myelofibrosis
MYELOFIBROSIS
Treatment Guideline Chart

A clonal myeloproliferative stem cell disorder characterized by reactive bone marrow fibrosis, extramedullary hematopoiesis, and abnormal cytokine expression leading to systemic symptoms.
It belongs to a group of heterogeneous disorders of the hematopoietic system which is collectively known as Philadelphia chromosome-negative myeloproliferative neoplasms (MPN).
May present either as a de novo disorder [primary myelofibrosis (PMF)] or can develop from the transformation of polycythemia vera (PV) and essential thrombocythemia (ET).

Choice of treatment for patients with myelofibrosus is based on the risk score and presence of symptoms

Myelofibrosis Treatment

Principles of Therapy

  • Choice of treatment for patients with MF is based on the risk score and presence of symptoms 

Goals of Treatment

  • Control symptoms
  • Decrease risk of hemorrhage and thrombosis 
  • Decrease risk of progression 
  • Improve quality of life 

Therapeutic Recommendations

  • Clinical trial is recommended for all patients 
  • Observation is an option for asymptomatic and symptomatic patients with lower-risk MF 
  • Pharmacological therapy is the preferred treatment option for patients with symptomatic splenomegaly 

Goals of Clinical Trials 

  • Decrease bone marrow fibrosis 
  • Improve cytopenias and symptom burden 
  • Restore transfusion independence 
  • Delay or prevent progression to AML

Pharmacotherapy

Interferons

  • Eg Interferon alfa, Peginterferon alfa-2a, Peginterferon alfa-2b 
  • Interferon alfa has limited use in the treatment of MF-associated splenomegaly 

JAK2 Inhibitors 

Fedratinib 

  • Selective JAK2 inhibitor which is approved for treatment of patients with higher-risk (intermediate-2-risk or high-risk) MF 
  • Treatment option for patients with higher-risk MF with platelet counts ≥50 x 109/L and with resistance or intolerance to Ruxolitinib 

Ruxolitinib 

  • Oral protein kinase inhibitor targeting JAK signalling 
  • Approved for treatment of patients with higher-risk (intermediate-risk or high-risk) MF 
    • 1st-line treatment for MF-associated splenomegaly and other MF-associated symptoms in patients with higher-risk MF
  • May be a treatment option for symptomatic patients with low-risk MF 
  • Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment (COMFORT) I and II studies have shown that continuous treatment in patients with intermediate-2-risk and high-risk MF is associated with significant benefits in particular reduction in spleen size, improvement of disease-related symptoms and quality of life 
    • Alternative for Hydroxyurea-resistant patients with splenomegaly 

Treatment Recommendations Based on Risk Stratification and Symptom Burden Assessment

Lower-risk MF 

  • Symptomatic patients may receive Ruxolitinib or Peginterferon alfa-2a 
  • Hydroxyurea (Hydroxycarbamide) is a treatment option for symptomatic patients with hyperproliferative manifestations (eg thrombocytosis or leukocytosis) of MF 
    • Cytoreductive therapy for symptomatic patients with high platelet counts 
    • Treatment option for MF-associated splenomegaly 

Higher-risk MF 

  • Options for treatment of patients ineligible for allogeneic HSCT is based on platelet count 
    • Ruxolitinib or Fedratinib or enrollment in clinical trials are treatment options for patients with platelet counts >50 x 109/L 
      • Hydroxyurea is an alternative for patients who are not eligible for Ruxolitinib or Fedratinib 
    • Patients with platelet counts <50 x 109/L are recommended for enrollment in clinical trials 
  • Continuation of Ruxolitinib or Fedratinib near to the start of conditioning therapy is recommended in patients eligible for allogeneic HSCT to reduce splenomegaly and improve other disease-related symptoms 

