior arterial thrombosis and systemic anticoagulation for prior venous thrombosis; combine ASA plus anticoagulation only when each is separately indicated, since dual therapy raises bleeding risk.

Agents:

  • Hydroxyurea
  • Interferon-α (if pregnant)
  • Anagrelide (↓PDE, ↑arterial thrombosis, bleeding, and fibrosis)
NO ruxolitinib, not approved (MAJIC-ET trial).
PMFPrimary myelofibrosis mOS 3 to 5 yr 20% → AML JAK2 50% to 60% CALR 30%, MPL 5% to 10% Major
  1. Megakaryocytic atypia and increased proliferation with reticulin/​collagen fibrosis (grade 2/3)
  2. JAK2+, CALR+, MPL+, or other clonal marker, or absence of reactive myelofibrosis
  3. Not meeting WHO criteria for another myeloid neoplasm
Minor
  1. Anemia not attributed to a comorbid condition
  2. WBC ≥11
  3. Splenomegaly (palpable, very common 85% to 100%)
  4. ↑LDH
  5. Leukoerythroblastosis
Diagnosis: all 3 major plus at least 1 minor Differentiate pre-PMF vs post-PV-MF and post-ET-MF. 		DIPSS-plus: first compute DIPSS (Hb <10 = 2 pts; age >65, constitutional symptoms, WBC >25K, blasts >=1% = 1 each), convert the DIPSS category to points (low 0, int-1 1, int-2 2, high 3), then add 1 each for unfavorable karyotype, platelets <100K, and RBC transfusion need. Categories: low 0, int-1 1, int-2 2 to 3, high >=4.
Hb <102 (DIPSS)
RBC transfusion need+1
WBC >25K1 (DIPSS)
PLT <100K+1
Circulating blasts ≥1%1 (DIPSS)
Unfavorable karyotype*+1
Constitutional symptoms1 (DIPSS)
Age >651 (DIPSS)
Low / Int-1Low: 0 pts (mOS 15.4 yr)
Int-1: 1 pt (6.5 yr)

Low / Int-1 (≤1 pt):

  • Asymptomatic → observation (especially CALR+)
  • Symptomatic anemia → EPO <500 use epoetin/​darbepoetin; EPO >500 use androgens, danazol, steroids
  • del(5q) → lenalidomide or thalidomide +/- steroids
  • Symptomatic or symptomatic splenomegaly → hydroxyurea/​JAKi/​splenectomy
Int-2 / HighInt-2: 2 to 3 pts (2.9 yr)
High: ≥4 pts (1.3 yr) MIPSS70/70+ high-molecular-risk: ASXL1, EZH2, SRSF2, IDH1/2 (type 1/type 1-like CALR is favorable; type 2 is not); MIPSS70: intermediate 2 to 4, high ≥5. MIPSS70-plus v2.0 differs (intermediate 3 to 4). GIPSS also used.

Int-2 / High (≥2 pts): allo-SCT; PLT >50K → ruxolitinib or fedratinib; PLT <50K → pacritinib.

Options:

  • Ruxolitinib: ↑infections, ↓counts, withdrawal syndrome, hold for PLT <50K if baseline PLT ≥100K; hold for PLT <25K if baseline PLT 50 to <100K
  • Fedratinib: Wernicke encephalopathy, check/give B1, diarrhea
  • Pacritinib: JAK2/FLT3, diarrhea, ↓spleen size, ok if PLT <50K
  • Momelotinib: good for cytopenia, especially anemia
  • Radiation to spleen or symptomatic extramedullary hematopoiesis
  • Luspatercept: for transfusion requirements, especially given with rux

Navitoclax and parsaclisib: investigational only, not approved; parsaclisib phase 3 LIMBER-304 discontinued 2023.
All MPNs can progress to advanced phase: PB or BM blasts 10% to 19% → accelerated-phase MPN; ≥20% → blast-phase MPN (i.e., AML).
*Unfavorable karyotype: complex, or +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-, or 11q23.

