CML & Myeloproliferative Neoplasms
Kinases stuck on, marrow making too much
Myeloproliferative Neoplasms: The Common Thread
Definition. Myeloproliferative neoplasms (MPNs) are clonal disorders of a hematopoietic stem cell in which a constantly active tyrosine kinase pathway drives overproduction of mature, functional cells. Unlike acute leukemia, maturation is preserved, so blasts are few in the chronic stage. The four classic MPNs are chronic myeloid leukemia (driven by BCR::ABL1) and three BCR::ABL1-negative neoplasms driven by JAK-STAT signaling: polycythemia vera, essential thrombocythemia, and primary myelofibrosis.
Shared features. Splenomegaly, hyperuricemia and gout from high cell turnover, thrombosis or bleeding, progressive marrow fibrosis, and a risk of transformation to AML.
| Neoplasm | Driver | Hallmark findings | Key therapy |
|---|---|---|---|
| CML | t(9;22) BCR::ABL1 | Very high WBC, basophilia, low LAP, massive spleen | Imatinib and other TKIs |
| Polycythemia vera | JAK2 V617F (~95%) or JAK2 exon 12 | High red cell mass with low EPO; pruritus, erythromelalgia | Phlebotomy, aspirin, hydroxyurea |
| Essential thrombocythemia | JAK2, CALR, or MPL | Platelets ≥450,000/μL; clotting and bleeding | Aspirin; hydroxyurea if high risk |
| Primary myelofibrosis | JAK2, CALR, or MPL | Teardrop cells, leukoerythroblastosis, dry tap, massive spleen | Ruxolitinib; transplant to cure |
Chronic Myeloid Leukemia
Pathogenesis. A reciprocal translocation t(9;22)(q34;q11) produces the Philadelphia chromosome, a shortened chromosome 22 carrying the BCR::ABL1 fusion gene. The fusion protein (usually p210) is a constitutively active cytoplasmic tyrosine kinase that drives proliferation and resists apoptosis. Because the lesion arises in a pluripotent stem cell, all myeloid lineages and some lymphoid cells carry it. FISH or RT-PCR confirms the diagnosis, and quantitative PCR tracks treatment response.
Presentation. CML affects adults and is often found on a routine CBC. The WBC is frequently above 100,000/μL and shows every stage of granulocyte maturation with prominent myelocytes, plus basophilia, eosinophilia, and often thrombocytosis; blasts are under 10% in chronic phase. Massive splenomegaly causes left upper quadrant fullness and early satiety, and fatigue, weight loss, and gout can occur.
CML vs leukemoid reaction. Severe infection, corticosteroids, or hemorrhage can push the WBC above 50,000/μL. The leukocyte alkaline phosphatase (LAP) score is the classic discriminator; LAP is GPI-anchored, so it is also low in PNH, and it is high in polycythemia vera and pregnancy.
| Feature | CML | Leukemoid reaction |
|---|---|---|
| LAP score | Low | High |
| Basophils, eosinophils | Increased | Not increased |
| Neutrophil morphology | Full maturation spectrum | Mostly mature; toxic granulation, Döhle bodies |
| Spleen | Massively enlarged | Usually normal |
| BCR::ABL1 | Present | Absent |
Phases. Untreated, CML evolves over years through three phases. The chronic phase (under 10% blasts) is where most patients are diagnosed. The accelerated phase brings 10–19% blasts, basophils of 20% or more, new cytogenetic abnormalities, and rising counts and spleen size. Blast crisis (20% or more blasts) behaves like acute leukemia: about two-thirds are myeloid and one-third B-lymphoblastic.
Tyrosine kinase inhibitors. Imatinib competitively occupies the ATP-binding pocket of BCR::ABL1 (and of KIT and PDGFR), so the kinase cannot phosphorylate its substrates. Daily oral therapy gives most chronic-phase patients near-normal life expectancy. Second-generation TKIs (dasatinib, nilotinib, bosutinib) are alternatives. Imatinib also treats GIST (KIT) and PDGFR-driven eosinophilic neoplasms; its adverse effects include fluid retention with edema, muscle cramps, and myelosuppression.
Resistance. Relapse on a TKI usually reflects point mutations in the ABL1 kinase domain. The T315I "gatekeeper" substitution prevents binding of imatinib, dasatinib, nilotinib, and bosutinib; ponatinib still binds, and asciminib avoids the problem by targeting the myristoyl pocket rather than the ATP site.
