Chronic Myeloproliferative Disorders

Chronic myeloproliferative disorders (now called myeloproliferative neoplasms, MPNs) are clonal stem-cell disorders in which one or more myeloid lineages (granulocytic, erythroid, megakaryocytic) proliferate without maturation arrest — so the marrow is hypercellular and the blood shows increased mature cells. This is the single biggest distinction from acute leukaemia (which has a maturation block and blast accumulation). The four classic entities — CML, polycythaemia vera (PV), essential thrombocythaemia (ET), and primary myelofibrosis (PMF) — are a perennial NEET PG favourite, especially the molecular markers (Philadelphia chromosome/BCR-ABL and JAK2 V617F).

Definition & Classification

An MPN is a clonal proliferation of a multipotent haematopoietic stem cell that retains the capacity to differentiate. Because differentiation is preserved, the peripheral blood fills with effective (mostly) mature cells, the marrow is hypercellular, and the spleen/liver enlarge from sequestration and extramedullary haematopoiesis.

The 2016/2022 WHO classification splits MPNs into:

Entity	Predominant lineage	Hallmark genetic marker
Chronic myeloid leukaemia (CML)	Granulocytic	BCR-ABL1 (t(9;22), Philadelphia chromosome) — defining
Polycythaemia vera (PV)	Erythroid	JAK2 V617F (~95%); JAK2 exon 12 (rest)
Essential thrombocythaemia (ET)	Megakaryocytic	JAK2 (~50–60%), CALR (~25–30%), MPL (~3–5%)
Primary myelofibrosis (PMF)	Megakaryocytic + fibroblast reaction	JAK2 (~60%), CALR (~25%), MPL (~8%)

High-yield: CML is the only classic MPN that is BCR-ABL1 positive. PV, ET and PMF are the BCR-ABL1–negative ("Ph-negative") MPNs and are unified by JAK2/CALR/MPL driver mutations.

The three Ph-negative MPNs share overlap and can transform into one another (e.g., ET or PV → post-ET/post-PV myelofibrosis → secondary AML). All four can ultimately undergo leukaemic (blast) transformation, though the rate differs.

Etiology & Pathophysiology

The unifying theme is constitutive activation of tyrosine-kinase signalling (JAK-STAT pathway) driving lineage proliferation independent of normal growth-factor control.

• CML — BCR-ABL1 fusion. The reciprocal translocation t(9;22)(q34;q11) fuses the BCR gene (chromosome 22) to ABL1 (chromosome 9). The product is the p210 BCR-ABL fusion protein — a constitutively active tyrosine kinase that drives unregulated granulocyte proliferation and resists apoptosis. The shortened chromosome 22 is the Philadelphia (Ph) chromosome.
• PV — JAK2 V617F. A point mutation (valine→phenylalanine at codon 617) in the JAK2 kinase causes ligand-independent activation of erythropoietin/thrombopoietin receptor signalling → erythrocytosis with low/suppressed erythropoietin (EPO).
• ET & PMF — JAK2 / CALR / MPL. All three mutations converge on hyperactive JAK-STAT. CALR (calreticulin) and MPL (thrombopoietin receptor) mutations are mutually exclusive with JAK2. CALR-mutated patients tend to have higher platelet counts and a comparatively better prognosis.

High-yield: JAK2 V617F is found in ~95% of PV, ~50–60% of ET, and ~60% of PMF. It is the most useful single screening mutation in the Ph-negative MPNs.

In PMF, the malignant megakaryocytes secrete fibrogenic cytokines (PDGF, TGF-β) that stimulate polyclonal, reactive fibroblasts → marrow fibrosis. The fibrosis is therefore a secondary, non-clonal phenomenon. As the marrow is replaced, haematopoiesis shifts to spleen and liver (extramedullary haematopoiesis) → massive splenomegaly.

