Monitoring

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 ≥35% spleen volume reduction as determined by MRI or CT scan constitutes a spleen response regardless of physical exam result. A <50% reduction is clinically significant and justifies continued use of JAK inhibitors. A change in symptom status may be a sign of disease progression and should prompt an evaluation of treatment efficacy and/or disease status. The 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), signs and symptoms of disease progression is recommended as clinically indicated during the course of therapy. Continuation of JAK inhibitors are recommended for patients with <50% symptom response as well as spleen reduction volume that does not meet the threshold of >35% upon the discretion of the physician.

Bone marrow aspirate and biopsy with NGS 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 myelofibrosis to assess for high molecular risk mutations which are associated with disease progression. Broad-based NGS testing to include AML-associated mutations is recommended as part of the initial work-up for patients with accelerated or blast phase MPN. ASXL1, EZH2 TET2, TP53, SRSF2, IDH1, and IDH2 gene mutations and other chromosomal abnormalities (in chromosome 1q and 9p) are associated with transformation to acute myeloid leukemia.

MPN-accelerated phase is characterized by the presence of 10-19% blasts in the peripheral blood or bone marrow and MPN blast phase is characterized by the presence of ≥20% blasts in the peripheral blood or bone marrow.

2013 IWG-MRT and ELN Response Criteria for Myelofibrosis

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
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 six 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.
MF: Myelofibrosis; ULN: Upper Limit Normal

Management of Accelerated/Blast Phase MPN

The treatment options for patients with disease progression are based on transplant eligibility. Workup includes bone marrow aspirate and biopsy with reticulin and trichome stain, bone marrow cytogenetics if the bone marrow is inaspirable, flow cytometry, and broad-based NGS panels to include acute myeloid leukemia-associated mutations.

Continuation of JAK inhibitors (eg Fedratinib, Momelotinib, Pacritinib, Ruxolitinib) 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 bridging therapy with hypomethylating agents (Azacitidine or Decitabine) with or without JAK inhibitor (eg Fedratinib, Momelotinib, Pacritinib, Ruxolitinib) or hypomethylating agents plus Venetoclax or with intensive acute myeloid leukemia-type induction chemotherapy followed by allogeneic hematopoietic stem cell transplant. Enrollment in clinical trials may be another option.

Transplant-ineligible Patients

Treatment with hypomethylating agents with or without JAK inhibitor or hypomethylating agents plus Venetoclax or low-intensity acute myeloid leukemia-type induction chemotherapy or enrollment in clinical trials is recommended.

Prognosis

Prognostic Markers

The presence of triple-negative mutation status (absence of JAK2, CALR, or MPL mutations) is associated with a worse prognosis in patients with primary myelofibrosis.

The presence of ASXL1, EZH2, SRSF2, TP53, IDH1, IDH2 or U2AF1 mutations are high-molecular risk mutation and are associated with shorter OS and leukemia-free survival in patients with primary myelofibrosis. ASXL1, EZH2, and SRSF2 mutations are predictive of OS. ASXL1, SRSF2, and IDH1 or IDH2 mutations are predictive of leukemic transformation.

The presence of TET2 or TP53 mutations is associated with a worse overall prognosis and an increased rate of leukemic transformation. The presence of U2AF1 mutations is associated with poorer survival in patients with primary myelofibrosis.

Myelofibrosis Follow Up

Disease Summary

Disease Background

Initial Assessment

Diagnostics

Differential Diagnosis

Management

Follow Up

Drug Summary

References

Monitoring

Prognosis