Ruxolitinib Treatment Protocol for Myelofibrosis and Polycythemia Vera
Indications and Patient Selection
Ruxolitinib is approved as first-line therapy for intermediate-2 or high-risk myelofibrosis with symptomatic splenomegaly, and as second-line therapy for polycythemia vera patients with hydroxyurea resistance or intolerance. 1, 2
Myelofibrosis Indications
- Intermediate-2 or high-risk disease: Ruxolitinib is recommended as first-line therapy for splenomegaly 1, 2
- Intermediate-1 risk disease: Use ruxolitinib only in patients with highly symptomatic splenomegaly (≥5 cm below left costal margin) 1, 2
- Low-risk disease: Observation is preferred if asymptomatic; ruxolitinib may be considered if symptomatic 2
Polycythemia Vera Indications
Ruxolitinib is indicated for patients meeting criteria for hydroxyurea resistance/intolerance, defined as ANY of the following 1:
- Need for phlebotomy to maintain hematocrit <45% after 3 months of ≥2 g/day hydroxyurea
- Uncontrolled myeloproliferation (platelets >400 × 10⁹/L AND leukocytes >10 × 10⁹/L) after 3 months of ≥2 g/day hydroxyurea
- Failure to reduce massive splenomegaly by ≥50% after 3 months of ≥2 g/day hydroxyurea
- Cytopenias at lowest effective hydroxyurea dose (ANC <1.0 × 10⁹/L OR platelets <100 × 10⁹/L OR hemoglobin <100 g/L)
- Unacceptable hydroxyurea toxicity (leg ulcers, mucocutaneous manifestations, gastrointestinal symptoms, pneumonitis, fever)
Dosing Protocol
Initial Dosing Based on Platelet Count
For myelofibrosis, starting dose is determined by baseline platelet count 3, 4:
- Platelets >200 × 10⁹/L: Start 20 mg twice daily
- Platelets 100-200 × 10⁹/L: Start 15 mg twice daily
- Platelets 50-100 × 10⁹/L: Start 5 mg twice daily
- Platelets <50 × 10⁹/L: Ruxolitinib is not recommended
Dose Titration Strategy
Dose adjustments should be made based on efficacy and tolerability, with the goal of maintaining ≥10 mg twice daily for sustained clinical benefit 5, 3:
- Assess response every 4 weeks initially 3
- May increase dose by 5 mg twice daily increments if inadequate response and acceptable blood counts 3
- Maximum dose: 25 mg twice daily 3
- Critical caveat: Most patients with anemia or thrombocytopenia at diagnosis can maintain doses ≥10 mg twice daily with appropriate monitoring 5
Dose Modifications for Cytopenias
Dose-dependent cytopenias are the primary toxicity requiring management through dose reduction or temporary interruption, not permanent discontinuation 3, 4:
- Monitor CBC with differential at baseline, then every 2-4 weeks until stable, then every 3-6 months 6
- For significant cytopenias: reduce dose by 5 mg twice daily or interrupt temporarily 3
- Transfusion support for anemia is preferred over dose reduction when possible 3, 4
- Only 1.1% of patients discontinue for anemia or thrombocytopenia in real-world practice 5
Monitoring Requirements
Baseline Laboratory Assessment
Before initiating ruxolitinib, obtain 6:
- Complete blood count with differential
- Comprehensive metabolic panel (liver and renal function)
- Lipid panel
- Tuberculosis screening
- Hepatitis B and C testing
- HIV testing in high-risk patients
Ongoing Monitoring Schedule
Laboratory monitoring frequency 6:
- Weeks 4-12: CBC with differential, liver function tests, renal function tests
- Maintenance (every 3-6 months): CBC with differential, comprehensive metabolic panel, lipid panel
- Disease-specific: Lactate dehydrogenase for MPN disease activity 6
- Spleen assessment: Regular palpation or imaging for splenomegaly 6
- Symptom burden: Use MPN Symptom Assessment Form (MPN-SAF) 6, 2
Important Monitoring Caveats
CRP and ESR may normalize due to JAK inhibition even when disease activity persists, potentially masking infections 6. Do not rely solely on these markers for infection surveillance.
Expected Clinical Outcomes
Myelofibrosis
Ruxolitinib provides survival benefit compared to placebo or best available therapy, with rapid and durable spleen reduction and symptom improvement 1, 3:
- Spleen volume reduction ≥35% in majority of patients 3
- Symptom improvement in approximately 80% of patients 5
- Benefits sustained with continued therapy 4
- Improvement in bone marrow fibrosis occurs in minority of patients with long-term therapy 1
Polycythemia Vera
Ruxolitinib achieves superior hematocrit control, spleen reduction, and symptom improvement compared to standard therapy 1, 4, 7:
- 60% achieve hematocrit control versus 20% with standard therapy 1
- 38% achieve ≥35% spleen volume reduction versus 1% with standard therapy 1
- Significant reduction in phlebotomy requirements (median 4.0 to 0 per year) 7
- Reduction in JAK2V617F allele burden 7
- Lower thromboembolic event rate (1/110 versus 6/112 with standard therapy) 4
Critical Management Considerations
Discontinuation Syndrome
Abrupt discontinuation of ruxolitinib leads to rapid symptom return within 1 week 3. When stopping therapy is necessary, taper gradually rather than abrupt cessation.
Infection Risk
There is no increased risk of infection with ruxolitinib therapy compared to ruxolitinib-naïve MPN patients 8. Infections that occur are primarily grade 1-2 8. However, maintain vigilance for serious infections and perform appropriate screening before initiation 6.
Treatment Duration
Long-term therapy is required for disease-modifying effects such as bone marrow fibrosis regression 1. Treatment should be continued as long as clinical benefit is maintained and toxicity is manageable, with 76% of patients remaining on therapy at nearly 2 years in real-world practice 5.
Special Populations
- Anemia or thrombocytopenia at diagnosis: These patients can tolerate and benefit from ruxolitinib with appropriate dose adjustments and supportive care 5
- Newly diagnosed PV: Ruxolitinib is feasible, well-tolerated, and efficient as first-line therapy in clinical trials, though currently approved only for second-line use 7
- Transplant candidates: Optimal duration of JAK inhibitor therapy before allogeneic HSCT remains unknown 1