Myelofibrosis Management

Last updated: 14 June 2024

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Evaluation 

Content:

Evaluation 

Risk Stratification

All patients should be categorized at baseline according to risks associated with myelofibrosis as it is necessary for deciding on treatment options. The International Prognostic Scoring System (IPSS), Dynamic International Prognostic Scoring System (DIPSS), and DIPSS-Plus are the most common prognostic scoring systems used for the risk stratification of patients with myelofibrosis.

IPSS is the recommended tool for risk stratification at the time of diagnosis and stratifies patients into low-risk, intermediate-1-risk, intermediate-2-risk, and high-risk. It estimates survival based on five independent risk factors including age of >65 years, hemoglobin of <10 g/dL, leukocyte count of >25 x109/L, circulating blasts of ≥1%, and the presence of constitutional symptoms.

DIPSS-Plus is the recommended tool for risk stratification during the course of treatment. DIPSS is an option if karyotyping is not available.

Mutation-enhanced international prognostic scoring systems for patients aged ≤70 years (MIPSS-70) or mutation- and karyotype-enhanced IPSS (MIPSS-70+ Version 2.0) are the preferred prognostic scoring systems for patients with primary myelofibrosis.

Myelofibrosis secondary to polycythemia vera and essential thrombocythemia prognostic model (MYSEC-PM) is the method used for patients diagnosed with post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis.

Prognostic Scoring Systems for Patients with Primary Myelofibrosis

Mutation-enhanced International Prognostic Scoring System (MIPSS-70) for Patients with Primary Myelofibrosis Aged ≤70 Years 

This stratifies patients into low-risk, intermediate-risk, and high-risk with corresponding median overall survival of 28 years, 7 years, and 2 years respectively and 5-year overall survival rates of 95%, 70%, and 29% respectively.

 Prognostic Variable  Points
Hemoglobin <10 g/dL
 1
Leukocytes >25 x 109/L 2
Platelets <100 x 109/L 2
Circulating blasts ≥2% 1
Bone marrow fibrosis grade ≥2 1
Constitutional symptoms 1
CALR type-1 unmutated genotype 1
High-molecular risk (HMR) mutations (presence of mutation in any of these genes: ASXL1, EZH2, SRSF2, or IDH1/2) 1
≥2 HMR mutations 2

Mutation and Karyotype-enhanced IPSS (MIPSS-70+ Version 2.0)  

Mutation and karyotype-enhanced IPSS stratifies patients into low-risk, intermediate-risk, high-risk, and very high-risk with corresponding 5-year overall survival rates of 91%, 66%, 42%, and 7% respectively. 

 Prognostic Variable  Points
Severe anemia (hemoglobin <9 g/dL in men and <8 g/dL in women)
 2
Moderate anemia (hemoglobin 9-10.9 g/dL in men and 8-9.9 g/dL in women)
 1
Circulating blasts ≥2%
 1
Constitutional symptoms
 2
Absence of CALR-1 type mutation
 2
HMR mutations (presence of mutation in any of these genes: ASXL1, EZH2, SRSF2, or IDH1/2)
 2
≥2 HMR mutations
 3
Complex karyotype1
 3
Very-high-risk (VHR) karyotype2
 4

1Includes sole or two abnormalities of +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-, or 11q23 rearrangement (+21, +19)
2Includes single or multiple abnormalities of -7, i(17q), inv(3)/3q21, 12p-/12p11.2, 11q-/11q23, or other autosomal trisomies excluding +8/+9 (+21, +19) 

Dynamic International Prognostic Scoring Systems (DIPSS)  

DIPSS may be used at any time during the course of the disease.

    Prognostic Variable
    Points
    0 1 2
    Age
    White blood cell count
    Hemoglobin
    Peripheral blood blast
    Constitutional symptoms    		 ≤65 years
    ≤25 x 109/L
    ≥10 g/dL
    <1%
    None    		 >65 years
    >25 x 109/L
    -
    ≥1%
    Present    		 -
    -
    <10 g/dL
    -
    -

Dynamic International Prognostic Scoring Systems-Plus (DIPSS-Plus) 

DIPSS-Plus is a refined prognostic scoring system for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status and is an alternative if molecular testing is not available. It stratifies patients into low-risk, intermediate-1-risk, intermediate-2-risk, and high-risk with corresponding median overall survival rates of 15.4 years, 6.5 years, 2.9 years, and 1.3 years respectively.

