How should I treat myelofibrosis?

Treatment of Myelofibrosis

Treatment of myelofibrosis is determined by risk stratification using DIPSS-Plus at diagnosis, with allogeneic hematopoietic stem cell transplantation (alloSCT) being the only curative option for intermediate-2 and high-risk patients, while JAK inhibitors provide symptom control for non-transplant candidates. 1, 2

Risk Stratification Framework

Begin by stratifying all patients using the International Prognostic Scoring System (IPSS) at diagnosis, then transition to Dynamic IPSS-Plus (DIPSS-Plus) for ongoing assessment. 1, 2

• DIPSS-Plus incorporates: age >65 years, constitutional symptoms, hemoglobin <10 g/dL, WBC >25 × 10^9/L, peripheral blood blasts ≥1%, platelet count <100 × 10^9/L, unfavorable karyotype, and transfusion dependency 2
• Risk categories: Low (score 0), Intermediate-1/INT-1 (score 1-2), Intermediate-2/INT-2 (score 3-4), High (score 5-6) 1, 2
• Assess symptom burden using MPN Symptom Assessment Form (MPN-SAF) at baseline for all patients 1, 2

Treatment by Risk Category

Low-Risk Disease (Score 0)

For asymptomatic low-risk patients, observation with monitoring every 3-6 months is appropriate. 1

• Monitor for signs/symptoms of disease progression including worsening cytopenias, increasing blast percentage, and constitutional symptoms 1, 3
• Bone marrow biopsy should be performed at diagnosis and when clinical progression is suspected 1
• For symptomatic patients, consider ruxolitinib or interferons (interferon alfa-2b, pegylated interferon alpha-2a, pegylated interferon alpha-2b) 1
• Clinical trial enrollment is an appropriate option 1

Intermediate-1 Risk Disease (INT-1)

Most INT-1 patients can be observed unless they have high-risk features warranting transplant evaluation. 1, 2

• Evaluate for alloSCT if any of the following are present: platelet count <100 × 10^9/L, complex cytogenetics, refractory transfusion-dependent anemia, peripheral blood blasts >2%, or high-risk mutations (ASXL1, SRSF2, U2AF1) 1, 2, 4
• For symptomatic patients not requiring transplant, initiate ruxolitinib 1
• Continue observation with monitoring every 3-6 months for asymptomatic patients without high-risk features 1

Intermediate-2 and High-Risk Disease (INT-2/High)

Allogeneic HCT is the recommended treatment for all INT-2 and high-risk patients who are transplant candidates, as it is the only curative therapy. 1, 2, 3

• Transplant candidacy is based on: age, performance status, major comorbidities, psychosocial status, patient preference, and caregiver availability 1
• Patients may proceed directly to transplant or receive bridging therapy to reduce marrow blasts to acceptable levels 1
• For non-transplant candidates with platelets >50 × 10^9/L: initiate ruxolitinib as first-line therapy 1
• For non-transplant candidates with platelets ≤50 × 10^9/L: consider pacritinib (FDA-approved for platelet counts <50 × 10^9/L) or clinical trial 1, 5

JAK Inhibitor Therapy

Ruxolitinib (First-Line for Most Patients)

Ruxolitinib is the standard first-line JAK inhibitor for symptomatic patients with adequate platelet counts (>50 × 10^9/L). 1, 4

• Provides symptom relief and splenic volume reduction but does not modify underlying disease or eliminate the malignant clone 2, 4
• Monitor response using International Working Group (IWG) criteria 1
• Clinical benefit may not reach IWG response thresholds; continuation is recommended based on clinician discretion if patient derives benefit 1
• Critical pitfall: Do not rely on JAK inhibitor monotherapy for disease modification—these agents provide symptom control only 2

Alternative JAK Inhibitors

For patients with platelet counts <50 × 10^9/L, pacritinib is FDA-approved and demonstrated 29% spleen volume reduction ≥35% at Week 24 versus 3.1% with best available therapy. 5

• Fedratinib is approved for patients failing ruxolitinib 4
• Momelotinib shows erythropoietic benefits in addition to spleen and symptom responses 4

Management of Myelofibrosis-Associated Anemia

Erythropoiesis-stimulating agents (ESAs) are first-line for patients with erythropoietin levels <125 mU/mL, producing improvements in 23-60% of patients. 2

• Androgens are second-line: testosterone enanthate 400-600 mg weekly, oral fluoxymesterone 10 mg three times daily, or danazol 400-600 mg daily improve anemia in 30-60% 2
• Corticosteroids and immunomodulators are additional options 1
• Transfusion need in the first year identifies patients with median survival <5 years, warranting transplant evaluation 3

Management of Splenomegaly

Hydroxyurea is first-line treatment for PMF-associated splenomegaly in patients not requiring JAK inhibitors. 1

• Splenectomy indications: symptomatic portal hypertension, drug-refractory painful splenomegaly, or frequent RBC transfusions 1
• Involved field radiotherapy for non-hepatosplenic extramedullary hematopoiesis and extremity bone pain 4

Disease Progression Management

Accelerated Phase (Blasts 10-19%)

Induce remission with hypomethylating agents (azacitidine or decitabine) or intensive induction chemotherapy, followed by alloSCT for transplant candidates. 1

Blast Phase/AML (Blasts ≥20%)

For transplant candidates, use hypomethylating agents or intensive induction chemotherapy followed by alloSCT. 1

• For non-transplant candidates, use hypomethylating agents or low-intensity induction chemotherapy 1

Monitoring Strategy

Perform regular monitoring every 3-6 months including complete blood counts, symptom assessment, and physical examination for splenomegaly. 1, 2

• Bone marrow biopsy at diagnosis and when clinical progression is suspected (increased symptoms, worsening cytopenias, rising blast count) 1
• Additional molecular marker monitoring with next-generation sequencing for higher-risk patients 1
• Watch for progression to accelerated/blast phase, new thrombosis, major bleeding, progressive splenomegaly, or worsening constitutional symptoms 6

Critical Pitfalls to Avoid

Delaying alloSCT evaluation in INT-2 and high-risk patients significantly shortens survival—transplantation is the only curative option and should be pursued urgently in eligible patients. 2, 3

• Do not use JAK inhibitors as disease-modifying therapy; they provide symptom control without eliminating the malignant clone 2
• Do not overlook high-risk features in INT-1 patients (low platelets, complex cytogenetics, high-risk mutations) that warrant transplant evaluation 2
• Recognize that transfusion dependency and unfavorable cytogenetics predict median survival <5 years, necessitating aggressive management 3