Myeloproliferative Neoplasm, Unclassifiable

MONDO:0019452 Pathograph 2 myeloproliferative neoplasm

Myeloproliferative neoplasm, unclassifiable (MPN-U) is a clonal myeloid neoplasm assigned when a case has myeloproliferative features but does not satisfy the full diagnostic criteria for a defined myeloproliferative neoplasm, or shows overlapping features across multiple MPN categories. The category is heterogeneous and can include early/prodromal MPNs, advanced fibrotic MPNs, and cases where inflammatory or neoplastic comorbidity obscures the clinicopathologic picture.

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2
Pathophys.
1
Histopath.
5
Phenotypes
2
Pathograph
3
Genes
4
Treatments
1
Deep Research
⚙

Pathophysiology

2
Clonal Myeloid Proliferation
MPN-U arises from a clonal hematopoietic stem or progenitor population with myeloproliferative behavior, increased production of one or more myeloid lineages, and insufficient integrated clinicopathologic features for assignment to a more specific MPN subtype at diagnosis.
hematopoietic stem cell link myeloid cell link
myeloid cell differentiation link ⚠ ABNORMAL
bone marrow link
Downstream
Thrombotic Complication Biology Clonal myeloproliferation creates a prothrombotic clinical phenotype in a subset of MPN-U patients.
Show evidence (2 references)
PMID:34830822 SUPPORT Human Clinical
"Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal hematopoietic stem cell disorders, characterized by increased proliferation of one or more myeloid lineages in the bone marrow."
This review defines the parent MPN biology as clonal hematopoietic stem cell disease with increased myeloid-lineage proliferation in marrow.
PMID:33751548 SUPPORT Human Clinical
"Myeloproliferative neoplasm-unclassifiable (MPN-U) presents an MPN-type phenotype that fails to meet diagnostic criteria for other MPN variants."
This cohort abstract supports MPN-U as MPN-type disease that remains unassignable to a defined MPN variant.
Thrombotic Complication Biology
MPN-U carries clinically important thrombotic risk, reflecting the prothrombotic behavior seen across myeloproliferative neoplasms and requiring vigilance even though management is not standardized specifically for MPN-U.
blood coagulation link ⚠ ABNORMAL
Show evidence (1 reference)
PMID:33751548 SUPPORT Human Clinical
"Thrombosis was common (21%), necessitating vigilance."
The retrospective MPN-U cohort directly reports thrombosis as a common complication.
✶

Histopathology

1
Clustered Pleomorphic Megakaryocytes
Bone marrow trephine biopsy may show clustered or pleomorphic megakaryocytes, supporting an MPN-type marrow morphology even when the case cannot be classified as a defined MPN subtype.
Show evidence (1 reference)
PMID:33751548 SUPPORT Human Clinical
"Albeit heterogeneous, common presentation features included raised lactate dehydrogenase, thrombocytosis and clustered/pleomorphic megakaryocytes on trephine biopsy."
This cohort abstract directly reports clustered or pleomorphic megakaryocytes on trephine biopsy.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Myeloproliferative Neoplasm, Unclassifiable Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

5
Blood 3
Thrombocytosis Thrombocytosis (HP:0001894)
Show evidence (1 reference)
PMID:33751548 SUPPORT Human Clinical
"Albeit heterogeneous, common presentation features included raised lactate dehydrogenase, thrombocytosis and clustered/pleomorphic megakaryocytes on trephine biopsy."
The cohort abstract identifies thrombocytosis as a common presentation feature of MPN-U.
Leukocytosis Increased total leukocyte count (HP:0001974)
Show evidence (1 reference)
PMID:33751548 SUPPORT Human Clinical
"significantly shortened in cases with lower platelet counts (<500 × 109 /l) and a leucocytosis (≥12 × 109 /l) at presentation."
The cohort abstract identifies leukocytosis at presentation as an adverse clinical feature in MPN-U.
Thrombosis OCCASIONAL Abnormal thrombosis (HP:0001977)
Show evidence (1 reference)
PMID:33751548 SUPPORT Human Clinical
"Thrombosis was common (21%), necessitating vigilance."
The 21% cohort frequency supports thrombosis as an occasional-to-common clinical complication.
Cardiovascular 1
Splenomegaly Splenomegaly (HP:0001744)
Show evidence (1 reference)
PMID:35217310 SUPPORT Human Clinical
"significant risk of thrombosis, bulky splenomegaly, and debilitating symptom burden."
The international practice survey abstract highlights bulky splenomegaly as a clinically important manifestation.
Constitutional 1
Fatigue Fatigue (HP:0012378)
Show evidence (1 reference)
PMID:35217310 PARTIAL Human Clinical
"significant risk of thrombosis, bulky splenomegaly, and debilitating symptom burden."
The survey abstract supports debilitating symptom burden but does not name fatigue specifically, so this evidence is partial.
🧬

Genetic Associations

3
JAK2 (Somatic activating variants)
Show evidence (1 reference)
PMID:36580136 PARTIAL Human Clinical
"high sensitive single target (RT-qPCR, ddPCR) or multi-target next-generation sequencing assays with a minimal sensitivity of VAF 1% are now important for a proper diagnostic identification of MPN cases with low allelic frequencies at initial presentation."
The ICC review supports sensitive molecular testing for low-allele-fraction MPN driver lesions; Falcon identified JAK2 among the recurrent MPN-U drivers, but the fetched abstract does not provide JAK2-specific MPN-U frequencies.
CALR (Somatic driver variants)
Show evidence (1 reference)
PMID:36580136 PARTIAL Human Clinical
"high sensitive single target (RT-qPCR, ddPCR) or multi-target next-generation sequencing assays with a minimal sensitivity of VAF 1% are now important for a proper diagnostic identification of MPN cases with low allelic frequencies at initial presentation."
The ICC review supports sensitive molecular testing for MPN driver lesions; CALR-specific MPN-U frequency is documented in the Falcon report but not in this fetched abstract.
MPL (Somatic driver variants)
Show evidence (1 reference)
PMID:36580136 PARTIAL Human Clinical
"high sensitive single target (RT-qPCR, ddPCR) or multi-target next-generation sequencing assays with a minimal sensitivity of VAF 1% are now important for a proper diagnostic identification of MPN cases with low allelic frequencies at initial presentation."
The ICC review supports sensitive molecular testing for MPN driver lesions; MPL-specific MPN-U frequency is documented in the Falcon report but not in this fetched abstract.
💊

Treatments

4
Phenotype-Directed Pharmacotherapy
Action: Pharmacotherapy NCIT:C15986
Management is individualized and phenotype-driven, addressing cytoses, splenomegaly, thrombosis risk, and symptom burden by extrapolation from related MPNs because MPN-U-specific treatment guidelines and trial evidence are limited.
Show evidence (1 reference)
PMID:35217310 SUPPORT Human Clinical
"Clinicians frequently manage these conditions according to the clinical concerns e.g. splenomegaly akin to the phenotype, but no evidence base exists."
The survey abstract supports phenotype-driven pharmacologic management and emphasizes the lack of an MPN-U-specific evidence base.
Hydroxyurea Cytoreduction
Action: Pharmacotherapy NCIT:C15986
Agent: hydroxyurea ↗
Hydroxyurea/hydroxycarbamide is used for cytoreduction in patients with proliferative blood-count phenotypes, although MPN-U-specific evidence and standardized thresholds remain limited.
Show evidence (1 reference)
PMID:35191542 PARTIAL Human Clinical
"A diagnosis of MPN-U leads to many challenges for both the patient and physician alike including lack of agreed monitoring and therapeutic guidelines, validated prognostic markers and licenced therapies coupled with exclusion from clinical trials."
This review supports the lack of licensed MPN-U-specific therapies; Falcon full-text synthesis identifies hydroxycarbamide as the most common cytoreductive agent in the UK cohort.
Ruxolitinib
Action: Pharmacotherapy NCIT:C15986
Agent: ruxolitinib ↗
Off-label JAK inhibition with ruxolitinib may be considered for selected patients with symptomatic splenomegaly or high symptom burden, extrapolating from related myeloproliferative neoplasms.
Show evidence (1 reference)
PMID:35191542 PARTIAL Human Clinical
"MPN-U has an inherent risk of an aggressive clinical course and transformation in some but who, and when to treat in the chronic phase, including identifying who may require more aggressive therapy at an earlier stage, remains elusive."
The review supports individualized treatment escalation in MPN-U; Falcon full-text synthesis identifies off-label ruxolitinib/JAK-inhibitor use for splenomegaly or symptoms.
Allogeneic Hematopoietic Stem Cell Transplantation
Action: hematopoietic stem cell transplantation MAXO:0000747
Allogeneic hematopoietic stem cell transplantation is considered only for selected aggressive, accelerated/blast-phase, or fibrotic presentations because most MPN-U care is individualized and evidence-limited.
Show evidence (1 reference)
PMID:35191542 PARTIAL Human Clinical
"MPN-U has an inherent risk of an aggressive clinical course and transformation in some but who, and when to treat in the chronic phase, including identifying who may require more aggressive therapy at an earlier stage, remains elusive."
The review supports the need to identify patients requiring aggressive therapy; Falcon full-text synthesis identifies allogeneic transplantation as an advanced-disease strategy.
🌍

