What are the treatment options for myelofibrosis?

Treatment Options for Myelofibrosis

Ruxolitinib is the first-line treatment for patients with intermediate-2 or high-risk myelofibrosis presenting with symptomatic splenomegaly and constitutional symptoms. 1

Disease Classification and Risk Stratification

Before initiating treatment, patients with myelofibrosis should be classified according to risk:

• Low-risk: Observation alone is recommended for asymptomatic patients
• Intermediate-1 risk: Observation for asymptomatic patients; consider treatment for symptomatic patients
• Intermediate-2 or high-risk: Active treatment recommended

Risk stratification is typically performed using the International Prognostic Scoring System (IPSS), Dynamic IPSS (DIPSS), or DIPSS-plus.

Treatment Algorithm Based on Risk and Symptoms

Low or Intermediate-1 Risk (Asymptomatic)

• Recommendation: Observation alone for patients who lack significant symptoms 1

Symptomatic Disease (Any Risk Category)

Treatment is guided by the predominant symptoms:

For Splenomegaly:

1. First-line:

   • Ruxolitinib (JAK1/JAK2 inhibitor) - particularly effective for intermediate-2 or high-risk disease
   • For intermediate-1 risk, ruxolitinib is recommended for highly symptomatic splenomegaly 1
   • Hydroxyurea - approximately 40% response rate, though effects often short-lived 1, 2

2. Second-line (after ruxolitinib failure):

   • Other JAK inhibitors (fedratinib) 3
   • Ruxolitinib rechallenge - can be effective in patients who previously discontinued treatment 4
   • Splenectomy - for drug-refractory cases with painful splenomegaly or associated cachexia 1
   • Low-dose splenic radiation - for patients ineligible for splenectomy 1

For Anemia:

1. First-line options:

   • Erythropoiesis-stimulating agents (23-60% response)
   • Androgens (30-60% response)
   • Danazol (35% response)
   • Immunomodulating drugs (thalidomide, lenalidomide) with prednisone (19-29% response) 1

2. For refractory anemia:

   • Corticosteroids alone may provide modest hemoglobin increases 1
   • Lenalidomide is preferred for patients with 5q deletion 1

For Extra-Medullary Hematopoiesis:

• Low-dose radiation therapy (0.1 to 1 Gy in 5-10 fractions) 1

Curative Option - Allogeneic Stem Cell Transplantation (AlloSCT)

AlloSCT is currently the only potentially curative treatment for myelofibrosis 1.

Recommended for:

• Patients younger than 70 years with intermediate-2 or high-risk disease
• Patients younger than 65 years with intermediate-1 risk disease who have poor-risk features:
  • Transfusion-dependent anemia

  • 2% circulating blasts

  • Adverse cytogenetics
  • High-risk mutations 1

Important considerations:

• Treatment-related mortality is approximately 30% with conventional conditioning
• 5-year median survival with reduced-intensity conditioning is approximately 45% 1
• JAK inhibitors may be used before transplantation to reduce spleen size and improve symptoms 1

Monitoring Response to Treatment

Monitoring should include assessment of:

• Spleen size
• Blood counts
• Constitutional symptoms
• JAK2 or MPL mutant allele burden (particularly in AlloSCT setting)
• Bone marrow morphology and fibrosis 1

Treatment of Blast-Phase MPN

Blast-phase myelofibrosis has poor prognosis (median survival ~6 months) 1:

• Consider experimental or palliative therapy
• Selected candidates may benefit from aggressive induction chemotherapy followed by AlloSCT

Key Considerations and Pitfalls

1. Ruxolitinib discontinuation: Sudden withdrawal can provoke a shock-like syndrome due to re-emergence of suppressed inflammatory cytokines. Always taper the drug gradually. 1

2. Splenectomy complications: High perioperative mortality (5-10%) and postoperative complications (~50%) including bleeding, thrombosis, abscess, and extreme thrombocytosis. Requires careful patient selection. 1

3. Ruxolitinib limitations: Despite its benefits for symptoms and splenomegaly, over half of patients discontinue treatment within 2-3 years due to loss of response or side effects. 5

4. Cytopenias management: Thrombocytopenia and anemia are common with JAK inhibitors and should be managed with dose adjustments rather than discontinuation when possible. 1, 6