Myeloproliferative Disorders (PV, ET, MF & CML)

Meet the patient

A 58-year-old man walks into the clinic ruddy-faced, embarrassed to admit that a hot shower leaves him itching for an hour and that his left big toe has throbbed all week. His haematocrit is 0.58, his serum erythropoietin is suppressed, and JAK2 V617F is positive. The registrar reaches for the venesection pack before the film is even back — and is mostly right.[2]

The question this vignette plants is the question every MPN stem turns on: is this overproduction clonal or reactive — and which lineage is the clone driving? Hold that question and the four diseases collapse into a single frame.[1]

The molecular fork — JAK2 for the trio, Philadelphia for CML

The MPN split on one molecular test: JAK2 V617F unites PV, ET and PMF; BCR-ABL1 (the Philadelphia chromosome) stands alone for CML. Before you label any sustained high count as an MPN, exclude BCR-ABL1 — because CML answers to a tyrosine-kinase inhibitor and almost nothing else does.[1]

William Dameshek grouped these four together in 1951 on clinical intuition alone — a decade before the Philadelphia chromosome and four decades before JAK2. He was right, and the reason is at the marrow level: the MPN clone retains the ability to differentiate into mature, working cells, so the damage comes from excess — hyperviscosity, thrombosis, organomegaly — not from marrow failure. Acute leukaemia, by contrast, floods the marrow with immature, non-functional blasts.[1]

The four entities are told apart by the dominant lineage that is overproduced (red cells in PV, platelets in ET, none effectively in PMF because the marrow is scarred, granulocytes in CML) and by the driver mutation:[1]

WHO 2016 and the 2022 ICC/WHO revisions integrate morphology, genetics and clinical features. The single subtype that earns the most viva marks is pre-fibrotic PMF (pre-PMF): it mimics ET on the count but carries a higher leukaemic-transformation risk, and it is separated by atypical megakaryocyte clusters, mild reticulin fibrosis (grade 0 to 1), a raised LDH, anaemia and constitutional symptoms. CML is defined by BCR-ABL1 and is excluded from the JAK2-driven trio by a negative test for the fusion.[1]

How common, who, and why a high count is never labelled first

A sustained high count is never labelled an MPN until the reactive causes are excluded and the driver mutation is confirmed. Reactive polycythaemia, thrombocytosis and leucocytosis are far commoner than any of these four — and a junior who labels first will be wrong more often than right.[1]

The MPN are diseases of middle and older age (median presentation 50 to 70 years), with two twists the examiner likes: CML has a younger peak, and ET occurs in young women, where pregnancy planning reshapes the whole management. Incidence is roughly 0.7 to 2.6 per 100,000 per year for PV, 0.6 to 2.5 for ET, 0.2 to 1.0 for PMF (the least common but most aggressive) and 1 to 2 for CML. ET has a slight female predominance; PV and CML a slight male predominance.[1][2][3]

Recognised risk factors are thin on the ground: increasing age, male sex for PV and CML, rare familial predisposition, and ionising-radiation or benzene/solvent exposure (classically linked to CML and AML). Almost all PV is JAK2 V617F positive (or exon 12); CALR and MPL account for most JAK2-negative ET and PMF. In CML the BCR-ABL1 fusion is acquired somatic (not inherited) and present in virtually 100 percent of cases.[1]

The JAK2 engine — why the clone runs without a key

The molecular spine of the BCR-ABL1-negative MPN is the JAK2 V617F mutation — a single gain-of-function hit that lets the clone proliferate without any cytokine signal. It is a valine-to-phenylalanine substitution at position 617 in the JAK2 pseudokinase (JH2) domain, which releases the kinase from autoinhibition and renders it constitutively active.[1]

JAK2 is the intracellular signalling partner of the erythropoietin (EPO) receptor, the thrombopoietin receptor (MPL) and the G-CSF receptor, so one mutation can drive three lineages. PV red-cell precursors form endogenous erythroid colonies (EEC) in culture without added EPO, and the autonomous red-cell mass suppresses serum EPO by negative feedback. That is the basis of the low serum EPO test — the single best discriminator of PV from secondary polycythaemia.[1]