Environmental Factors

1
Smoking
Smoking has been associated with increased risk of MPN development in a Danish population-based cohort, with the strongest subtype-specific signal reported for MPN-U; the association should be interpreted cautiously because MPNs are rare and diagnosis-code misclassification is possible.
Show evidence (1 reference)
PMID:30318865 SUPPORT Human Clinical
"For essential thrombocytosis, polycythemia vera, myelofibrosis, and MPN-unclassified, the HRs were 1.8 (95% CI: 0.5-5.8), 1.7 (95% CI: 0.5-5.8), 4.3 (95% CI: 0.9-19), and 6.2 (95% CI: 1.5-25), respectively."
This population-based cohort found increased hazard for MPN-unclassified among daily smokers compared with never-smokers.
🔬

Biochemical Markers

1
Raised Lactate Dehydrogenase
Show evidence (1 reference)
PMID:33751548 SUPPORT Human Clinical
"Albeit heterogeneous, common presentation features included raised lactate dehydrogenase, thrombocytosis and clustered/pleomorphic megakaryocytes on trephine biopsy."
The cohort abstract identifies raised lactate dehydrogenase as a common presentation feature.
{ }

Source YAML

click to show 
name: Myeloproliferative Neoplasm, Unclassifiable
creation_date: "2026-05-11T14:55:10Z"
updated_date: "2026-05-11T16:17:05Z"
description: >-
  Myeloproliferative neoplasm, unclassifiable (MPN-U) is a clonal myeloid
  neoplasm assigned when a case has myeloproliferative features but does not
  satisfy the full diagnostic criteria for a defined myeloproliferative
  neoplasm, or shows overlapping features across multiple MPN categories. The
  category is heterogeneous and can include early/prodromal MPNs, advanced
  fibrotic MPNs, and cases where inflammatory or neoplastic comorbidity obscures
  the clinicopathologic picture.
categories:
- Hematologic Malignancy
- Myeloproliferative Neoplasm
parents:
- myeloproliferative neoplasm
synonyms:
- MPN-U
- MPN, unclassifiable
- MPN not otherwise specified
- MPN-NOS
- chronic myeloproliferative disease, unclassifiable
notes: >-
  Falcon deep research surfaced pruritus as a cohort phenotype from the
  full-text UK series, but the fetched PubMed abstract for the cohort does not
  contain a direct quotable pruritus statement, so pruritus is retained here as
  report-derived context rather than modeled as evidence-backed phenotype data.
disease_term:
  preferred_term: myeloproliferative neoplasm, unclassifiable
  term:
    id: MONDO:0019452
    label: myeloproliferative neoplasm, unclassifiable
pathophysiology:
- name: Clonal Myeloid Proliferation
  description: >-
    MPN-U arises from a clonal hematopoietic stem or progenitor population with
    myeloproliferative behavior, increased production of one or more myeloid
    lineages, and insufficient integrated clinicopathologic features for
    assignment to a more specific MPN subtype at diagnosis.
  evidence:
  - reference: PMID:34830822
    reference_title: "The Classification of Myeloproliferative Neoplasms: Rationale, Historical Background and Future Perspectives with Focus on Unclassifiable Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal
      hematopoietic stem cell disorders, characterized by increased
      proliferation of one or more myeloid lineages in the bone marrow.
    explanation: >-
      This review defines the parent MPN biology as clonal hematopoietic stem
      cell disease with increased myeloid-lineage proliferation in marrow.
  - reference: PMID:33751548
    reference_title: "Clinicopathological characterisation of myeloproliferative neoplasm-unclassifiable (MPN-U): a retrospective analysis from a large UK tertiary referral centre."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Myeloproliferative neoplasm-unclassifiable (MPN-U) presents an MPN-type
      phenotype that fails to meet diagnostic criteria for other MPN variants.
    explanation: >-
      This cohort abstract supports MPN-U as MPN-type disease that remains
      unassignable to a defined MPN variant.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  - preferred_term: myeloid cell
    term:
      id: CL:0000763
      label: myeloid cell
  biological_processes:
  - preferred_term: myeloid cell differentiation
    modifier: ABNORMAL
    term:
      id: GO:0030099
      label: myeloid cell differentiation
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  downstream:
  - target: Thrombotic Complication Biology
    description: >-
      Clonal myeloproliferation creates a prothrombotic clinical phenotype in a
      subset of MPN-U patients.
    evidence:
    - reference: PMID:33751548
      reference_title: "Clinicopathological characterisation of myeloproliferative neoplasm-unclassifiable (MPN-U): a retrospective analysis from a large UK tertiary referral centre."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thrombosis was common (21%), necessitating vigilance.
      explanation: >-
        This cohort abstract supports thrombosis as a common downstream clinical
        complication of MPN-U.
- name: Thrombotic Complication Biology
  description: >-
    MPN-U carries clinically important thrombotic risk, reflecting the
    prothrombotic behavior seen across myeloproliferative neoplasms and requiring
    vigilance even though management is not standardized specifically for MPN-U.
  evidence:
  - reference: PMID:33751548
    reference_title: "Clinicopathological characterisation of myeloproliferative neoplasm-unclassifiable (MPN-U): a retrospective analysis from a large UK tertiary referral centre."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thrombosis was common (21%), necessitating vigilance.
    explanation: >-
      The retrospective MPN-U cohort directly reports thrombosis as a common
      complication.
  biological_processes:
  - preferred_term: blood coagulation
    modifier: ABNORMAL
    term:
      id: GO:0007596
      label: blood coagulation
phenotypes:
- category: Hematologic
  name: Thrombocytosis
  description: >-
    Increased platelet count can be present when the unclassifiable neoplasm
    overlaps essential thrombocythemia-like biology.
  phenotype_term:
    preferred_term: Thrombocytosis
    term:
      id: HP:0001894
      label: Thrombocytosis
  evidence:
  - reference: PMID:33751548
    reference_title: "Clinicopathological characterisation of myeloproliferative neoplasm-unclassifiable (MPN-U): a retrospective analysis from a large UK tertiary referral centre."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Albeit heterogeneous, common presentation features included raised lactate
      dehydrogenase, thrombocytosis and clustered/pleomorphic megakaryocytes on
      trephine biopsy.
    explanation: >-
      The cohort abstract identifies thrombocytosis as a common presentation
      feature of MPN-U.
- category: Hematologic
  name: Leukocytosis
  description: >-
    Increased leukocyte count can occur as part of the myeloproliferative
    blood-count pattern.
  phenotype_term:
    preferred_term: Leukocytosis
    term:
      id: HP:0001974
      label: Increased total leukocyte count
  evidence:
  - reference: PMID:33751548
    reference_title: "Clinicopathological characterisation of myeloproliferative neoplasm-unclassifiable (MPN-U): a retrospective analysis from a large UK tertiary referral centre."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      significantly shortened in cases with lower platelet counts (<500 × 109
      /l) and a leucocytosis (≥12 × 109 /l) at presentation.
    explanation: >-
      The cohort abstract identifies leukocytosis at presentation as an adverse
      clinical feature in MPN-U.
- category: Abdominal
  name: Splenomegaly
  description: >-
    Splenic enlargement may reflect extramedullary hematopoiesis or disease
    burden in myeloproliferative neoplasms.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:35217310
    reference_title: "Diagnostic and management strategies for Myeloproliferative Neoplasm-Unclassifiable (MPN-U): An international survey of contemporary practice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      significant risk of thrombosis, bulky splenomegaly, and debilitating
      symptom burden.
    explanation: >-
      The international practice survey abstract highlights bulky splenomegaly
      as a clinically important manifestation.
- category: Cardiovascular
  name: Thrombosis
  frequency: OCCASIONAL
  description: >-
    Arterial or venous thrombosis, including atypical-site thrombosis, is a major
    complication and may be present at or near diagnosis.
  phenotype_term:
    preferred_term: Thrombosis
    term:
      id: HP:0001977
      label: Abnormal thrombosis
  evidence:
  - reference: PMID:33751548
    reference_title: "Clinicopathological characterisation of myeloproliferative neoplasm-unclassifiable (MPN-U): a retrospective analysis from a large UK tertiary referral centre."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thrombosis was common (21%), necessitating vigilance.
    explanation: >-
      The 21% cohort frequency supports thrombosis as an occasional-to-common
      clinical complication.
- category: Constitutional
  name: Fatigue
  description: >-
    Fatigue is included as a representative constitutional symptom contributing
    to the debilitating symptom burden described in MPN-U.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:35217310
    reference_title: "Diagnostic and management strategies for Myeloproliferative Neoplasm-Unclassifiable (MPN-U): An international survey of contemporary practice."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      significant risk of thrombosis, bulky splenomegaly, and debilitating
      symptom burden.
    explanation: >-
      The survey abstract supports debilitating symptom burden but does not name
      fatigue specifically, so this evidence is partial.
histopathology:
- name: Clustered Pleomorphic Megakaryocytes
  description: >-
    Bone marrow trephine biopsy may show clustered or pleomorphic
    megakaryocytes, supporting an MPN-type marrow morphology even when the case
    cannot be classified as a defined MPN subtype.
  evidence:
  - reference: PMID:33751548
    reference_title: "Clinicopathological characterisation of myeloproliferative neoplasm-unclassifiable (MPN-U): a retrospective analysis from a large UK tertiary referral centre."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Albeit heterogeneous, common presentation features included raised lactate
      dehydrogenase, thrombocytosis and clustered/pleomorphic megakaryocytes on
      trephine biopsy.
    explanation: >-
      This cohort abstract directly reports clustered or pleomorphic
      megakaryocytes on trephine biopsy.
biochemical:
- name: Raised Lactate Dehydrogenase
  notes: >-
    Elevated serum lactate dehydrogenase can accompany the proliferative disease
    burden in MPN-U.
  evidence:
  - reference: PMID:33751548
    reference_title: "Clinicopathological characterisation of myeloproliferative neoplasm-unclassifiable (MPN-U): a retrospective analysis from a large UK tertiary referral centre."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Albeit heterogeneous, common presentation features included raised lactate
      dehydrogenase, thrombocytosis and clustered/pleomorphic megakaryocytes on
      trephine biopsy.
    explanation: >-
      The cohort abstract identifies raised lactate dehydrogenase as a common
      presentation feature.
genetic:
- name: JAK2
  gene_term:
    preferred_term: JAK2
    term:
      id: hgnc:6192
