What is the management approach for bone marrow fibrosis?

Management of Bone Marrow Fibrosis

Risk Stratification Determines Treatment Intensity

Allogeneic hematopoietic stem cell transplantation (AHSCT) is the only curative treatment for myelofibrosis and should be offered to transplant-eligible patients with intermediate-2 or high-risk disease (median survival <5 years), as well as selected patients younger than 65 years with intermediate-1 risk disease who have poor-risk features including transfusion dependence, >2% circulating blasts, or adverse cytogenetics. 1

• Use the International Prognostic Scoring System (IPSS) at diagnosis or Dynamic IPSS (DIPSS) at any time during disease course to stratify patients 1, 2
• AHSCT is justified when median survival is expected to be <5 years, which includes IPSS intermediate-2 and high-risk categories 1
• For transplant-eligible patients (age <70 years for intermediate-2/high-risk; age <65 years for intermediate-1 with poor-risk features), AHSCT offers 40-70% cure rates despite 30% treatment-related mortality at 1 year 1
• Reduced-intensity conditioning regimens have broadened AHSCT availability to older patients, though direct comparison to myeloablative conditioning is lacking 1

JAK Inhibitors for Non-Transplant Candidates

Ruxolitinib is the first-line pharmacologic therapy for symptomatic myelofibrosis, achieving ≥35% spleen volume reduction and improving overall survival in intermediate-2 and high-risk patients, though it is not curative and has limited disease-modifying effects. 1

• Ruxolitinib improves survival compared to placebo and best available therapy despite extensive crossover in COMFORT-I and COMFORT-II trials 1
• The drug is effective regardless of JAK2 mutational status 1
• Ruxolitinib reduces JAK2 allele burden and improves bone marrow fibrosis in only a minority of patients 1, 3
• Main adverse events include thrombocytopenia and worsening anemia, especially early in therapy; increased infection risk also occurs 1
• Critical warning: Abrupt ruxolitinib withdrawal can provoke shock-like syndrome due to re-emergence of suppressed inflammatory cytokines; withdrawal must be tapered 1

Symptom-Directed Management

Anemia Management

• Initiate treatment when hemoglobin <10 g/dL 1
• First-line options include corticosteroids (0.5-1.0 mg/kg/day), androgens (testosterone enanthate 400-600 mg weekly or oral fluoxymesterone 10 mg three times daily), or danazol 600 mg/day with response rates of 30-40% 1
• Lenalidomide is preferred in patients with del(5q) 1
• Thalidomide 50 mg/day combined with prednisone 15-30 mg/day shows approximately 20% response rates 1
• Erythropoiesis-stimulating agents can be considered 1

Splenomegaly Management

• Hydroxyurea is the drug of choice for symptomatic splenomegaly, achieving approximately 40% spleen volume reduction 1
• Alternative myelosuppressive agents for hydroxyurea-refractory disease include intravenous cladribine (5 mg/m²/day for 5 consecutive days, repeated for 4-6 monthly cycles), oral melphalan (2.5 mg three times weekly), or oral busulfan (2-6 mg/day with close blood count monitoring) 1
• Involved-field radiotherapy (0.1-0.5 Gy in 5-10 fractions) provides transient symptomatic relief (median duration 3-6 months) but carries >10% mortality risk 1

Splenectomy Considerations

• Indications: symptomatic portal hypertension (variceal bleeding, ascites), drug-refractory marked splenomegaly causing pain or severe cachexia, or established transfusion-dependent anemia 1
• Perioperative mortality is 5-10% with complications occurring in approximately 50% of patients 1
• Requires good performance status and absence of disseminated intravascular coagulation 1
• Prophylactic cytoreduction and anticoagulation are mandatory; maintain platelet count <400 × 10⁹/L to prevent postoperative extreme thrombocytosis 1
• Splenectomy is generally not recommended before AHSCT 1

Constitutional Symptoms

• Constitutional symptoms (fatigue, weight loss, cachexia, night sweats, fever, bone pain) often respond to treatment directed at splenomegaly 1
• JAK inhibitors provide significant symptom improvement; in the RESPONSE trial, 49% of ruxolitinib patients achieved ≥50% reduction in total symptom score versus 5% with standard therapy 1

Non-Hepatosplenic Extramedullary Hematopoiesis

• Low-dose radiation therapy (0.1-1 Gy in 5-10 fractions) is the treatment of choice for symptomatic non-hepatosplenic extramedullary hematopoiesis, most commonly affecting the thoracic vertebral column 1

Monitoring and Response Assessment

• Monitor JAK2V617F allele burden post-AHSCT to predict relapse 1
• Assess disease activity using spleen size, blood counts, peripheral blood leukoerythroblastosis, serum lactate dehydrogenase, circulating CD34 cells, and bone marrow morphology/fibrosis 1
• Regular assessment every 3-6 months should include complete blood counts, evaluation for thrombotic/bleeding events, and splenomegaly progression 4, 2

Special Considerations

Thrombosis Prevention

• Low-dose aspirin (81-100 mg daily) should be initiated for all patients without contraindications 4
• Cytoreductive therapy (hydroxyurea first-line for older patients; interferon for younger patients or those of childbearing age) should be used to control myeloproliferation and reduce thrombotic risk 4

Blast-Phase Transformation

• Blast-phase myelofibrosis has median survival of 6 months with extremely poor treatment outcomes 1
• Selected candidates should receive aggressive induction chemotherapy followed by consolidation with AHSCT 1
• Complete remission may not be required before transplantation if disease reverts to chronic phase 1