This review restates what the classic myeloproliferative neoplasms are — essential thrombocythaemia, polycythaemia vera and primary myelofibrosis as clonal stem-cell disorders driven by gain-of-function mutations in JAK2, CALR or MPL — and makes a point about timing that changes how the disease is framed. These mutations arise decades before clinical disease, and what shapes whether and how they declare themselves is the accumulation of comutations in epigenetic, splicing and signalling genes, together with inflammation, which enhances clonal dominance and drives both fibrotic progression and thrombosis.
Against that, current therapy is described bluntly: it controls symptoms, thrombosis and splenomegaly, and does little to the disease, with pegylated interferon alfa and JAK2 inhibitors as partial exceptions in some patients. Evolution to secondary acute myeloid leukaemia remains the outcome nothing currently prevents.
The direction of travel is selective targeting of the mutant protein rather than the pathway — immunotherapy against mutant CALR, and inhibitors selective for JAK2 V617F over wild-type JAK2. The distinction matters clinically: existing JAK inhibitors suppress signalling in normal and mutant cells alike, which is why they relieve symptoms without reducing the clone. An agent that spares the wild-type allele is the plausible route to disease modification.
- Frame current therapy honestly with patients: symptom and thrombosis control, not disease modification
- Pegylated interferon alfa is the agent with the best claim to modifying the clone in selected patients
- Thrombotic risk drives management decisions more than counts alone
- Watch for the distinction between JAK2-selective and pan-JAK agents as new drugs appear
- Progression to secondary acute myeloid leukaemia remains the unaddressed endpoint
Why it matters
It separates what JAK inhibition actually does from what patients often believe it does.
Don't overread it
A narrative review: the CALR-directed immunotherapy and mutant-selective inhibitors it describes are investigational.
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