      label: JAK2
  association: Somatic activating variants
  notes: >-
    Somatic JAK2 variants may be present in MPN-U, particularly in cases with
    polycythemia vera-like or thrombocythemia-like features. Falcon deep
    research reports full-text UK cohort frequencies of JAK2 V617F in 53.7%
    and JAK2 exon 12 mutations in 2.4% of patients; these frequency data are not
    present in the fetched PubMed abstract.
  evidence:
  - reference: PMID:36580136
    reference_title: "International Consensus Classification of myeloid and lymphoid neoplasms: myeloproliferative neoplasms."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      high sensitive single target (RT-qPCR, ddPCR) or multi-target
      next-generation sequencing assays with a minimal sensitivity of VAF 1% are
      now important for a proper diagnostic identification of MPN cases with low
      allelic frequencies at initial presentation.
    explanation: >-
      The ICC review supports sensitive molecular testing for low-allele-fraction
      MPN driver lesions; Falcon identified JAK2 among the recurrent MPN-U
      drivers, but the fetched abstract does not provide JAK2-specific MPN-U
      frequencies.
- name: CALR
  gene_term:
    preferred_term: CALR
    term:
      id: hgnc:1455
      label: CALR
  association: Somatic driver variants
  notes: >-
    Somatic CALR variants may occur in MPN-U, especially in cases with
    thrombocythemia-like or prefibrotic myelofibrosis-like features. Falcon
    deep research reports full-text UK cohort frequencies of CALR type 1 in
    8.5% and CALR type 2 in 4.8% of patients; these frequency data are not
    present in the fetched PubMed abstract.
  evidence:
  - reference: PMID:36580136
    reference_title: "International Consensus Classification of myeloid and lymphoid neoplasms: myeloproliferative neoplasms."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      high sensitive single target (RT-qPCR, ddPCR) or multi-target
      next-generation sequencing assays with a minimal sensitivity of VAF 1% are
      now important for a proper diagnostic identification of MPN cases with low
      allelic frequencies at initial presentation.
    explanation: >-
      The ICC review supports sensitive molecular testing for MPN driver lesions;
      CALR-specific MPN-U frequency is documented in the Falcon report but not in
      this fetched abstract.
- name: MPL
  gene_term:
    preferred_term: MPL
    term:
      id: hgnc:7217
      label: MPL
  association: Somatic driver variants
  notes: >-
    Somatic MPL variants may occur in MPN-U and implicate thrombopoietin receptor
    signaling in a subset of cases. Falcon deep research reports a full-text UK
    cohort frequency of MPL mutations in 6.1% of patients; these frequency data
    are not present in the fetched PubMed abstract.
  evidence:
  - reference: PMID:36580136
    reference_title: "International Consensus Classification of myeloid and lymphoid neoplasms: myeloproliferative neoplasms."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      high sensitive single target (RT-qPCR, ddPCR) or multi-target
      next-generation sequencing assays with a minimal sensitivity of VAF 1% are
      now important for a proper diagnostic identification of MPN cases with low
      allelic frequencies at initial presentation.
    explanation: >-
      The ICC review supports sensitive molecular testing for MPN driver lesions;
      MPL-specific MPN-U frequency is documented in the Falcon report but not in
      this fetched abstract.
environmental:
- name: Smoking
  effect: Risk factor
  notes: >-
    Smoking has been associated with increased risk of MPN development in a
    Danish population-based cohort, with the strongest subtype-specific signal
    reported for MPN-U; the association should be interpreted cautiously because
    MPNs are rare and diagnosis-code misclassification is possible.
  evidence:
  - reference: PMID:30318865
    reference_title: "Smoking is associated with increased risk of myeloproliferative neoplasms: A general population-based cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For essential thrombocytosis, polycythemia vera, myelofibrosis, and
      MPN-unclassified, the HRs were 1.8 (95% CI: 0.5-5.8), 1.7 (95% CI:
      0.5-5.8), 4.3 (95% CI: 0.9-19), and 6.2 (95% CI: 1.5-25), respectively.
    explanation: >-
      This population-based cohort found increased hazard for MPN-unclassified
      among daily smokers compared with never-smokers.
treatments:
- name: Phenotype-Directed Pharmacotherapy
  description: >-
    Management is individualized and phenotype-driven, addressing cytoses,
    splenomegaly, thrombosis risk, and symptom burden by extrapolation from
    related MPNs because MPN-U-specific treatment guidelines and trial evidence
    are limited.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:35217310
    reference_title: "Diagnostic and management strategies for Myeloproliferative Neoplasm-Unclassifiable (MPN-U): An international survey of contemporary practice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinicians frequently manage these conditions according to the clinical
      concerns e.g. splenomegaly akin to the phenotype, but no evidence base
      exists.
    explanation: >-
      The survey abstract supports phenotype-driven pharmacologic management
      and emphasizes the lack of an MPN-U-specific evidence base.
- name: Hydroxyurea Cytoreduction
  description: >-
    Hydroxyurea/hydroxycarbamide is used for cytoreduction in patients with
    proliferative blood-count phenotypes, although MPN-U-specific evidence and
    standardized thresholds remain limited.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hydroxyurea
      term:
        id: CHEBI:44423
        label: hydroxyurea
  evidence:
  - reference: PMID:35191542
    reference_title: "How I manage myeloproliferative neoplasm-unclassifiable: Practical approaches for 2022 and beyond."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A diagnosis of MPN-U leads to many challenges for both the patient and
      physician alike including lack of agreed monitoring and therapeutic
      guidelines, validated prognostic markers and licenced therapies coupled
      with exclusion from clinical trials.
    explanation: >-
      This review supports the lack of licensed MPN-U-specific therapies; Falcon
      full-text synthesis identifies hydroxycarbamide as the most common
      cytoreductive agent in the UK cohort.
- name: Ruxolitinib
  description: >-
    Off-label JAK inhibition with ruxolitinib may be considered for selected
    patients with symptomatic splenomegaly or high symptom burden, extrapolating
    from related myeloproliferative neoplasms.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ruxolitinib
      term:
        id: CHEBI:66919
        label: ruxolitinib
  evidence:
  - reference: PMID:35191542
    reference_title: "How I manage myeloproliferative neoplasm-unclassifiable: Practical approaches for 2022 and beyond."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MPN-U has an inherent risk of an aggressive clinical course and
      transformation in some but who, and when to treat in the chronic phase,
      including identifying who may require more aggressive therapy at an earlier
      stage, remains elusive.
    explanation: >-
      The review supports individualized treatment escalation in MPN-U; Falcon
      full-text synthesis identifies off-label ruxolitinib/JAK-inhibitor use for
      splenomegaly or symptoms.
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    Allogeneic hematopoietic stem cell transplantation is considered only for
    selected aggressive, accelerated/blast-phase, or fibrotic presentations
    because most MPN-U care is individualized and evidence-limited.
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: MAXO:0000747
      label: hematopoietic stem cell transplantation
  evidence:
  - reference: PMID:35191542
    reference_title: "How I manage myeloproliferative neoplasm-unclassifiable: Practical approaches for 2022 and beyond."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MPN-U has an inherent risk of an aggressive clinical course and
      transformation in some but who, and when to treat in the chronic phase,
      including identifying who may require more aggressive therapy at an earlier
      stage, remains elusive.
    explanation: >-
      The review supports the need to identify patients requiring aggressive
      therapy; Falcon full-text synthesis identifies allogeneic transplantation
      as an advanced-disease strategy.
diagnosis:
- name: Exclusionary Clinicopathologic Classification
  description: >-
    Diagnosis requires an MPN phenotype that fails to satisfy diagnostic criteria
    for other classical or non-classical MPNs, with molecular and morphologic
    workup used to improve specificity and exclude defined entities.
  evidence:
  - reference: PMID:35217310
    reference_title: "Diagnostic and management strategies for Myeloproliferative Neoplasm-Unclassifiable (MPN-U): An international survey of contemporary practice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Myeloproliferative Neoplasm-Unclassifiable (MPN-U) is defined as an MPN
      that fails to meet the diagnostic criteria for any of the other defined
      classical or 'non-classical' MPNs.
    explanation: >-
      The survey abstract gives the operational diagnostic definition.
  - reference: PMID:34830822
    reference_title: "The Classification of Myeloproliferative Neoplasms: Rationale, Historical Background and Future Perspectives with Focus on Unclassifiable Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The latter are currently defined as MPNs with clinical-pathological
      findings not fulfilling the diagnostic criteria for any other entity.
    explanation: >-
      This classification review states the defining exclusionary nature of
      MPN-U.
  - reference: PMID:36580136
    reference_title: "International Consensus Classification of myeloid and lymphoid neoplasms: myeloproliferative neoplasms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this regard, high sensitive single target (RT-qPCR, ddPCR) or
      multi-target next-generation sequencing assays with a minimal sensitivity
      of VAF 1% are now important for a proper diagnostic identification of MPN
      cases with low allelic frequencies at initial presentation.
    explanation: >-
      The ICC review supports sensitive molecular testing as part of resolving
      early or low-allele-fraction MPN presentations.
progression:
- phase: Variable clinical course
  notes: >-
    Event-free survival is variable and is shortened by low platelet count and
    leukocytosis at presentation in the largest contemporary cohort surfaced by
    the Falcon report.
  evidence:
  - reference: PMID:33751548
    reference_title: "Clinicopathological characterisation of myeloproliferative neoplasm-unclassifiable (MPN-U): a retrospective analysis from a large UK tertiary referral centre."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median event-free survival was 11·25 years (95% confidence interval
      9·3-not reached), significantly shortened in cases with lower platelet
      counts (<500 × 109 /l) and a leucocytosis (≥12 × 109 /l) at presentation.
    explanation: >-
      The cohort abstract directly reports median event-free survival and
      adverse presentation features.
datasets:
📚