Prognostic Variable Points
DIPSS low-risk
 0
DIPSS intermediate-risk 1 (INT-1)
 1 
DIPSS intermediate-risk 2 (INT-2)
 2
DIPSS high-risk
 3
Platelets <100 x 109/L
 1
Transfusion need 1
Unfavorable karyotype1
 1
1Includes complex karyotype or sole or 2 abnormalities which include trisomy 8, 7/7q-, i(17q), 5/5q-, 12p-, inv(3), or 11q23 rearrangement 

Risk Stratification

Based on the prognostic scoring systems, patients may be classified into lower, intermediate, and higher risk.  

Lower Risk 

  • MIPSS-70: ≤3
  • MIPSS-70+ Version 2.0: ≤3
  • DIPSS-Plus: ≤1 (0)
  • DIPSS: ≤2 (0)
  • MYSEC-PM: <14

Intermediate Risk

  • MIPSS-70: 2-4
  • Intermediate risk 1 (INT-1)
    • DIPSS-Plus: 1
    • DIPSS: 1 or 2
  • Intermediate risk 2 (INT-2)
    • DIPSS-Plus: 2 or 3
    • DIPSS: 3 or 4 

Higher Risk 

  • MIPSS-70: ≥4
  • MIPSS-70+ Version 2.0: ≥4
  • DIPSS-Plus: >1 (4 to 6)
  • DIPSS: >2 (5 or 6)
  • MYSEC-PM: ≥14 

Prognostic Scoring Systems for Patients with Post-Polycythemia Vera and Post-Essential Thrombocythemia Myelofibrosis  

Myelofibrosis Secondary to Polycythemia Vera and Essential Thrombocythemia-Prognostic Model (MYSEC-PM)  

MYSEC-PM stratifies patients into low-risk, intermediate-1-risk, intermediate-2-risk, and high-risk.

Prognostic Variable Points 
Age at diagnosis  0.15 per patient’s year of age
Hemoglobin <11 g/dL
 2
Circulating blasts ≥3%
 2
Absence of CALR-1 type mutation
2
Platelets <150 x 109/L
1 
Constitutional symptoms 1

Assessment of Symptom Burden

The assessment of symptom burden is recommended for all patients at baseline and during the course of treatment. Myelofibrosis Symptom Assessment Form (MS-SAF) is a 20-item questionnaire used to assess myelofibrosis-associated symptoms including fatigue; constitutional symptoms such as night sweats, bone pain, fever, itching, and weight loss; symptoms associated with splenomegaly which include abdominal pain or discomfort, early satiety, inactivity, and cough; and quality of life.

Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)

MPN-SAF TSS is a recommended assessment tool for symptoms at baseline and for monitoring symptom status during the course of treatment. Assessment is done by the patients themselves and scoring is from 0 (absent) to 10 (worst) on the following symptoms: Fatigue (tiredness or weariness) during the past 24 hours, early satiety, abdominal discomfort, inactivity, problems with concentration compared to before the onset of disease, night sweats, itching or pruritus, bone pain not associated with joint pain or arthritis, fever, and unintentional weight loss in the last 6 months. This represents the sum of all individual scores which can range from 0 to 100.

Principles of therapy 

The choice of treatment for patients with myelofibrosis is based on the risk score and the presence of symptoms. 

Goals of Treatment  

The goals of treatment in myelofibrosis are to control symptoms, decrease the risk of hemorrhage and thrombosis, decrease the risk of progression, and improve quality of life.  

Therapeutic Recommendations  

A clinical trial is recommended for all patients. Observation is an option for asymptomatic and symptomatic patients with lower-risk myelofibrosis. Pharmacological therapy is the preferred treatment option for patients with symptomatic splenomegaly.

Goals of Clinical Trials  

The goals of clinical trials are to decrease bone marrow fibrosis, improve cytopenias and symptom burden, restore transfusion independence, and delay or prevent progression to acute myeloid leukemia. 

