Epidemiology

• The annual incidence of CML is between 1 and 2 cases per 100,000.^[2]
• CML represents about 14% of all leukaemias and is less common than acute myeloid leukaemia and chronic lymphocytic leukaemia.
• Presentation can occur at any age; however, it is rare in children (CML represents only 5% of childhood leukaemia). The median age at diagnosis is 60-65 years.^[2]

Aetiology

The initiating event or events are unknown: there are no known hereditary, familial, geographic, ethnic or economic associations. There may be an increased risk after exposure to the atomic bombs dropped on Hiroshima and Nagasaki but not with lower levels of radiation.^[3]

Cytogenetics

• CML is characterised by a consistent cytogenetic abnormality - a reciprocal translocation between the long arms of chromosomes 22 and 9, t(9;22). The result is a shortened chromosome 22, known as the Ph chromosome.
• The translocation is significant because it places an oncogene (abl) from the long arm of chromosome 9 to the long arm of chromosome 22 in the BCR region. The BCR-ABL fusion gene encodes a chimeric protein with strong tyrosine kinase activity. This constitutively active BCR-ABL tyrosine kinase causes CML but how the presence of this oncoprotein leads to the CML phenotype is not fully understood.
• CML's hallmark is the presence of BCR-ABL rearrangement and is considered diagnostic when present in a patient with clinical manifestations of CML.

Presentation

85-90% of patients are diagnosed in the chronic phase and in recent years about half have been diagnosed before any symptoms developed, with incidental abnormalities spotted on a blood test.

Symptoms

Symptoms can be insidious in onset and include:

• Fatigue.
• Night sweats.
• Weight loss.
• Abdominal fullness or abdominal distension.
• Left upper quadrant pain due to splenic infarction.

Signs

• Splenomegaly - the most common physical finding, which may extend towards the right iliac fossa.
• Hepatomegaly.
• Enlarged lymph nodes are also a possibility.
• Anaemia can produce a hyperdynamic circulation.
• Easy bruising.
• Fever.
• Gout due to rapid cell turnover.
• Hyperviscosity syndrome due to leukocytosis - visual disturbance (fundoscopy may show papilloedema, venous obstruction and retinal haemorrhages), priapism, cerebrovascular accident (CVA), confusion.

Investigations

At presentation:

• FBC:
  • Leukocytosis is common.
  • Differential shows granulocytes at all stages of development and increased numbers of eosinophils and basophils.
  • Platelets may be elevated, decreased or normal levels.
  • A mild-to-moderate, usually normochromic and normocytic, anaemia is common.
• Peripheral blood smear - all stages of maturation seen; often resembles a bone marrow aspiration.
• Biochemistry - U&Es are usually normal at presentation, lactate dehydrogenase is usually raised, serum urate may be raised.
• Bone marrow aspiration and biopsy are essential to quantify the percentage of blasts and basophils, to assess the degree of fibrosis and to obtain material for cytogenetic-molecular analyses.
• The leukocyte alkaline phosphatase test is largely of historical interest, as it has been superseded by cytogenetic tests; however, it was used previously to differentiate CML from other myeloproliferative disorders.
• Cytogenetics - the characteristic feature in CML is the Ph chromosome and is found in about 90% of cases. Of those with a negative Ph chromosome, a third to one half test positive for the abnormal gene, or the abnormal protein associated with the chromosome, when more sensitive studies, such as dual fluorescence in situ hybridisation (FISH) or polymerase chain reaction (PCR), are used. They have a similar prognosis and response to treatment as patients with classical Ph CML.
• HLA typing for patients and family members if stem cell transplantation (SCT)is contemplated.

During treatment:

• Cytogenetic response is monitored by regular karyotyping or FISH studies looking at the percentage of bone marrow cells with Ph+ cells.
• Molecular response is monitored by looking at PCR studies demonstrating BCR-ABL transcript levels. Rising levels can indicate loss of response to treatment.^[4]
• BCR-ABL mutation analysis to determine likely susceptibility to treatment.