References & Deep Research

Deep Research

1
Falcon ▸
1. Disease Information
Edison Scientific Literature 43 citations 2026-05-11T11:32:37.450668

1. Disease Information

Overview / definition

Myeloproliferative neoplasm, unclassifiable (MPN-U) is defined as a myeloproliferative neoplasm with clinical/hematologic/morphologic features of an MPN that does not fulfill diagnostic criteria for any other defined MPN entity; it is described as rare, heterogeneous, and often requiring “dynamic review over time” because some cases may later become classifiable as PV/ET/PMF or another MPN. (mclornan2022howimanage pages 1-1, mclornan2022howimanage pages 1-2)

Current classification terminology (WHO vs ICC)

Both WHO-HAEM5 and the International Consensus Classification (ICC) retain a “catch-all” entity for otherwise unclassifiable MPNs, but with different names: MPN-NOS in WHO-HAEM5 versus MPN-unclassifiable in the ICC. (xiao2024apracticalapproach pages 2-4)

Synonyms / alternative names

Commonly used names include “myeloproliferative neoplasm, unclassifiable” and “MPN not otherwise specified (NOS)” in WHO-era usage. (mclornan2022howimanage pages 1-1, xiao2024apracticalapproach pages 2-4, pizzi2021theclassificationof pages 7-8)

Key identifiers (available in retrieved sources)

  • ICD-10: in a Danish population cohort using registry codes, MPN-U/MPN-NOS was identified using ICD-10 D47.1. (pedersen2018smokingisassociated pages 2-3)

Identifiers not found in retrieved corpus: MONDO ID, Orphanet ID, and MeSH term mappings were not present in the excerpts retrieved for this run.

Evidence type note (patient-level vs aggregated)

Evidence spans (i) aggregated cohort/registry studies (UK tertiary-center cohort; population-based Danish and Swedish studies) and (ii) expert review/survey synthesis. (deschamps2021clinicopathologicalcharacterisationof pages 2-3, hargreaves2022diagnosticandmanagement pages 6-7, landtblom2018secondmalignanciesin pages 3-4, pedersen2020twofoldriskof pages 1-2)

2. Etiology

Disease causal factors (current understanding)

MPN-U is best understood as a clonal hematopoietic stem/progenitor cell disorder that manifests as myeloproliferation but lacks sufficient integrated clinicopathologic criteria to be assigned to a specific MPN subtype at a given timepoint. Clonality is commonly supported by canonical MPN “driver” mutations (JAK2/CALR/MPL) and/or other myeloid neoplasm–associated mutations and cytogenetic abnormalities. (gianelli2023internationalconsensusclassification pages 13-14, pizzi2021theclassificationof pages 7-8)

Risk factors

Smoking (lifestyle/environmental): In a Danish general-population cohort (DANHES), smoking was associated with higher risk of incident MPN overall and particularly high relative risks for MPN-U. Multivariable HR for any MPN was 2.5 (95% CI 1.3–5.0) for daily smokers versus never-smokers; subtype analysis showed MPN-U HR 6.2 (1.5–25) for daily smokers and MPN-U HR 6.2 (1.8–21) for occasional/ex-smokers. (pedersen2018smokingisassociated pages 1-2)

Other environmental/occupational risk factors were mentioned only qualitatively as conflicting/limited in the retrieved excerpts; no robust, MPN-U-specific quantitative estimates beyond smoking were retrieved. (pedersen2018smokingisassociated pages 5-6)

Protective factors

No protective genetic or environmental factors were identified in the retrieved evidence set.

Gene–environment interactions

No explicit gene–environment interaction evidence (e.g., JAK2 genotype-by-smoking) was available in the retrieved excerpts.