Pharmacological therapy 

Interferons

Example drugs: Interferon alfa, Peginterferon alfa-2a, Peginterferon alfa-2b  

Interferon alfa has limited use in the treatment of myelofibrosis-associated splenomegaly.

JAK2 Inhibitors

Fedratinib  

Fedratinib is a selective JAK2 inhibitor that is approved for the treatment of patients with higher-risk (intermediate-2-risk or high-risk) myelofibrosis. It is a treatment option for patients with higher-risk myelofibrosis with platelet counts of ≥50 x 109/L and with resistance or intolerance to Ruxolitinib.  

Pacritinib  

Pacritinib is an oral protein kinase inhibitor targeting wild-type JAK2, mutant JAK2, and FMS-like tyrosine kinase 3 (FLT3). It is a treatment option for patients with higher-risk myelofibrosis with platelet counts of <50 x 109/L ineligible for transplant with a history of therapy with one JAK inhibitor.  

Ruxolitinib  

Ruxolitinib is an oral protein kinase inhibitor targeting JAK signaling. It is approved for the treatment of patients with higher-risk (intermediate-risk or high-risk) myelofibrosis. It is a first-line treatment for myelofibrosis-associated splenomegaly and other myelofibrosis-associated symptoms in patients with higher-risk myelofibrosis. It may be a treatment option for symptomatic patients with low-risk myelofibrosis.  

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 myelofibrosis is associated with significant benefits in particular reduction in spleen size, improvement of disease-related symptoms, and quality of life. It is an alternative for Hydroxyurea-resistant patients with splenomegaly. 

Treatment Recommendations Based on Risk Stratification and Symptom Burden Assessment

Lower-risk Myelofibrosis  

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 myelofibrosis. Cytoreductive therapy may be used for symptomatic patients with high platelet counts. It is also a treatment option for myelofibrosis-associated splenomegaly.  

Higher-risk Myelofibrosis  

The options for treatment of patients ineligible for allogeneic hematopoietic stem cell transplant is based on the platelet count. Ruxolitinib or Fedratinib or enrollment in clinical trials are treatment options for patients with platelet counts of ≥50 x109/L. Hydroxyurea is an alternative for patients who are not eligible for Ruxolitinib or Fedratinib. Patients with platelet counts of <50 x109/L are recommended for Pacritinib therapy or enrollment in clinical trials.  

The continuation of Ruxolitinib or Fedratinib near the start of conditioning therapy is recommended in patients eligible for allogeneic hematopoietic stem cell transplant to reduce splenomegaly and improve other disease-related symptoms.  

Management of Myelofibrosis-Associated Anemia

Anemia is a negative prognostic risk factor for a patient’s survival. Coexisting causes of anemia (hemolysis, bleeding, and iron, vitamin B12, and folate deficiency) should be ruled out and treated before other treatment options are considered. Transfusion of leuko-reduced RBC is recommended for symptomatic anemia. Ruxolitinib or Fedratinib may be continued to reduce splenomegaly and improve other disease-related symptoms. Enrollment in clinical trials should be considered for all patients with myelofibrosis-associated anemia and is the preferred option for patients with serum EPO of ≥500 mU/mL. The treatment options are based on EPO level.  

Serum EPO of <500 mU/mL  

Erythropoiesis-stimulating Agents (ESAs)

Example drugs: Darbepoetin alfa, Epoetin alfa  

ESAs are recommended for the treatment of anemia and should be continued in patients with anemia response, although it is not effective for transfusion-dependent anemia. Patients with loss of response or no response should be tried with androgens or immunomodulating agents.  

Serum EPO of ≥500 mU/mL  

Continuation of present treatment is recommended in patients with treatment response. Patients without response or with loss of response should be treated with agents, either Danazol or immunomodulating agents, not previously used.  

Androgens

Example drugs: Danazol, Fluoxymesterone, Methandrostenolone, Nandrolone, Oxymetholone, Testosterone enanthate  

Danazol is a synthetic attenuated androgen and is the androgen of choice to improve hemoglobin concentration in patients with myelofibrosis and transfusion-dependent anemia. It has been shown to decrease spleen size and improve platelet counts. It may be an option in patients with EPO of ≥500 mU/mL and is the treatment option for patients with EPO of <500 mU/mL and treated with ESAs who have not achieved treatment response or with loss of response.  

