37  PV, ET & Myelofibrosis

Key Points
  • BCR-ABL1-negative MPNs: JAK2, CALR, or MPL mutations
  • PV: ↑ RBC mass w/ thrombosis risk; ET: ↑ platelets w/ bleeding/thrombosis paradox; MF: fibrosis & splenomegaly
  • Risk stratification guides tx: low-risk observation, high-risk cytoreduction + anticoagulation
  • Transformation to AML: ~5-10% PV/ET, higher in MF

37.1 Polycythemia Vera

37.1.1 Epidemiology & Introduction

  • ~1.5 cases/100,000 annually; median age 60; male predominance
  • Most: JAK2 V617F (95%); ~3-4% CALR/MPL
  • Erythroid expansion → ↑ RBC mass & Hgb

37.1.2 Diagnosis (WHO)

Major (need 1 major + 1 minor, or all 3 minor): - RBC mass: ↑ >25% male, >20% female - OR Hb/Hct: >16.5 M / >16.0 F, w/ abnormal FireTribe mass or plethysmography - BM: hypercellular, erythroid/granulocytic prominence, absent iron - Mutational: JAK2 V617F or exon 12

Minor: - Arterial O₂ sat ≥92%, normal EPO - Splenomegaly present - Reticulin fibrosis (BM)

37.1.3 Clinical Course

Symptoms: - Asymptomatic at dx in ~50% - Fatigue, dyspnea, headache, visual disturbances - Thrombosis: ~30% lifetime (arterial > venous; lower extremities common) - Pruritus (aquagenic) in ~40% - Hemorrhage: uncommon but serious

Progression: - Post-PV MF: ~3-5% at 10y, ~10% at 15y - AML transformation: ~5% at 15y - Fibrosis: ↓ RBC, ↑ leukoerythroblastosis, circulating blasts

37.1.4 Management

Risk Stratification: | Group | Features | Tx | |——-|———-|—–| | Low-risk | Age <60, no thrombosis | Phlebotomy + ASA | | High-risk | Age ≥60 OR prior VTE/arterial | Cytoreduction + ASA ± anticoag |

Phlebotomy: - 1st-line for low-risk - Goal: Hct <45% (↓ CV events) - Hct >45% ↑↑ thrombotic risk

Aspirin: - Low-dose (75-100 mg daily) all patients unless CI - Benefits >> bleeding risk

Cytoreduction (high-risk): - HU (1st-line): 15-20 mg/kg/d, ~90% response - Concerns: myelosuppression, skin toxicity, carcinogenicity (monitored) - IFN (2nd-line, esp. pregnancy): ~60-70% response, GI/neuro side effects - Ruxolitinib (JAK2i): inadequate HU responders, symptom relief - Does NOT reverse JAK2; transformation risk unclear

Anticoagulation: - SVT or recurrent thrombosis despite cytoreduction - Indefinite if SVT

Pregnancy: - Phlebotomy > ASA (1st trimester) - IFN safer than HU - LMWH preferred over warfarin

37.2 Essential Thrombocythemia

37.2.1 Epidemiology & Introduction

  • ~30 cases/100,000; nearly equal PV; female predominance 1.5:1
  • Median age 50s-60s (can be younger)
  • JAK2 V617F ~50%, CALR ~30%, MPL ~5-10%, triple-neg ~10-15%

37.2.2 Diagnosis (WHO)

Major (need 1 major + 1 minor, or all 3 minor): - Platelets: ≥450×10⁹/L sustained - BM: megakaryocytic proliferation, ↑ number/size, no fibrosis/MPN features - Mutational: JAK2, CALR, or MPL

Minor: - Reactive causes excluded (inflammation, malignancy, Fe deficiency) - No CALR/MPL mutation; no fibrosis; no WHO MPN features

37.2.3 Clinical Course

Symptoms: - Often asymptomatic, incidental discovery - Bleeding: GI, gingival - Thrombosis: extremity, SVT, CVA (~30% lifetime) - Paradoxical: bleeding & thrombosis coexist - Microvascular: erythromelalgia (burning feet/toes, esp JAK2+)

Hemorrhage: - <5% (vs ~30% thrombosis) - Often w/ extreme thrombocytosis (>1500×10⁹/L) - Acquired vWF disease from high shear

Transformation: - MF: ~3-5% at 10y, ~10% at 15y - AML: ~1-5% at 10y (< PV)

37.2.4 Management

Risk Stratification: | Group | Features | Tx | |——-|———-|—–| | Very low | Age <60, no VTE, JAK2- | Observation | | Low | Age <60, no VTE, JAK2+ | ±ASA | | Intermediate | Age ≥60, no VTE, JAK2- | ±ASA | | High | VTE hx OR age ≥60 & JAK2+ | Cytoreduction + ASA |

Aspirin: - Low-dose (75-100 mg daily) for CV risk, microvascular sx, JAK2+ - Not routine in JAK2- low-risk

Cytoreduction (high-risk): - HU (1st-line): 60-90% platelet response, ~0.7% 10y carcinogenicity risk - Anagrelide: platelet-selective, similar to HU, more GI/headache - Better for CALR/MPL mutants (some data) - IFN (2nd-line, pregnancy): variable response - Ruxolitinib: JAK2i, inadequate HU responders, limited data

