What are the management options for myelofibrosis?

Management of Myelofibrosis

Management of myelofibrosis is fundamentally determined by risk stratification using DIPSS-Plus scoring, with allogeneic hematopoietic stem cell transplantation (alloSCT) being the only curative option for intermediate-2 and high-risk patients, while ruxolitinib serves as first-line therapy for symptomatic splenomegaly in non-transplant candidates. 1

Initial Risk Stratification

Risk assessment must be performed at diagnosis using the International Prognostic Scoring System (IPSS), with Dynamic IPSS-Plus (DIPSS-Plus) preferred for ongoing risk stratification throughout the disease course. 1, 2

• DIPSS-Plus incorporates adverse prognostic factors including age >65 years, constitutional symptoms, hemoglobin <10 g/dL, white blood cell count >25 × 10^9/L, peripheral blood blasts ≥1%, platelet count <100 × 10^9/L, unfavorable karyotype, and transfusion dependency 3
• Risk categories are: Low (risk score 0), Intermediate-1 (INT-1, score 1-2), Intermediate-2 (INT-2, score 3-4), and High (score 5-6) 1
• Additional high-risk mutations (ASXL1, EZH2, IDH1/IDH2, SRSF2) should be assessed as they adversely affect survival and inform transplant decisions 1, 3

Management by Risk Category

Low-Risk Disease (Risk Score 0)

Asymptomatic low-risk patients should be observed with monitoring every 3-6 months for disease progression. 1, 2

• For symptomatic patients, assess symptom burden using MPN-SAF TSS-10 items 1
• Treatment options include ruxolitinib or interferons (interferon alfa-2b, pegylated interferon alpha-2a, pegylated interferon alpha-2b) 1
• Clinical trial enrollment should be considered 1

Intermediate-1 Risk Disease

INT-1 patients who are asymptomatic should be observed, while symptomatic patients should receive ruxolitinib. 1, 2

• Observation with monitoring every 3-6 months is appropriate for asymptomatic patients 1
• Ruxolitinib is recommended for symptomatic patients with splenomegaly 1
• Allogeneic HCT should be evaluated for INT-1 patients with low platelet counts (<100 × 10^9/L), complex cytogenetics, refractory transfusion-dependent anemia, peripheral blood blasts >2%, or high-risk mutations 1

Intermediate-2 and High-Risk Disease

All INT-2 and high-risk patients should be evaluated for allogeneic HCT, which is the only curative therapy and recommended for all transplant-eligible patients. 1, 2

For Transplant Candidates:

• Allogeneic HCT should be performed in transplant-eligible patients younger than 70 years with INT-2 or high-risk disease 1, 2, 3
• Ruxolitinib is widely used for spleen reduction before transplantation 2
• The transplant procedure should be performed in a controlled setting 1

For Non-Transplant Candidates:

• Ruxolitinib is the first-line therapy for symptomatic splenomegaly in patients with platelets >50 × 10^9/L 1, 2
• Ruxolitinib achieves spleen volume reduction ≥35% in approximately 60% of myelofibrosis patients and provides durable symptom control 4
• Ruxolitinib improves overall survival in INT-2 or high-risk myelofibrosis compared to placebo and best available therapy 4, 2
• For patients with platelets ≤50 × 10^9/L, clinical trial enrollment is preferred 1
• Patients with symptomatic anemia only should be managed according to anemia-specific protocols 1

Management of Myelofibrosis-Associated Anemia

For anemia with hemoglobin <10 g/dL, treatment should be initiated based on erythropoietin levels and transfusion dependency. 1

• Erythropoiesis-stimulating agents are first-line for patients with erythropoietin levels <125 mU/mL, producing improvements in 23-60% of patients 1
• If no response after 3 months, erythropoiesis-stimulating agents should be stopped 1
• Androgens (testosterone enanthate 400-600 mg weekly, oral fluoxymesterone 10 mg three times daily) or danazol 400-600 mg daily improve anemia in 30-60% of patients 1
• Danazol should be maintained for at least 6 months, then progressively reduced to the minimum necessary dose 1
• Low-dose thalidomide (50 mg/day) combined with prednisone (15-30 mg/day) provides 23-29% response rates 1
• Lenalidomide combined with low-dose prednisone produces 19% response rates and is the treatment of choice for MF patients with 5q deletion 1
• Corticosteroids alone (0.5-1.0 mg/kg/day) may be used for refractory anemia in patients unresponsive to other therapies 1

Special Considerations and Monitoring

Ruxolitinib-Specific Considerations

• Ruxolitinib is effective independent of JAK2V617F, CALR, or MPL mutational status 2
• The drug provides symptom control and reduces splenomegaly but does not eliminate the malignant clone 4
• Only a minority of patients experience reduction in JAK2 allelic burden or improvement in bone marrow fibrosis with ruxolitinib monotherapy 4, 2
• Myelosuppression is a common adverse effect that may limit use in patients with baseline cytopenias 4

Monitoring Requirements

• Assess symptom burden at baseline using MPN Symptom Assessment Form (MPN-SAF-20 items) for all patients 1
• Monitor for signs and symptoms of disease progression every 3-6 months 1
• Bone marrow aspirate and biopsy should be performed at diagnosis and as clinically indicated when supported by increased symptoms and signs of progression 1
• Regular blood count monitoring is essential to detect cytopenias and assess response 2

Hydroxyurea Considerations

• Hydroxyurea is a human carcinogen with reported secondary leukemia and skin cancer in patients receiving long-term therapy for myeloproliferative disorders 5
• Monitor for myelosuppression, vasculitic toxicities, and pulmonary toxicity 5
• Avoid live vaccines in patients taking hydroxyurea 5
• Reduce dose by 50% in patients with creatinine clearance <60 mL/min 5

Critical Pitfalls to Avoid

• Do not delay allogeneic HCT evaluation in INT-2 and high-risk patients, as this is the only curative option and survival is significantly shortened without transplantation 1, 2, 3
• Avoid using hydroxyurea as first-line therapy in myelofibrosis, as it is associated with leukemogenic risk and is not recommended in current guidelines 5
• Do not rely solely on JAK inhibitor monotherapy for disease modification, as these agents primarily provide symptom control without eliminating the malignant clone 4, 2
• Referral to specialized centers with expertise in MPN management is strongly recommended for all patients diagnosed with myelofibrosis 1
• Do not withhold treatment in symptomatic INT-1 patients, as they may benefit from ruxolitinib or should be considered for transplant if high-risk features are present 1