Monitoring of LFTs and screening for prostate cancer in men is recommended for patients with Danazol treatment.  

Immunomodulatory Agents

Example drugs: Lenalidomide, Thalidomide  

Lenalidomide with or without Prednisone or Thalidomide with or without Prednisone may be treatment options for patients with EPO of ≥500 mU/mL. Patients with del(5q) mutation have better response rates with Lenalidomide. It is also a treatment option for patients with EPO of <500 mU/mL and treated with ESAs but have not achieved treatment response or with loss of response.  

Luspatercept  

Luspatercept is a recombinant fusion protein that functions as an erythroid maturation agent. It is a treatment option, preferably within a clinical trial, for patients with EPO of ≥500 mU/mL who failed an ESA and require ≥2 RBC units over an 8-week period. 

Supportive Therapy

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

Blood transfusion is part of the supportive therapy for patients with myelofibrosis and this includes platelet transfusion for thrombocytopenic bleeding or platelet counts of <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

Antifibrinolytic agents may be given for bleeding that is not responsive to transfusions.  

Iron Chelation  

Iron chelation may be performed in lower-risk patients who received >20 transfusions and/or with ferritin of >2,500 ng/dL.

Cytoreductive Therapy

Example drug: Hydroxyurea  

Cytoreductive therapy is recommended for the management of leukocytosis or thrombocytosis. It is a treatment option for postsplenectomy myeloproliferation.  

Monitoring and Treatment of Infections

Monitoring for signs and symptoms of infection is recommended and serious infection should be treated before initiation of Ruxolitinib. Antibiotic prophylaxis and vaccination are recommended for recurrent infections. Growth factors may be considered in patients with recurrent infection and neutropenia. 

Prophylaxis for Tumor Lysis Syndrome

Prophylaxis for tumor lysis syndrome must be considered in patients undergoing induction chemotherapy for advanced-stage myelofibrosis or leukemic transformation. This includes hydration and/or diuresis and management of hyperuricemia with Allopurinol or Rasburicase. Rasburicase is preferred as an initial treatment in patients with rapidly increasing blast counts, elevated uric acid, and in the presence of renal impairment.  

Transjugular Intrahepatic Portosystemic Shunts (TIPS)

TIPS is an option for patients with an intrahepatic obstruction or to alleviate symptoms of portal hypertension.  

Symptom Management

Pruritus  

Patient should be advised to practice sensitive skin care (eg short showers, mild soap, application of moisturizer). Antihistamines such as Cetirizine or Diphenhydramine and topical steroids may be considered.  

Bone Pain  

Other causes of pain should be evaluated such as arthralgias. Nonsteroidal anti-inflammatory drugs (NSAIDs) and Loratadine have been used for myelofibrosis-associated bone pain.  

Headache and Tinnitus  

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

Surgery 

Splenectomy  

Splenectomy is an option for patients with symptomatic splenomegaly refractory to pharmacological therapy. The indications for splenectomy include 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), and significant splenic infarction.

Radiation Therapy 

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

Other Therapy: Allogeneic Hematopoietic Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation is the only potentially curative treatment option and modality capable of prolonging the survival of patients with myelofibrosis. All patients with higher-risk myelofibrosis should be evaluated for transplant eligibility. The selection of recipients for allogeneic hematopoietic stem cell transplantation is based on performance status, age, presence of major comorbid conditions, psychosocial status, patient preference, and availability of caregiver. It may be performed immediately upon diagnosis or a bridging therapy may be given to reduce marrow blasts to an acceptable level before transplant.

It is the recommended treatment option for higher-risk myelofibrosis patients who are eligible for transplant. It is associated with significant benefit in patients with intermediate-2-risk and high-risk primary myelofibrosis and better outcomes in patients with low-risk or intermediate-risk myelofibrosis although transplant-related morbidity and mortality is high.  

It may also be a treatment option for patients with CALR(-)/ASXL(+) mutation which is associated with poor prognosis. It is also the only curative option for transplant-eligible patients with disease progression who achieved a complete response to induction chemotherapy.