CML and chronic myelofibrosis

1. Chronic myeloproliferative neoplasms (MPN) — overview

MPNs are clonal stem cell disorders characterized by overproduction of blood cells in the bone marrow.

Common themes:

• Often a chronic phase with long course
• Can progress to:
  • blast crisis (AML-like transformation)
  • myelofibrosis (marrow failure + extramedullary hematopoiesis)
• Extramedullary hematopoiesis → hepatosplenomegaly (± mild lymphadenopathy)
• Many are driven by constitutively active tyrosine kinase signaling

Major classic MPNs (as in the notes): CML, ET, PMF, PV

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2. Chronic myeloid leukemia (CML)

Definition

CML is a clonal bone marrow stem cell disorder with proliferation of mature granulocytes and their precursors.

Epidemiology

• Typically middle age (25–60), peak ~35–45 years.

Pathogenesis (high-yield)

• BCR–ABL fusion gene due to t(9;22) translocation.
• Chromosome 22 carrying BCR–ABL is the Philadelphia chromosome.
• BCR–ABL protein is an abnormal constitutively active tyrosine kinase → growth-factor–like signaling → uncontrolled proliferation.

(Philadelphia chromosome can be present in multiple lineages, but granulocytic precursors dominate clinically.)

Morphology / labs

• Marked leukocytosis (often >100,000/µL)
• Predominantly neutrophils + myelocytes/metamyelocytes (“left shift”)
• Small number of blasts
• Hypercellular marrow; thrombocytosis may be present
• Splenomegaly due to extramedullary hematopoiesis

Clinical features

• Insidious onset; fatigue, weakness, weight loss
• Abdominal discomfort from massive splenomegaly
• Can resemble leukemoid reaction; distinguished by Philadelphia chromosome / BCR–ABL

Phases

1. Chronic phase: can last years; typical CML picture

2. Accelerated phase:

• worsening anemia and thrombocytopenia
• 10–20% blasts in blood/marrow

3. Blast phase (blast crisis):

• 20% blasts in marrow → AML-like picture

• severe anemia, infections, bleeding

Treatment (principles)

• Tyrosine kinase inhibitors (TKIs):
  • Imatinib binds kinase site and blocks activity
  • Resistance can occur via kinase domain mutations; dasatinib can retain activity against many resistant mutations
• Other options: chemotherapy, bone marrow transplantation

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3. Primary myelofibrosis (PMF)

Definition

PMF features clonal proliferation of granulocytic and megakaryocytic lineages; marrow fibrosis is secondary (reactive to cytokines).

Epidemiology / genetics

• Older individuals (>60 years)
• Often associated with JAK2 pathway mutations (as noted)

Biphasic course

Cellular phase

• Hypercellular marrow with atypical megakaryocytes + granulocytes
• Elevated platelets and granulocytes
• No fibrosis yet

Fibrotic phase

• Neoplastic megakaryocytes release PDGF and TGF-β
• Stimulates fibroblasts → collagen deposition → marrow fibrosis
• Leads to pancytopenia + extramedullary hematopoiesis → hepatosplenomegaly
• Peripheral blood: leukoerythroblastic picture (nRBCs + immature myeloid cells)

Clinical

• Early: nonspecific symptoms; may resemble CML
• Later: complications from cytopenias
• Platelet dysfunction → thrombosis and bleeding
• Susceptibility to infections
• Median survival ~4–5 years

💡 High-yield: CML = BCR–ABL (t(9;22), Philadelphia) → constitutive tyrosine kinase; chronic → accelerated (10–20% blasts) → blast crisis (>20%). PMF: megakaryocyte PDGF/TGF-β → fibrosis → leukoerythroblastosis + massive splenomegaly.