Primary myelofibrosis

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Primary Myelofibrosis (PMF).

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Primary Author(s)*

T. Niroshi Senaratne, UCLA

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	Myeloid proliferations and neoplasms
Family	Myeloproliferative neoplasms
Type	Myeloproliferative neoplasms
Subtype(s)	Primary myelofibrosis

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

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Signs and Symptoms	EXAMPLE: Asymptomatic (incidental finding on complete blood counts) EXAMPLE: B-symptoms (weight loss, fever, night sweats) EXAMPLE: Fatigue EXAMPLE: Lymphadenopathy (uncommon)
Laboratory Findings	EXAMPLE: Cytopenias EXAMPLE: Lymphocytosis (low level)

editv4:Clinical Features

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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)

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Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: 3'ABL1 / 5'BCR	EXAMPLE: der(22)	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add reference)	Yes	No	Yes	EXAMPLE: The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).

editv4:Chromosomal Rearrangements (Gene Fusions)

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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].

editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

Please incorporate this section into the relevant tables found in:

• Chromosomal Rearrangements (Gene Fusions)
• Individual Region Genomic Gain/Loss/LOH
• Characteristic Chromosomal Patterns
• Gene Mutations (SNV/INDEL)

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].

Individual Region Genomic Gain / Loss / LOH

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Chr #	Gain / Loss / Amp / LOH	Minimal Region Genomic Coordinates [Genome Build]	Minimal Region Cytoband	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7:1- 159,335,973 [hg38]	EXAMPLE: chr7	Yes	Yes	No	EXAMPLE: Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8:1-145,138,636 [hg38]	EXAMPLE: chr8	No	No	No	EXAMPLE: Common recurrent secondary finding for t(8;21) (add reference).

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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

Characteristic Chromosomal Patterns

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Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: Co-deletion of 1p and 18q	Yes	No	No	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

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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].

Gene Mutations (SNV / INDEL)

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Gene; Genetic Alteration	Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)	Prevalence (COSMIC / TCGA / Other)	Concomitant Mutations	Mutually Exclusive Mutations	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: TP53; Variable LOF mutations EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations	EXAMPLE: TSG	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add Reference)	EXAMPLE: IDH1 R123H	EXAMPLE: EGFR amplification				EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

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Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations	EXAMPLE:  Histone modification, chromatin remodeling	EXAMPLE:  Abnormal gene expression program

editv4:Genes and Main Pathways Involved

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

Genetic 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.

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].

Additional Information

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Links

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References

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Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome. *Citation of this Page: “Primary myelofibrosis”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:Primary_myelofibrosis.