Myelofibrosis Management Guidelines (NCCN)

Risk Stratification

• Diagnosis should begin with the International Prognostic Scoring System (IPSS) and transition to Dynamic IPSS‑Plus (DIPSS‑Plus) for ongoing risk assessment. The DIPSS‑Plus incorporates clinical and laboratory variables to refine prognosis. 1
• DIPSS‑Plus risk categories: Low (score 0), Intermediate‑1 (score 1‑2), Intermediate‑2 (score 3‑4), High (score 5‑6). 1
• Baseline symptom burden should be quantified with the Myeloproliferative Neoplasm Symptom Assessment Form (MPN‑SAF). 1

Treatment by Risk Category

Low‑Risk Disease (Score 0)

• Asymptomatic low‑risk patients are managed with observation and routine monitoring every 3–6 months. 1
• Monitoring includes assessment for disease progression (worsening cytopenias, rising blast percentage, new constitutional symptoms). 1
• Bone‑marrow biopsy is required at diagnosis and when clinical progression is suspected. 1
• Symptomatic low‑risk patients may receive ruxolitinib or interferon‑based therapy. 1
• Enrollment in clinical trials is an appropriate option for eligible patients. 1

Intermediate‑1 Risk Disease (INT‑1)

• Most INT‑1 patients can be observed unless high‑risk features (e.g., low platelets, complex cytogenetics, refractory transfusion‑dependent anemia, peripheral blasts > 2 %, or high‑risk mutations such as ASXL1, SRSF2, U2AF1) are present, which warrant transplant evaluation. 1
• Symptomatic INT‑1 patients not requiring transplant should be started on ruxolitinib. 1
• Asymptomatic INT‑1 patients without high‑risk features continue observation with monitoring every 3–6 months. 1

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

• Allogeneic hematopoietic stem‑cell transplantation (allo‑HSCT) is the recommended curative therapy for transplant‑eligible INT‑2 and high‑risk patients. 1
• Transplant candidacy is determined by age, performance status, comorbidities, psychosocial factors, patient preference, and caregiver support. 1
• Patients may proceed directly to transplant or receive bridging therapy to lower marrow blast burden before transplantation. 1
• Non‑transplant‑eligible patients with platelet counts > 50 × 10⁹/L should receive ruxolitinib as first‑line therapy. 1
• Non‑transplant‑eligible patients with platelet counts ≤ 50 × 10⁹/L may be treated with pacritinib (FDA‑approved for low platelets) or enrolled in clinical trials. 1

JAK‑Inhibitor Therapy

• Ruxolitinib is the standard first‑line JAK inhibitor for symptomatic patients with adequate platelets (> 50 × 10⁹/L). 1
• Therapeutic response should be evaluated using International Working Group (IWG) criteria. 1, 2
• If patients derive clinical benefit despite not meeting formal IWG response thresholds, continuation of ruxolitinib is advised at the clinician’s discretion. 1

Management of Myelofibrosis‑Associated Anemia

• Corticosteroids and immunomodulatory agents are additional therapeutic options for anemia management. 3, 4

Management of Splenomegaly

• Hydroxyurea is the first‑line agent for splenomegaly in patients who do not require JAK‑inhibitor therapy. 3, 4
• Splenectomy is indicated for patients with symptomatic portal hypertension, drug‑refractory painful splenomegaly, or frequent red‑cell transfusion requirements. 3, 4

Disease‑Progression Management

• Accelerated phase (blasts 10‑19 %): induce remission with hypomethylating agents (azacitidine or decitabine) or intensive induction chemotherapy, followed by allo‑HSCT for transplant‑eligible patients. 1
• Blast phase/AML (blasts ≥ 20 %): transplant‑eligible patients receive hypomethylating agents or intensive induction chemotherapy followed by allo‑HSCT; non‑eligible patients receive hypomethylating agents or low‑intensity induction chemotherapy. 1

Monitoring Strategy

• Perform routine monitoring every 3–6 months, including complete blood counts, symptom assessment, and physical examination for splenomegaly. 1
• Repeat bone‑marrow biopsy at diagnosis and when clinical progression is suspected (e.g., increased symptoms, worsening cytopenias, rising blast count). 1
• For higher‑risk patients, incorporate serial molecular profiling with next‑generation sequencing to track emerging high‑risk mutations. 1

Management of Myelofibrosis

Initial Risk Stratification

• The National Comprehensive Cancer Network recommends risk assessment at diagnosis using the International Prognostic Scoring System (IPSS), with Dynamic IPSS-Plus (DIPSS-Plus) preferred for ongoing risk stratification throughout the disease course 5, 6.
• 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 7.
• 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) 5, 6.

Management by Risk Category

• The National Comprehensive Cancer Network recommends allogeneic hematopoietic stem cell transplantation (alloSCT) for intermediate-2 and high-risk patients, as it is the only curative option 5, 8.
• Ruxolitinib is recommended as first-line therapy for symptomatic splenomegaly in non-transplant candidates 5, 8.
• 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, allogeneic HCT should be evaluated 5, 8, 6.

Management of Myelofibrosis-Associated Anemia

• The American Society of Clinical Oncology recommends erythropoiesis-stimulating agents as first-line for patients with erythropoietin levels <125 mU/mL, producing improvements in 23-60% of patients 9.
• 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 10, 9.

Special Considerations and Monitoring

• The National Comprehensive Cancer Network recommends assessing symptom burden at baseline using MPN Symptom Assessment Form (MPN-SAF-20 items) for all patients 5, 11, 6, 12.
• Regular blood count monitoring is essential to detect cytopenias and assess response 13.

Critical Pitfalls to Avoid

• Delaying allogeneic HCT evaluation in INT-2 and high-risk patients can significantly shorten survival, and transplantation is the only curative option 8, 13, 7.
• Relying solely on JAK inhibitor monotherapy for disease modification is not recommended, as these agents primarily provide symptom control without eliminating the malignant clone 14, 13.