What are the treatment options for myelofibrosis?

Treatment Approach for Myelofibrosis

Treatment for myelofibrosis should be risk-stratified using the Dynamic International Prognostic Scoring System (DIPSS-Plus), with specific therapies determined by risk category and symptom burden. 1

Risk Stratification

First, all patients with myelofibrosis must undergo proper risk stratification:

• Assessment tools: DIPSS-Plus is preferred for risk stratification of myelofibrosis 1
• Required testing:
  • Bone marrow aspirate and biopsy with trichrome and reticulin stain
  • Bone marrow cytogenetics (karyotype ± FISH)
  • Molecular testing for JAK2 V617F mutations; if negative, test for CALR and MPL mutations
  • Assessment of symptom burden using MPN Symptom Assessment Form (MPN-SAF)
  • Complete blood count with differential
  • HLA testing if considering allogeneic stem cell transplantation

Treatment Algorithm by Risk Category

Low-Risk Myelofibrosis (Risk score = 0)

• Asymptomatic patients:

  • Observation with monitoring every 3-6 months for disease progression 1
  • Consider clinical trial enrollment

• Symptomatic patients:

  • Ruxolitinib for symptom control 1
  • Interferons (Interferon alfa-2b, pegylated interferon alpha-2a, or pegylated interferon alpha-2b) 1

Intermediate-1 Risk Myelofibrosis (INT-1) (IPSS=1, DIPSS-Plus=1, DIPSS=1-2)

• Observation if asymptomatic with monitoring for disease progression
• Ruxolitinib if symptomatic 1
• Allogeneic HCT for selected patients with low platelet counts and complex cytogenetics 1
• Clinical trial enrollment when available

Intermediate-2 (INT-2) or High-Risk Myelofibrosis

• Transplant candidates:

  • Allogeneic hematopoietic cell transplantation (HCT) - the only potentially curative treatment 1, 2

• Non-transplant candidates:

  • Ruxolitinib for symptom control and splenomegaly 3
  • Fedratinib for patients with symptomatic splenomegaly 3
  • Pacritinib for patients with platelet counts <50 × 10^9/L 4
  • Clinical trial enrollment when available

Management of Specific Complications

Anemia Management

• For hemoglobin <10 g/dL, consider:
  • Erythropoiesis-stimulating agents
  • Corticosteroids (0.5 to 1.0 mg/kg/d)
  • Androgens (testosterone enanthate 400-600 mg weekly or fluoxymesterone 10 mg tid)
  • Danazol (600 mg/d) - response rates of 30-40% 1
  • Low-dose thalidomide (50 mg/d) with prednisone (15-30 mg/d) 1, 2
  • Lenalidomide for patients with del(5)(q31) 1

Splenomegaly Management

• JAK inhibitors:

  • Ruxolitinib - demonstrated 35% or greater reduction in spleen volume in 37% of patients 1
  • Fedratinib - showed significant spleen volume reduction in JAKARTA trial 3
  • Pacritinib - particularly effective for patients with thrombocytopenia (platelet count <50 × 10^9/L) 4

• Splenectomy: Consider for patients with:

  • Refractory symptomatic splenomegaly
  • Refractory cytopenias
  • Significant portal hypertension
  • Frequent RBC transfusions with poor post-transfusion increments 1

Constitutional Symptom Management

• JAK inhibitors:
  • Ruxolitinib - improves fatigue, weight loss, night sweats, and bone pain 1, 5
  • Fedratinib - demonstrated 40% reduction in Total Symptom Score in JAKARTA trial 3

Special Considerations

• Thrombocytopenia: Pacritinib is specifically approved for patients with platelet counts <50 × 10^9/L 4

• JAK inhibitor discontinuation: Should be done gradually to avoid withdrawal syndrome with rebound of inflammatory symptoms 6

• Monitoring: All patients should be monitored every 3-6 months for:

  • Signs/symptoms of disease progression
  • Blood counts
  • Spleen size
  • Symptom burden using MPN-SAF TSS-10 1

Emerging Therapies

For patients who fail standard therapies, consider:

• Bromodomain inhibitors
• BCL-2/BCL-xL inhibitors
• Telomerase inhibitors
• TGF-β ligand traps (luspatercept, KER-050) for anemia 7
• Antifibrotic agents (PRM-151) 7

Common Pitfalls to Avoid

1. Delaying treatment in intermediate or high-risk patients - early intervention with JAK inhibitors may improve survival 8

2. Overlooking anemia management - anemia is associated with reduced survival and should be actively treated 9

3. Focusing solely on spleen reduction rather than symptom improvement and quality of life 5

4. Inappropriate risk stratification - using outdated prognostic models instead of DIPSS-Plus 1

5. Failure to refer to specialized centers with expertise in MPN management, which is strongly recommended for all patients diagnosed with myelofibrosis 1