Chronic Myeloproliferative Neoplasms

Classifications

Chronic Myelogeneous Leukaemia (CML)

Classical Myeloproliferative neoplasms

Polycythaemia Vera (PV)

Essential thrombocytosis (ET)

Primary myelofibrosis (PMF)

Rare

Chronic Eoisinophilic Leukaemia (CEL)

Chronic neutrophilic leukaemia (CNL)

Myeloproliferative neoplasm not otherwise specified (NOS)

Defining MPNs

  1. Originally morpholigical assessment
  1. Disease defining molecular abnormalities (CML)

3.Disease asssociated molecular abnormalities (PV/ET/MF)

  1. Genetic abnormalities

Translocations / point mutations

Chronic Myeloid Leukemia (CML)

Genetics

Philadephia chromosome

t(9;22) translocation

brc-alb Gene

Fusion protein tyrosine kinase

Epidemiology

Median age 45-55

Incidence increases with age

Male predominance

Causes

Ionising radiation

  1. Atomic bomb survivors
  1. Women with uterine cervical carcinoma treatment
  1. Ankylosisng spondylitis pts treatment

Presentations

Aysmptomatic picked up on Blood test (↑WBC)

Symptoms of anaemia

Anorexia and weight loss

Splenolmegaly

Clinical Phases

  1. Chronic phase
  1. Advanced phases

Accelerated phase

Blastic phase - blast crisis

Treatment

Tyrosine kinase inhibitors

MOA

No 2nd messanger

Cell death

Blocks active site of tyrosine kinase

DAsatinib

Nilotinib

Bosutinib

Ponatinib

Imatinib

Allogeneic bone marrow transplant

Myeloproliferative Neoplasms (MPN)

Types

Polycythemia Vera

Essential thrombocytosis

Primary Myelofibrosis

Genetics

  1. Philadelphia chromosome negative
  1. Aquired cloncal stem cell disorders
  1. Molecular / cytogeneic abnormalites

Definition

A collection of haematological malignancies characterised by the overproduction of one or more types of blood cells, occurin gin the abscence of an identifiable stimulus

Presentation / Clinical features

Increased risk of thrombosis and bleed

Propensity to transform to acute leukemia

Bone marrow fibrosis

Extramedullary haematopoiesis (big spleen)

Driver Mutations

Mutations in haematopoietic stem cells that result in increased mature myeloid cells

JAK2 gene

MPL gene

CaLR gene

Enhanced signalling in abscence of Erythropoeitin

Polycythaemia

Types

Absoloute Polycythemia

Relative Polycythemia

Primary Polycythemia Vera

JAK2 positive

Secondary Polycythemia

  1. Tissue hypoxia causing ↑EPO production
    Lung disease
    CV disease
    High altitude
  1. Haemoglobin variants
  1. Inapproapriate EPO production
    Renal tumour producing EPO

Polycythemia Vera

Epidemiology

Older pts

M=F

Presentation

Gradual onset symptoms

Headaches, dizziness

Generalised pruritus especially after bath

Bleeding episodes

Plethoric appearance

Splenomegaly

Gout

Thrombotic episodes

WHO critera for diagnosis

Major Criteria

  1. Bone marrow biobsy showing hypercellularity
  1. JAK2 mutation V617F or JAK2 exon 12 mutation
  1. Haemoglobin > 16.5 g/dL in men or 16 g/dL in women
    HCT > 49% m or 48% w
    More than 25 % increased in red cell volume

Minor Criteria

Subnormal EPO level

Dx

All 3 major

First 2 major + 1 minor

Treatment

Aggressive Phlebotomy

Aspirin 75mg daily

  • Reduction in MI and Stroke

Essential Thrombocytosis

Causes of ↑Platelets

Reactive

Haemorrhage

Trauma

Chronic Iron deficiency

Malignancy

Chronic infections

Post-operative

Connective tissue disease

Endogenous

Essential thrombocytosis

Chronic myeloid leukemia

Polycythemia vera

Myelofibrosis

WHO Criteria for Dx

Major Criteria

  1. sustained thrombocytosis with platelets >450x10^9 / L
  1. Presence of clonal marker sucha s
    JAK2 V617F
    CALR
    MPL
  1. No evidence of alternative myeloid malignancy
  1. Bone marrow biopsy showing proliferation of mainly megakaryocyte lineage
    No significatn increase in granulopoiese
    Less than grade 1 bone marrow fibrosis

Minor Criteria

Presence of a clonal marker

No evidence of a reactive process

Dx

All 4 major

First 3 major + all minor criteria

Risk of Thrombosis

High

Age >60

Hx of previous thrombosis

Pl count >1500

Tx

Lower platelet count

Aspiring

Low

Age <40

No hx of thrombosis

Tx

Aspirin alone

Myelofibrosis

Epidemiology

Rarest of classic myeloproliferative disorders

Older pt with hx of ET / PV

Male predominance

Presentation / Clincal Features

Pathogenesis

Progressive generalised fibrosis of bone marrow - reactive process

Development of haematopoiesis in spleen / liver - extramedullary

Pain 2* to massive hepatosplenomegaly

Anaemia

Hypermetabolic symptoms

  • Night sweats
  • Pruritus
  • Weight loss

Labratory Investigation

Leucoerythroblastic blood picture

Treat poikilocytes

Fatigue

High symptom burden

Normal fibroblast respond to abnormal cytokines released by megakaryocytes

Cytokines - TGF-β , PDGF, FGF

Prognostic Factors

  1. Hb
  1. Constitutional symptoms
  1. WBC
  1. PB blasts
  1. Age

Treatment

JAK2 inhibitors

  • Ruxolitinib

Allogeneic transplant

Blood transfusion for anaemia

SUpportitive

Goals of Treatments

  1. Cure
  1. Prevent thrombosis / bleeding
  1. Prevent transformation
  1. Ameliorate symptoms
  1. Ameliorate symptoms
  1. Improve blood counts
  1. Cytogenetic / molecular responses

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