The downstream damage is lineage-specific — and each line below is a viva answer in itself:[1]

• PV — hyperviscosity. The raised red-cell mass thickens the blood: sluggish flow, endothelial activation and thrombosis (stroke, MI, Budd-Chiari). High cell turnover drives hyperuricaemia and gout, and histamine from basophils causes aquagenic pruritus — itch triggered by a warm bath or shower.
• ET — platelet dysfunction. The clone makes large, dysregulated platelets that aggregate in arterioles, producing microvascular thrombosis (erythromelalgia, transient visual disturbance, atypical chest pain). The paradox trap: at counts over 1500, platelets adsorb high-molecular-weight von Willebrand factor, producing acquired von Willebrand disease and bleeding — the counterintuitive "high count, bleed not clot" picture.
• PMF — fibrosis and extramedullary haematopoiesis. Abnormal megakaryocytes and monocytes release TGF-beta, PDGF and bFGF, stimulating fibroblasts to lay down reticulin and collagen and efface the marrow. Haematopoiesis shifts to the spleen and liver, producing massive organomegaly; mechanically distorted cells leave the film with tear-drop (dacryocyte) poikilocytes and nucleated red cells — the leukoerythroblastic picture.
• CML — the BCR-ABL1 kinase. The Philadelphia chromosome t(9;22) fuses ABL1 (chromosome 9) with the BCR breakpoint on chromosome 22, generating the p210 BCR-ABL1 fusion protein — a constitutively active tyrosine kinase firing RAS/MAPK, JAK/STAT and PI3K/AKT, with characteristic basophilia.[3][4]

The alternative drivers in the JAK2-negative trio are CALR (calreticulin) and MPL. The clinically useful rule: CALR-mutated disease runs a higher platelet count, a lower thrombotic risk and a better survival than JAK2-mutated disease, and is the commonest driver in JAK2-negative ET and PMF. Triple-negative MPN (JAK2, CALR and MPL all wild-type) carries a distinct, often less favourable prognosis and demands meticulous exclusion of mimics.[1][7][8]

Four faces at the bedside — read the count, read the film

Each MPN announces itself in a different lineage on the full blood count and film, and the film usually steers the diagnosis before the molecular panel returns. The MPN present either as an incidental abnormal count or with symptoms of hyperviscosity, thrombosis, bleeding, organomegaly or hypermetabolism.[1]

Polycythaemia vera is the plethoric patient: a ruddy complexion, headache, dizziness, tinnitus and blurred vision (hyperviscosity), aquagenic pruritus (intense itch after a warm bath — virtually pathognomonic), splenomegaly with early satiety, gout from hyperuricaemia, and thrombosis (stroke, MI, peripheral arterial occlusion, or Budd-Chiari and splanchnic vein thrombosis). Erythromelalgia — warm, red, painful swollen hands and feet relieved by aspirin — is shared with ET.[2][9]

Essential thrombocythemia is most often an incidental thrombocytosis on a routine count. Symptomatic disease brings microvascular thrombosis — erythromelalgia, atypical chest pain, headache, visual disturbance and transient ischaemic attacks — and, less often, major arterial or venous thrombosis or bleeding (mucocutaneous, at extreme thrombocytosis from acquired von Willebrand disease). Splenomegaly is mild and present in roughly half.[1]

Primary myelofibrosis is the constitutional and abdominal patient: fatigue, weight loss, night sweats, low-grade fever, and massive splenomegaly (early satiety, abdominal discomfort, splenic infarction pain, portal hypertension and ascites) — the spleen can reach the pelvis. Add hepatomegaly, bone pain, gout, pruritus and the symptoms of cytopenias (infection, bleeding, exertional dyspnoea from anaemia).[1]

Chronic myeloid leukaemia in chronic phase is frequently discovered on a routine count showing marked leucocytosis with a left shift, basophilia, eosinophilia and thrombocytosis. Symptomatic patients describe fatigue, weight loss, early satiety, left-upper-quadrant fullness from splenomegaly (often massive), night sweats and gout.[3][4]