Frequency of monitoring will depend upon local protocols.

Differential diagnosis

The Ph chromosome is diagnostic but, where it is negative, consider:

• Polycythaemia rubra vera.
• Thrombocythaemia.
• Myelofibrosis.
• Leukaemoid reaction - no haematological malignancy but there may be an underlying solid tumour.

Management

Goals of treatment are:

• Haematologic remission (normal FBC count, physical examination, ie no organomegaly).
• Cytogenetic remission (normal chromosome returns with 0% Ph-positive cells).
• Molecular remission (negative PCR result for the mutational BCR-ABL m-RNA).

Drug treatment is superior to allogeneic stem cell transplantation (alloSCT) in first-line therapy of CML, because of transplant-related mortality.^[5]

Drug therapies

In recent years, tyrosine kinase inhibitors (TKIs) have come to dominate the treatment of CML. In the past, myelosuppressive drug treatment has included:

• Busulfan - an oral drug in use since the 1950s and the first agent to provide effective haematological control in CML patients. It tends to be reserved now for palliative treatment, due to severe side-effects (severe prolonged myelosuppression in 10% of patients, idiosyncratic pulmonary reactions, marrow or endocardial fibrosis), failure to produce complete remission and worse outcome after alloSCT.
• Hydroxyurea - this is less toxic than busulfan, provides good debulking and allows for rapid control of the blood count in 50-80% patients. However, it does not alter the natural history of CML and should not be considered as definitive treatment. It does not seem to have an adverse effect on bone marrow transplants. Its main toxic affects are nausea, vomiting, diarrhoea and mucosal or skin ulceration.
• Interferon alfa - this provides better results than traditional chemotherapy, with complete cytogenetic remission (CCGR) achieved in about 25%, associated with improved survival (78% alive at 10 years). Sustained disappearance of all Ph cells (complete molecular remission) is achieved in 5-10% and follow-up suggests these patients remain well at 10 years and probably are cured. Side-effects of interferon alfa occur in 90%, require dose reduction in 50% and cessation of treatment in 20%. They include fever, anorexia, postnasal drip, fatigue, depression, weight loss and peripheral neuropathy.

TKIs

Imatinib:

• Imatinib was one of the first drugs designed on an understanding of a disease's molecular biology. It is a selective inhibitor of the tyrosine kinase encoded by BCR-ABL fusion gene; it inhibits proliferation and induces apoptosis in cells positive for BCR-ABL and Ph+ leukaemic clones. Imatinib is now firmly established as an effective therapy for newly diagnosed patients with CML.^[6][7]
• Rates of CCGR among patients receiving imatinib were 69% by 12 months and 87% by 60 months. These patients had a significantly lower risk of disease progression. Only 7% of patients progressed to accelerated-phase CML or blast crisis over five years and the estimated overall survival of patients who received imatinib as initial therapy was 89% at the same time period.^[8]
• It has very quickly become standard therapy for CML because of its remarkable efficacy and mild side-effect profile.^[9]

Second- and third-generation TKIs:

• Imatinib seems particularly effective in chronic-phase CML. In more advanced disease, patients are less likely to be sensitive and often display a short-lived response to the drug. Failure of imatinib therapy associated with progression in the accelerated or blastic phase carries a particularly poor prognosis.^[10]
• Primary and secondary drug resistance at all stages of the disease has been observed. The underlying mechanisms of drug resistance are beginning to be understood and second-generation drugs such as nilotinib (a more potent BCR-ABL inhibitor) and dasatinib (a dual ABL/SRC inhibitor) have been developed.^[11][12] Trials have shown that these drugs are effective in patients previously exposed to imatinib.^[13][14]
• Third-generation TKIs are being developed to target further mutations associated with drug resistance, and combination therapy may be a strategy to pre-empt resistance.^[15]

For first-line treatment of CML, the National Institute for Health and Clinical Excellence (NICE) recommends the following:^[16]

• Standard-dose imatinib is recommended as an option for the first-line treatment of adults with chronic-phase Philadelphia chromosome-positive CML.
• Nilotinib is recommended as an option for the first-line treatment of adults with chronic-phase Philadelphia chromosome-positive CML if the manufacturer makes nilotinib available with the discount agreed as part of the patient access scheme.
• Dasatinib is not recommended for the first-line treatment of chronic-phase Philadelphia chromosome-positive CML.