3. Phenotypes (clinical features) and HPO suggestions

Typical phenotype spectrum

MPN-U shows a broad phenotype that can include constitutional symptoms, hepatosplenomegaly, thrombosis (including splanchnic vein thrombosis), and variable blood-count abnormalities; cases may represent a prodromal/pre-proliferative stage of classical MPN. (mclornan2022howimanage pages 2-2)

Quantified phenotype frequencies from a contemporary cohort (UK tertiary center)

In a single-center cohort of 82 MPN-U patients (median age 49.7 years; 56% female): splenomegaly 27%, pruritus 36%, constitutional symptoms 29%, transfusion dependency 2.4%; thrombocytosis 78% (median platelets 650×10^9/L); LDH elevated 72%; peripheral blood film features included teardrop cells (18.3%), leukoerythroblastosis (7%), and prominent large granular lymphocytes (19.7%). (deschamps2021clinicopathologicalcharacterisationof pages 2-3)

Thrombotic phenotype (including timing)

In the same cohort, thrombosis occurred in ~21% (arterial 10; portal vein 4; other venous 3), with median time from diagnosis to thrombotic event 0.2 months (0–208.3); 47% of those with thrombosis presented with a “heralding” thrombosis (9.9% of the whole cohort). (deschamps2021clinicopathologicalcharacterisationof pages 2-3)

Suggested HPO terms (non-exhaustive; mapping requires ontology validation)

  • Thrombocytosis — HP:0001894 (supported by cohort frequency) (deschamps2021clinicopathologicalcharacterisationof pages 2-3)
  • Elevated lactate dehydrogenase — HP:0003287 (deschamps2021clinicopathologicalcharacterisationof pages 2-3)
  • Splenomegaly — HP:0001744 (deschamps2021clinicopathologicalcharacterisationof pages 2-3)
  • Pruritus — HP:0000989 (deschamps2021clinicopathologicalcharacterisationof pages 2-3)
  • Constitutional symptoms / weight loss / night sweats — consider HP:0004377 (weight loss) and related terms (symptom list in review) (mclornan2022howimanage pages 2-2)
  • Portal vein thrombosis / splanchnic vein thrombosis — consider HP:0030244 (portal vein thrombosis) and related SVT terms (deschamps2021clinicopathologicalcharacterisationof pages 2-3, pizzi2021theclassificationof pages 7-8)
  • Anemia — HP:0001903 (not frequent in the cohort, but part of advanced phenotype in reviews) (pizzi2021theclassificationof pages 7-8)

Quality-of-life: MPN-SAF symptom scores ranged 0–73/100 in a subset, indicating wide symptom-burden variability, but no standardized QoL instruments (EQ-5D/SF-36) or comparative QoL statistics were available in retrieved excerpts. (deschamps2021clinicopathologicalcharacterisationof pages 3-5)

4. Genetic/Molecular Information

Molecular hallmarks and clonality support

Diagnosis requires exclusion of reactive conditions (infection/toxin/drug-related) and can be supported by detection of canonical MPN driver mutations or other myeloid neoplasm–associated mutations (e.g., ASXL1, EZH2, TET2, IDH1/2, SRSF2, SF3B1) and/or cytogenetic abnormalities. (gianelli2023internationalconsensusclassification pages 13-14, pizzi2021theclassificationof pages 7-8)

Driver mutation frequencies (cohort data)

In the 82-patient UK cohort: * JAK2 V617F: 53.7% (44/82) * JAK2 exon 12: 2.4% (2/82) * CALR type 1: 8.5% (7/82) * CALR type 2: 4.8% (4/82) * MPL: 6.1% (5/82) * Triple-negative (JAK2/CALR/MPL negative): 24% (20/82) No PDGFRA/B, CSF3R, BCR/ABL1, FGFR1, or PCM1-JAK2 rearrangements were detected in that series. (deschamps2021clinicopathologicalcharacterisationof pages 1-2)

Additional somatic mutations / cytogenetics

Extended molecular testing identified additional non-driver mutations in 24% (7/29) of those tested in the UK cohort. (deschamps2021clinicopathologicalcharacterisationof pages 1-2) Reviews summarize cytogenetic abnormalities in ~20–30% (or ~30%) of MPN-U cases; in the UK cohort with available cytogenetics, 88.5% were normal (suggesting cohort and testing differences). (gianelli2023internationalconsensusclassification pages 13-14, deschamps2021clinicopathologicalcharacterisationof pages 1-2)

Variant classification / allele frequency / germline vs somatic

Not available in the retrieved excerpts (no ClinVar/gnomAD-style allele frequency reporting was present).

Epigenetics / transcriptomics / proteomics / metabolomics

Not available in the retrieved excerpts.

5. Environmental Information

Beyond smoking (Section 2), no specific toxins/radiation/pollution or infectious triggers with reproducible quantitative evidence specific to MPN-U were available in the retrieved excerpts. (pedersen2018smokingisassociated pages 5-6)

6. Mechanism / Pathophysiology (high-level)

Mechanistically, MPN-U is interpreted as clonal myeloid proliferation driven by canonical MPN signaling lesions (JAK2/CALR/MPL) in many cases, with additional cooperating mutations in epigenetic regulators and splicing factors in subsets; however, the defining feature of MPN-U is not a unique pathway but rather failure to meet integrated diagnostic thresholds for a specific MPN subtype at the time of evaluation. (gianelli2023internationalconsensusclassification pages 13-14, pizzi2021theclassificationof pages 7-8)

Mechanistic details (e.g., JAK-STAT pathway activation, inflammatory cytokine loops) were not available as primary mechanistic experiments in this evidence set; only epidemiologic/mechanistic plausibility statements linking smoking to inflammatory signaling were present. (pedersen2018smokingisassociated pages 5-6)

Suggested GO biological-process terms (hypothesis-driven; requires validation): * “myeloid cell proliferation” (GO:0008283 related), “hematopoietic stem cell proliferation” (GO terms vary)

Suggested CL cell types (hypothesis-driven; requires validation): * Hematopoietic stem cell (CL:0000037), myeloid progenitor (CL:0000763), megakaryocyte (CL:0000554)

7. Anatomical Structures Affected

Primary anatomic sites include: * Bone marrow (hypercellularity; megakaryocytic clustering/pleomorphism; variable fibrosis) (deschamps2021clinicopathologicalcharacterisationof pages 2-3) * Spleen (splenomegaly; extramedullary hematopoiesis mentioned in reviews) (deschamps2021clinicopathologicalcharacterisationof pages 2-3, mclornan2022howimanage pages 2-2) * Splanchnic vasculature (portal vein thrombosis and broader SVT association; a major clinical presentation route) (deschamps2021clinicopathologicalcharacterisationof pages 2-3, pizzi2021theclassificationof pages 7-8)

Suggested UBERON terms (requires validation): * Bone marrow — UBERON:0002371 * Spleen — UBERON:0002106 * Portal vein — UBERON:0001189

Subcellular localization was not addressed in retrieved excerpts.

8. Temporal Development

MPN-U is commonly conceptualized as including: * Early/prodromal phase with incompletely developed subtype-specific morphology (often overlapping ET/pre-PMF) and fewer organomegaly features (gianelli2023internationalconsensusclassification pages 13-14, pizzi2021theclassificationof pages 7-8) * Advanced fibrotic phase with cytopenias, organomegaly, fibrosis-related marrow changes, and higher transformation risk (pizzi2021theclassificationof pages 7-8)

In the UK cohort, transformation to accelerated/blast phase occurred in 7/82 (8.5%) with median time to transformation 88.2 months (15.6–183.9). (deschamps2021clinicopathologicalcharacterisationof pages 2-3)

9. Inheritance and Population

Inheritance

MPN-U is generally discussed as a somatic clonal neoplasm; explicit Mendelian inheritance patterns were not described in the retrieved excerpts.

Epidemiology (proportion among MPNs)

MPN-U is estimated at ~5–10% of MPNs in reviews/classification discussions. (pizzi2021theclassificationof pages 7-8, gianelli2023internationalconsensusclassification pages 11-13) In a UK tertiary registry, MPN-U constituted 82/1512 = 5.4% of MPN patients. (deschamps2021clinicopathologicalcharacterisationof pages 1-2)

Age/sex distribution

In the UK cohort: median age 49.7 years (range 13–79) and 56% female. (deschamps2021clinicopathologicalcharacterisationof pages 2-3)

10. Diagnostics (limited to retrieved evidence)

Diagnostic framing

Diagnosis is clinicopathologic and by exclusion: “features of an MPN are present” but criteria for defined entities are not met, and exclusionary rearrangements/fusions (e.g., BCR::ABL1, PCM1-JAK2; PDGFRA/B; FGFR1) must be absent; reactive drivers such as infection/toxin/drug exposure should be ruled out. (gianelli2023internationalconsensusclassification pages 13-14, mclornan2022howimanage pages 1-2)

WHO vs ICC placement

WHO-HAEM5 uses MPN-NOS; ICC uses MPN-unclassifiable. (xiao2024apracticalapproach pages 2-4)

Molecular testing sensitivity / contemporary updates

ICC-focused review text recommends highly sensitive molecular techniques for identifying JAK2/CALR/MPL driver mutations, with “minimal level of VAF 1%” as a recommended diagnostic backbone (in the ICC MPN classification paper’s conclusion). (gianelli2023internationalconsensusclassification pages 14-15)

Differential diagnosis (high-level)

Key exclusions include entities defined by specific lesions (e.g., BCR::ABL1; eosinophilia with tyrosine kinase fusions), and careful separation from MDS/MPN overlap neoplasms when dysplasia predominates. (gianelli2023internationalconsensusclassification pages 13-14)

Not available in retrieved evidence: complete WHO-HAEM5/ICC “major/minor criteria” tables for MPN-NOS/MPN-U, SNOMED/LOINC mappings, and structured genetic testing panel recommendations beyond general statements.