Treatment recap (recent agents)

  • Allo-HSCT is the only curative option for PMF (for intermediate-2 / high-risk fit patients).
  • JAK inhibitors in MF: ruxolitinib (1st line), fedratinib, momelotinib (especially for anemic patients), pacritinib (especially for thrombocytopenic patients, PLT <50K).
  • PV: phlebotomy (goal HCT <45%) + low-dose ASA for all; hydroxyurea or peg-interferon (ropeginterferon) for high-risk; ruxolitinib for HU-refractory.
  • CALR-mutated ET has lower thrombosis risk than JAK2-mutated ET but higher bleeding risk at very high platelet counts (acquired vWD).

Eosinophilia overview

  • Hypereosinophilia: persistent AEC ≥1.5 ×109/L (on ≥2 measurements ≥2 weeks apart) (eosinophilia grading: mild 0.5 to 1.5; moderate 1.5 to 5; severe >5 ×109/L). AEC does not correlate with disease severity; eosinophilia with cytopenia or blasts warrants immediate bone marrow biopsy.
  • Secondary (reactive): allergy/drug, infection (helminths), immunodeficiency, pulmonary, GI, autoimmune (EGPA, GPA); malignancy-associated (reactive: T-cell lymphoma, Hodgkin, ALL, mastocytosis, solid tumor; clonal: AML, MDS, MPN, CML).
  • Clonal / neoplastic:
    • Fusion-driven myeloid/lymphoid neoplasms: PDGFRA (FIP1L1, imatinib-responsive, add steroids for cardiac involvement), PDGFRB (ETV6 t(5;12), imatinib), FGFR1 (aggressive; pemigatinib, FDA Aug 2022 for relapsed/refractory disease; chemo then transplant), PCM1-JAK2, FLT3, ETV6-ABL1.
    • CEL (WHO5) / CEL,NOS (ICC): clonality plus abnormal/dysplastic marrow morphology after excluding kinase-fusion entities and other myeloid neoplasms; increased blasts are NOT required. When present, blast thresholds are >=2% PB or >=5% marrow, and blasts must stay <20%.
    • Lymphocytic variant (L-HES): aberrant CD3-CD4+ T-cell clone producing IL-5.
    • Idiopathic HES: diagnosis of exclusion with end-organ damage.
  • Treatment: steroids frontline; imatinib for FIP1L1-PDGFRA or PDGFRB; mepolizumab (anti-IL-5, FDA September 2020) for HES.

MDS quick reference

  • Risk stratification: IPSS-R, IPSS-M (includes molecular).
  • Lower-risk MDS: supportive care, ESA, lenalidomide (del 5q), luspatercept (transfusion-dependent, 1st line regardless of ring sideroblasts per COMMANDS, FDA Aug 2023), imetelstat (FDA June 2024), low-dose HMA.
  • Higher-risk MDS: azacitidine, decitabine, venetoclax + azacitidine (phase 3 VERONA negative for OS, 2025; not standard), allo-HSCT (only curative).
  • Therapy-related MDS/AML: prior cytotoxic exposure; alkylating-related (5 to 7 yr latency, complex/-7) vs topoisomerase II-related (1 to 3 yr, 11q23/MLL).

High-yield MPN/MDS pearls

  • JAK2 V617F is the most common driver in MPNs.
  • PV: phlebotomy + ASA + HU/IFN if high risk.
  • PMF cure = allo-HSCT.
  • Momelotinib for myelofibrosis with anemia; pacritinib for myelofibrosis with thrombocytopenia.
  • CALR-mutated ET has lower thrombosis risk than JAK2-mutated.
  • Imatinib for FIP1L1-PDGFRA HES; avapritinib for KIT D816V mastocytosis.
  • Lenalidomide for del(5q) MDS; luspatercept for transfusion-dependent lower-risk MDS (1st line regardless of ring sideroblasts, COMMANDS).
  • IPSS-M incorporates molecular markers (latest MDS prognostic tool).
Veli Bakalov MD, Board Review Notes 2026