Primary Myelofibrosis (PMF)

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This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition Table of Contents.

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Primary Author(s)*

T. Niroshi Senaratne, UCLA

Cancer Category/Type

Myeloproliferative neoplasm (MPN)

Cancer Sub-Classification / Subtype

Primary myelofibrosis (PMF)

Definition / Description of Disease

Clonal MPN characterized by proliferation of predominantly abnormal megakaryocytes and granulocytes in the bone marrow.

Prefibrotic/early PMF (pre-PMF) is associated with hypercellular bone marrow with absent or minimal reticulin fibrosis.

Overt fibrotic PMF (classic PMF) is associated with marked reticulin or collagen fibrosis in the bone marrow, often with osteosclerosis, leukoerythroblastosis in the blood, hepatomegaly, and splenomegaly.

Synonyms / Terminology

Chronic idiopathic myelofibrosis; myelofibrosis/sclerosis with myeloid metaplasia; agnogenic myeloid metaplasia; megakaryocytic myelosclerosis; idiopathic myelofibrosis; myelofibrosis with myeloid metaplasia; myelofibrosis as a result of myeloproliferative disease

Epidemiology / Prevalence

Estimated annual incidence of overt PMF is 0.5-1.5 cases per 100,000 population, with both genders nearly equally affected. Incidence of pre-PMF is not known. The age of occurrence is commonly during 60s-70s.

Clinical Features

As many as 30% of patients with PMF may be asymptomatic at the time of diagnosis, and are found by detection of splenomegaly, anemia, leukocytosis and/or thrombocytosis. More than 50% of patients experience constitutional symptoms.

Leukemic transformation may occur in 4-20% of patients and is associated with a poor prognosis.

Sites of Involvement

The bone marrow and blood are always involved. In later stages of the disease there is also extramedullary hematopoiesis, particularly in the spleen.

Morphologic Features

Pre-PMF: hypercellular bone marrow, with increase in neutrophils and atypical megakaryocytes

Overt PMF: reticulin or collagen fibrosis (fibrosis grades 2 or 3), often with collagen fibrosis and osteosclerosis. Most often the bone marrow is normo- or hypocellular. Atypical megakaryocytes are present in large clusters or sheets.

Immunophenotype

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Finding	Marker
Positive (universal)	EXAMPLE CD1
Positive (subset)	EXAMPLE CD2
Negative (universal)	EXAMPLE CD3
Negative (subset)	EXAMPLE CD4

Chromosomal Rearrangements (Gene Fusions)

Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence
N/A	N/A	N/A	N/A

Note: By definition, PMF should be negative for BCR-ABL1 fusion. In very rare cases, a BCR-ABL1 rearrangement is acquired [Ref]

Balanced translocations are rare in PMF and few are recurrent. One recurrent unbalanced translocation has been described, der(6)t(1;6)(q21;p21) resulting in gain of 1q and loss of 6p [Dingli et al 2005; Djordjevic et al., 2007].

Characteristic Chromosomal Aberrations / Patterns

Approximately 30-42.6% of PMF cases show cytogenetic abnormalities, with more advanced cases showing increasing frequency of abnormalities. The most common are del(20q) (19-33%) and del(13q) (14-23%), with additional abnormalities including trisomy 8 (8-16%), trisomy 9 (3-14%), and abnormalities of chromosome 1 (6-28%).

Disease progression is associated with additional abnormalities, including gain of 1q (3-19%), del(5q) (3-6%), chromosome 7 abnormalities (5-10%), del(17p) and in rare cases i(17q) [Ref: Vandenberghe and Michaux, 2015 in Cancer Cytogenetics (Eds: Heim and Mitelman); see also Wassie et al 2015].

Genomic Gain/Loss/LOH

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Chromosome Number	Gain/Loss/Amp/LOH	Region
2	EXAMPLE Gain	EXAMPLE chr8:0-1000000
3	EXAMPLE Loss	EXAMPLE chr7:0-1000000

Gene Mutations (SNV/INDEL)

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Gene	Mutation	Oncogene/Tumor Suppressor/Other	Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)	Prevalence (COSMIC/TCGA/Other)
EXAMPLE TP53	EXAMPLE R273H	EXAMPLE Tumor Suppressor	EXAMPLE LOF	EXAMPLE 20%

Other Mutations

Type	Gene/Region/Other
Concomitant Mutations	EXAMPLE IDH1 R123H
Secondary Mutations	EXAMPLE Trisomy 7
Mutually Exclusive	EXAMPLE EGFR Amplification

Epigenomics (Methylation)

Put your text here

Genes and Main Pathways Involved

JAK2 mutations result in constitutive activation of JAK2 signalling. CALR and MPL mutations also result in activation of the same pathway.

Diagnostic Testing Methods

Initial testing for JAK2 V617F mutation, followed by testing for CALR and MPL if negative. Karyotype studies as well as next generation sequencing panels for genes associated with myeloid neoplasms provide important prognostic information.

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

Since the mutations and chromosome aberrations detected in PMF can also be found in other MPN, genetic findings alone cannot be used to make the diagnosis of PMF.

There are multiple prognostic systems for PMF that take into account genetic information. In 2011 the DIPSS (Dynamic International Prognostic Scoring System for primary myelofibrosis) was updated to incorporate prognostic information from karyotype [Gangat et al 2011]. More recently, a scoring system incorporating both cytogenetic and molecular information was developed, the Mutation-Enhanced International Prognostic Score System or MIPSS70-plus [Guglielmelli et al 2018], as well as prognostic scoring system based only on genetics, the Genetically Inspired Prognostic Scoring System or GIPSS [Tefferi et al 2018a] were developed.

DIPSS-plus (2011): “Unfavorable karyotype” including complex karyotypes or the presence of one or two abnormalities including +8, −7/7q−, i(17q), inv(3), −5/5q−, 12p− or 11q23 rearrangement.

MIPSS70-plus (2018): “Very high risk (VHR) karyotype” defined as single/multiple abnormalities of -7, i(17q), inv(3)/3q21, 12p-/12p11.2, 11q-/11q23, or other autosomal trisomies not including + 8/ + 9 (e.g., +21, +19); “Favorable” including normal karyotype or sole abnormalities of 13q-, +9, 20q-, chromosome 1 translocation/duplication or sex chromosome abnormality including -Y; and “Unfavorable” including all other abnormalities. [Tefferi et al 2018b]

“HMR” (high molecular risk) mutations defined as presence of one or more mutations in EZH2, ASXL1, IDH1/IDH2, and SRSF2 [Vannucchi et al 2013], subsequently updated to also include mutations in U2AF1 [Tefferi et al 2018c].

GIPSS (2018): Karyotype classification using same definition as described above for MIPSS70-plus. Molecular findings associated with high risk were absence of type 1/like CALR mutations [Tefferi et al 2018e] or presence of mutations in ASXL1, SRSF2, or U2AF1Q157 (EZH2 and IDH1/2 mutations remained non-significant during multivariable analysis).

In terms of therapeutic options, the preferred option for high risk patients is allogenic stem cell transplant, while low risk patients may be followed with observation only. For intermediate risk patients, treatments including JAK2 inhibitors may be used [Tefferi et al 2018d].

Familial Forms

Rare familial cases of bone marrow fibrosis in children have been reported but it is unclear how many of these have a myeloproliferative neoplasm [Rumi and Cazzola 2017].

Other Information