What are the recommendations for using JAK (Janus Kinase) 2 inhibitors, such as Ruxolitinib (Jakafi), in the treatment of myeloproliferative neoplasms?

JAK2 Inhibitors in Myeloproliferative Neoplasms

Ruxolitinib is the first-line JAK2 inhibitor for intermediate-2 or high-risk myelofibrosis with symptomatic splenomegaly, and the preferred second-line therapy for polycythemia vera patients who are resistant or intolerant to hydroxyurea. 1, 2

Primary Indications and Evidence Base

Myelofibrosis (MF)

• Ruxolitinib improves overall survival in intermediate-2 or high-risk MF compared to placebo and best available therapy, despite extensive crossover in trials 1
• The drug provides rapid and durable reduction in splenomegaly (51% response rate) and constitutional symptoms (42% response rate) regardless of JAK2 mutation status 1, 3, 4
• Ruxolitinib is effective independent of JAK2V617F, CALR, or MPL mutational status 1
• In a minority of patients, ruxolitinib reduces JAK2 allelic burden and improves bone marrow fibrosis 1

Polycythemia Vera (PV)

• Ruxolitinib is approved for second-line treatment of PV after hydroxyurea resistance or intolerance 1
• In the RESPONSE trial, 60% of ruxolitinib patients achieved hematocrit control versus 20% with standard therapy, and 49% achieved ≥50% reduction in total symptom score versus 5% 1
• Spleen volume reduction ≥35% was achieved in 38% of ruxolitinib patients 1
• After 10 years of postmarketing data, ruxolitinib demonstrates sustained efficacy in blood count control, symptom improvement, and reduction of JAK2V617F allele burden 5

Dosing Strategy and Management

Starting Doses

• Dosing must be based on baseline platelet counts to minimize myelosuppression 6
• Starting doses should follow prescribing information recommendations based on platelet levels 6
• Dose-escalation approach at therapy initiation is only recommended for patients with platelet counts 50-100 × 10⁹/L 6

Dose Optimization

• Maximum tolerated doses should be maintained whenever possible to prevent loss of treatment response 6
• Extended treatment interruptions should be avoided as discontinuation leads to symptom return within 1 week 4
• Close monitoring of blood counts, particularly during the first 8-12 weeks, is essential to avoid unnecessary cytopenias that may prompt premature discontinuation 6
• Dose adjustments are required if hemoglobin, absolute lymphocyte count, or absolute neutrophil count fall below specific thresholds 7

Laboratory Monitoring Requirements

Baseline Testing

• Complete blood count with differential, liver function tests, renal function tests, and lipid panel must be obtained before initiating therapy 7
• Tuberculosis screening, hepatitis B and C testing should be performed prior to initiation 7
• HIV testing should be considered in high-risk patients 7

Ongoing Monitoring Schedule

• All laboratory tests should be repeated 4-12 weeks after initiation 7
• Laboratory monitoring should continue every 3-6 months during maintenance therapy 7
• For MF patients, lactate dehydrogenase (LDH) should be monitored as a marker of disease activity 7
• Regular spleen size assessment and symptom burden evaluation using validated instruments (MPN-SAF) are recommended 7, 2

Critical Monitoring Pitfall

• CRP and ESR may normalize due to JAK inhibition even when disease activity persists, potentially masking infections 7
• Disease-specific activity measures that don't rely solely on CRP or ESR should be used 7

Hematologic Toxicity Management

Expected Cytopenias

• Myelosuppression is the primary toxicity, with decreases in hemoglobin and platelet counts particularly during the first 8-12 weeks 6, 4
• Anemia and thrombocytopenia are dose-dependent and manageable through careful dose titration 8, 6

Management Approach

• Dose reductions should be implemented based on platelet count thresholds per prescribing information 6
• For abrocitinib specifically, treatment is not recommended if platelet count is below a certain threshold and should be stopped if platelets fall further 7
• Blood count monitoring and dose titration are essential to optimize therapy 4

Combination Therapy and Special Populations

Rational Combinations in MF

• Ruxolitinib combined with panobinostat (HDAC inhibitor) at 15 mg twice daily and 25 mg three times weekly showed reductions in spleen volume and JAK2 allelic burden at earlier time points than ruxolitinib alone 1
• Ruxolitinib plus azacitidine produced 82% response rate with median time to response of 1 month; 27% had improvement in bone marrow fibrosis grade 1
• Ruxolitinib is safely combined with hypomethylating agents in patients with elevated blasts 3

Refractory Disease

• Ruxolitinib remains active in patients previously treated with another JAK inhibitor 3
• For patients with post-MPN myelodysplastic syndrome or acute myeloid leukemia, azacitidine produced 52% overall response rate with median overall survival of 11 months 1

Allogeneic Stem Cell Transplantation Considerations

• Allogeneic HSCT remains the only potential cure for MF and is recommended for transplant-eligible patients younger than 70 years with intermediate-2 or high-risk disease 1
• HSCT is also recommended for patients younger than 65 years with intermediate-1 risk disease who have red cell transfusion dependence, >2% circulating blasts, or adverse cytogenetics 1
• Ruxolitinib is widely used for spleen shrinkage before HSCT, though optimal duration of JAK inhibitor therapy before transplantation remains unknown 1
• There is emerging interest in using JAK1/2 inhibitors post-HSCT for treating graft-versus-host disease 1

Safety Considerations

• Specific precautions apply to patients with or at risk of serious infections 4
• Regular skin examinations should be performed for detection of skin cancer 7
• Lipid panel monitoring is necessary as JAK inhibitors increase total cholesterol, HDL, LDL, and triglycerides 7