Polycythemia Vera and Its Mimics
Mechanism. JAK2 V617F, present in about 95% of cases (most of the rest carry JAK2 exon 12 mutations), activates signaling downstream of the EPO receptor, so erythroid precursors proliferate without erythropoietin. Red cell mass rises, often with leukocytosis, thrombocytosis, and splenomegaly, and the high red cell mass suppresses serum EPO. A low EPO is therefore the key laboratory clue.
Clinical features. Hyperviscosity causes headache, dizziness, blurred vision, and a ruddy face (plethora). Aquagenic pruritus (itching after a warm bath or shower, from histamine released by basophils and mast cells), erythromelalgia (burning, red hands and feet from platelet occlusion of small vessels), gout, and thrombosis are classic. Clots favor unusual sites such as the hepatic veins (Budd-Chiari syndrome) and other splanchnic veins. Erythromelalgia responds dramatically to low-dose aspirin, which blocks thromboxane A2–driven platelet activation.
Treatment. All patients receive phlebotomy to keep the hematocrit below 45% and low-dose aspirin. High-risk patients (age 60 or older, or prior thrombosis) also receive cytoreduction with hydroxyurea, an S-phase-specific inhibitor of ribonucleotide reductase; interferon-α or the JAK1/JAK2 inhibitor ruxolitinib are alternatives. Over time, PV can progress to post-PV myelofibrosis or to AML.
| Type | Red cell mass | EPO | Examples and clues |
|---|---|---|---|
| Polycythemia vera | High | Low | JAK2 V617F; high WBC and platelets, splenomegaly, pruritus |
| Secondary, appropriate | High | High | Hypoxia: COPD, high altitude, sleep apnea, cyanotic heart disease, smoking (carbon monoxide) |
| Secondary, inappropriate | High | High | EPO-secreting tumors: renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma, uterine leiomyoma, pheochromocytoma |
| Relative | Normal | Normal | Low plasma volume: dehydration, diuretics, burns |
Essential Thrombocythemia and Primary Myelofibrosis
Essential thrombocythemia. ET is a sustained platelet count of at least 450,000/μL with large, clustered marrow megakaryocytes, driven by JAK2 V617F, CALR, or MPL mutations. It is a diagnosis of exclusion: reactive thrombocytosis from iron deficiency, inflammation, or asplenia must be ruled out, and BCR::ABL1 testing excludes CML, which can present with isolated thrombocytosis. Patients are prone to both thrombosis (including erythromelalgia) and bleeding. At very high counts (above about 1,000,000/μL), the platelet mass adsorbs and clears large von Willebrand factor multimers, producing acquired von Willebrand syndrome. Low-dose aspirin is used for most, with hydroxyurea for high-risk patients.
Primary myelofibrosis. Clonal megakaryocytes carrying JAK2, CALR, or MPL mutations secrete PDGF and TGF-β, which stimulate fibroblasts to deposit reticulin and then collagen. Aspiration yields a dry tap, and hematopoiesis shifts to the spleen and liver (extramedullary hematopoiesis), producing massive splenomegaly. Red cells squeezed through the fibrotic marrow become teardrop cells (dacrocytes), and the smear is leukoerythroblastic, with nucleated red cells and immature granulocytes. Older adults present with fatigue, anemia, night sweats, weight loss, and early satiety.
- Clonal megakaryocytesJAK2, CALR, or MPL mutation
- PDGF and TGF-β releasefibroblasts deposit reticulin and collagen
- Marrow fibrosisdry tap; hematopoiesis moves to spleen and liver
- Peripheral findingsmassive splenomegaly, teardrop cells, leukoerythroblastosis
Treatment. Ruxolitinib, a JAK1/JAK2 inhibitor, shrinks the spleen and relieves constitutional symptoms regardless of mutation status, but it is not curative; its adverse effects include anemia, thrombocytopenia, and infections such as herpes zoster. Allogeneic stem cell transplant is the only cure.
Transformation: any MPN can evolve into AML (blast phase) with a poor prognosis, CML blast crisis being the classic example, and PV and ET can progress to secondary (post-PV or post-ET) myelofibrosis.