Imatinib is also recommended as an option for the treatment of people with Philadelphia chromosome-positive CML who initially present in the accelerated phase or with blast crisis, and as an option for people who present in the chronic phase and then progress to the accelerated phase or blast crisis if they have not received imatinib previously.^[17]

For CML resistant to standard-dose imatinib, NICE currently recommends the following:^[18]

• Nilotinib is recommended for the treatment of chronic- or accelerated-phase Philadelphia chromosome-positive CML in adults: whose CML is resistant to treatment with standard-dose imatinib or who have imatinib intolerance and if the manufacturer makes nilotinib available with the discount agreed as part of the patient access scheme.
• Dasatinib is not recommended for the treatment of chronic, accelerated or blast-crisis phase CML in adults with imatinib intolerance or whose CML is resistant to treatment with standard-dose imatinib.
• High-dose imatinib is not recommended for the treatment of chronic, accelerated or blast-crisis phase Philadelphia chromosome-positive CML that is resistant to standard-dose imatinib.

Transplant therapies^[19]

CML has been the most common indication for a bone marrow transplant but the place of SCTs in the treatment of CML post-imatinib is debated. It remains an important option particularly for younger individuals with HLA-identical siblings with the hope of cure. Risks of SCT include:

• Graft-versus-host disease (GVHD).
• Veno-occlusive disease.
• Life-threatening infections.
• Risk of secondary malignancies.
• Poorer overall quality of life.

AlloSCT should ideally be undertaken in the chronic phase of CML when it is associated with 3- to 5-year survival rates of 40-80% and 10-year survival rates of 30-60%. The optimal time of transplantation is controversial but thought to be up to 24 months following diagnosis. Transplantation-related mortality ranges from 5-50% depending on factors including the patient's age, donor origin (related vs unrelated), degree of HLA matching, host cytomegalovirus status, use of conditioning regimens and institutional expertise.

Only about a third to a half of all patients may have a suitable HLA-matched sibling. Options for these individuals include the use of matched unrelated donors (MUDs) or autologous SCT. The use of stringent molecular typing in finding MUDs decreases the risk of GVHD but reduces availability.

In autologous SCT, cells from the patient's own bone marrow are withdrawn before destroying the bone marrow with chemotherapy or radiation. The transplant cells are then infused and repopulate the bone marrow. There is a risk that the transplanted stem cells may still contain the Ph chromosome. A recent meta-analysis suggested that it conferred no survival benefit and should be avoided as initial treatment for CML.^[20] It may still have a role in instances such as drug-resistant CML.

Prognosis

Prognosis for long-term survival with CML has improved over the years:

• The median survival rates with hydroxyurea therapy were 4-5 years. With interferon therapy used alone or in combination with cytarabine (Ara-C), these numbers are almost doubled.
• The introduction of imatinib is hoped further to improve the prognoses of CML patients:
  • There is a higher rate of major cytogenetic remission (MCR) achieved with imatinib compared with interferon (85% vs 7-37%)^[21] and the hope is that this will translate into survival benefit - as it does with interferon.
  • Estimates, based on this premise, suggest an absolute increment in the 10-year survival rate of about a third.^[22]
  • Observational studies are still in progress so evidence for long-term (10 years and beyond) survival benefit of this new drug is not available yet.
  • Follow-up at five years suggests an enduring response to imatinib in a high proportion of patients and an overall five-year survival rate of 89%.^[8]