Presenting emergencies — sober, not curious: Budd-Chiari or splanchnic vein thrombosis (abdominal pain, ascites, tender hepatomegaly); stroke or MI from hyperviscosity in PV or ET; splenic infarction and hyperuricaemic acute kidney injury in PMF; leucostasis (pulmonary or cerebral) in extreme hyperleucocytosis of CML blast phase; priapism in CML; and, in any MPN, rising blasts signalling transformation to acute myeloid leukaemia.[1]

The classic atypical presentation — and a favourite exam trap — is a JAK2-positive splanchnic vein thrombosis with a NORMAL peripheral count: occult MPN. A young woman with recurrent pregnancy loss and a high platelet count may have ET with antiphospholipid overlap.[1]

Primary or secondary? The single discriminator is serum EPO

The single best discriminator of primary from secondary polycythaemia is serum EPO — low in PV, high or normal in secondary. Order it on every unexplained raised haematocrit, alongside JAK2, before the marrow is even discussed.[2]

The classic trap: a normal oxygen saturation does not exclude a clonal cause. The clone makes red cells autonomously — it does not need hypoxia — so check EPO and JAK2, not the pulse oximeter alone. The flip side is equally dangerous: a high EPO with hypoxia is appropriate secondary polycythaemia, and venesecting it treats a number, not a patient.[2]

Thrombocytosis is separated from ET by excluding reactive causes — infection, inflammation (CRP high), iron deficiency (check ferritin), post-splenectomy, post-bleed, malignancy, rebound after marrow recovery — using CRP, ferritin, history and persistence over time. A clonal JAK2, CALR or MPL mutation or typical marrow morphology confirms ET. Reactive thrombocytosis settles as the trigger resolves and rarely exceeds 1000 x10^9/L.[2]

Leucocytosis with a left shift and splenomegaly (the CML picture) is mimicked by leukaemoid reaction — massive reactive leucocytosis from sepsis, with toxic granulation and a high leucocyte alkaline phosphatase score, in contrast to CML's low score. Also consider chronic neutrophilic leukaemia, other myeloid neoplasms and severe infection; the discriminator is BCR-ABL1 testing, blood film and the clinical context.[1]

Massive splenomegaly with a leukoerythroblastic film (the PMF picture) also occurs with metastatic carcinoma, miliary tuberculosis, visceral leishmaniasis, storage disorders (Gaucher), hairy cell leukaemia and other marrow-infiltrative processes — separated by marrow biopsy and the relevant infection or typing screens.[1]

Splanchnic (Budd-Chiari, portal or mesenteric) vein thrombosis should always prompt JAK2, CALR and MPL testing even with a normal blood count, because occult MPN is a leading cause and the count may not yet be abnormal. This is the single highest-yield trap in the topic.[1]

The bedside round — which lineage is overproduced?

Bedside examination in a suspected MPN rarely makes the diagnosis on its own; its job is to suggest the lineage and reveal the complications. Run it in this order:[1]

• General — a plethoric (ruddy) complexion and conjunctival suffusion point to PV; cachexia and sweating to PMF; pallor and bruising to cytopenias (PMF, blast phase).
• Hands and skin — erythromelalgia (warm red swollen digits relieved by aspirin) in PV and ET; gouty tophi; scratch marks from pruritus; bruising from acquired vWD or cytopenias.
• Abdomen — palpate for splenomegaly (mild in PV and ET, moderate in CML, massive in PMF) and hepatomegaly; assess for ascites (portal hypertension in PMF or Budd-Chiari).
• Cardiovascular and neurological — signs of thrombosis (focal neurology, ischaemic limb, hypertension) and a hepatic bruit or ascites (Budd-Chiari).
• Lymph nodes — generally not enlarged in MPN; prominent lymphadenopathy points to lymphoma or blast-phase transformation.[1]

Named signs worth knowing for the viva: plethora (PV), aquagenic pruritus (PV, after a warm bath), erythromelalgia (PV and ET), splenomegaly graded in centimetres below the costal margin, and the leukoerythroblastic film (PMF and marrow infiltration).[1]

