Myelofibrosis (MF), is a rare condition in which bone marrow scarring interferes with the normal production of blood cells. It is one of the diseases historically typed as classic Philadelphia-negative myeloproliferative neoplasms. More recently, in 2018, the World Health Organization (WHO) published the 2016 classification and diagnostic criteria for hematopoietic and lymphoid neoplasms.1 The WHO classified primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET) as chronic myeloid neoplasms, further subgrouped as JAK2 myeloproliferative neoplasms.2 

The WHO, the National Comprehensive Cancer Network (NCCN), and the European Society for Medical Oncology (ESMO) have published guidelines for the diagnosis and management of PMF.3 In 2013, the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) collaborated with the European LeukemiaNet to publish revised response criteria for newly developed pharmaceutical treatments for MF.4

In 2015, the ESMO published clinical practice guidelines for the diagnosis, treatment, and monitoring of patients with Philadelphia chromosome-negative chronic myeloproliferative neoplasms, including MF.5 The NCCN published updated clinical practice guidelines (version 3) for myeloproliferative neoplasms, including MF, in September 2022.6 

Diagnosis Guidelines for MF

Assessments for MF Diagnosis

The NCCN guidelines recommend the following workup for the diagnosis of MF3:

  • Complete blood cell (CBC) count with differential
  • Serum iron and erythropoietin levels
  • Comprehensive metabolic panel, including liver function tests, lactate dehydrogenase (LDH) levels, and uric acid levels
  • Peripheral blood smear analysis
  • Coagulation studies to rule out von Willebrand disease and other coagulopathies
  • Real-time polymerase chain reaction (RT-PCR) or fluorescence in situ hybridization (FISH) to rule out chronic myeloid leukemia (CML)
  • Bone marrow aspiration and biopsy with trichrome and reticulin stain
  • Bone marrow cytogenetics
  • Human leukocyte antigen (HLA) testing if allogeneic hematopoietic cell transplant (HCT) is under consideration
  • Molecular blood testing or multigene next-generation sequencing to assess for JAK2 V617F, CALR, and MPL mutations

Both the NCCN and the ESMO follow the WHO criteria for the most accurate diagnosis and risk stratification of patients with PMF.3,5,6 

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Diagnostic Classification of MF

The 2016 WHO criteria can distinguish the diagnosis of PMF into one of two subtypes: prefibrotic and overtly fibrotic. Major criteria for prefibrotic PMF include1:

  • Megakaryocytic proliferation and atypia without reticulin/collagen fibrosis (> grade 1) along with increased age-adjusted bone marrow cellularity, granulocyte proliferation, and often decreased erythropoiesis;
  • Absence of PV, ET, myelodysplastic syndrome (MDS), BCR-ABL1-positive CML, or any other type of myeloid neoplasm; and
  • Presence of JAK2, MPL, or CALR mutations, or, in their absence, presence of other clonal markers or absence of reactive bone marrow reticulin fibrosis.

In contrast, major criteria for overtly fibrotic PMF include1:

  • Megakaryocytic proliferation and atypia with reticulin/collagen fibrosis (grade 2 or 3);
  • Absence of PV, ET, myelodysplastic syndrome (MDS), BCR-ABL1-positive CML, or any other type of myeloid neoplasm; and
  • Presence of JAK2, MPL, or CALR mutations, or, in their absence, presence of other clonal markers or absence of reactive bone marrow reticulin fibrosis.

Minor criteria for both subtypes of PMF require the confirmation of 2 consecutive assessments and include1:

  • Anemia not attributed to other conditions;
  • Palpable splenomegaly;
  • Leukocytosis ≥11 x 109/L;
  • LDH levels above the upper limit of normal in the institutional reference range; and
  • Leukoerythroblastosis (only a minor criterion for overtly fibrotic PMF).

All 3 major criteria and at least one or more minor criteria must be present for a diagnosis of PMF.1

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Risk Stratification Guidelines for MF

Guidelines recommend different prognostic scoring systems, depending on disease type and primary purpose. The Mutation-Enhanced International Prognostic Scoring System (MIPSS) or Dynamic International Prognostic Scoring System (DIPSS) are used to assess risk in patients with PMF, and the Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM) is used to assess risk in patients with secondary MF.6

MIPSS for Initial Risk Stratification

Both the NCCN and the ESMO clinical practice guidelines recommend use of the MIPSS for initial risk stratification after a diagnosis of MF.3 

MIPSS70 classifies patients with PMF into 3 risk categories (low, intermediate, and high), whereas MIPSS70-Plus classifies patients with PMF into 4 risk categories (low, intermediate, high, and very high). MIPSS assesses for the following risk factors, which are predictive of a poor prognosis6

  • Hemoglobin level <10 g/dL
  • Leukocyte count >25 × 109/L
  • Platelet count <100 × 109/L
  • Circulating blast cells ≥2%
  • Bone marrow fibrosis grade ≥MF-2
  • Presence of constitutional symptoms
  • Absence of CALR type 1 mutation
  • Presence of ≥2 high-molecular-risk (HMR) mutations (ASXL1, EZH2, SRSF2, and IDH1/2)