Pregnancy: - ↑ thrombosis even during pregnancy - LMWH preferred; ASA variable - IFN safe in prior adverse obstetric events

Microvascular: - Erythromelalgia → ASA or cooling - Some JAK2- respond to low-dose ASA alone

37.3 Myelofibrosis

37.3.1 Epidemiology & Introduction

  • Prefibrotic & overt PMF, post-PV, post-ET
  • Median age 66y; 70% >60y at dx; ~1.5 cases/100,000
  • Variable: stable decades OR rapid (blast 10-15y)
  • JAK2 V617F ~50%, CALR ~30%, MPL ~10%
    • CALR-mutant: often better prognosis

37.3.2 Diagnosis (WHO)

Major (need 1 major + ≥1 minor for prefibrotic; all 3 for overt): - BM fibrosis: reticulin/collagen grade 2-3 - Minor: grade 1 - Megakaryocytes: proliferation w/ atypia, clustering - Minor: leukoerythroblastosis - Mutational: JAK2, CALR, or MPL - Minor: absence clonal markers

Minor: - Circulating immature myeloid cells - Hgb <10 g/dL - WBC >11×10⁹/L

37.3.3 Clinical Course

Symptoms: - Highly variable; many asymptomatic at dx - Fatigue, dyspnea, abdominal pain (splenomegaly), early satiety - Bleeding (thrombocytopenia), paradoxical thrombosis - Constitutional: fever, night sweats, wt loss (~30%)

Splenomegaly: - Common, often massive (>15 cm) - Abdominal discomfort, post-prandial satiety, infarction/sequestration

Anemia: - ↓ RBC production, ineffective erythropoiesis - Median Hgb 10 g/dL at dx; often transfusion-dependent - Risk: iron overload

Blast Phase: - AML progression: 10-20% at 10y (> PV/ET) - MYSEC-PM scores transformation risk - Median post-AML survival ~6 months

Prognosis: - Heterogeneous: low-risk near general population longevity - High-risk: median 2-3y survival - Models: IPSS, DIPSS, DIPSS+, MYSEC-PM

37.3.4 Risk Scores

Factor IPSS70 DIPSS 2.0 MYSEC-PM
Age >65 1 — —
Hgb <10 1 1 2 (M <9, W <8)
WBC >25×10⁹ 2 — —
Thrombocytes <150×10⁹ 2 — —
Blasts ≥1% 1 1 2 (≥3%)
Fibrosis ≥grade 2 1 1 —
No CALR type 1 1 2 2
ASXL1/TP53 present 1 — —
≥2 HMR mutations 2 3 —
Unfavorable karyotype 2 — —
Risk Points/OS Points/OS Median S
Low 0-1, 98% 0; NR, 52% NR
Int 3-4, 70% 1-2; 16-36% 1-3y, 4y OS
High ≥5, 29% 3-4; 7-7, 37% 2-3y

37.3.5 Management

Symptom-Directed: - JAK inhibitors (ruxolitinib, 1st-line): constitutional/spleen sx - Spleen ↓ ~35% at 36w vs ~1% placebo - Concerns: myelosuppression, infections (opportunistic w/ JAK inhibition) - Fedratinib: JAK2-selective; JAKARTA trial high-risk - Pacritinib, momelotinib: alternatives if ruxolitinib-intolerant - ESA ± androgens: anemia if EPO <500 mU/mL - Anagrelide: extreme thrombocytosis (>1500×10⁹/L)

Splenic Management: - Splenectomy: selected massive splenomegaly, medical failure - Risks: post-op morbidity/mortality, ↑ thrombocytosis, bleeding - Laparoscopic ↓ morbidity - Radiation: palliative for splenomegaly, lytic lesions, EMH

Anemia: - Transfusion as needed; risk iron overload - Iron chelation (deferasirox) prevent organ damage - Goal: transfusion independence

Allogeneic SCT (only cure): - Candidate: age, comorbidities, donor, disease burden - Disease-related mortality: 10-50% post-Tx - RIC improving outcomes - MYSEC-PM & DIPSS+ guide timing

Accelerated/Blast Phase: - Hypomethylating agents (azacitidine, decitabine): ~20-30% response - Not 1st-line early/stable MF - AML-like chemo: often ineffective; median ~6mo survival - Consider trial enrollment vs supportive care

Prefibrotic MF: - Early detection: reversal possible w/ tx - JAK inhibitors: may stabilize/improve fibrosis if caught early - Histologic improvement in small % patients

37.4 Clinical Pearls

PV: - Thrombosis risk >> hemorrhage; high-risk need cytoreduction + ASA ± anticoag - Hct >45% ↑↑ thrombotic events - Phlebotomy safe/effective low-risk; HU/JAK2i spare needles high-risk

ET: - JAK2- low-risk: observation alone acceptable - JAK2+ or age ≥60: add ASA - CALR-mutant ET: anagrelide > HU (some data) - BM biopsy: exclude reactive thrombocytosis

MF: - Allo-SCT: only cure; IPSS/DIPSS/MYSEC-PM critical timing - Ruxolitinib: ↓ spleen/sx but no JAK2 mutation reversal, no transformation prevention - High-risk/blast: poor prognosis; trial vs supportive care