Investigations — bloods, film, marrow, and the molecular fork

First-line bloods in any suspected MPN: full blood count with film, JAK2 V617F mutation screen, serum erythropoietin, urea and electrolytes, liver function tests, urate, LDH, ferritin and CRP — add CALR and MPL if JAK2 is negative and PV is excluded. The film steers the diagnosis before the panel returns: PV is densely packed with red cells; ET shows large platelets; PMF shows tear-drop poikilocytes, nucleated red cells and a leukoerythroblastic picture; CML shows a full granulocytic left shift with basophilia and eosinophilia.[1][2]

Bone-marrow aspirate and trephine with reticulin staining is central to all four. PV: hypercellular marrow with panmyelosis and pleomorphic megakaryocytes, absent iron stores. ET: megakaryocytic hyperplasia with large mature megakaryocytes, near-normal cellularity. PMF: atypical megakaryocyte clusters with reticulin (grade 2 to 3) or collagen fibrosis, often osteosclerosis and a "dry tap". CML: marked granulocytic hyperplasia with small dwarf megakaryocytes. Cytogenetics exclude CML (BCR-ABL1 negative) in PV, ET and PMF and flag high-risk lesions (complex karyotype, del(5q), -7/del(7q), i(17q), +8, 12p-).[1]

In suspected CML the defining tests are karyotyping for t(9;22), FISH for BCR-ABL1, and quantitative RT-PCR for the BCR-ABL1 transcript (p210) on blood or marrow — and the same RT-PCR then monitors response to tyrosine-kinase therapy on the International Scale (IS).[3][4]

Diagnostic criteria (reproduced)

WHO 2016 — Polycythaemia vera (diagnosis requires either all 3 major, or the first 2 major plus 1 minor):

• Major 1 — Haemoglobin over 18.5 g/dL in men / over 16.5 g/dL in women, OR haematocrit over 0.52 in men / over 0.48 in women, OR raised red-cell mass over 25 percent above predicted.
• Major 2 — JAK2 V617F or JAK2 exon 12 mutation.
• Minor — Bone marrow trilineage myeloproliferation; subnormal serum EPO; or endogenous erythroid colony (EEC) growth.[2]

WHO 2016 — Essential thrombocythemia (all 4 major required):

• Platelets over 450 x10^9/L sustained.
• Bone marrow proliferation mainly megakaryocytic, with enlarged mature megakaryocytes; no significant granulocytic or erythroid left-shift.
• Does not meet criteria for CML (BCR-ABL1 negative), PV, PMF or MDS.
• JAK2, CALR or MPL clonal marker present, OR reactive thrombocytosis excluded.[2]

WHO 2016 — Primary myelofibrosis distinguishes overt (fibrotic) PMF from pre-fibrotic PMF by reticulin grade; both require clonal markers, megakaryocytic atypia, and exclusion of CML, MDS and reactive fibrosis. Unfavourable PMF cytogenetics include complex karyotype, del(5q), -7/del(7q), i(17q), +8 and 12p-.[1]

Risk scores (reproduced)

DIPSS — Dynamic International Prognostic Scoring System for PMF (Passamonti). Scored at any point in the disease; each factor carries the points shown:[1]

DIPSS categories and median survival: Low (0 points) ~11.3 years; Intermediate-1 (1 to 2) ~7.9 years; Intermediate-2 (3 to 4) ~4 years; High (5 to 6) ~2.3 years. Intermediate-2 and High risk in a transplant-eligible patient trigger consideration of allogeneic stem cell transplant.[1]

IPSET-thrombosis — ET (International Prognostic Score for Thrombosis in WHO-essential thrombocythemia) assigns points for independent predictors of thrombosis: age over 60 (1 point), prior thrombosis (1 point), cardiovascular risk factors (1 point), and JAK2 V617F (2 points). Risk groups: Low (0 points), Intermediate (1 to 2), High (3 points or more) — but in routine practice most clinicians use the simpler low-risk (under 60, no thrombosis) vs high-risk (over 60 or prior thrombosis) split, with JAK2 positivity nudging borderline patients toward treatment.[2]

CML phases are defined by blood and marrow: chronic phase (blasts under 10 percent), accelerated phase (blasts 10 to 19 percent, basophilia over 20 percent, platelets under 100 or over 1000 x10^9/L unrelated to therapy, clonal cytogenetic evolution, or progressive splenomegaly), and blast phase (blasts 20 percent or more — about 30 percent lymphoid, 70 percent myeloid). Phase decides prognosis and whether an allogeneic transplant is on the table.[3][4]

