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 Management

Treatment Response Monitoring

  • MPN-SAF TSS is used as a monitoring tool for treatment response 
  • Symptom response requires a reduction of ≥50% in the MPN-SAF TSS 
  • A <50% reduction is clinically significant and justifies continued used of Ruxolitinib 
  • Change in symptom status may be a sign of disease progression and should prompt evaluation of treatment efficacy and/or disease status 
    • Assessment of treatment response involves performing CBC to assess normalization of blood counts, monitoring symptom status using MPN-SAF TSS and monitoring spleen size by imaging or palpation 
  • Monitoring response (anemia response, spleen response and symptom response) is recommended every 3-6 months during the course of therapy 
    • Continuation of Ruxolitinib or Fedratinib is recommended for patients with <50% symptom response upon the discretion of the physician 
    • Ruxolitinib should be discontinued if without response or improvement of symptoms after 6 months 
  • Bone marrow aspirate and biopsy should be performed when increased symptoms or signs of progression are present 
  • Molecular testing with multigene NGS panel may be performed in patients with higher-risk MF to assess for high-molecular-risk mutations which is associated with disease progression 
    • ASXL1, TET2, TP53, SRSF2, IDH1 and IDH2 gene mutations and other chromosomal abnormalities (in chromosome 1q and 9p) are associated with transformation to AML 
  • Disease progression of MF to accelerated phase (MF-AP) is characterized by the presence of <50 x 109/L platelets, chromosome 17 abnormalities and ≥10% (10-19%) blasts in bone marrow or peripheral blood 
  • Disease progression of MF in blast phase (MF-BP) is synonymous to AML and is characterized by the presence of ≥20% myeloid blasts in peripheral blood or bone marrow

2013 IWG-MRT and ELN Response Criteria for MF 

Response Categories Required Criteria (response should last ≥12 weeks)
Complete response Bone marrow:
• Age-adjusted normocellularity
• <5% blasts
• ≤grade 1 MF
and
Peripheral blood:
• Hemoglobin ≥10 g/dL and <ULN
• Neutrophil count ≥1 x 109/L and <ULN
• Platelet count ≥100 x 109/L and <ULN
• <2% immature myeloid cells
Clinical:
• Resolution of disease symptoms
• Liver and spleen not palpable
• No evidence of extramedullary hematopoiesis
Partial response Peripheral blood:
• Hemoglobin ≥10 g/dL and <ULN
• Neutrophil count ≥1 x 109/L and <ULN
• Platelet count ≥100 x 109/L and <ULN
• <2% immature myeloid cells
or
Bone marrow:
• Age-adjusted normocellularity
• <5% blasts
• ≤grade 1 MF
and
Peripheral blood:
• Hemoglobin ≥8.5 but <10 g/dL and <ULN
• Neutrophil count ≥1 x 109/L and <ULN
• Platelet count ≥50 but <100 x 109/L and <ULN
• <2% immature myeloid cells
Clinical:
• Resolution of disease symptoms
• Liver and spleen not palpable
• No evidence of extramedullary hematopoiesis
Progressive disease • Appearance of a new splenomegaly, palpable at least 5 cm below the left costal margin (LCM) or
• ≥100% increase in palpable distance, below LCM, for baseline splenomegaly of 5-10 cm or
• 50% increase in palpable distance, below LCM, for baseline splenomegaly of >10 cm or
• Leukemic transformation confirmed by a bone marrow blast count ≥20% or
• Peripheral blood blast content ≥20% associated with an absolute blast count of ≥1 x 109/L that lasts for ≥2 weeks
Clinical improvement (CI) Achievement of anemia, spleen, or symptoms response without progressive disease or increase in severity of anemia, thrombocytopenia, or neutropenia
Relapse • Not meeting the criteria for at least CI after achieving complete response, partial response or CI or
• Loss of anemia response persisting for ≥1 month or
• Loss of spleen response persisting for ≥1 month
Anemia response • Transfusion-independent patients: Hemoglobin level increase of ≥2 g/dL
• Transfusion-dependent patients: Conversion to transfusion-independent
Spleen response • Baseline splenomegaly palpable at 5-10 cm below LCM becomes non-palpable
or
• Baseline splenomegaly palpable >10 cm below LCM, decreases by ≥50%
• Baseline splenomegaly palpable <5 cm below LCM, not eligible for spleen response
• Spleen response required confirmation by MRI or CT showing ≥35% spleen volume reduction
Symptom response ≥50% reduction in the MPN-SAF TSS
Stable disease Belonging to none of the above listed response categories
Adapted from: 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 Aug;122(8):1395-1398.

Management of MF-Associated Anemia

  • Anemia is a negative prognostic risk factor for 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 MF-associated anemia and is the preferred option for patients with serum EPO ≥500 mU/mL 
  • Treatment options are based on EPO level 

Serum EPO <500 mU/mL 

Erythropoiesis-stimulating Agents (ESAs) 

  • Eg Darbepoetin alfa, Epoetin alfa 
  • Recommended for treatment of anemia and should be continued in patients with anemia response 
  • Not effective for transfusion-dependent anemia 
  • Patients with loss of response or no response should be tried with androgens or immunomodulating agents 

Serum EPO ≥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 

  • Eg 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 MF and transfusion-dependent anemia 
    • Has been shown to decrease spleen size and improve platelet counts 
    • May be an option in patients with EPO ≥500 mU/mL 
      • Treatment option for patients with EPO <500 mU/mL and treated with ESAs and 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 

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

Luspatercept

  • A recombinant fusion protein that functions as an erythroid maturation agent
  • Treatment option, preferrably within a clinical trial, for patients with EPO ≥500 mU/mL who failed an ESA and require ≥2 RBC units over an 8-week period

Management of Disease Progression

  • Treatment options are based on transplant eligibility 
  • Workup includes bone marrow aspirate and biopsy with reticulin and trichome stain, bone marrow cytogenetics if bone marrow is inaspirable, flow cytometry and molecular testing for AML-associated mutations 
  • Continuation of Ruxolitinib or Fedratinib to the start of conditioning therapy is recommended to reduce splenomegaly and improve other disease-related symptoms 

Transplant-eligible Patients 

  • Reduction of blast counts or disease control may be achieved with hypomethylating agents (Azacitidine or Decitabine) or with intensive AML-type induction chemotherapy followed by allogeneic HSCT 
  • Enrollment in clinical trials may be another option 

Transplant-ineligible Patients 

  • Treatment with hypomethylating agents or low-intensity AML-type induction chemotherapy or enrollment in clinical trials are recommended
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