23rd July 2024

Chronic myeloid leukaemia

Background of CML

CML is a myeloproliferative disorder caused by clonal proliferation of mature and maturing granulocytes, predominantly neutrophils. Cell differentiation is relatively preserved, in contrast to AML. CML accounts for 15-20% of adult leukaemias. Median age of presentation is 50 years and it has a slight male predominance.

Ionising radiation is the only known risk factor.

Translocation between chromosomes 9 and 22, t(9;22)(q34;q11), causes formation of an abnormal chromosome 22, called the Philadelphia chromosome. This is pathognomonic for CML. The translocation results in formation of the BCR-ABL1 fusion gene, an oncogene that produces the BCR-ABL1 protein, a dysregulated and constitutively active tyrosine kinase.

Presentation and diagnosis of CML

CML is a triphasic or biphasic disease:

• Chronic phase: <10% blasts in BM
• Accelerated phase: 10-19% blasts in BM (some patients go straight from the chronic phase to a blast crisis)
• Blast crisis: ≥20% blasts in BM, resembles an acute leukaemia

Signs and symptoms depend on which phase patients present in. Around 85% of patients present in the chronic phase. As a result, up to half of patients are asymptomatic on presentation, being picked up incidentally on an FBC.

Splenomegaly, present in ~75% of patients, can cause abdominal pain or early satiety. Patients can also present with constitutional symptoms of fatigue, weight loss and sweats. Patients in a blast crisis can present with BM failure.

Diagnostic workup includes:

• Blood tests: FBC (raised WCC)
• Blood film: mature/maturing myeloid cells
• BM biopsy: to confirm disease phase

Definitive diagnosis is made by cytogenetic confirmation of the presence of the Philadelphia chromosome, and hence the BCR-ABL1 fusion gene, by fluorescent in situ hybridisation or quantitative reverse transcription polymerase chain reaction.

Image Source: Wikimedia Commons (2009). Chronic Myeloid Leukemia smear 2009-04-09, Licensed under a creative commons licence. Available for free at: https://en.wikipedia.org/wiki/Chronic_myelogenous_leukemia#/media/File:Chronic_Myeloid_Leukemia_smear_2009-04-09.JPG (Accessed: 16 January 2024).

Management and prognosis of CML

Management options for CML include:

1. Tyrosine kinase inhibitors (TKI): first line TKIs include the first-generation imatinib and second-generation medications dasatinib and nilotinib. TKIs are generally continued indefinitely as long as they are working, and they provide good disease control long-term.
2. Allogeneic SCT: can be considered in any patient not responding to initial therapy or with relapse.
3. Hydroxycarbamide: can be used for symptom control while awaiting a diagnosis for patients with significant leucocytosis, systemic symptoms or symptomatic splenomegaly. It has no bearing on survival.

Patients in the chronic phase are treated with a TKI with a generally very good response.

Patients in the accelerated phase or blast crisis are treated with the same TKIs but have a lower likelihood of response and higher risk of relapse. As such, allogeneic SCT is more likely to be required and considered earlier.

TKIs allow patients with CML to have a near normal life expectancy. Stage of disease at presentation has the strongest impact on outcome.