Resuscitation — treat the thrombus, then the clone

Treat the acute event first, then initiate disease control. In the resuscitation block the tone stays flat — these are clotting, bleeding or blast crises, and there is no room for flourish.[1][2]

• Acute thrombosis (stroke, MI, Budd-Chiari) — standard anticoagulation or reperfusion as indicated plus urgent cytoreduction: venesection in PV to drive the haematocrit toward 0.45, and hydroxycarbamide and/or plateletpheresis in ET with extreme thrombocytosis.
• Budd-Chiari and splanchnic vein thrombosis — therapeutic-dose low-molecular-weight heparin then warfarin or a direct oral anticoagulant, lifelong if an MPN is confirmed; screen JAK2, CALR and MPL regardless of count.
• Leucostasis (CML blast phase with very high WBC) — hydration, hydroxycarbamide, leucapheresis, an urgent tyrosine-kinase inhibitor, allopurinol and tumour-lysis prophylaxis.
• Hyperuricaemic acute kidney injury — aggressive hydration, allopurinol 300 mg oral daily (or rasburicase), and cytoreduction of the underlying cell turnover.
• Acquired von Willebrand bleeding at extreme thrombocytosis — stop the aspirin, cytoreduce urgently; von Willebrand factor-containing concentrate if bleeding is severe.[1]

Definitive therapy — risk-adapted, four diseases

Management is risk-adapted: the goal in PV and ET is thrombosis prevention; in PMF it is symptom, spleen and cytopenia control (and cure for the transplant-eligible minority); in CML it is a deep molecular response on a tyrosine-kinase inhibitor, with the option of treatment-free remission.[1][2][3]

Polycythaemia vera

1. Venesect to a haematocrit under 0.45 — the CYTO-PV / Marchioli target. Tight control (under 0.45) versus liberal control (0.45 to 0.50) roughly halves cardiovascular death and major thrombosis. Start with 400 to 500 mL removed every few days (250 to 300 mL in older or cardiac patients), tapering to monthly once the target is held; the inevitable iron deficiency actually helps suppress erythropoiesis.[9]
2. Low-dose aspirin 75 to 100 mg oral daily — the ECLAP trial (Landolfi, NEJM 2004) reduced cardiovascular death, MI, stroke and major thrombosis without excess major bleeding; avoid in active bleeding or acquired vWD.[6]
3. Cytoreduce when high-risk (age over 60, prior thrombosis, platelet-driven symptoms, venesection intolerance): hydroxycarbamide 15 to 35 mg/kg oral daily, dose-adjusted every two to four weeks to hold counts and platelets under 400 x10^9/L. In younger patients or pregnancy use pegylated interferon alpha-2a 90 micrograms weekly (or interferon-alpha 3 million units three times weekly); in resistant or intolerant disease, ruxolitinib 10 mg oral twice daily (RESPONSE trials).[2]
4. Supportive — allopurinol 300 mg oral daily for hyperuricaemia or gout; antihistamines and SSRIs for pruritus; statin and antihypertensive cardiovascular-risk control; thrombosis prophylaxis perioperatively and in hospital.

Essential thrombocythemia

1. All patients — control cardiovascular risk factors (smoking, hypertension, diabetes, lipids).
2. Low-risk (under 60, no thrombosis) — observation, or low-dose aspirin 75 mg oral daily if JAK2-positive, microvascular symptoms, or cardiovascular risk factors; cytoreduce only for symptoms or extreme thrombocytosis.
3. High-risk (over 60 or prior thrombosis) — low-dose aspirin 75 mg oral daily (unless contraindicated) plus cytoreduction. First-line hydroxycarbamide 15 mg/kg oral daily, dose-adjusted to platelets under 400 to 600 x10^9/L. The PT-1 / MRC-PT1 trial showed hydroxycarbamide superior to anagrelide for the composite of arterial thrombosis, major bleeding and transformation. Anagrelide 0.5 mg twice daily titrated (usual 1 to 2 mg twice daily) is second-line and platelet-selective but causes headache, palpitations, fluid retention and arrhythmia. Pegylated interferon alpha-2a is an alternative, especially in younger patients.[2]
4. Extreme thrombocytosis over 1500 with bleeding (acquired vWD) — hold the aspirin, urgent cytoreduction (hydroxycarbamide); plateletpheresis if bleeding is life-threatening.
5. Refractory or intolerant — switch to interferon-alpha or anagrelide; busulfan in selected older patients.

