Myelofibrosis Management

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 Dynamic International Prognostic Scoring System (DIPSS), DIPSS-Plus, Mutation-Enhanced International Prognostic Scoring System for patients aged ≤70 (MIPSS-70) and MIPSS-70 Plus are prognostic scoring systems used for the risk stratification of patients with myelofibrosis.

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

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 OS of 28 years, 7 years, and 2 years respectively and 5-year OS rates of 95%, 70%, and 29% respectively.

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 median OS rates of not reached, 10.3 years, 7.0 years, 3.5 years, and 1.8 years respectively and 10-year survival rates of 86&, 50%, 30%, and <3% respectively.

¹Includes any abnormal karyotype other than normal karyotypes or sole abnormalities of 20q-, 13q-, +9, chromosome 1 translocation/duplication, or -Y or sex chromosome abnormality other than -Y 
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. This stratifies patients into low-risk, intermediate 1-risk, intermediate-2-risk and high-risk with corresponding median survival rates of not reached, 14 years, 4 years, and 1.5 years respectively.

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 survival rates of 15.4 years, 6.5 years, 2.9 years, and 1.3 years respectively.

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 different scoring systems, patients can be classified into the following:  

MIPSS-70

• Low risk = 0-1 point
• Intermediate risk = 2-4 points
• High risk = ≥5 points

MIPSS-70+ version 2.0

• Very low risk = 0 point
• Low risk = 1-2 points
• Intermediate risk = 3-4 points
• High risk = 5-8 points
• Very high risk = ≥9 points

DIPSS

• Low risk = 0 point
• Intermediate-1 risk = 1-2 points
• Intermediate-2 risk = 3-4 points
• High risk = 5-6 points

DIPSS-Plus

• Low risk = 0 point
• Intermediate-1 risk = 1 point
• Intermediate-2 risk = 2 or 3 points
• High risk = 4-5 points

MYSEC-PM

• Low risk = ≤11 points
• Intermediate-1 risk = 12-13 points
• Intermediate-2 risk = 14-15 points
• High risk = ≥16 points

 

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 and corresponding median survival of not reached, 9 years, 4 years, and 2 years respectively.

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 0-100.

Principles of Therapy

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

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  

Peginterferon alfa-2a may be a treatment option in symptomatic lower-risk MF patients. It may have activity in lower-risk MF but are not recommended for higher-risk MF. Interferon alfa has limited use in the treatment of myelofibrosis-associated splenomegaly.
 
JAK2 Inhibitors

Fedratinib  

Fedratinib is a selective JAK2 and FMS-like tyrosine kinase 3 (FLT3) 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 with symptomatic splenomegaly and/or constitutional symptoms who are ineligible for transplant or for whom transplant is not currently feasible.

Momelotinib  

Momelotinib is a selective JAK2 inhibitor and activin A receptor type 1/activin receptor-like kinase-2 (ACVR1/ALK2) inhibitor. It may be used as initial and subsequent therapy in symptomatic lower-risk MF patients with loss of response or without response after initial therapy (eg clinical trial, Ruxolitinib, Peginterberon alfa-2a, Hydroxyurea). It is a treatment option for patients with higher-risk MF with platelet counts <50 x 10⁹/L ineligible for transplant or with platelet counts ≥50 x 10⁹/L with symptomatic splenomegaly and/or constitutional symptoms who are ineligible for transplant or for whom transplant is not currently feasible. Lastly, it is also a treatment option for patients with higher-risk MF (intermediate- or high-risk) with anemia.   

Pacritinib  

Pacritinib is an oral protein kinase inhibitor targeting JAK2, interleukin 1 receptor-associated kinase 1 (IRAK1) and FLT3. It is a preferred treatment option for patients with higher-risk myelofibrosis with platelet counts of <50 x 10⁹/L ineligible for transplant. It is a treatment option for patients with higher-risk MF with platelet counts ≥50 x 10⁹/L with symptomatic splenomegaly and/or constitutional symptoms who are ineligible for transplant or for whom transplant is not currently feasible. 

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 is a treatment option for patients with higher-risk MF with platelet counts ≥50 x 10⁹/L with symptomatic splenomegaly and/or constitutional symptoms who are ineligible for transplant or for whom transplant is not currently feasible. 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, quality of life, and OS. 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, Peginterferon alfa-2a, Pacritinib for patients with platelets <50 x 10⁹/L and Momelotinib.

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. Fedratinib or Momelotinib or Pacritinib or Ruxolitinib or enrollment in clinical trials are treatment options for patients with platelet counts of ≥50 x10⁹/L. Patients with platelet counts <50 x 10⁹/L are recommended for Pacritinib (preferred) or Momelotinib therapy or enrollment in clinical trials.

The continuation of JAK inhibitors 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. JAK inhibitors (eg Fedratinib, Momelotinib, Pacritinib, Ruxolitinib) 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 the presence or absence of symptomatic splenomegaly and/or constitutional symptoms.  

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. Combining these agents with Ruxolitinib is a treatment option for patients with anemia and symptomatic splenomegaly and/or constitutional symptoms controlled or not controlled on a JAK inhibitor and serum EPO <500 mU/mL. These are treatment options for patients with anemia without symptomatic splenomegaly and/or constitutional symptoms and with serum EPO <500 mU/mL.
 
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. Androgens in combination with Ruxolitinib is a treatment option for patients with anemia and symptomatic splenomegaly and/or constitutional symptoms controlled or not controlled on a JAK inhibitor. Androgens are treatment options for patients with anemia without symptomatic splenomegaly and/or constitutional symptoms. Monitoring of LFTs and screening for prostate cancer in men is recommended for patients with Danazol treatment.  

JAK Inhibitors  

Example drugs: Momelotinib, Pacritinib, Ruxolitinib  

Momelotinib is a preferred treatment option for patients with anemia and symptomatic splenomegaly and/or constitutional symptoms not controlled on a JAK inhibitor and a treatment option for patients with anemia and symptomatic splenomegaly and/or constitutional symptoms controlled on a JAK inhibitor and patients with anemia without symptomatic splenomegaly and/or constitutional symptoms.  

Pacritinib is a treatment option for patients with anemia and symptomatic splenomegaly and/or constitutional symptoms controlled or not controlled on a JAK inhibitor and patients with anemia without symptomatic splenomegaly and/or constitutional symptoms. Ruxolitinib in combination with ESAs or Luspatercept-aamt or Danazol is a treatment option for patients with anemia and symptomatic splenomegaly and/or constitutional symptoms controlled or not controlled on a JAK inhibitor.

Immunomodulatory Agents

Example drugs: Lenalidomide, Thalidomide  

Lenalidomide with Prednisone or Thalidomide with Prednisone may be a treatment option for patients with anemia without symptomatic splenomegaly and/or constitutional symptoms with del(5q) mutation. 

Luspatercept-aamt 

Luspatercept is a recombinant fusion protein that functions as an erythroid maturation agent. It is a treatment option for patients with anemia without symptomatic splenomegaly and/or constitutional symptoms. Combination with Ruxolitinib is a treatment option for patients with anemia and symptomatic splenomegaly and/or constitutional symptoms controlled or not controlled on a JAK inhibitor.

Nonpharmacological

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. Vaccination with recombinant zoster vaccine should be considered for patients on, or prior to treatment with JAK inhibitor. 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  

Patients 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.

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. This should be considered in patients with refractory, transfusion-dependent anemia, circulating blast cells >2% in the peripheral blood, adverse cytogenetics or molecular abnormalities. 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 with accelerated/ blast phase MPN who achieved a complete response to induction chemotherapy.

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).