Diagnosing Myelofibrosis

Myelofibrosis Is Diagnosed by Exclusion

Myelofibrosis is an uncommon MPN that may not initially be suspected because its signs and symptoms overlap with other malignant and hematologic disorders.1 An enlarged spleen may be detected on physical examination, or blood testing may yield abnormal results; anemia is a common finding.1

WHO Diagnostic Criteria Facilitate Diagnosis of Primary Myelofibrosis

Diagnostic criteria for primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET) were revised in 2016 by the World Health Organization (WHO).2

A diagnosis of PMF requires all 3 major criteria and at least 1 minor criterion confirmed in 2 consecutive determinations.2

WHO criteria for diagnosis of primary myelofibrosis (PMF)
Major criteria:
  • Proliferation and atypia of megakaryocytes accompanied by either reticulin and/or collagen fibrosis grades 2 or 3 on a scale of 0 to 3
  • Not meeting WHO criteria for ET, PV, BCR-ABL1+ CML, myelodysplastic syndrome, or other myeloid neoplasm
  • Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another clonal markera or absence of reactive myelofibrosisb
Minor criteria:
  • Anemia not attributed to a comorbid condition
  • Leukocytosis ≥11 × 109/L
  • Palpable splenomegaly
  • LDH increased to above upper normal limit of institutional reference range
  • Leukoerythroblastosis
BCR-ABL = breakpoint cluster region-Abelson CALR = calreticulin CML = chronic myelogenous leukemia ET = essential thrombocythemia
JAK = Janus-associated kinase LDH = lactate dehydrogenase MPL = myeloproliferative leukemia virus oncogene
aIn the absence of any of the 3 major clonal mutations, the search for the most frequent accompanying mutations (eg, ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1) is of help in determining the clonal nature of the disease. bBone marrow fibrosis secondary to infection, autoimmune disorder, or other chronic inflammatory conditions, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies.

IWG-MRT Diagnostic Criteria Facilitate Diagnosis of Post–PV and Post–ET Myelofibrosis

PV and ET can progress to myelofibrosis, resulting in post–PV MF and post–ET MF, respectively.3-5

The International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) has established a set of diagnostic criteria specific to post–PV MF and post–ET MF. As shown in the table to the right, the diagnoses require documentation of previous PV or ET by WHO criteria, presence of moderate to severe bone marrow fibrosis, and meeting 2 or more additional criteria.3,6

Diagnosing PPV- or PET-MF
PV 10% transformation rate per 10 years6
Post–PV myelofibrosis3
  • IWG Diagnostic Criteria for Post–PV Myelofibrosis
Required criteria
  • Documentation of previous diagnosis of PV or ET as defined by WHO criteria
  • Grade 2 or 3 bone marrow fibrosis (0–3 scale) or grade 3 or 4 bone marrow fibrosis (0–4 scale)
Required criteria
  • Documentation of previous diagnosis of PV or ET as defined by WHO criteria
  • Grade 2 or 3 bone marrow fibrosis (0–3 scale) or grade 3 or 4 bone marrow fibrosis (0–4 scale)
Additional criteria (2 required)
  • Anemia or sustained loss of need for either phlebotomy or cytoreductive therapy
  • Leukoerythroblastosis
  • ≥5 cm increase in palpable splenomegaly or new splenomegaly
  • Development of ≥1 of 3 constitutional symptomsa
ET <4% transformation rate per 10 years6
Post–ET myelofibrosis3
  • IWG Diagnostic Criteria for Post–ET Myelofibrosis
Required criteria
  • Documentation of previous diagnosis of PV or ET as defined by WHO criteria
  • Grade 2 or 3 bone marrow fibrosis (0–3 scale) or grade 3 or 4 bone marrow fibrosis (0–4 scale)
Additional criteria (2 required)
  • Anemia and a decrease of ≥2 mg/mL from baseline hemoglobin level
  • Leukoerythroblastosis
  • ≥5 cm increase in palpable splenomegaly or new splenomegaly
  • Increased serum LDH level
  • Development of ≥1 of 3 constitutional symptomsa
aConstitutional symptoms include >10% weight loss in 6 months, night sweats, and unexplained fever (>37.5°C).
ET = essential thrombocythemia IWG = International Working Group LDH = lactate dehydrogenase PET-MF = post–essential thrombocythemia myelofibrosis
PPV-MF = post–polycythemia vera myelofibrosis PV = polycythemia vera WHO = World Health Organization
References

1. Barosi G. J Clin Oncol. 1999;17:2954-2970. 2. Arber DA, Orazi A, Hasserjian R, et al. Blood. 2016;127(20):2391-2405. 3. Barosi G, Mesa RA, Thiele J, et al; International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). Leukemia. 2008;22:437-438. 4. Verstovsek S. Clin Cancer Res. 2010;16:1988-1996. 5. Mesa RA. Hematology Am Soc Hematol Educ Program. 2007:355-362. 6. Tefferi A. Am J Hematol. 2008;83:491-497.

 
Resources
By: World Health Organization (WHO)
A diagnostic worksheet from the WHO for primary MF, PV, and ET.
By: International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)
Diagnostic criteria from the IWG-MRT.