Primary myelofibrosis

1. Ruxolitinib (oral JAK1/2 inhibitor) for splenomegaly and constitutional symptoms — validated by COMFORT-I and COMFORT-II (Harrison, NEJM 2012) with durable spleen reduction and symptom benefit. Dose by platelet count: 20 mg twice daily if platelets over 200, 15 mg twice daily if 100 to 200; watch for cytopenias, infection (tuberculosis, herpes zoster) and a withdrawal syndrome on abrupt cessation (taper). Newer agents: fedratinib, pacritinib (for thrombocytopenic PMF) and momelotinib (also improves anaemia).[5]
2. Anaemia — transfusion to a symptomatic target; danazol 200 mg three times daily, erythropoiesis-stimulating agents (if EPO low), lenalidomide or thalidomide (especially with del(5q)), luspatercept.
3. Splenomegaly refractory to ruxolitinib — consider radiotherapy for painful splenomegaly; splenectomy is controversial (high morbidity — thrombosis, bleeding, infection, and post-splenectomy leucocytosis/thrombocytosis).
4. Allogeneic stem cell transplant — the only curative therapy — for Intermediate-2 or High DIPSS and fit, younger patients with a donor; myeloablative or reduced-intensity conditioning. The decision balances transplant-related mortality (~10 to 30 percent) against the disease's natural history.[1]
5. Supportive and palliative — transfusion support (iron chelation with deferasirox if heavy), antimicrobial prophylaxis, symptom control and management of portal hypertension.

Chronic myeloid leukaemia

Tyrosine-kinase inhibitors have transformed CML from a near-fatal disease (median survival 3 to 5 years in the pre-imatinib era) to a near-normal life expectancy. Start a TKI immediately on confirmed BCR-ABL1-positive chronic phase; the choice of TKI and lifelong molecular monitoring follow the European LeukemiaNet (ELN) 2020 recommendations.[3][4]

Allogeneic stem cell transplant is no longer first-line in CML; it is reserved for T315I mutation, failure of two or more TKIs, accelerated phase not responding to a TKI, or blast phase (ideally after achieving a second chronic phase with a TKI plus chemotherapy).[3][4]

Escalation triggers across the MPN: failure to reach the target haematocrit on venesection; intolerance or resistance to hydroxycarbamide; progressive splenomegaly or worsening symptoms in PMF; rising blasts (transformation to AML); and transplant-eligibility assessment. In CML, loss of a previously achieved molecular response is itself an escalation trigger prompting mutation testing.[1]

The long view — subtypes, evolution, and what to watch for

• Pre-fibrotic PMF (pre-PMF) mimics ET but is separated by atypical megakaryocyte clusters, mild reticulin fibrosis (grade 0 to 1), a raised LDH, anaemia and more constitutional symptoms. It carries a higher leukaemic-transformation risk than ET, so it earns closer surveillance and earlier consideration of transplant.
• Post-PV and post-ET myelofibrosis — PV and ET may each evolve into a myelofibrotic phase (post-PV MF, post-ET MF) over years; suspect it when splenomegaly worsens, new cytopenias or tear-drop cells appear, and LDH rises; management parallels PMF.
• JAK2-positive splanchnic vein thrombosis with normal counts — treat as occult MPN: lifelong anticoagulation, cytoreduction if counts later rise, and surveillance.
• CML treatment-free remission (TFR) — patients with stable deep molecular response (MR4.5) for two or more years on a TKI, in a specialist centre, may attempt to discontinue the TKI under close molecular monitoring; roughly 40 to 60 percent maintain remission, the rest relapse (usually within 6 months) and regain response on restarting.
• CML blast phase — myeloid versus lymphoid; treated with TKI plus chemotherapy appropriate to the phenotype to achieve a second chronic phase, then allogeneic stem cell transplant.
• Pregnancy and the MPN — see Special Populations below.[1]

