Chronic myeloid leukaemia

Question 1

Chronic myeloid leukaemia (CML) is a myeloproliferative neoplasm characterised by dysregulated and uncontrolled proliferation of mature/maturing granulocytes (predominantly neutrophils).
(Granulocytes: neutrophils, basophils, eosinophils)

Epidemiology
15-20% of adult leukaemias
Incidence: 1-2 cases per 100,000
Age: any age group, median 50-60 years
Sex: slight male perdominance

Question 2

Pathophysiology of CML

Answer 2

1. Translocation t(9:22): produces BCR-ABL1 fusion protein
   3 possible breakpoints in BCR gene:
   - P210 (commonest): major breakpoint M-bcr
   - P190: minor breakpoint m-bcr
   - P230: micro breakpoint u-bcr
2. BCR-ABL1 fusion protein has unregulated tyrosine kinase activity which activates multiple downstream signaling pathways of cell control, proliferation, differentiation, adhesion, apoptosis
   - RAS/MAPK pathway:increased cell proliferation
   - PI3K/AKT/mTOR pathway: cell survival, proliferation and inhibits apoptosis
   - JAK/STAT pathway: cytokine-independent growth and survival, genomic instability

Question 3

Clinical presentation of patients with CML

Answer 3

1. Asymptomatic in 50% patients - incidental findings on routine blood test
2. Non-specific constitutional symptoms:
   - Fatigue, weakness
   - LOW, LOA, early satiety
   - Fever, night sweats
3. Abdominal discomfort (massive splenomegaly > hepatomegaly) without lymphadenopathy
4. Platelet dysfunction: bleeding or thrombosis

5`. Gout - hyperuricaemia from increased turnover

Question 4

Clinical phase classification of CML

Answer 4

A. Chronic phase (CP-CML)
- Duration: many years with asymptomatic or non-specific symptoms
- Blood: leukocytosis >25 or even > 100 (left shift)
- Neutrophilia, basophilia, eosinophilia
- Anaemia
- Thrombocytosis or thrombocytopenia
- Peripheral blast percentage: < 2%
- Bone marrow: hypercellular marrow with granulocytic hyperplasia, myeloid:erythroid ratio high 10:1 to 30:1, with full spectrum of myeloid maturation, blast < 5%

B. Accelerated phase (AP-CML)
- Peripheral blast percentage: 10-19%
- Bone marrow blast: 10-19%
- Peripheral blood basophils > 20%
- Persistent thrombocytosis or thrombocytopenia
- New cytogenetic abnormalities: trisomy 8, 17q, trisomy 19, second Ph chromosome

C. Blast phase (BP-CML)
- Peripheral blasts / bone marrow blast > 20%
- Extremadullary blast prolfieration: myeloid sarcoma

Question 5

Diagnostic investigations for CML

Answer 5

1. FBC
2. PBF
3. BMAT
4. FISH or qRT-PCR for BCR-ABL1
5. Leukocyte ALP (LAP) score low to absent
6. TLS labs: uric acid, LDH, hypocalcaemia, hypophosphataemia, hyperkalaemia

Question 6

Management of CML

Answer 6

1. Cytoreduction: hydroxyurea
   1A. TLS prophylaxis: allopurinol, hyperhydration
2. Tyrosine kinase inhibitors
   2A. First generation: imatinib
   2B. Second generation: dasatinib, nilotinib
   2C. Third generation: ponatinib
   2D. STAMP inhibitor: asciminib

Complications: prolonged QTc (nilotinib), thromboembolism (nilotinib), pleural effusion (dasatinib), thrombocytopenia (dasatinib)

3. Blast transformation: 3+7 cytarabine anthracycline
4. Allogenic haematopoietic stem cell transplant (allo-HSCT) if fail 2 or more TKIs or progression despite TKI

Question 7

Monitoring of TKI Response
- ELN and NCCN guideline

Answer 7

A. Haematological response (HR)
B. Cytogenetic resposne (CyR) - complete/partial/major/minor/nil
C. Molecular response (MR) - early/major/deep

Monitoring frequency: every 3 months after achieving MMR; then 3-6 monthly after DMR achieved

Question 8

Comms: can patients discontinue TKI ever?

Answer 8

Yes, if fulfilling eligibility criteria:
1. In CP-CML
2. Duration of TKI >3-5 years
3. DMR depth and duration
4. Typical BCR-ABL1 transcripts

40-60% patients who went on treatment free remission (TMR) remain stable in MMR off TKI long term

Question 9

Comms: how do you manage pregnancy in CML

Answer 9

TKI is contraindicated - teratogenicity
Interferon-alpha for control of WBC
Leukapharesis if very high counts

Question 10

Red flag symptoms of CML transformation from chronic to blast phase

Answer 10

1. Worsening fatigue and weakness
2. Unexplained weight loss
3. Persistent fever with no clear source of infection
4. Worsened constitutional symptoms
5. Declining functional status
6. Worsening pancytopenia (bone marrow failure)
7. Bone pain
8. Muscle pain - myeloid sarcoma
9. Skin changes - leukaemia cutis

Urgent evaluation with FBC, PBF, bone marrow to ascertain blast percentage