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 |
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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 |
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Anemia response |
• Transfusion-independent patients: Hemoglobin level increase of ≥2 g/dL
• Transfusion-dependent patients: Conversion to transfusion-independent |
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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 |
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Symptom response | ≥50% reduction in the MPN-SAF TSS | |
Stable disease | Belonging to none of the above listed response categories | |
References: 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; National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: myelofibrosis. Version 2.2022. |
Recommendations for the Assessment of Treatment-induced Cytogenetic and Molecular Changes | |
Cytogenetic remission | Cytogenic response evaluation should include ≥10 metaphases and confirmed using repeat testing within 6 months Complete remission: Clearance of a pre-existing abnormality Partial remission: ≥50% reduction in abnormal metaphases (for patients with ≥10 abnormal metaphases at baseline) |
Molecular remission | Peripheral blood analysis should be included in the evaluation of molecular response and confirmed using repeat testing within 6 months Complete remission: Clearance of a pre-existing abnormality Partial remission: ≥50% decrease in allele burden (for patients with ≥20% mutant allele burden at baseline) |
Cytogenetic/molecular remission | Re-emergence of a pre-existing cytogenetic or molecular abnormality that is confirmed by repeat testing |
References: 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; National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: myelofibrosis. Version 2.2022. |
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