Complications, and the traps that cost marks

Disease complications: arterial and venous thrombosis (stroke, MI, peripheral arterial occlusion, Budd-Chiari — the leading cause of death in PV and ET), major bleeding from acquired von Willebrand disease at extreme thrombocytosis, evolution to post-PV or post-ET myelofibrosis, and transformation to acute myeloid leukaemia (risk highest in PMF, ~10 to 20 percent; ~5 to 10 percent in PV; ~2 to 5 percent in ET). In PMF add massive splenomegaly (splenic infarction, portal hypertension, cachexia) and transfusion iron overload. In CML, untreated or resistant disease progresses through accelerated to blast phase, with worsening cytopenias, infection and bleeding.[1][3]

Treatment complications — know them by drug: hydroxycarbamide (cytopenias, oral and leg ulcers, mucocutaneous pigmentation; leukaemogenicity debated but generally low-risk at standard doses); anagrelide (headache, palpitations, fluid retention, tachyarrhythmia, pulmonary hypertension); interferon-alpha (flu-like illness, depression, autoimmune phenomena, thyroid dysfunction); ruxolitinib (cytopenias, immunosuppression with tuberculosis and herpes zoster reactivation, and a withdrawal syndrome on abrupt cessation). For the TKIs: imatinib (fluid retention, periorbital oedema, cytopenias, nausea); dasatinib (pleural effusion, pulmonary arterial hypertension); nilotinib (QT prolongation, hyperglycaemia, pancreatitis, vascular events).[1]

The classic diagnostic pitfalls — the ones that cost marks:[1]

• Labelling "secondary" polycythaemia without checking serum EPO and JAK2 — a normal oxygen saturation does not exclude a clonal cause.
• Treating extreme thrombocytosis in ET with more aspirin when the cause of bleeding is acquired von Willebrand disease — aspirin must be stopped, not given.
• Calling leucocytosis with splenomegaly "CML" without a BCR-ABL1 test — a leukaemoid reaction from sepsis has a high LAP score and settles with treatment.
• Missing pre-fibrotic PMF behind a label of ET — check the marrow, LDH and megakaryocyte morphology.
• Forgetting that JAK2-positive splanchnic vein thrombosis can have a normal blood count.[1]

Prognosis — DIPSS decides PMF, TKIs rewrote CML

PV and ET have a near-normal or modestly reduced life expectancy with good control — median survival roughly 14 years (PV) and 20 years (ET) — but this is cut by thrombosis (the leading cause of death) and by transformation. PV carries a roughly 5 to 10 percent lifetime risk of AML and a 10 to 15 percent risk of progression to post-PV myelofibrosis; ET transforms to AML in 2 to 5 percent and to post-ET MF in roughly 10 percent.[1]

PMF carries the worst prognosis of the BCR-ABL1-negative trio (median survival 4 to 7 years overall, but dictated by DIPSS — from ~11 years in low-risk to ~2 years in high-risk); younger, transplant-eligible patients may be cured by allogeneic stem cell transplant.[1]

CML prognosis has been transformed by TKIs: 10-year overall survival of 85 to 90 percent with first-line imatinib, and even better with second-generation TKIs; the leading causes of death are now cardiovascular disease and second cancers rather than CML itself, and many patients on a TKI have a near-normal life expectancy. Blast-phase CML has a poor prognosis (median survival under a year without transplant).[3][4]

Adverse factors across the MPN include high-risk cytogenetics (complex karyotype, del(5q), monosomy 7 in PMF), high LDH and circulating blasts. Leukaemic transformation is highest in PMF. Follow-up is by serial full blood counts, holding the haematocrit under 0.45 in PV, monitoring symptoms and spleen size in PMF, BCR-ABL1 RT-PCR quarterly in CML, and surveillance for transformation (rising blasts, new cytopenias) alongside cardiovascular risk factor control.[1]