Chronic Myeloid Leukaemia (CML)

Clinical features

• Typically middle age (40–60 yr); insidious onset.
• Fatigue, weight loss, night sweats, early satiety from massive splenomegaly (often the largest spleens in medicine, alongside myelofibrosis and kala-azar/CML).
• Hypermetabolic symptoms; rarely priapism or hyperviscosity from very high counts.

Investigations

• Peripheral smear: marked leucocytosis (often >100,000/µL) with a full spectrum of granulocyte maturation — myelocytes and neutrophils predominate, with a characteristic "myelocyte bulge" and basophilia + eosinophilia.
• Leucocyte alkaline phosphatase (LAP/NAP score): LOW in CML — the classic exam discriminator.
• Cytogenetics/FISH/RT-PCR: confirm t(9;22) / BCR-ABL1. RT-PCR also used for monitoring minimal residual disease.
• Marrow: hypercellular, low myeloid maturation arrest absent.

High-yield: LAP score is LOW in CML and HIGH in a leukaemoid reaction (and in PV). This single fact is among the most repeated CML MCQs.

High-yield: A peripheral picture mimicking CML but with high LAP, no basophilia, toxic granulation, and an obvious infection = leukaemoid reaction, not CML.

Phases

Chronic phase (<10% blasts) → accelerated phase (10–19% blasts, rising basophils ≥20%, refractory counts) → blast crisis (≥20% blasts; ~two-thirds myeloid, one-third lymphoid — the lymphoid blast crisis can mimic ALL).

Treatment

Drug of choice = a tyrosine-kinase inhibitor (TKI), first-line imatinib (a BCR-ABL inhibitor). Later-generation TKIs: dasatinib, nilotinib, bosutinib; ponatinib for the resistant T315I mutation. Allogeneic stem-cell transplant is reserved for TKI failure/blast crisis. Imatinib transformed CML into a chronic, manageable disease.

High-yield: Imatinib = drug of choice for chronic-phase CML. Resistance via the T315I (gatekeeper) mutation → use ponatinib.

Polycythaemia Vera (PV)

Clinical features

• Plethora, facial redness, aquagenic pruritus (itching after a hot bath/shower — very classic), headache, dizziness, visual disturbance.
• Erythromelalgia — burning red painful extremities (also seen in ET).
• Thrombosis (arterial & venous) is the leading cause of morbidity — including unusual sites such as Budd-Chiari syndrome (hepatic vein thrombosis). Bleeding can also occur (acquired von Willebrand defect at very high platelet counts).
• Splenomegaly, hypertension, gout (high cell turnover → hyperuricaemia).

Diagnosis (WHO — needs all 3 major, or first 2 major + minor)

• Major: ↑Hb/Hct or red cell mass; bone-marrow trilineage hypercellularity with pleomorphic megakaryocytes; JAK2 V617F or exon 12 mutation.
• Minor: subnormal serum erythropoietin.

High-yield: PV = raised Hb/Hct + LOW EPO + JAK2 mutation. This triad separates PV from secondary polycythaemia (where EPO is normal/high) and from relative polycythaemia (dehydration, normal red cell mass).

Differentiating polycythaemias

Feature	Polycythaemia vera	Secondary polycythaemia	Relative (Gaisböck)
Red cell mass	↑	↑	Normal
Plasma volume	Normal/↓	Normal	↓
Serum EPO	Low	High/normal	Normal
JAK2	Positive	Negative	Negative
Splenomegaly	Present	Absent	Absent
O₂ saturation	Normal	Often low (hypoxia)	Normal

Treatment

Therapeutic phlebotomy to keep **haematocrit <45%** + **low-dose aspirin** (antithrombotic). **Hydroxyurea** is the cytoreductive agent of choice for high-risk patients (age >60, prior thrombosis). Ruxolitinib (JAK1/2 inhibitor) for hydroxyurea-resistant cases. Allopurinol for hyperuricaemia.

High-yield: Phlebotomy target Hct <45% improves outcomes; aspirin reduces thrombosis. Hydroxyurea = preferred cytoreduction.