11. Outcome / Prognosis

Cohort-based survival estimates

In the UK cohort (n=82): * Median event-free survival (EFS) 11.25 years (95% CI 9.3–not reached) * Median OS not reached; 10-year OS 88.8% (95% CI 77.7–100.0%) (deschamps2021clinicopathologicalcharacterisationof pages 2-3)

Transformation/progression

  • Transformation to accelerated/blast phase: 8.5% (7/82), median 88.2 months (deschamps2021clinicopathologicalcharacterisationof pages 2-3)
  • Overall progression (accelerated/transformation or fibrosis): ~19.2% in treated subgroup reporting (deschamps2021clinicopathologicalcharacterisationof pages 3-5, deschamps2021clinicopathologicalcharacterisationof pages 5-6)

Prognostic factors (EFS)

Lower platelets and leukocytosis stratified higher-risk groups: low platelet quartile HR 3.45 (95% CI 1.43–8.32) and leukocytosis HR 2.91 (95% CI 1.11–7.64) in multivariable analysis. (deschamps2021clinicopathologicalcharacterisationof pages 5-6, deschamps2021clinicopathologicalcharacterisationof media cb1fee4a)

Complications and comorbidity burden (population-based)

  • Pneumonia and respiratory mortality: In a Danish cohort, myelofibrosis/unclassifiable MPN had HR 3.03 (95% CI 1.86–4.93) for pneumonia and HR 2.40 (95% CI 1.11–5.19) for respiratory death (subtypes combined). (pedersen2020twofoldriskof pages 1-2)
  • Second malignancies: In a Swedish population cohort (9379 MPN patients; 1113 MPN-U), the hazard ratio for non-hematologic second malignancies in MPN-U was HR 1.9 (95% CI 1.5–2.5) versus controls. (landtblom2018secondmalignanciesin pages 3-4)

12. Treatment (evidence-limited; phenotype-driven)

There are no licensed, MPN-U-specific therapies highlighted in the retrieved evidence; management is explicitly described as challenging due to “lack of agreed guidelines” and is generally phenotype- and complication-driven (treating cytoses, symptoms/splenomegaly, and thrombosis risk similarly to classical MPNs). (hargreaves2022diagnosticandmanagement pages 6-7, hargreaves2022diagnosticandmanagement pages 3-6)

Real-world approaches are summarized in the management artifact (cytoreduction, antithrombotics, ruxolitinib off-label, allo-HCT escalation, and key MPN registries/trials). | Management domain | Therapy/approach | Real-world implementation in MPN-U / MPN-NOS | Quantitative details | Citation | |---|---|---|---|---| | Cytoreduction | Any cytoreductive therapy | Commonly used in practice, but indications are phenotype-driven rather than guideline-standardized | In the UK cohort, 51/82 patients (62.2%) received cytoreductive therapy; in the survey, 66% of centres would offer cytoreduction for thrombocytosis | (deschamps2021clinicopathologicalcharacterisationof pages 1-2, hargreaves2022diagnosticandmanagement pages 6-7) | | Cytoreduction | Hydroxycarbamide / hydroxyurea | Most commonly used first-line cytoreductive agent in cohort and survey practice | UK cohort: 40/82 (48.8%) received hydroxycarbamide; survey: 14 centres (41%) targeted platelets around 400 × 10^9/L, and 20 centres (59%) combined hydroxycarbamide with extended postoperative thromboprophylaxis | (deschamps2021clinicopathologicalcharacterisationof pages 1-2, hargreaves2022diagnosticandmanagement pages 6-7, hargreaves2022diagnosticandmanagement pages 3-6) | | Cytoreduction | Interferon / pegylated interferon | Used in a minority overall; may be considered in selected settings such as pregnancy or younger patients, but not a common first-choice agent in survey responses | UK cohort: 14/82 (17.1%) received interferon; survey of thrombocytosis management: no centres selected interferon as agent of choice; pregnancy-focused recommendations note interferon-based approaches at some centres | (deschamps2021clinicopathologicalcharacterisationof pages 1-2, hargreaves2022diagnosticandmanagement pages 6-7, hargreaves2022diagnosticandmanagement pages 3-6, mclornan2022howimanage pages 4-5) | | Cytoreduction | Anagrelide | Used infrequently for platelet control in selected patients | UK cohort: 8/82 (9.8%) received anagrelide | (deschamps2021clinicopathologicalcharacterisationof pages 1-2) | | Symptom/spleen-directed therapy | Ruxolitinib / JAK inhibitor | Off-label, phenotype-driven use for splenomegaly and symptom burden; many centres report little or no use, reflecting uncertainty and lack of approval | UK cohort: 5/82 (6.1%) received a JAK inhibitor; survey/review: about half of centres reported off-label ruxolitinib use for splenomegaly and/or symptoms, while many centres had no MPN-U patients on ruxolitinib | (deschamps2021clinicopathologicalcharacterisationof pages 1-2, hargreaves2022diagnosticandmanagement pages 3-6, mclornan2022howimanage pages 7-7) | | Antithrombotic management | Aspirin | Frequently used, especially with thrombocytosis and in pregnancy; does not eliminate thrombosis risk | Review suggests aspirin 75 mg once daily in selected phenotype-driven strategies; pregnancy recommendations include aspirin throughout pregnancy; cohort noted thromboses still occurred despite low-dose aspirin plus effective cytoreduction | (mclornan2022howimanage pages 8-9, mclornan2022howimanage pages 4-5, deschamps2021clinicopathologicalcharacterisationof pages 3-5) | | Antithrombotic management | LMWH | Used particularly in pregnancy and postpartum; also part of broader thrombosis management strategies extrapolated from other MPNs | Pregnancy guidance: antenatal LMWH plus standard 6-week postpartum prophylaxis | (mclornan2022howimanage pages 4-5) | | Antithrombotic management | VKA / warfarin | Common choice after venous thromboembolism, especially in heterogeneous real-world practice | Survey: most centres preferred warfarin/VKA after VTE; some reserved VKA specifically for splanchnic vein thrombosis | (hargreaves2022diagnosticandmanagement pages 3-6) | | Antithrombotic management | DOACs | Used by some centres; authors cautiously support DOACs in uncomplicated acute SVT, but liver dysfunction may limit use | Review notes VKA vs DOAC decisions are individualized; cohort/international data cited as showing comparable recurrent thrombosis and bleeding rates with DOACs in selected settings | (mclornan2022howimanage pages 5-6, hargreaves2022diagnosticandmanagement pages 3-6) | | Cytoreduction triggers | Thrombosis history | Many centres start cytoreduction after arterial or venous thrombosis, despite lack of MPN-U-specific evidence | 81% of surveyed centres initiate cytoreduction after venous or arterial thrombosis | (mclornan2022howimanage pages 7-7) | | Cytoreduction triggers | Blood count thresholds | Centres variably use platelet/WBC thresholds to start therapy | Survey: platelet threshold >450 × 10^9/L in 20% of centres, >1500 × 10^9/L in 72%, WBC >15 × 10^9/L in 45% | (mclornan2022howimanage pages 7-7) | | Response in cohort | Cytoreductive treatment outcomes | Outcomes are mixed, reinforcing need for better prognostic tools and standardized management | Among treated cohort patients, ~50% achieved adequate cytoreduction, 26.9% had stable blood counts, and 19.2% progressed (accelerated/transformation or fibrosis) | (deschamps2021clinicopathologicalcharacterisationof pages 3-5) | | Transplant | Allogeneic hematopoietic cell transplantation | Rare but considered for accelerated, blast-phase, fibrotic, or otherwise aggressive disease; early referral is recommended in suitable patients | UK cohort: 5/82 (6.1%) considered for allo-HCT and 2/82 (2.4%) transplanted; survey: observation 7%, HMA with planned allo-SCT 61%, induction chemotherapy then allo-SCT 7%, upfront allo-SCT 24% for progressive/accelerating disease | (deschamps2021clinicopathologicalcharacterisationof pages 1-2, hargreaves2022diagnosticandmanagement pages 6-7, mclornan2022howimanage pages 6-7, deschamps2021clinicopathologicalcharacterisationof pages 3-5) | | Transplant outcomes | Allo-HCT registry data | Best evidence comes from retrospective registry series rather than MPN-U-specific trials | Reported 3-year OS after allo-SCT approximately 55% with myeloablative conditioning vs 44% with reduced-intensity conditioning; relapse rates 23% vs 36% | (hargreaves2022diagnosticandmanagement pages 6-7) | | Monitoring/implementation | Practice framework | Management is individualized because there are no agreed guidelines; cases often managed similarly to classical MPNs and re-reviewed over time | Survey explicitly reports “lack of agreed guidelines” and wide heterogeneity in MDT review, genomic testing, anticoagulant choice, pregnancy care, and transplant referral | (hargreaves2022diagnosticandmanagement pages 1-2, hargreaves2022diagnosticandmanagement pages 6-7, hargreaves2022diagnosticandmanagement pages 3-6) | | Relevant trial/registry | NCT07362225 | Large observational registry tracking symptoms, treatments, and disease progression in people with MPNs; relevant because MPN-U patients are commonly excluded from interventional studies but can be captured in broad registries | Recruiting; observational; target enrollment 5000 | (xiao2024apracticalapproach pages 2-4) | | Relevant trial/registry | NCT03618485 | Taiwan MPN registry; observational real-world resource potentially capturing unclassifiable cases under broader MPN umbrella | Active, not recruiting; observational; target enrollment 500 | (xiao2024apracticalapproach pages 2-4) | | Relevant trial/registry | NCT07384039 | Supportive-care/exercise intervention in patients with MPNs; relevant to symptom burden and quality-of-life research though not MPN-U-specific | Not yet recruiting; interventional; target enrollment 80 | (xiao2024apracticalapproach pages 2-4) | | Relevant trial/registry | NCT06661915 | Phase 2 study in advanced MPNs using ASTX727 with or without iadademstat; relevant for transformed/advanced phenotypes that may include unclassifiable MPN biology | Recruiting; phase 2; target enrollment 62 | (xiao2024apracticalapproach pages 2-4) | | Relevant trial/registry | NCT04282187 | Phase 2 study of decitabine with ruxolitinib/fedratinib/pacritinib for accelerated/blast-phase MPN; relevant to aggressive MPN-U scenarios managed as advanced MPN | Recruiting; phase 2; target enrollment 25 | (xiao2024apracticalapproach pages 2-4) | | Relevant trial/registry | NCT03566446 | CALR-mutant peptide vaccine study in CALR-mutant MPN; relevant to molecularly defined subsets that may overlap with some MPN-U cases | Completed; phase 1; enrollment 10 | (xiao2024apracticalapproach pages 2-4) |