Special populations

• Pregnancy (chiefly ET in young women; PV and PMF are rarer) — low-dose aspirin 75 mg throughout pregnancy, interferon-alpha (safe in pregnancy) if cytoreduction is needed, avoid hydroxycarbamide and anagrelide, and postpartum low-molecular-weight heparin for six weeks (the highest-risk period). JAK2-positive status increases pregnancy loss, and a history of thrombosis or recurrent loss adds prophylactic LMWH. Coordinate a joint haematology-obstetric plan.
• Elderly — favour hydroxycarbamide (PV/ET) and imatinib (CML) for tolerability; consider reduced-intensity conditioning transplant in carefully selected older PMF patients; manage comorbidity and polypharmacy.
• Children and young adults — prefer interferon-alpha (ET/PV, fertility-sparing) and second-generation TKIs in CML aiming for deep response and possible treatment-free remission; transplantation for high-risk PMF.
• Immunocompromised — caution with ruxolitinib (tuberculosis, herpes zoster risk) and aggressive TKIs; screen for hepatitis and tuberculosis before immunosuppressive therapy.
• Anticoagulated patients — manage the dual risk of thrombosis and bleeding; avoid unnecessary antiplatelet plus anticoagulant combinations; balance splanchnic-vein thrombosis risk against bleeding from acquired vWD or cytopenias.
• Surgery — venesect PV to under 0.45 preoperatively, hold anagrelide or aspirin per bleeding risk, and ensure thromboprophylaxis.[1]

The trials that rewrote these diseases

Landmark trials and what they changed: the ECLAP / Landolfi (NEJM 2004) trial established that low-dose aspirin reduces cardiovascular death and major thrombosis in PV; the CYTO-PV / Marchioli study set the haematocrit-under-0.45 venesection target; the COMFORT-I and COMFORT-II (Harrison, NEJM 2012) trials validated ruxolitinib for splenomegaly and symptom control in myelofibrosis; the RESPONSE trials supported ruxolitinib in resistant or intolerant PV; the PT-1 / MRC-PT1 trial showed hydroxycarbamide superior to anagrelide in ET; and the IRIS trial established imatinib as first-line CML therapy, with long-term follow-up confirming durable responses.[5][6][9]

The WHO 2016 and ICC/WHO 2022 revisions redefined MPN diagnosis around driver mutations (JAK2, CALR, MPL) integrated with marrow morphology, and recognised pre-fibrotic PMF as a distinct, higher-risk entity. CALR was discovered in 2013 (Nangalia, NEJM) as the dominant JAK2-negative driver in ET and PMF, and CALR-mutated disease carries a lower thrombotic risk and better survival than JAK2-mutated disease. Large genomic studies (Grinfeld, NEJM 2018) have begun to deliver personalised prognosis from integrated mutation profiles.[7][8]

Guideline bodies: NCCN (US), European LeukemiaNet (ELN 2020 for CML), BCSH / European Society for Medical Oncology, WHO, and in India ICMR / Blood Cancer India epidemiology and the Indian Council of Medical Research guidance. For CML, ELN 2020 is the global reference for TKI selection and molecular milestones.[4]

Controversies: whether hydroxycarbamide is leukaemogenic (generally low-risk at standard doses, but debated in young patients); the role of early ruxolitinib in PV/ET; the milder phenotype of CALR-driven disease; transplant timing and intensity in PMF; JAK-inhibitor withdrawal; and the selection of patients for CML treatment-free remission versus lifelong TKI.[1]

Exam pearls

• PV vs ET vs PMF — distinguished by the dominant lineage (red cells, platelets, fibrosis) and the film; the shared driver is JAK2 V617F.
• CML — distinguished by BCR-ABL1 (Philadelphia t(9;22)), high WBC with basophilia, and dwarf megakaryocytes on marrow; treated with TKIs.
• DIPSS for PMF — age over 65, Hb under 100 g/L, WBC over 25, blasts, constitutional symptoms; the Hb under 100 g/L factor carries the heaviest weight (2 points).
• CML milestones — BCR-ABL1 IS under 10 percent at 3 months (early molecular response), under 0.1 percent by 12 months (major molecular response).[1]

The mantra

JAK2 for PV, ET and myelofibrosis; Philadelphia for CML — and a high platelet that bleeds is still an MPN.[1][2]

Ward-round test — four stems, thirty seconds each