Chronic Myeloid Leukaemia (CML)

Chronic myeloid leukaemia (CML) is a myeloproliferative disorder of pluripotent haemopoietic stem cells, affecting one or all cell lines (erythroid, platelet and myeloid). Over time, the leukaemic cells proliferate due to stepped-up production and failed apoptosis.
CML has become a model for cancer research since it was the first malignancy to have a specific chromosomal abnormality (the Philadelphia or Ph chromosome) uniquely linked to it almost 50 years ago.¹ Since then, advances in understanding of CML's molecular biology have begun to translate into targeted therapies such as imatinib mesylate.

• CML is a rare disease with a fairly uniform incidence globally, affecting about 1 per 100,000 people per year. This translates to about 430 new cases per year in England and Wales (based on 1984-93 figures).²
• It represents about 14% of all leukaemias and is less common than acute myeloid leukaemia and chronic lymphocytic leukaemia.
• It is uncommon in children where it represents just 5% of all leukaemias.
• Half of all patients are over 60.

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.²

CML is characterized by a consistent cytogenetic abnormality - a reciprocal translocation between the long arms of chromosomes 22 and 9 (or t(9;22)). The result is a shortened chromosome 22, known as the Philadelphia (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.

85 to 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
• LUQ pain due to splenic infarction

Signs

• Splenomegaly - commonest physical finding, may extend towards the RIF
• Hepatomegaly
• Enlarged lymph nodes are also a possibility
• Anaemia (20% at diagnosis) and this can produce a hyperdynamic circulation
• Easy bruising
• Fever
• Gout due to rapid cell turnover
• Hyperviscosity syndrome due to high WCC - visual disturbance (fundoscopy may show papilloedema, venous obstruction and retinal haemorrhages), priapism, CVA, confusion

• Full blood count:
  • Leukocytosis is common - WCC as high as100x10⁹/L is found in 50 to 70%.
  • Differential shows granulocytes at all stages of development and increased numbers of eosinophils and basophils.
  • Platelets are elevated in 30 to 50%, sometimes with levels above 1,000x10⁹/L
  • Anaemia is present in 20%
• Peripheral blood smear - all stages of maturation seen, often resembles a bone marrow aspiration.
• Biochemistry - U and Es 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 leucocyte alkaline phosphatase test is largely of historical interest as it has been superseded by cytogenetic tests but was used previously to differentiate CML from other myeloproliferative disorders.
• Cytogenetics - the characteristic feature in CML is the Philadelphia (Ph) chromosome and is found in about 90% 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 FISH (Dual-Fluorescence In Situ Hybridization) or PCR (polymerase chain reaction), 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 SCT contemplated.

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

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

CML typically progresses through three stages. The duration of these phases has been altered by conventional chemotherapy, but not the clinical course.

Chronic phase

The immune system is competent and patients are asymptomatic for prolonged periods - typically, about 4-5 years.

Accelerated phase

In about 2/3 patients, the chronic phase transforms into an accelerated phase characterised by a moderate increase in blast cells, increasing anaemia or thrombocytopenia. After a variable amount of time (usually months) the accelerated phase progresses to acute blastic transformation. Features of accelerated phase include:

• Progressive maturation arrest
• Increased bone marrow or peripheral blasts (15-30%)
• Increased bone marrow or peripheral basophils and eosinophils (≥20%)
• Resistance to therapy
• Increased constitutional symptoms
• Progressive splenomegaly
• Cytogenetic clonal evolution
• Leukocytosis
• Thrombocytosis or thrombocytopenia

The accelerated phase is not clearly defined - different classifications use slightly different cut-offs for haematological values but use of different criteria can lead to difficulty comparing trial results.

Blast crisis or blastic phase

About a third of patients will move directly from the chronic phase of CML to blastic crisis. This is an aggressive acute leukaemia with marrow exhaustion, highly refractory to chemotherapy and usually rapidly fatal. Features of blastic phase include:

• Bone marrow or peripheral blasts≥30%
• Severe constitutional symptoms due to tumour burden(weight loss, fever, night sweats, bone pain)
• Infection and bleeding
• Extramedullary blastic foci

Goals of treatment are:

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

Drug therapies

Busulphan

Busulphan is an oral drug in use since the 1950s and was the first agent to provide effective haematological control in CML patients. It tends to be reserved these days 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 allogenic SCT.

Hydroxyurea

Hydroxyurea is less toxic than busulphan, provides excellent 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 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. It can be given orally and dose is adjusted to keep WCC between about 2 and 10x10⁹/L.

Interferon alpha

Interferon alpha gives better results in terms of 5 years survival than traditional chemotherapy.The addition of cytosine arabinoside(ara-c) seems to improve response. Recombinant human interferon can produce a complete cytogenetic remission (CCGR) in about 25% - this is 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.
Interferon is tried for up to 12 months before changing therapeutic tack. If successful, patients receive it for at least 2 years or until a CCGR has been documented. Side effects of INF occur in 90%, require dose reduction in 50% and cessation of treatment in 20%. They include:

• Fever
• Anorexia
• Postnasal drip
• Fatigue
• Depression
• Weight loss
• Peripheral neuropathy

Imatinib mesylate

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.
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 5 years and the estimated overall survival of patients who received imatinib as initial therapy was 89% at the same time period.³

It has very quickly become standard therapy for CML because of its remarkable efficacy and mild side-effect profile.⁴ NICE recommendations⁵ in 2003 for its use:

• Consider as first-line treatment in an adult diagnosed with Ph CML in the chronic phase.
• Consider as an option for an adult who is diagnosed in the accelerated or blast crisis phase.
• Consider imatinib an option for an adult who has progressed to the accelerated or blast crisis phase but has not previously had the drug.
• Where a person has been taking imatinib for CML in the chronic phase, but disease still progresses, continue only as part of a research study.

Patients who respond to imatinib should continue taking it indefinitely - currently evidence suggests rapid relapse even after long periods with undetectable BCR-ABL on discontinuation.
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.⁶ 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 newer drugs such as nilotinib (a more potent BCR-ABL inhibitor) and dasatinib (a dual ABL/SRC inhibitor) are being trialled.^7,8

Transplant therapies

CML has been the commonest indication for a bone marrow transplant but the place of stem cell transplants (SCT) 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

Allogenic SCT⁹

Allogenic SCT should ideally be undertaken in the chronic phase of CML when it is associated with 3-5 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 CMV status
• Use of conditioning regimens
• Institutional expertise

Only one third to one half of all patients may have a suitable HLA-matched sibling. Options for these individuals include the used of matched unrelated donors (MUDs) or autologous SCT. The use of stringent molecular typing in finding MUDs decreases the risk of graft-versus-host disease (GVHD) but reduces availability.
Acute GVHD occurs in 10-60% of patients and is the cause of death in 10-15%. Chronic GVHD occurs in 75% with an associated mortality of 10%.
Recurrence rates are 20% and plateau at 5-7 years post-transplant.

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.¹⁰ It may still have a role in instances such as drug resistant CML.

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

• The median survival rates with hydroxyurea therapy was 4-5 years
• With interferon therapy used alone or in combination with Ara-C, these numbers are almost doubled.
• The introduction of imatinib will further improve the prognoses of CML patients, it is hoped:
  • There is a higher rate of major cytogenetic remission rate (MCR) achieved with imatinib compared to interferon (85% versus 7-37%)¹¹ 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.¹²
  • 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 5 years suggests an enduring response to imatinib in a high proportion of patients and an overall 5 year survival rate of 89%.³