What are the dosing guidelines and monitoring recommendations for ruxolitinib in patients with intermediate- or high-risk myelofibrosis, hydroxyurea‑resistant polycythemia vera, and steroid‑refractory acute graft‑versus‑host disease?

Ruxolitinib Dosing and Monitoring Guidelines

Myelofibrosis: Intermediate-2 or High-Risk Disease

Ruxolitinib is the first-line JAK inhibitor for intermediate-2 or high-risk myelofibrosis with symptomatic splenomegaly, providing marked and durable reductions in spleen size and constitutional symptoms regardless of JAK2 mutation status. 1, 2

Initial Dosing Strategy

• Starting dose is determined by baseline platelet count: 2
  • Platelets 100-200 × 10⁹/L: Start 15 mg twice daily
  • Platelets >200 × 10⁹/L: Start 20 mg twice daily
  • Platelets 50-100 × 10⁹/L: Start 5 mg twice daily (based on trials in patients with low platelet counts) 2

Dose Titration and Management

• Titrate dose based on efficacy and tolerability, with adjustments every 2-4 weeks 2
• Primary dose-limiting toxicities are anemia and thrombocytopenia, which are managed with dose reduction, treatment interruption, or transfusions rather than discontinuation 2, 3
• Expected response timeline: 3
  • Spleen volume reduction ≥35% achieved in 32% of patients by week 24
  • Median duration of response not reached, with 80% maintaining response at 12 months

Monitoring Requirements

• Complete blood counts: Monitor at baseline, every 2-4 weeks during dose titration, then regularly to detect cytopenias 1, 2
• Spleen assessment: Use imaging (MRI or CT) or palpation to assess spleen volume reduction 3
• Symptom burden: Utilize MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) to quantify symptom improvement 4, 1
• Bone marrow examination: Perform as clinically indicated to monitor disease progression 1

Special Considerations for Transplant Candidates

• Allogeneic stem cell transplantation remains the only curative option for myelofibrosis 1, 5
• Ruxolitinib is widely used for spleen reduction before transplant, though optimal duration before HSCT is unknown 4, 1
• Transplant eligibility criteria: 4, 1
  • Age <70 years with intermediate-2 or high-risk disease
  • Age <65 years with intermediate-1 risk disease plus poor-risk features (transfusion dependence, >2% circulating blasts, adverse cytogenetics)

Polycythemia Vera: Hydroxyurea-Resistant or Intolerant

Ruxolitinib is the preferred second-line therapy for polycythemia vera patients who meet criteria for hydroxyurea resistance or intolerance, achieving hematocrit control in 60% and symptom reduction ≥50% in 49% of patients. 4, 1

Defining Hydroxyurea Resistance/Intolerance

Patients must meet at least one of the following criteria: 4

1. Need for phlebotomy to maintain hematocrit <45% after 3 months of ≥2 g/day hydroxyurea
2. Uncontrolled myeloproliferation (platelets >400 × 10⁹/L AND WBC >10 × 10⁹/L) after 3 months of ≥2 g/day hydroxyurea
3. Failure to reduce massive splenomegaly (>10 cm from costal margin) by ≥50% or relieve splenomegaly symptoms after 3 months of ≥2 g/day hydroxyurea
4. Cytopenias at lowest effective hydroxyurea dose (ANC <1.0 × 10⁹/L, platelets <100 × 10⁹/L, or hemoglobin <10 g/dL)
5. Unacceptable hydroxyurea toxicity (leg ulcers, mucocutaneous manifestations, GI symptoms, pneumonitis, fever)

Dosing and Expected Outcomes

• Use same platelet-based dosing strategy as myelofibrosis 2
• Primary endpoint achievement at 32 weeks: 4
  • Hematocrit control without phlebotomy: 60% vs 20% with best available therapy
  • Spleen volume reduction ≥35%: 38% vs 1%
  • Complete hematologic remission: 24% vs 9%
  • Symptom burden reduction ≥50%: 49% vs 5%

Long-Term Efficacy and Safety (80-week data)

• Probability of maintaining complete hematologic remission for ≥80 weeks: 69% 4
• 90% of patients on ruxolitinib at week 32 required no phlebotomies through week 80 4
• Thromboembolic event rates per 100 patient-years: 4
  • Ruxolitinib arm: 1.8% (all grades), 0.9% (grade 3/4)
  • Best available therapy: 8.2% (all grades), 2.7% (grade 3/4)

Monitoring and Safety Considerations

• Herpes zoster infection risk is elevated: 4
  • 6.4% incidence through week 32 vs 0% with standard therapy
  • Rate of 5.3-5.4 per 100 patient-years with extended follow-up
  • Consider prophylactic antiviral therapy in high-risk patients
• Infection rates (all grades): 41.8% with ruxolitinib vs 36.9% with standard therapy 4
• Grade 3/4 anemia: 2% with ruxolitinib vs 0% with best available therapy 4

Steroid-Refractory Acute Graft-Versus-Host Disease

Ruxolitinib received FDA approval in May 2019 for steroid-refractory acute GVHD in patients ≥12 years old, based on the Phase II REACH1 trial demonstrating efficacy in this setting. 6

Dosing for GVHD

• Standard dose: 5 mg twice daily 7
• Continue until stable engraftment is achieved 7

Peritransplantation Use in Myelofibrosis Patients

Continuing ruxolitinib through transplant (2 × 5 mg daily until stable engraftment) dramatically reduces acute GVHD incidence without increasing graft failure. 7

• Acute GVHD incidence at day +100: 7
  • Grade II-IV: 8% (only 1 patient each with grade I or II)
  • No nonrelapse mortality observed
• Engraftment outcomes: 7
  • Median leukocyte engraftment: 12 days (range 11-18)
  • Complete chimerism: 11/12 patients at median 40 days
  • Molecular clearance of driver mutation: 10/12 patients at median 32 days

Safety Monitoring for GVHD Indication

• CMV reactivation occurred in 41% of patients, all resolved with ganciclovir 7
• Cytopenia after engraftment may require discontinuation (occurred in 2/12 patients on days 17-18) 7
• No withdrawal syndrome observed except one case of fever of unknown origin 7
• Inflammatory cytokine levels (IL-8, IL-10, IL-6, TNFR2, INF-α, INF-β) were reduced after ruxolitinib treatment 7

Late GVHD After Immunosuppression Taper

• After day +100,4/12 patients developed acute GVHD following cyclosporine taper (grades I-III) 7
• All patients remained alive at median 17-month follow-up 7

Critical Precautions Across All Indications

• Dose-related cytopenias are common but rarely require discontinuation; manage with dose modification and transfusion support 2, 3
• Ruxolitinib is effective independent of JAK2V617F, CALR, or MPL mutational status 4, 1, 2
• Disease-modifying activity is limited; consider rational combinations with other targeted agents, particularly in myelofibrosis 4, 8
• Appropriate dose titration based on platelet counts and clinical response is essential to optimize benefit 2