What is myelofibrosis and how is it managed?

Myelofibrosis: Definition and Management

What is Myelofibrosis?

Myelofibrosis is a Philadelphia chromosome-negative myeloproliferative neoplasm characterized by bone marrow fibrosis, extramedullary hematopoiesis, splenomegaly, and constitutional symptoms, with a prevalence of approximately 13,000 cases in the United States. 1

Key Pathologic Features

• Bone marrow shows megakaryocyte proliferation with atypia (small to large megakaryocytes with aberrant nuclear/cytoplasmic ratio, hyperchromatic, bulbous, or irregularly folded nuclei) accompanied by reticulin or collagen fibrosis 1
• In prefibrotic disease, increased bone marrow cellularity with granulocytic proliferation and decreased erythropoiesis may occur without significant reticulin fibrosis 1
• Peripheral blood demonstrates leukoerythroblastosis (immature white and red blood cells) 1

Molecular Mutations

• JAK2 V617F mutation is present in approximately 50-60% of patients 1
• CALR mutations occur in 60-80% of JAK2/MPL-unmutated patients 1
• MPL mutations (W515K/L) are found in 5-8% of cases 1
• 10-15% remain "triple negative" for all three driver mutations 1

Diagnostic Criteria

WHO 2008 Criteria for Primary Myelofibrosis

Diagnosis requires all 3 major criteria plus 2 of 4 minor criteria: 1

Major Criteria:

1. Megakaryocyte proliferation and atypia with reticulin/collagen fibrosis (or prefibrotic changes) 1
2. Exclusion of PV, BCR-ABL1+ CML, MDS, and other myeloid disorders 1
3. JAK2 V617F, MPL, or CALR mutation present, OR absence of reactive causes of bone marrow fibrosis 1

Minor Criteria:

1. Leukoerythroblastosis 1
2. Elevated serum lactate dehydrogenase 1
3. Anemia 1
4. Palpable splenomegaly 1

Essential Diagnostic Workup

All patients require the following at diagnosis: 1

• Complete blood count with peripheral blood smear examination 1
• Bone marrow aspirate and biopsy with trichrome and reticulin staining 1
• Bone marrow cytogenetics (karyotype ± FISH) 1
• Molecular testing: JAK2 V617F first; if negative, test for CALR and MPL mutations 1
• Serum erythropoietin level 1
• Serum lactate dehydrogenase 1
• Assessment of symptom burden using MPN Symptom Assessment Form (MPN-SAF) 1
• HLA typing if considering allogeneic hematopoietic cell transplant 1

Risk Stratification

The Dynamic International Prognostic Scoring System (DIPSS)-Plus is the preferred risk stratification tool for myelofibrosis. 1, 2

DIPSS-Plus Risk Factors

Adverse prognostic factors include: 2

• Age >65 years 2
• Constitutional symptoms (weight loss >10% in 6 months, night sweats, fever >37.5°C) 2
• Hemoglobin <10 g/dL 2
• White blood cell count >25 × 10⁹/L 2
• Peripheral blood blasts ≥1% 2
• Platelet count <100 × 10⁹/L 2
• Transfusion dependency 2
• Unfavorable karyotype 2

Risk Categories

• Low risk: Risk score = 0 1
• Intermediate-1 (INT-1): IPSS = 1, DIPSS = 1-2, DIPSS-Plus = 1 1
• Intermediate-2 (INT-2): IPSS = 2, DIPSS = 3-4, DIPSS-Plus = 2-3 1
• High risk: IPSS ≥3, DIPSS = 5-6, DIPSS-Plus = 4-6 1

Management Strategy

Low-Risk Disease (Risk Score = 0)

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

For symptomatic patients: 1

• Ruxolitinib is recommended for symptom control 1
• Interferons (interferon alfa-2b, pegylated interferon alpha-2a, pegylated interferon alpha-2b) are alternative options 1
• Clinical trial enrollment should be considered 1

Intermediate-1 Risk Disease

Symptomatic patients should receive ruxolitinib as first-line therapy. 1, 3

Allogeneic hematopoietic cell transplant should be evaluated for patients with: 1

• Low platelet counts (<100 × 10⁹/L) 1
• Complex cytogenetics 1
• High-risk mutations (particularly ASXL1) 1, 2

Asymptomatic patients may be observed with close monitoring every 3-6 months. 1

Intermediate-2 and High-Risk Disease

Allogeneic hematopoietic cell transplant is recommended for all transplant-eligible patients, as it is the only curative therapy. 1, 2, 4

For transplant-ineligible patients: 1

• If platelets >50 × 10⁹/L: Ruxolitinib is the standard first-line treatment 1
• If platelets ≤50 × 10⁹/L: Clinical trial enrollment is preferred; manage anemia-specific symptoms (see below) 1
• Clinical trial participation should be strongly encouraged for all patients 1

Management of Myelofibrosis-Associated Anemia

For hemoglobin <10 g/dL, initiate treatment with one of the following: 1

• Corticosteroids: Prednisone 0.5-1.0 mg/kg/day with response rates of 30-40% 1
• Androgens: Testosterone enanthate 400-600 mg weekly OR oral fluoxymesterone 10 mg three times daily, with response rates of 30-40% 1
• Danazol: 600 mg/day with response rates of 30-40% 1
• Thalidomide: 50 mg/day in combination with prednisone 15-30 mg/day, with response rates of approximately 20% 1
• Lenalidomide: Particularly effective in patients with del(5)(q31), with response rates of approximately 20% 1

Ruxolitinib: Standard of Care

Ruxolitinib is the first FDA-approved JAK1/JAK2 inhibitor for intermediate or high-risk myelofibrosis and demonstrates significant improvements in splenomegaly and symptom burden. 4, 5

Key efficacy data: 4, 5

• Reduces splenomegaly in the majority of patients 4, 5
• Improves constitutional symptoms and quality of life 4, 5
• Extends overall survival compared to conventional therapy 3, 5
• Does not demonstrate disease-modifying potential or curative effects 4, 6

Common adverse events: 4, 5

• Thrombocytopenia (most common hematologic toxicity) 4, 5
• Anemia (frequently requires dose modification) 4, 5
• Infections (generally manageable) 5
• Grade ≥3 nonhematologic events are rare 5
• Discontinuation due to adverse events is uncommon 5

Dose modifications and re-treatment after interruptions can optimize outcomes without compromising efficacy. 5

Monitoring During Treatment

Patients should be monitored every 3-6 months for: 1

• Disease progression (worsening cytopenias, increasing blast percentage) 1, 2
• Symptom burden using MPN-SAF 1
• Spleen size 1
• Complete blood counts 1

Bone marrow biopsy is indicated only to assess for: 1

• Hematologic transformation to acute leukemia 1
• Disease progression 1
• Response assessment after allogeneic transplant 1

Sequential JAK2 V617F allele burden monitoring is not routinely recommended except after allogeneic transplant or possibly during interferon treatment. 1

Prognosis

Median survival varies significantly by risk category: 2

• Patients with transfusion dependency in the first year have median survival <5 years 2
• Cytogenetic abnormalities are associated with median survival <5 years 2
• CALR+/ASXL1− patients have the longest overall survival 2
• Risk of leukemic transformation approaches 20% in the first 10 years 1

Allogeneic transplant remains the only curative option but carries significant transplant-related morbidity and mortality. 2, 4

Referral Recommendations

Referral to specialized centers with expertise in myeloproliferative neoplasm management is strongly recommended for all patients diagnosed with myelofibrosis. 1