Overview:

• Chronic myeloproliferative neoplasms are clonal hematopoietic stem cell disorders characterized by proliferation of one or more of terminally differentiated myeloid (i.e. granulocytic, erythroid and megakaryocytic) lineage cells within bone marrow.
• In most of these, activation of tyrosine kinase pathway is frequently implicated in pathogenesis.
• Although trilineage cell involvement is characteristic of MPN, one cell line is more prominently affected than the others.
• It is associated with relatively normal maturation that is effective.
• Splenomegaly & hepatomegaly are commonly seen due to
  • Sequestration of excessive blood cells
  • Extra medullary hematopoiesis
  • Leukemic infiltration
• Peripheral smear generally shows following features
  • Anemia / Polycythemia
  • Leukoerythroblastosis
  • Leucocytosis
  • Thrombocytosis with bizarre platelets
• Bone marrow shows following features
  • Hypercellularity
  • Variable amounts of granulocytic/ erythroid maturation
  • Fibrosis of varying grades
• Most of them slowly progress to marrow failure which is due to myelofibrosis or acute blast phase. 
• Finding of 10-19% of blasts signifies disease acceleration and 20% or more is sufficient for a diagnosis of blast phase.

Epidemiology

• Commonly seen in adults – 50 – 70 years
• 6 – 9/ 1,00,000 population

Diseases included in this category:

• Chronic myeloid leukemia
• Chronic neutrophilic leukemia
• Chronic eosinophilic leukemia- NOS
• Polycythemia vera
• Primary myelofibrosis
• Essential Thrombocythemia
• Juvenile myelomonocytic leukaemia
• Chronic myeloproliferative disease, unclassifiable.

Driver mutations seen MPN:

• JAK-2 Mutation
  • V617F is the common mutation, that results in substitution of phenyl alanine for valine at codon 617
  • Other common mutation is Exon 12.
  • Total 17 mutations have been described so far.
  • Normally JH-2 binds to JH1 and causes auto-inhibition of activated JAK2 kinase
  • Mutation leads to loss of auto-inhibition, which results in persistent activation of downstream signaling pathways (JAK/STAT, PI3K/AKT, MAPK/ERK), which causes excessive cell proliferation.
  • It is observed in
    • 98% of PV
    • 50-60% of ET and PMF
    • 50% of  Refractory anemia with ringed sideroblasts with marked thrombocytosis
  • Precise phenotype depends on additional constitutional and and/or acquired modifiers. JAK 2 mutation by itself will not initiate neoplasia.
  • Ratio of mutant and wild type of JAK2 is also important in determining disease phenotype.
  • Testing is done commonly by PCR
  • Specific JAK 2 inhibitors include Ruxolitinib, Fedratinib, Momelotinib, Pacritinib
• MPL Mutation:
  • Encodes thrombopoietin receptor
  • 5 mutations are described
  • Seen in 5-10% of patients with ET and PMF.
• CAL-R mutations:
  • Seen in 60-80% of JAK-2 negative MPNs
  • Seen in 25-35% of ET and PMF patients
  • CAL-R and JAK2 mutations are mutually exclusive.
  • CAL-R mutation is associated with low risk of thrombosis and higher survival.
• Additional mutations observed in MPN patients include: 
  • TET2, ASXL1, DNMT3A
  • Mutations affecting splicing regulators: SRSF2, SF3B1, U2AF1, ZRSR2) 
  • Regulators of epigenetic functions: EZH2, IDH1, IDH2, CBL, KRAS, NRAS
  • TP53 (Poor prognosis)
• BCR-ABL
  • Presence of this is enough for diagnosis of CML in a suspected MPN patient
• Germline mutations in JAK2 and other genes also have been identified.

Grading of fibrosis in MPN:

• MF-0- Scattered linear reticulin with no intersections (cross-overs) corresponding to normal BM
• MF-1- Loose network of reticulin with many intersections, especially in perivascular areas
• MF-2- Diffuse and dense increase in reticulin with many intersections, occasionally with focal bundles of collagen and/or focal osteosclerosis
• MF-3- Diffuse and dense increase in reticulin with extensive intersections and coarse bundles of collagen, often associated with osteosclerosis

MPN Symptom scoring:

• Needed for monitoring of symptoms when patients are on treatment
• Every symptom is graded from 1 to 10 and then total score is measured.
• Following symptoms are included:
  • Fatigue

• Early satiety
• Abdominal discomfort
• Inactivity
• Problems with concentration
• Night sweats
• Pruritus
• Bone pain
• Fever
• Unintentional weight loss last 6 months

Myeloproliferative Neoplasm- NOS (Unclassifiable):  

• This term is applied only to cases that have definite clinical, laboratory and morphological features of a MPN, but that fails to meet the criteria for any of the specific MPN entities or present with features that overlap two or more of the categories.
• Criteria for diagnosis:
  • Requires the presence of all 3 criteria:
    • Any 1 of following : Features of an MPN (Splenomegaly, leukocytosis, thrombocytosis etc)/ Bone marrow hypercellularity with panmyelosis, in the absence of dysplastic features/ 
    • WHO criteria for any other MPN, MDS, MDS/MPN are not met (Negative for BCR-ABL, PDGFRA, PDGFRB, FGFR1, JAK2 fusions, ETV6::ABL1, and other ABL1 rearrangements)
    • Presence of driver mutations such as JAK2, CALR, or MPL mutation, or another clonal marker (e.g. ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2, and SF3B1 mutations)
  • Requires the absence of both these criteria:
    • Insufficient clinical data or inadequate bone marrow specimen for accurate evaluation and classification
    • Recent history of cytotoxic or growth factor therapy, particularly when dysplastic features are seen
• Treatment:
  • Hydroxyurea +/- Aspirin
  • Allogeneic stem cell transplantation