Essential Thrombocythaemia (ET)

Clinical features

• Often asymptomatic with incidental persistent thrombocytosis (platelets ≥450,000/µL, frequently >1,000,000).
• Thrombosis and, paradoxically, bleeding (acquired von Willebrand syndrome when platelets are extremely high — large multimers are consumed).
• Erythromelalgia and vasomotor/neurological symptoms responsive to aspirin.
• Mild splenomegaly.

Diagnosis

Persistent platelet count ≥450,000/µL; marrow shows proliferation of large, mature, hyperlobated ("staghorn") megakaryocytes with no significant fibrosis; presence of JAK2/CALR/MPL mutation; and exclusion of CML (no BCR-ABL — vital, since CML can present with thrombocytosis), PV, PMF and reactive causes (iron deficiency, infection, inflammation, post-splenectomy).

High-yield: Always exclude BCR-ABL before diagnosing ET — CML can masquerade as isolated thrombocytosis. Reactive thrombocytosis (commonest cause of high platelets overall) must also be excluded.

Treatment

• Low-risk: low-dose aspirin (and observation).
• High-risk (age >60, prior thrombosis, very high counts): hydroxyurea + aspirin. Anagrelide (reduces platelet production) is an alternative; interferon-α is preferred in pregnancy.

Primary Myelofibrosis (PMF)

Clinical features

• Older adults; massive splenomegaly (extramedullary haematopoiesis) with dragging abdominal pain, early satiety.
• Constitutional symptoms (weight loss, fever, night sweats), progressive anaemia, fatigue.
• Hepatomegaly; bleeding/thrombosis.

Investigations — the classic picture

• Peripheral smear: leukoerythroblastic picture = immature granulocytes (myelocytes) + nucleated red cells (normoblasts) + teardrop cells (dacrocytes). This is a high-yield buzzword combination.
• Bone marrow aspirate = "dry tap" (aspiration fails because of fibrosis). Trephine biopsy shows increased reticulin/collagen fibrosis with clusters of atypical megakaryocytes — biopsy is the investigation of choice.
• JAK2/CALR/MPL mutation; absence of BCR-ABL.

High-yield: Teardrop RBCs (dacrocytes) + leukoerythroblastic blood film + dry tap on aspiration = primary myelofibrosis. Trephine biopsy is diagnostic.

Treatment

• Supportive: transfusions, EPO for anaemia.
• Ruxolitinib (JAK1/2 inhibitor) — reduces spleen size and symptoms (mainstay symptomatic therapy).
• Allogeneic stem-cell transplant = only curative option, for fit high-risk patients.
• Hydroxyurea / splenectomy / splenic irradiation for symptomatic splenomegaly.

Putting the four together

Feature	CML	PV	ET	PMF
Dominant cell ↑	Neutrophils (all stages)	Red cells	Platelets	Marrow fibrosis + cytopenias
Genetic marker	BCR-ABL1	JAK2 (95%)	JAK2/CALR/MPL	JAK2/CALR/MPL
LAP score	Low	High	Normal/high	Variable
Splenomegaly	Massive	Moderate	Mild	Massive
Smear clue	Basophilia, myelocyte bulge	Erythrocytosis	Giant platelets	Teardrop cells, leukoerythroblastic
First-line therapy	Imatinib (TKI)	Phlebotomy + aspirin	Aspirin ± hydroxyurea	Ruxolitinib / transplant
Curative option	Allo-SCT	—	—	Allo-SCT

Diagnostic flow for suspected MPN: Persistent unexplained myeloid count ↑ → check BCR-ABL → if positive = CML → if negative, test JAK2 V617F → if Hct/Hb high = PV; if platelets high = ET; if cytopenias + fibrosis + teardrop cells = PMF → if JAK2 negative, test CALR then MPL.

Complications

• Thrombosis (arterial & venous) — major killer in PV and ET, including Budd-Chiari, portal/splenic vein thrombosis, stroke, MI.
• Haemorrhage — acquired von Willebrand syndrome at extreme platelet counts.
• Hyperuricaemia / gout / urate nephropathy from high turnover.
• Leukaemic transformation to AML — highest risk in PMF; lowest in ET.
• Progressive myelofibrosis (post-PV / post-ET MF — "spent phase" of PV).
• Massive splenomegaly with infarction, hypersplenism.