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DIPSS for Treatment Monitoring

In the absence of molecular testing or karyotyping, use of the DIPSS-Plus is recommended. DIPSS-Plus is also used during treatment to monitor risk.3

DIPSS-Plus stratifies patients with PMF into 4 categories (low, intermediate-1, intermediate-2, and high). The original DIPSS score is based on 5 risk factors, including6:

  • Age >65 years;
  • Presence of constitutional symptoms;
  • Hemoglobin level <10 g/dL (2 points assigned for hemoglobin level <10 g/dL);
  • Leukocyte count >25 × 109/L; and
  • Circulating blast cells ≥1%.

Clinicians calculate the original DIPSS score and add 1 point for each of the following6

  • Platelet count <100 × 109/L
  • Red blood cell transfusion requirement
  • Unfavorable karyotype

Low-risk patients have none of the above risk factors. Intermediate-1 patients have 1 risk factor, and intermediate-2 patients have 2 or 3 risk factors. High-risk patients have 4 or more risk factors.6 

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MYSEC-PM for Secondary MF Risk Stratification

The MYSEC-PM stratifies patients with MF secondary to ET or PV into 4 risk groups (low, intermediate-1, intermediate-2, and high) on the basis of the following6

  • Patient age
  • Hemoglobin level <11 g/dL
  • Circulating blasts ≥3%
  • CALR mutation status
  • Platelet count <150 × 109/L
  • Presence of constitutional symptoms

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Treatment Guidelines for MF

Symptom Assessment

The NCCN clinical practice guidelines recommend that the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS, or MPN-10) be used to assess the patient’s symptom burden at the time of diagnosis and throughout treatment.3,6 Symptoms assessed include fatigue, early satiety, poor concentration, weight loss, fever, abdominal discomfort, inactivity, itching, night sweats, and bone pain. A change in symptoms may indicate MF progression and necessitate a re-evaluation of the efficacy of current treatment and the patient’s risk stratification.3

The NCCN recommends that low-risk, asymptomatic patients be monitored for signs and symptoms of disease progression every 3 to 6 months.3

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Therapy Guidelines

Jakafi® (ruxolitinib), Hydrea® or Droxia® (hydroxyurea), and Pegasys® (peginterferon alfa-2a) are recommended for low-risk patients who are symptomatic.5,6

All patients with MF should be evaluated to determine if they are candidates for allogeneic HCT. Both the NCCN and ESMO guidelines recommend HCT only for high-risk patients with MF. High-risk patients who are not candidates for HCT are indicated for treatment with Jakafi (ruxolitinib), Inrebic® (fedratinib), or enrollment in a current clinical trial.3,5,6

Induction chemotherapy with Vidaza® (azacitidine) or Dacogen® (decitabine) or other intensive induction chemotherapy is recommended before HCT for patients with advanced MF; Vidaza, Dacogen, or other low-intensity induction chemotherapy is recommended for patients who are not candidates for HCT.3,6

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Supportive Care

Supportive care includes red blood cell transfusions, platelet transfusions, antifibrinolytic agents, iron chelation, erythropoietin-stimulating agents, granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor, vaccination, antibiotic treatment and prophylaxis for current and recurrent infections, and prophylaxis for tumor lysis syndrome.3,6

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Follow-up Monitoring Guidelines for MF

The 2015 ESMO guidelines recommend frequent (every week to every 3 months) follow-ups for patients with MF, depending on their general status, risk stratification, current treatment, and blood cell abnormalities. No firm evidence suggests a specific frequency of follow-up visits; the suggestions are based on expert opinion.5

The more recent NCCN guidelines recommend that patients undergoing treatment be monitored every 3 to 6 months with bone marrow aspiration and biopsies be repeated as indicated to assess for disease progression.6

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  1. Barbui T, Thiele J, Gisslinger H, et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 2018;8(2):15. doi:10.1038/s41408-018-0054-y
  2. Tefferi A. Primary myelofibrosis: 2021 update on diagnosis, risk-stratification and management. Am J Hematol. 2021;96(1):145-162. doi:10.1002/ajh.26050
  3. Lal A. Primary myelofibrosis guidelines: guidelines summary. Medscape. Updated September 21, 2022. Accessed December 3, 2022.
  4. Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood. 2013;122(8):1395-1398. doi:10.1182/blood-2013-03-488098
  5. Vannucchi AM, Barbui T, Cervantes F, et al. Philadelphia chromosome-negative chronic myeloproliferative neoplasms: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26:v85-v99. doi:10.1093/annonc/mdv203
  6. Gerds AT, Gotlib J, Ali H, et al. Myeloproliferative neoplasms, version 3.2022, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2022;20(9):1033-1062. doi:10.6004/jnccn.2022.0046

Reviewed by Harshi Dhingra, MD, on 12/15/2022.