Chronic and myeloid disorders

Chronic myeloid leukaemia

Overview

Myeloproliferative neoplasm driven by BCR::ABL1, progressing through chronic, accelerated and blast phases if uncontrolled.

  • Caused by the Philadelphia chromosome t(9;22) (BCR::ABL1)1.
  • Mechanism: the BCR part of the fusion protein makes it pair up and switch itself on, so the ABL tyrosine kinase is permanently active. It drives the same growth and survival signals (RAS, JAK/STAT) as growth factors, but without needing them. Because maturation is not blocked, the blood fills with mature and maturing granulocytes and platelets2,3.
  • Philadelphia chromosome: the shortened chromosome 22 seen in 90-95%. The rest have complex or hidden rearrangements, so BCR::ABL1 must be shown by FISH or PCR in every case2,3.
  • Stem cell disease: CML starts in a pluripotent stem cell. That is why blast crisis can be myeloid (about 70%) or lymphoid, usually pre-B (most of the rest)3.
  • Why it progresses: the clone is genetically unstable and picks up extra changes (a second Philadelphia chromosome, trisomy 8, isochromosome 17q or TP53 loss) as it moves to accelerated and blast phase2,3.
  • Peak incidence is in middle age (40s to 60s), slightly more in men. Only high-dose radiation is a clear cause2,3.
  • Untreated: chronic phase (indolent, may last 5-6 years), accelerated phase (worsening anaemia, thrombocytopenia or thrombocytosis, splenomegaly, clonal evolution, rising basophils, blasts up to 19%) then blast phase1.
Presentation

Often incidental leucocytosis; fatigue, weight loss, night sweats, early satiety or splenomegaly. Film shows granulocytic left shift and basophilia.

  • Early "benign" stage is nonspecific (malaise, anorexia, weight loss). Accelerated/blast phases bring splenomegaly, pallor, bruising/bleeding, fever, lymphadenopathy and skin changes1.
  • Film shows immature granulocytes, basophilia and eosinophilia, which helps distinguish CML from reactive leucocytosis such as infection1.
  • Spleen: mild to moderate splenomegaly is the most common sign, from extramedullary blood production. It can cause early satiety, a dragging feeling, or sudden left upper quadrant pain from splenic infarction. Splenomegaly that persists on treatment suggests acceleration2,3.
  • Leucostasis or thrombosis are occasional presentations: visual disturbance, stroke, MI, venous thrombosis, priapism or breathlessness2.
  • In later stages, histamine from the increased basophils can cause itch, flushing and diarrhoea2.
  • Signs of progression: unexplained fever, weight loss, bone pain, bleeding, infection, or needing more treatment to control the count. Nodes or myeloid sarcoma are late, poor-prognosis features2.
Urgent features

Leucostasis symptoms, blast transformation, severe splenic pain/infarction or tumour lysis requires urgent haematology assessment.

  • Blast phase behaves like acute leukaemia and needs specialist-led therapy, sometimes with TKI plus chemotherapy and allogeneic transplant1.
Diagnosis

FBC/film, marrow assessment and demonstration of BCR::ABL1 by molecular/cytogenetic testing.

  • Diagnosis: peripheral smear, bone marrow aspirate and demonstration of the Philadelphia chromosome1. Differential: other myeloproliferative neoplasms and reactive leucocytosis.
  • Film in chronic phase: high white count (often above 100 x 10^9/L) made up mainly of myelocytes, metamyelocytes, bands and neutrophils, with blasts usually under 5%. Basophils and eosinophils are increased, platelets are usually high, and there is mild normocytic anaemia2,3.
  • Marrow: very hypercellular with a raised myeloid-to-erythroid ratio, small megakaryocytes, sometimes "sea-blue" histiocytes, and increased reticulin2,3.
  • Leucocyte alkaline phosphatase is low in CML, unlike in a reactive (leukaemoid) neutrophilia2.
  • Accelerated phase: anaemia not explained by bleeding or therapy, new clonal changes, blasts 10-19%, basophils 20% or more, or platelets under 100 x 10^9/L. Blast phase: blasts 20% or more, behaving as acute leukaemia2.
Management

Tyrosine-kinase inhibitor therapy with serial molecular monitoring. Adherence, interactions and cardiovascular/metabolic adverse effects are important. Transplant is reserved for selected resistant or advanced disease.

  • In chronic phase, TKIs (imatinib, nilotinib, dasatinib, bosutinib, ponatinib) are the initial treatment; they are very effective but not curative1. Allogeneic stem cell transplant is reserved for TKI failure or progression to accelerated/blast phase1.
  • Why TKIs control but may not cure: they shrink the BCR::ABL1-positive cell population but leave a small reservoir of CML stem cells. Their biggest benefit is lowering the risk of progression to blast crisis. Resistance often comes from new mutations in the BCR::ABL1 kinase itself, which later-generation TKIs were designed to overcome3.
References
  1. Merck Manual Professional: Chronic myeloid leukemia (CML)
  2. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, editors. Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012. Chapter 109, Acute and chronic myeloid leukemia.
  3. Kumar V, Abbas AK, Aster JC, editors. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Philadelphia: Elsevier Saunders; 2015. Chapter 13, Diseases of white blood cells, lymph nodes, spleen, and thymus.

Last updated from Sen’s notes on 22 October 2026.