Table: This table summarizes how MPN-U/MPN-NOS is managed in real-world cohorts, surveys, and broader MPN studies. It highlights the absence of standardized guidelines, the phenotype-driven use of cytoreduction and antithrombotic therapy, transplant escalation in advanced disease, and relevant current trial or registry infrastructure.

Suggested MAXO terms (requires ontology validation): * Cytoreductive therapy — e.g., MAXO term for “cytoreductive therapy” * Antiplatelet therapy (aspirin) * Anticoagulation therapy * Allogeneic hematopoietic stem cell transplantation

13. Prevention

No primary-prevention interventions specific to MPN-U were identified. Smoking is a modifiable risk factor associated with MPN risk including MPN-U in one large cohort; smoking cessation is therefore a plausible risk-reduction strategy, although direct evidence for prevention of MPN-U is not established. (pedersen2018smokingisassociated pages 1-2)

Secondary/tertiary prevention in practice focuses on prevention of thrombosis/bleeding and monitoring for disease evolution or transformation, but no consensus prevention protocols were available in the retrieved excerpts. (hargreaves2022diagnosticandmanagement pages 3-6, mclornan2022howimanage pages 7-7)

14. Other Species / Natural Disease

No cross-species naturally occurring MPN-U analogs were identified in the retrieved evidence set.

15. Model Organisms

The retrieved evidence set did not include dedicated model-organism studies for MPN-U. Mechanistic model systems for canonical MPN driver mutations (e.g., JAK2/CALR/MPL) are widely used in the broader MPN field, but explicit, citable details were not present in the retrieved excerpts and therefore are not asserted here.

“Expert opinion” synthesis (authoritative-source analysis)

Across expert reviews and international survey data, a consistent expert conclusion is that MPN-U is a heterogeneous, diagnosis-of-exclusion category with meaningful thrombotic and transformation risks but insufficient evidence for standardized, disease-specific guidelines, leading to high inter-center practice variability and reliance on extrapolation from classical MPN management and individualized risk assessment. (mclornan2022howimanage pages 1-2, hargreaves2022diagnosticandmanagement pages 6-7, hargreaves2022diagnosticandmanagement pages 3-6)

References (URLs and publication dates from retrieved sources)

  • Xiao W et al. A practical approach on the classifications of myeloid neoplasms and acute leukemia: WHO and ICC. Jul 2024. https://doi.org/10.1186/s13045-024-01571-4 (xiao2024apracticalapproach pages 2-4)
  • Gianelli U et al. International Consensus Classification… myeloproliferative neoplasms. Dec 2023. https://doi.org/10.1007/s00428-022-03480-8 (gianelli2023internationalconsensusclassification pages 14-15, gianelli2023internationalconsensusclassification pages 13-14)
  • McLornan DP et al. How I manage myeloproliferative neoplasm-unclassifiable: Practical approaches for 2022 and beyond. Feb 2022. https://doi.org/10.1111/bjh.18087 (mclornan2022howimanage pages 1-2, mclornan2022howimanage pages 4-5)
  • Hargreaves R et al. Diagnostic and management strategies for MPN-U: an international survey. Jul 2022. https://doi.org/10.1016/j.retram.2022.103338 (hargreaves2022diagnosticandmanagement pages 6-7, hargreaves2022diagnosticandmanagement pages 3-6)
  • Deschamps P et al. Clinicopathological characterisation of MPN-U… UK tertiary referral centre. Mar 2021. https://doi.org/10.1111/bjh.17375 (deschamps2021clinicopathologicalcharacterisationof pages 2-3)
  • Pizzi M et al. Classification of MPNs… focus on unclassifiable cases. Nov 2021. https://doi.org/10.3390/cancers13225666 (pizzi2021theclassificationof pages 7-8)
  • Pedersen KM et al. Smoking is associated with increased risk of MPNs. Oct 2018. https://doi.org/10.1002/cam4.1815 (pedersen2018smokingisassociated pages 1-2, pedersen2018smokingisassociated pages 2-3)
  • Pedersen KM et al. Two-fold risk of pneumonia and respiratory mortality in individuals with MPN. Apr 2020. https://doi.org/10.1016/j.eclinm.2020.100295 (pedersen2020twofoldriskof pages 1-2)
  • Landtblom AR et al. Second malignancies in patients with MPNs… 9379 patients. Jan 2018. https://doi.org/10.1038/s41375-018-0027-y (landtblom2018secondmalignanciesin pages 3-4)

PMIDs: Not available in the retrieved excerpts for the above sources in this run; therefore PMID numbers cannot be reliably provided from the current evidence context.

References

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  11. (deschamps2021clinicopathologicalcharacterisationof media cb1fee4a): Paul Deschamps, Mufaddal Moonim, Deepti Radia, Natalia Curto‐Garcia, Claire Woodley, Sarah Bassiony, Jennifer O'Sullivan, Patrick Harrington, Kavita Raj, Yvonne Francis, Shahram Kordasti, Sahra Ali, Claire N. Harrison, and Donal P. McLornan. Clinicopathological characterisation of myeloproliferative neoplasm‐unclassifiable (mpn‐u): a retrospective analysis from a large uk tertiary referral centre. British Journal of Haematology, 193:792-797, Mar 2021. URL: https://doi.org/10.1111/bjh.17375, doi:10.1111/bjh.17375. This article has 19 citations and is from a domain leading peer-reviewed journal.

  12. (hargreaves2022diagnosticandmanagement pages 6-7): Rupen Hargreaves, Claire N Harrison, and Donal P McLornan. Diagnostic and management strategies for myeloproliferative neoplasm-unclassifiable (mpn-u): an international survey of contemporary practice. Current Research in Translational Medicine, 70:103338, Jul 2022. URL: https://doi.org/10.1016/j.retram.2022.103338, doi:10.1016/j.retram.2022.103338. This article has 6 citations and is from a peer-reviewed journal.

