2 Clinical need and practice

2.1 CML is one of the most common types of leukaemia in England and Wales. In CML, the bone marrow produces an excessive number of abnormal stem cells. The abnormal cells eventually suppress the production of normal white blood cells, which act to protect the body against infection.

2.2 CML accounts for more than one in six leukaemias in adults, with around 600 new cases being registered in England and Wales each year; the annual case rates are 1.0 per 100,000 men and 0.8 per 100,000 women. In England and Wales, around 2660 people have CML.

2.3 Ninety-five percent of people with CML have a chromosomal abnormality caused by a reciprocal translocation between parts of the long arms of chromosome 22 and chromosome 9; this produces what is commonly known as the 'Philadelphia chromosome'. As a consequence of the translocation, a bcr-abl fusion gene is produced. The abnormal protein encoded by this fusion gene is a constitutively active tyrosine kinase, which influences cellular processes such as proliferation, differentiation and survival. Cells containing the abnormal gene and protein replicate quickly and may be protected from programmed cell death. They therefore become predominant, initially in the bone marrow and subsequently in the bloodstream, impairing the production of normal white cells.

2.4 CML is diagnosed by the presence of a characteristic blood and bone marrow cellular picture, together with cytogenetic and molecular diagnostic techniques (such as fluorescence in situ hybridisation, Southern and Western blotting techniques, reverse transcriptase polymerase chain reaction, and CRKL phosphorylation assay).

2.5 CML usually has three identifiable phases: the chronic phase, the accelerated phase and the blast-crisis phase. The chronic phase is the initial phase of CML; it is usually relatively stable and benign, and typically lasts around 3–5 years following diagnosis. The accelerated phase is seen in about two-thirds of people affected; others progress directly to blast crisis. The accelerated phase typically lasts for 2–15 months before progression to the blast-crisis phase occurs. The blast-crisis phase lasts 3–6 months and inevitably leads to death. Typically, the annual progression from chronic to blast-crisis phase is 5–10% in the first 2 years, and 20% in subsequent years.

2.6 Current treatment options for CML include allogeneic stem cell transplant (SCT), IFN-α, imatinib (for the accelerated and blast-crisis phases, and second-line therapy in the chronic phase), and conventional chemotherapy (usually with hydroxyurea [HU; also known as hydroxycarbamide] or busulfan). Treatment depends on the general health and age of the person and, for transplantation, on the availability of a suitable matched stem cell donor.

2.7 SCT remains the only potentially curative option for CML. However, the shortage of donors, patient-related factors such as age, and risks associated with the procedure, limit the number of people for whom SCT is an option. SCT is generally thought to be more successful in young people and those who are at a relatively early stage of CML. Treatment-related mortality associated with SCT is estimated to be between 20% and 40%. Conventional chemotherapy and immunotherapy (with IFN-α) do not offer a cure; they are used with the aim of maintaining the person in – or returning him or her to – the chronic phase.

2.8 Most people in the chronic phase who are not suitable candidates for SCT are offered IFN-α, which is regarded as superior to conventional chemotherapeutic agents in improving survival. However, 15–25% of people with CML discontinue IFN-α therapy because of intolerable side effects. The immediate side effects of IFN-α include fever, chills and anorexia; more serious chronic side effects are fatigue, depression, insomnia, weight loss, peripheral neuropathy, alopecia, stomatitis, diarrhoea and short-term memory loss. For those who are intolerant of IFN-α, or in whom IFN-α treatment has failed, imatinib is the treatment of choice, in line with the previous guidance issued by the Institute in September 2002 (NICE Technology Appraisal Guidance No. 50).

2.9 The treatment strategies for the accelerated and blast-crisis phases of CML are less well defined. Most people will have received prolonged treatment in the chronic phase of the disease, usually with IFN-α, imatinib or HU, and in the accelerated phase disease control may be maintained in some people by increasing the doses of these drugs. High-dose combination chemotherapy is commonly used for people in blast crisis; the agents used include mercaptopurine, dexamethasone, prednisolone, idarubicin hydrochloride, etoposide, cytosine arabinoside, vincristine sulphate and daunorubicin.