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Types

Myelofibrosis (MF) is a type of chronic myeloproliferative neoplasm in which early hematopoietic stem cells undergo genetic mutations that result in their increased survival and clonal reproduction.¹ Proliferation of these neoplastic hematopoietic stem cells disrupts the production of healthy blood cells within the bone marrow, leading to abnormal numbers of granulocytes, erythrocytes, and platelets in the peripheral blood.² Additionally, these cancer cells produce inflammatory chemicals, which lead to fibrotic scar tissue replacing the bone marrow.¹ MF is characterized by splenomegaly, bone marrow fibrosis, anemia, and extracellular hematopoiesis.³

MF is one of 3 disorders within a group of Philadelphia (Ph)-negative myeloproliferative neoplasms, also including polycythemia vera (PV) and essential thrombocythemia (ET).² While these 3 conditions share similar mutations in the JAK2, CALR, or MPL genes that result in the proliferation of cancerous stem cells and similar overlapping clinical and laboratory features, phenotypic presentation and disease progression vary widely from patient to patient.^4,5

Similar to the heterogeneous phenotypes among the 3 types of myeloproliferative neoplasms, patients with MF also demonstrate a range of clinical and laboratory presentations along a mutational spectrum, allowing for the subdivision of MF into two types: primary and secondary myelofibrosis.²

Primary Myelofibrosis

The first type, primary MF, occurs idiopathically in the absence of underlying conditions. In some cases, it can be linked to genetic mutations. It predominantly occurs in individuals older than 50 years of age.^2,6

Primary MF can be further subdivided into two subtypes — prefibrotic and overtly fibrotic — as defined by diagnostic guidelines.⁷

Read more about MF guidelines

Diagnostic Comparison of Prefibrotic and Overtly Fibrotic Primary MF

Both types of primary MF (prefibrotic and overtly fibrotic) must clinically demonstrate⁸:

bone marrow megakaryocytic proliferation and atypia;
presence of JAK2, CALR, MPL, or other clonal markers; and
failure to meet the diagnostic criteria for other myeloid neoplasms.

The 2016 revised World Health Organization (WHO) classification of myeloid neoplasms emphasizes the importance of evaluating bone marrow reticulin fibrosis to help classify types and subtypes.⁸ Prefibrotic primary MF is characterized by the absence of grade 2 or higher bone marrow reticulin fibrosis. Overt primary MF is characterized by the presence of grade 2 or higher bone marrow reticulin fibrosis.⁸

In a study comparing the differences in patient presentations between types of primary MF, patients with prefibrotic primary MF demonstrated higher hemoglobin levels and platelet counts, higher likelihood of thrombocytosis, and lower likelihood of constitutional symptoms, palpable splenomegaly, and circulating blasts in the peripheral blood.⁸

Additionally, patients diagnosed with prefibrotic primary MF typically scored lower on the risk stratification measurements compared with overtly fibrotic MF patients.⁸

Patients with prefibrotic primary MF were more often triple-negative for JAK2, CALR, and MPL mutations compared with overtly fibrotic patients (22% vs. 9%; P =.02).⁸

Read more about MF clinical features

Secondary Myelofibrosis

Secondary MF is the type of MF that is attributable to the presence of other underlying conditions, particularly blood disorders, including PV, ET, multiple myeloma, lymphoma, and chronic myeloid leukemia.⁶

Secondary MF may also develop following tuberculosis, human immunodeficiency virus (HIV) infection, systemic lupus erythematosus, systemic sclerosis, pulmonary hypertension, or cancer that has metastasized to the bones.⁶

Given the similarities in developmental pathogenesis, PV and ET may progress to secondary MF, also known as post-PV MF or post-ET MF. PV transforms into secondary MF in around 4.9% to 6% of patients after 10 years and 6% to 14% of patients after 15 years. ET transforms into secondary MF in around 0.8% to 4.9% of patients after 10 years and 4% to 11% of patients after 15 years.⁹

Risk factors for transformation of PV into secondary MF include⁹:

Advanced age;
Reticulin fibrosis;
Leukocytosis;
Splenomegaly; and
JAK2 V617F allele burden.

Risk factors for transformation of ET into secondary MF include⁹:

Advanced age;
Anemia;
Leukocytosis;
Reticulin fibrosis;
Absence of the JAK2 V617F mutation;
Presence of the ASXL1 mutation; and
Use of anagrelide.

Other studies have shown that male sex, low hemoglobin concentration, high white cell count at diagnosis, hypercellularity in the bone marrow, and increased serum lactate dehydrogenase also increase the risk for ET progression to myelofibrosis.^9,10

Read more about MF risk factors

References

Myelofibrosis. Cleveland Clinic. Accessed December 12, 2022.
Mills KI, McMullin MF. Mutational spectrum defines primary and secondary myelofibrosis. Haematologica. 2014;99(1):2-3. doi:10.3324/haematol.2013.101279
Wong WJ, Baltay M, Getz A, et al. Gene expression profiling distinguishes prefibrotic from overtly fibrotic myeloproliferative neoplasms and identifies disease subsets with distinct inflammatory signatures. PLoS One. 2019;14(5):e0216810. doi:10.1371/journal.pone.0216810
Rumi E, Trotti C, Vanni D, Casetti IC, Pietra D, Sant’Antonio E. The genetic basis of primary myelofibrosis and its clinical relevance. Int J Mol Sci. 2020;21(23):8885. doi:10.3390/ijms21238885
Lal A. Primary myelofibrosis: Practice essentials. Medscape. Updated on September 21, 2022. Accessed December 12, 2022.
Liesveld J. Myelofibrosis. Merck Manual Consumer Version. Accessed December 12, 2022.
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
Mudireddy M, Shah S, Lasho T, et al. Prefibrotic versus overtly fibrotic primary myelofibrosis: clinical, cytogenetic, molecular and prognostic comparisons. Br J Haematol. 2018;182(4):594-597. doi:10.1111/bjh.14838
Cerquozzi S, Tefferi A. Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors. Blood Cancer J. 2015;5(11):e366. doi:10.1038/bcj.2015.95
Abdulkarim K, Ridell B, Johansson P, Kutti J, Safai-Kutti S, Andréasson B. The impact of peripheral blood values and bone marrow findings on prognosis for patients with essential thrombocythemia and polycythemia vera. Eur J Haematol. 2011;86(2):148-155. doi:10.1111/j.1600-0609.2010.01548.x

Reviewed by Hasan Avcu, MD, on 1/11/2023.

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.

Myelofibrosis (MF)