  13. (hargreaves2022diagnosticandmanagement pages 3-6): Rupen Hargreaves, Claire N Harrison, and Donal P McLornan. Diagnostic and management strategies for myeloproliferative neoplasm-unclassifiable (mpn-u): an international survey of contemporary practice. Current Research in Translational Medicine, 70:103338, Jul 2022. URL: https://doi.org/10.1016/j.retram.2022.103338, doi:10.1016/j.retram.2022.103338. This article has 6 citations and is from a peer-reviewed journal.

  14. (mclornan2022howimanage pages 4-5): Donal P. McLornan, Rupen Hargreaves, Juan Carlos Hernández‐Boluda, and Claire N. Harrison. How i manage myeloproliferative neoplasm‐unclassifiable: practical approaches for 2022 and beyond. British Journal of Haematology, 197:407-416, Feb 2022. URL: https://doi.org/10.1111/bjh.18087, doi:10.1111/bjh.18087. This article has 11 citations and is from a domain leading peer-reviewed journal.

  15. (mclornan2022howimanage pages 7-7): Donal P. McLornan, Rupen Hargreaves, Juan Carlos Hernández‐Boluda, and Claire N. Harrison. How i manage myeloproliferative neoplasm‐unclassifiable: practical approaches for 2022 and beyond. British Journal of Haematology, 197:407-416, Feb 2022. URL: https://doi.org/10.1111/bjh.18087, doi:10.1111/bjh.18087. This article has 11 citations and is from a domain leading peer-reviewed journal.

  16. (mclornan2022howimanage pages 8-9): Donal P. McLornan, Rupen Hargreaves, Juan Carlos Hernández‐Boluda, and Claire N. Harrison. How i manage myeloproliferative neoplasm‐unclassifiable: practical approaches for 2022 and beyond. British Journal of Haematology, 197:407-416, Feb 2022. URL: https://doi.org/10.1111/bjh.18087, doi:10.1111/bjh.18087. This article has 11 citations and is from a domain leading peer-reviewed journal.

  17. (deschamps2021clinicopathologicalcharacterisationof pages 3-5): Paul Deschamps, Mufaddal Moonim, Deepti Radia, Natalia Curto‐Garcia, Claire Woodley, Sarah Bassiony, Jennifer O'Sullivan, Patrick Harrington, Kavita Raj, Yvonne Francis, Shahram Kordasti, Sahra Ali, Claire N. Harrison, and Donal P. McLornan. Clinicopathological characterisation of myeloproliferative neoplasm‐unclassifiable (mpn‐u): a retrospective analysis from a large uk tertiary referral centre. British Journal of Haematology, 193:792-797, Mar 2021. URL: https://doi.org/10.1111/bjh.17375, doi:10.1111/bjh.17375. This article has 19 citations and is from a domain leading peer-reviewed journal.

  18. (mclornan2022howimanage pages 5-6): Donal P. McLornan, Rupen Hargreaves, Juan Carlos Hernández‐Boluda, and Claire N. Harrison. How i manage myeloproliferative neoplasm‐unclassifiable: practical approaches for 2022 and beyond. British Journal of Haematology, 197:407-416, Feb 2022. URL: https://doi.org/10.1111/bjh.18087, doi:10.1111/bjh.18087. This article has 11 citations and is from a domain leading peer-reviewed journal.

  19. (mclornan2022howimanage pages 6-7): Donal P. McLornan, Rupen Hargreaves, Juan Carlos Hernández‐Boluda, and Claire N. Harrison. How i manage myeloproliferative neoplasm‐unclassifiable: practical approaches for 2022 and beyond. British Journal of Haematology, 197:407-416, Feb 2022. URL: https://doi.org/10.1111/bjh.18087, doi:10.1111/bjh.18087. This article has 11 citations and is from a domain leading peer-reviewed journal.

  20. (deschamps2021clinicopathologicalcharacterisationof media 1f80ac50): Paul Deschamps, Mufaddal Moonim, Deepti Radia, Natalia Curto‐Garcia, Claire Woodley, Sarah Bassiony, Jennifer O'Sullivan, Patrick Harrington, Kavita Raj, Yvonne Francis, Shahram Kordasti, Sahra Ali, Claire N. Harrison, and Donal P. McLornan. Clinicopathological characterisation of myeloproliferative neoplasm‐unclassifiable (mpn‐u): a retrospective analysis from a large uk tertiary referral centre. British Journal of Haematology, 193:792-797, Mar 2021. URL: https://doi.org/10.1111/bjh.17375, doi:10.1111/bjh.17375. This article has 19 citations and is from a domain leading peer-reviewed journal.

  21. (pedersen2018smokingisassociated pages 2-3): Kasper M. Pedersen, Marie Bak, Anders L. Sørensen, Ann‐Dorthe Zwisler, Christina Ellervik, Morten K. Larsen, Hans C. Hasselbalch, and Janne S. Tolstrup. Smoking is associated with increased risk of myeloproliferative neoplasms: a general population‐based cohort study. Cancer Medicine, 7:5796-5802, Oct 2018. URL: https://doi.org/10.1002/cam4.1815, doi:10.1002/cam4.1815. This article has 47 citations and is from a peer-reviewed journal.

  22. (landtblom2018secondmalignanciesin pages 3-4): Anna Ravn Landtblom, Hannah Bower, Therese M.-L. Andersson, Paul W. Dickman, Jan Samuelsson, Magnus Björkholm, Sigurdur Yngvi Kristinsson, and Malin Hultcrantz. Second malignancies in patients with myeloproliferative neoplasms: a population-based cohort study of 9379 patients. Leukemia, 32:2203-2210, Jan 2018. URL: https://doi.org/10.1038/s41375-018-0027-y, doi:10.1038/s41375-018-0027-y. This article has 107 citations and is from a highest quality peer-reviewed journal.

  23. (pedersen2020twofoldriskof pages 1-2): Kasper Mønsted Pedersen, Yunus Çolak, Hans Carl Hasselbalch, Christina Ellervik, Børge Grønne Nordestgaard, and Stig Egil Bojesen. Two-fold risk of pneumonia and respiratory mortality in individuals with myeloproliferative neoplasm: a population-based cohort study. EClinicalMedicine, 21:100295, Apr 2020. URL: https://doi.org/10.1016/j.eclinm.2020.100295, doi:10.1016/j.eclinm.2020.100295. This article has 9 citations and is from a peer-reviewed journal.

  24. (pedersen2018smokingisassociated pages 1-2): Kasper M. Pedersen, Marie Bak, Anders L. Sørensen, Ann‐Dorthe Zwisler, Christina Ellervik, Morten K. Larsen, Hans C. Hasselbalch, and Janne S. Tolstrup. Smoking is associated with increased risk of myeloproliferative neoplasms: a general population‐based cohort study. Cancer Medicine, 7:5796-5802, Oct 2018. URL: https://doi.org/10.1002/cam4.1815, doi:10.1002/cam4.1815. This article has 47 citations and is from a peer-reviewed journal.

  25. (pedersen2018smokingisassociated pages 5-6): Kasper M. Pedersen, Marie Bak, Anders L. Sørensen, Ann‐Dorthe Zwisler, Christina Ellervik, Morten K. Larsen, Hans C. Hasselbalch, and Janne S. Tolstrup. Smoking is associated with increased risk of myeloproliferative neoplasms: a general population‐based cohort study. Cancer Medicine, 7:5796-5802, Oct 2018. URL: https://doi.org/10.1002/cam4.1815, doi:10.1002/cam4.1815. This article has 47 citations and is from a peer-reviewed journal.

  26. (gianelli2023internationalconsensusclassification pages 11-13): Umberto Gianelli, Jürgen Thiele, Attilio Orazi, Naseema Gangat, Alessandro M. Vannucchi, Ayalew Tefferi, and Hans Michael Kvasnicka. International consensus classification of myeloid and lymphoid neoplasms: myeloproliferative neoplasms. Virchows Archiv, 482:53-68, Dec 2023. URL: https://doi.org/10.1007/s00428-022-03480-8, doi:10.1007/s00428-022-03480-8. This article has 61 citations and is from a peer-reviewed journal.

  27. (gianelli2023internationalconsensusclassification pages 14-15): Umberto Gianelli, Jürgen Thiele, Attilio Orazi, Naseema Gangat, Alessandro M. Vannucchi, Ayalew Tefferi, and Hans Michael Kvasnicka. International consensus classification of myeloid and lymphoid neoplasms: myeloproliferative neoplasms. Virchows Archiv, 482:53-68, Dec 2023. URL: https://doi.org/10.1007/s00428-022-03480-8, doi:10.1007/s00428-022-03480-8. This article has 61 citations and is from a peer-reviewed journal.