What is the recommended use and dosing of Ruxolitinib (Jakafi) in patients with myelofibrosis or polycythemia vera?

Ruxolitinib (Jakafi): Class, Pharmacology, and Clinical Use

Drug Classification and Mechanism

Ruxolitinib is a selective JAK1/JAK2 (Janus kinase) inhibitor that blocks the JAK/STAT signaling pathway, which is constitutively activated in myeloproliferative neoplasms regardless of mutation status. 1

• The drug inhibits both JAK1 and JAK2 kinases with high potency and selectivity 2, 3
• It works through both canonical and noncanonical JAK2 pathways to reduce cytokine signaling 1
• The therapeutic effect occurs independent of JAK2V617F, CALR, or MPL mutation status 1, 4

FDA-Approved Indications

Myelofibrosis (Primary Indication)

Ruxolitinib received full FDA approval in November 2011 for intermediate-2 or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. 3

Polycythemia Vera (Second-Line)

Ruxolitinib is approved as second-line therapy for polycythemia vera in patients who have inadequate response to or are intolerant of hydroxyurea. 1, 2

Recommended Use by Disease and Risk Category

For Myelofibrosis-Associated Splenomegaly

In intermediate-2 or high-risk disease, ruxolitinib is recommended as first-line therapy for splenomegaly. 5, 1

In intermediate-1 risk disease with highly symptomatic splenomegaly, ruxolitinib is recommended as first-line therapy. 1, 5

• For intermediate-1 risk without severe symptoms or low-risk disease, hydroxyurea remains first-line, with ruxolitinib reserved for hydroxyurea-refractory or intolerant patients 5
• Ruxolitinib demonstrated 28-32% of patients achieving ≥35% spleen volume reduction at weeks 24-48 versus 0% with best available therapy 4, 3
• The median duration of response was not reached, with 80% maintaining response at 12 months median follow-up 4

For Polycythemia Vera

Ruxolitinib is recommended as second-line therapy for PV patients with resistance or intolerance to hydroxyurea, defined by specific ELN criteria. 1

• In the RESPONSE trial, 21% of ruxolitinib patients achieved the composite endpoint (hematocrit control + ≥35% spleen reduction) versus 1% with standard therapy 6
• Hematocrit control was achieved in 60% versus 20% with standard therapy 6
• Complete hematologic remission occurred in 24% versus 9% with standard therapy 6

Clinical Benefits Beyond Spleen Reduction

Ruxolitinib provides significant symptom improvement and quality of life benefits in myelofibrosis. 4, 3

• 46% of patients achieved ≥50% reduction in total symptom score versus 5% with placebo 3
• In PV, 49% achieved ≥50% symptom reduction versus 5% with standard therapy 6
• The drug improves overall survival in intermediate-2 and high-risk myelofibrosis compared to placebo and best available therapy 1

Dosing Considerations and Monitoring

Dose-dependent cytopenias require careful blood count monitoring and dose titration to optimize therapy. 2

Key Hematologic Toxicities

• Grade 3-4 anemia occurs in 2% of patients 6
• Grade 3-4 thrombocytopenia occurs in 5% of patients 6
• These are managed with dose reduction, treatment interruption, or transfusion rather than discontinuation 4, 2
• Only one patient discontinued due to thrombocytopenia in major trials 4

Non-Hematologic Considerations

• Herpes zoster infection occurred in 6% of PV patients (all grade 1-2) 6
• Specific precautions apply for patients with or at risk of serious infections 2
• Nonhematologic adverse events are generally rare and mostly grade 1-2 4

Critical Clinical Pitfalls

Discontinuation of ruxolitinib leads to symptom return within 1 week, requiring careful management of treatment interruptions. 2

Ruxolitinib has limited disease-modifying effects—it does not significantly reduce bone marrow fibrosis, mutant allele burden, or prevent progression to acute myeloid leukemia. 7

• JAK2 allelic burden reduction and bone marrow fibrosis improvement occur only in a minority of patients 1
• The drug does not convincingly reduce thromboembolic events in PV 7
• Allogeneic stem cell transplantation remains the only curative option for myelofibrosis 1, 5

Role in Treatment Algorithm

For transplant-eligible patients with high or intermediate-2 risk myelofibrosis, allogeneic stem cell transplantation should be considered as the only curative approach, with ruxolitinib used for symptom control and spleen management. 1, 5

• The optimal duration of JAK inhibitor therapy before transplantation remains unknown 1
• Transplant is also recommended for intermediate-1 risk patients with refractory transfusion-dependent anemia, >2% peripheral blood blasts, adverse cytogenetics, or high-risk mutations 1, 5