CML

Question 1

What?

Answer 1

Myeloproliferative disorder of pluripotent haemopoietic stem cells
Affects one or all cell lines (erythroid, platelet and myeloid)
Leukaemic cells proliferate due to increased production and failed apoptosis
>90% result from the Philadelphia chromosome genetic abnormality
Typically progressed through 3 stages

Question 2

Philadelphia chromosome

Answer 2

Translocation in long arm of chr 9 and 22 t(9:22)(q3;q11)
Part of ABL proto-oncogene from chr 9 fused with BCR gene from chr 22
The shortened chr 22 is the Philidelphia chromosome
BCR-ABL codes for a fusion protein which has excess tyrosine kinase activity
The increased tyrosine kinase activity causes the CML but the exact mechanism remains unclear

Question 3

3 phases

Answer 3

Chronic phase
Accelerated phase
Blast crisis/blastic phase

Question 4

Chronic phase

Answer 4

> 90% patients diagnosed in initial chronic phase
Immune system is competent
Patients often asymptomatic for prolonged periods - typically 4-5 years

Question 5

Accelerated phase

Answer 5

In about two thirds of patients, the chronic phase transforms into an accelerated phase
Progressive maturation arrest
Moderate increase in blast cells - 15-30% blasts in blood or bone marrow
Increased blood or BM basophils and eosinophils (>20%)
Thrombocytopenia or thrombocytosis; leukocytosis
Increasing anaemia
Resistance to therapy
Increased constitutional symptoms
Cytogenetic clonal evolution (Ph+)

Question 6

Blast crisis/blastic phase

Answer 6

After a variable amount of time - usually months - accelerated phase progresses to acute blastic transformation (80% like AML, 20% like ALL)
Around one third of patients will move directly from chronic phase to blastic crisis
≥30% blasts in blood or BM or extramedullary blastic infiltration
Aggressive acute leukaemia - marrow exhaustion
Highly refractory to chemo, usually rapidly fatal
Severe constitutional symptoms due to tumour burden - weight loss, fever, night sweats, bone pain
Infection
Bleeding
Extramedullary blastic foci

Question 7

Epidemiology

Answer 7

15% adult leukaemia
Can occur at any age
Rare in children (5% of leukaemias)
Median age 60-65
May be increase after the atomic bombs but not with lower levels of radiation

Question 8

Presentation

Answer 8

90% diagnosed in chronic phase - 40% prior to any symptoms due to incidental abnormalities spotted on blood test
Middle age
Insidious onset
Fatigue, weight loss, night sweats, anaemia
Abdominal fullness/distension, LUQ pain due to splenic infarction

Marked splenomegaly - may extend towards RIF - MOST COMMON FINDING
Hepatomegaly, perhaps enlarged LNs
Easy bruising, fever
Gout (rapid cell turnover)
Hyperviscosity (leukocytosis) - visual disturbance (papilloedema, venous obstruction and retinal haemorrhages); priapism, CVA, confusion

Question 9

Investigations - at presentation

Answer 9

FBC: Leukocytosis, granulocytes at all stages of development, increased eosinophils and basophils; normochromic, normocytic anaemia; platelets may be high, low or normal
Peripheral blood smear: all stages of maturation seen, often looks like a BM aspirate
U+Es: usually normal
LDH: raised
Urate: may be raised
BM aspirate and biopsy: essential to quantify percentage of blasts and basophils, assess degree of fibrosis and for cytogenetic-molecular analysis
Cytogenetics - Ph chr in 90%
Decreased leukocyte alkaline phosphatase (now largely historical due to cytogenetics, but can differentiate CML from other myeloproliferative disorders)
HLA typing of patient and family members if SCT is contemplated

Question 10

Investigations - during treatment

Answer 10

Regular karyotyping or FISH studies - % of BM cells with Ph+
PCR for BCR-ABL transcript levels - molecular response; rising levels may indicate loss of response to treatment
BCR-ABL mutation analysis - likely susceptibility to treatment

Question 11

Management - goals of therapy and options

Answer 11

Haematological remission - normal FBC and physical examination (no splenomegaly)
Cytogenetic remission - normal chr with 0% Ph+ cells
Molecular remission - negative PCR for mutational BCR-ABL mRNA

TKIs, chemo, SCT
Drug treatment superior to SCT first line due to transplant related mortality

Question 12

Management - chemo/myelosuppression

Answer 12

Hydroxyurea

Interferon alpha

Question 13

Management - tyrosine kinase inhibitors

Answer 13

First line treatment!
Imantinib first line - very high response rate in chronic phase CML - selective inhibitor of TK encoded by BCR-ABL. Inhibits proliferative and induces apoptosis in cells + for BCR-ABL and Ph+ laeukaemic clones. Mild SE profile. Also used if present in accelerated and blast phase or progress to AP or BP and haven’t previously had imantinib
2nd generation TKIs include nilotinib - only available with discount through patient access scheme.

Question 14

Management -SCT

Answer 14

Important option, esp for younger people with HLA identical sibling with hope of cure
Ideally undertaken in CP, optimal time thought to be up to 24 months from diagnosis.
Risks include: GvHD, veno-occlusive disease, life-threatening infections, secondary malignancies, reduced QoL.
Mortality is 5-50% depending on: age, whether donor is related, degree of HLA matching, host CMV status, use of conditioning regimens and institutional expertise.
There is also autologous SCT but it’s not that good as may still contain Ph+ cells. Maybe no survival benefit but consider in drug-resistant CML, no matched donor available

Question 15

Prognosis

Answer 15

Improving massively
With introduction of interferon alpha, median survival doubled compared to just hydroxyurea
Imanitinib is too new to compare as yet, but initial results are promising with 5 year survival looking to be about 90%