What is the initial treatment approach for patients with primary myelofibrosis (MPN-PMF)?

Initial Treatment Approach for Primary Myelofibrosis

The initial treatment of primary myelofibrosis must be stratified by risk category using MIPSS70+ version 2.0 or GIPSS scoring systems, with observation alone for very low/low-risk disease, allogeneic stem cell transplantation for very high/high-risk transplant-eligible patients, and symptom-directed therapy for intermediate-risk or transplant-ineligible patients. 1, 2, 3

Risk Stratification Is the Critical First Step

Before initiating any treatment, all patients require comprehensive risk assessment using validated prognostic systems 1, 2:

• MIPSS70+ version 2.0 incorporates genetic mutations (ASXL1, SRSF2, U2AF1-Q157, RAS/CBL), karyotype abnormalities, and clinical factors (age, hemoglobin, white blood cell count, platelet count, constitutional symptoms) 2, 3
• GIPSS uses exclusively mutations and karyotype, offering lower complexity 2, 3
• Both systems stratify patients into risk categories with dramatically different 10-year survival estimates: very low/low risk (56%-92%), intermediate (30%), high/very high (0-13%) 1, 2, 3

Key genetic markers to identify:

• Adverse mutations: SRSF2, ASXL1, U2AF1-Q157 (predict inferior survival); RAS/CBL (predict ruxolitinib resistance) 2
• Favorable mutations: Type 1/like CALR (associated with superior survival) 2
• Very high-risk karyotype: -7, inv(3), i(17q), +21, +19, 12p-, 11q- 2
• Favorable karyotype: normal, isolated +9, 13q-, 20q-, 1q abnormalities, loss of Y 2

Treatment Algorithm by Risk Category

Very Low and Low Risk Disease (10-year survival 56%-92%)

Observation alone without active treatment is recommended 1, 2, 3

• Treatment should only be initiated when specific symptoms develop requiring intervention 4
• Regular monitoring for disease progression and symptom development 1

Very High and High Risk Disease (10-year survival 0-13%)

Allogeneic hematopoietic stem cell transplantation (AHSCT) is the preferred treatment and only potentially curative option 1, 5, 2, 3

• AHSCT achieves cure rates of 40-70% despite 30% treatment-related mortality at 1 year 1
• Justified when median survival expected to be less than 5 years 1
• Reduced-intensity conditioning regimens enable transplantation in patients aged 45-70 years 6
• Complete remission is not required before transplantation if disease reverts to chronic phase 1

Intermediate Risk Disease (10-year survival 30%)

Selected patients younger than 65 years with poor-risk features should be considered for AHSCT 1

For transplant-ineligible intermediate-risk patients or those declining transplant, treatment should be symptom-directed 1, 2, 3:

• Ruxolitinib for symptomatic splenomegaly or constitutional symptoms 1, 5, 2
• Hydroxyurea for less severe splenomegaly or myeloproliferation 1, 5
• Enrollment in clinical trials is strongly encouraged 2, 3

Symptom-Directed Management for Non-Transplant Candidates

For Anemia (Hemoglobin <10 g/dL)

Initiate treatment with one of four proven effective agents 4, 1:

1. Corticosteroids: 0.5-1.0 mg/kg/day (response rate 30-40%) 4
2. Androgens: testosterone enanthate 400-600 mg weekly OR fluoxymesterone 10 mg three times daily (response rate 30-40%) 4
3. Danazol: 600 mg/day (response rate 30-40%) 4
4. Lenalidomide: preferred in presence of del(5q) (response rate ~20%) 4, 1

Common pitfall: Thalidomide at low doses (50 mg/day) combined with prednisone (15-30 mg/day) shows only ~20% response rate and is poorly tolerated 4

For Symptomatic Splenomegaly

The treatment hierarchy depends on risk category and symptom severity 1, 5:

First-line for intermediate-2/high-risk or highly symptomatic intermediate-1 risk:

• Ruxolitinib 200 mg twice daily achieves 35% spleen volume reduction and improves overall survival 1, 5, 2
• Effective regardless of JAK2 mutational status 1
• Main adverse events: thrombocytopenia, worsening anemia (especially early), increased infection risk 1

First-line for intermediate-1 risk without severe symptoms or low-risk:

• Hydroxyurea achieves ~40% spleen volume reduction 4, 1, 5
• Also controls symptomatic thrombocytosis and leukocytosis 4

For hydroxyurea-refractory disease:

• Alternative myelosuppressive agents: intravenous cladribine (5 mg/m²/day for 5 days, repeated monthly for 4-6 cycles), oral melphalan (2.5 mg three times weekly), or oral busulfan (2-6 mg/day with close blood count monitoring) 4, 1, 5

For drug-refractory symptomatic splenomegaly:

• Splenectomy remains viable with specific indications: symptomatic portal hypertension, drug-refractory marked splenomegaly, or established transfusion-dependent anemia 1, 5
• Perioperative mortality 5-10%, complications in ~50% of patients 1, 5
• Requires good performance status and absence of disseminated intravascular coagulation 1
• Prophylactic cytoreduction and anticoagulation recommended; maintain platelet count <400 × 10⁹/L to prevent postoperative extreme thrombocytosis 5

For transient symptomatic relief:

• Involved-field radiotherapy provides 3-6 months of relief from mechanical discomfort 4, 5
• Splenic irradiation: 0.1-0.5 Gy in 5-10 fractions, associated with >10% mortality from cytopenia consequences 4

For Constitutional Symptoms

Ruxolitinib is the treatment of choice for profound constitutional symptoms including fatigue, weight loss, cachexia, pruritus, night sweats, fever, and bone/joint pain 4, 2

Novel JAK2 Inhibitors for Specific Scenarios

Pacritinib is FDA-approved for patients with platelet count <50 × 10⁹/L 7, 2:

• Dosage: 200 mg orally twice daily 7
• Achieves 29% rate of ≥35% spleen volume reduction at Week 24 (vs 3.1% with best available therapy) 7
• Median spleen volume reduction 27.3% vs 0.9% with best available therapy 7
• Requires baseline CBC, coagulation testing, and ECG before starting 7
• Discontinue 7 days prior to elective surgery due to hemorrhage risk 7

Fedratinib is utilized in patients failing ruxolitinib 2

Momelotinib shows erythropoietic benefits in addition to spleen and symptom responses 2

Critical Management Principles

Thrombosis Prevention

Low-dose aspirin (81-100 mg daily) is recommended for all patients without contraindications 1, 5

Monitoring Disease Activity

Assess using multiple parameters: spleen size, blood counts, peripheral blood leukoerythroblastosis, serum lactate dehydrogenase, circulating CD34 cells, and bone marrow morphology/fibrosis 1

Important Caveats

• JAK2 inhibitors are palliative, not curative: Ruxolitinib has limited disease-modifying effects despite improving survival 1, 2
• Interferon therapy is poorly tolerated and has limited efficacy in PMF 4
• No firm data support iron chelation therapy in PMF 4
• Blast-phase transformation has median survival of 6 months; selected candidates should receive aggressive induction chemotherapy followed by AHSCT consolidation 1
• Leukemic transformation risk approaches 20% in first 10 years, highest in PMF (14.2%) vs PV (6.8%) or ET (3.8%) 4, 8