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

  • Allogeneic HSCT is the only potentially curative treatment option and modality capable of prolonging survival of patients with MF 
  • All patients with higher-risk MF should be evaluated for transplant eligibility 
  • Selection of recipients for allogeneic HSCT is based on performance status, age, presence of major comorbid conditions, psychosocial status, patient preference and availability of caregiver 
    • May be performed immediately upon diagnosis or a bridging therapy may be given to reduce marrow blasts to an acceptable level before transplant 
  • Recommended treatment option for higher-risk MF patients who are eligible for transplant 
  • Associated with significant benefit in patients with intermediate-2-risk and high-risk PMF and better outcomes in patients with low-risk or intermediate-risk MF although transplant-related morbidity and mortality is high 
  • May be a treatment option for patients with CALR(-)/ASXL(+) mutation which associated with poor prognosis 
  • Only curative option for transplant-eligible patients with disease progression who achieved a complete response to induction chemotherapy 

Supportive Therapy

  • Includes assessment and monitoring of symptom status during the course of treatment, counseling for the identification, evaluation and management of cardiovascular risk factors such as thrombotic and hemorrhagic risk factors, exercise, diet and smoking 

Transfusion 

  • Includes platelet transfusion for thrombocytopenic bleeding or platelet counts <10,000 m3 and RBC transfusion for symptomatic anemia 
    • Transfusion of leukocyte-reduced blood products is recommended for transplant-eligible patients to prevent HLA autoimmunization and reduce the risk of cytomegalovirus transmission 

Antifibrinolytic Agents 

  • May be given for bleeding that is not responsive to transfusions 

Iron Chelation 

  • May be performed in lower-risk patients who received >20 transfusions and/or with ferritin >2500 ng/dL 

Cytoreductive Therapy

  • Eg Hydroxyurea 
  • Recommended for the management of leukocytosis or thrombocytosis 
  • Treatment option for post-splenectomy myeloproliferation 

Monitoring and Treatment of Infections

  • Monitoring for signs and symptoms of infection is recommended 
  • Serious infection should be treated before initiation of Ruxolitinib 
  • Antibiotic prophylaxis and vaccination is recommended for recurrent infections 
  • Growth factor may be considered in patients with recurrent infection and neutropenia 

Prophylaxis For Tumor Lysis Syndrome 

  • Must be considered in patients undergoing induction chemotherapy for advanced-stage MF or leukemic transformation 
  • Include hydration and/or diuresis, and management of hyperuricemia with Allopurinol or Rasburicase 
    • Rasburicase is preferred as initial treatment in patients with rapidly increasing blast counts, elevated uric acid and in the presence of renal impairment 

Splenectomy 

  • Option for symptomatic splenomegaly refractory to pharmacological therapy 
  • Indications: 
    • Severe thrombocytopenia 
    • Splenic abdominal pain and discomfort 
    • Symptomatic portal hypertension (eg bleeding varices, ascites) 
    • Frequent RBC transfusions 
    • Drug-refractory anemia 
    • Severe catabolic symptoms (eg cachexia) 
    • Significant splenic infarction 

Transjugular Intrahepatic Portosystemic Shunts (TIPS) 

  • Option for patients with intrahepatic obstruction or to alleviate symptoms of portal hypertension 

Radiotherapy 

  • Alternative to splenectomy in patients with symptomatic splenomegaly but not eligible for surgery 
  • Patient must have adequate platelet count (>50 x 109/L)
  • Low-dose irradiation is the preferred treatment for extramedullary hematopoiesis at other sites (eg peritoneum, pleura) 

Symptom Management 

Pruritus 

  • Advice patient to practice sensitive skin scare (eg short showers, mild soap, application of moisturizer) 
  • Antihistamines such as Cetirizine or Diphenhydramine and topical steroids may be considered 

Bone Pain 

  • Evaluate for other causes of pain such as arthralgias 
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) and Loratadine have been used for MF-associated bone pain 

Headache and Tinnitus 

  • Evaluate patients for thrombosis as patients with MF have an increased risk of vascular complications 
  • Low-dose Aspirin (80-100 mg/day) helps to improve vasomotor symptoms 
  • Clopidogrel is an alternative and may be given alone or in combination with Aspirin
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