High-yield: Budd-Chiari syndrome in a young patient — think occult JAK2-positive MPN (especially PV) as the underlying cause; check Hct and JAK2.

Key Differentials

• Leukaemoid reaction vs CML → high vs low LAP, infection present, no basophilia, no Ph chromosome.
• Secondary/relative polycythaemia vs PV → EPO high/normal, JAK2 negative, no splenomegaly.
• Reactive (secondary) thrombocytosis vs ET → ferritin/CRP, underlying iron deficiency/infection/inflammation, JAK2/CALR negative.
• Secondary myelofibrosis (metastatic carcinoma, TB, leukaemia, irradiation) vs PMF → look for underlying cause; leukoerythroblastosis is not unique to PMF.
• Chronic myelomonocytic leukaemia (CMML) — overlaps MPN/MDS; monocytosis ≥1,000/µL.

Mnemonics & Eitems

• "PV makes you Plethoric and itches after a Vat (bath)" — aquagenic pruritus of PV.
• Teardrops fall in fibrosis — dacrocytes = myelofibrosis.
• Philadelphia = 9 + 22 → "92" translocation t(9;22) of CML.
• CALR / MPL / JAK2 are the three drivers of Ph-negative MPNs (J-C-M).
• Eponyms: Philadelphia chromosome (city where discovered, 1960 by Nowell & Hungerford); Gaisböck syndrome (relative/stress polycythaemia); Budd-Chiari (hepatic vein thrombosis).

Recently asked / exam angle

• Marker matching is the most reliable question: BCR-ABL → CML; JAK2 V617F → PV (and PV's low EPO); CALR/MPL → ET/PMF.
• LAP/NAP score low in CML (vs high in leukaemoid reaction and PV) — repeatedly tested image/discriminator MCQ.
• Teardrop cells + leukoerythroblastic film + dry tap → myelofibrosis — classic single-best-answer.
• Aquagenic pruritus / erythromelalgia → PV (or ET).
• Drug of choice for chronic-phase CML = imatinib; T315I resistance → ponatinib.
• Phlebotomy target Hct <45% in PV; treatment of choice + aspirin.
• Budd-Chiari in a young adult → screen for JAK2-positive MPN.
• Massive splenomegaly differentials: CML, myelofibrosis, kala-azar, malaria, Gaucher disease.
• Highest leukaemic transformation risk among Ph-negative MPNs = PMF; lowest = ET.

Rapid revision

1. MPN = clonal stem-cell proliferation with maturation preserved → mature cells flood the blood (opposite of acute leukaemia).
2. CML is the only BCR-ABL1–positive classic MPN; t(9;22) = Philadelphia chromosome → p210 fusion kinase.
3. LAP score: LOW in CML, HIGH in leukaemoid reaction and PV.
4. CML smear: basophilia + eosinophilia + myelocyte bulge; chronic → accelerated → blast crisis.
5. Imatinib = DOC for CML; ponatinib for the T315I mutation.
6. PV = high Hct + LOW EPO + JAK2 V617F (95%). Aquagenic pruritus is classic.
7. PV treatment = phlebotomy to Hct <45% + aspirin, hydroxyurea if high-risk.
8. ET = persistent platelets ≥450,000/µL, giant megakaryocytes; exclude BCR-ABL first.
9. PMF = teardrop cells + leukoerythroblastic blood + dry tap; trephine biopsy diagnostic; massive splenomegaly from extramedullary haematopoiesis.
10. Ruxolitinib (JAK1/2 inhibitor) is key therapy in myelofibrosis; allo-SCT is the only cure.
11. CALR and MPL are JAK2-mutually-exclusive drivers in ET and PMF.
12. Budd-Chiari in a young patient → underlying JAK2-positive MPN; PMF has the highest AML transformation risk, ET the lowest.