Abstract
Chronic myeloid leukaemia (CML) can be considered as a paradigm for neoplasias that evolve through a multi-step process. CML is also one of the best examples of a disease that can be targeted by molecular therapy; however, the success of new 'designer drugs' is largely restricted to the chronic phase of the disease. If not cured at this stage, CML invariably progresses and transforms into an acute-type leukaemia undergoing a 'blast crisis'. The causes of this transformation are still poorly understood. What mechanisms underlie this progression, and are they shared by other common cancers?
Introduction
For various reasons, chronic myeloid leukaemia (CML) is probably one of the most comprehensively studied human malignancies. CML was the first human cancer to be associated with a consistent chromosomal abnormality — the Philadelphia (Ph) chromosome — a balanced, reciprocal translocation involving the long arms of chromosomes 9 and 22.[1, 2] CML is characterized by distinct clinical phases: most patients present in chronic phase (CP), a phase in which mature granulocytes are still produced, but patients have an increased number of myeloid progenitor cells in the peripheral blood. As the disease progresses, patients enter an accelerated phase (AP) followed by blast crisis (BC), in which haematopoietic differentiation has become arrested and immature blasts accumulate in the bone marrow (BM) and spill into the circulation. The CP is relatively long-lasting, so researchers have the opportunity to study malignant cells with an 'indolent' behaviour and to identify the changes associated with transformation to the 'aggressive' phenotype of blast crisis. Furthermore, CML is unusual in that a single genetic lesion, or 'hit', occurring in a haematopoietic stem cell generates a fusion oncogene, BCR-ABL, which encodes a protein tyrosine kinase that is necessary and sufficient for cell transformation.[3,4,5] Access to the neoplastic clone is relatively straightforward without the need for invasive surgery, which simplifies the collection of samples for studying the disease. Finally, CML was the first haematological malignancy for which a programme of rational drug design yielded an effective targeted molecular therapy (imatinib mesylate, Gleevec or Glivec).[6,7] In this Review we consider how the current state of knowledge regarding the biology of advanced phase CML compares with other human cancers. In particular, we discuss those features that, if not universal, are still relevant for most human cancers, including differentiation arrest, genomic instability (which includes failures of genome surveillance, deficiencies of DNA repair and mutator phenotype), telomere shortening and the loss of tumour-suppressor functions (Fig. 1; Table 1 ). The role of gene-expression profiling as a means of identifying candidate genes involved in disease progression is also highlighted.
Leukaemias
What are Leukemias
Neoplasm of white blood cell and its precursor
Clonal proliferations and accumulation of cells in marrow
Classify as
· Acute leukaemias
· Chronic leukaemias
Types of Leukaemia
Introduction- CML
· Clonal malignant myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate
· Results in increases in myeloid cells, erythroid cells and platelets in peripheral blood and marked myeloid hyperplasia in the bone marrow
· Originate in a single abnormal haemopoietic stem cell
· Incidence :1 per 100,000 (UK)
· Accounts for 7-15% of all leukaemia in adults
· Median age : 53 years
· All age groups, including children, can be affected
Etiology
· Not clear
· Little evidence of genetic factors linked to the disease
· Increased incidence
o Survivors of the atomic disasters at Nagasaki & Hiroshima
o Post radiation therapy
Leukaemogenesis
· Philadelphia chromosome is an acquired cytogenetic anomaly that is characterizes in all leukaemic cells in CML
· 90-95% of CML pts have Ph chromosome
· Reciprocal translocation of chromosome 22 and chromosome 9
· BCR (breakpoint cluster region) gene on chromosome 22 fused to the ABL (Ableson leukemia virus) gene on chromosome 9
· Ph chromosome is found on myeloid, monocytic, erythroid, megakaryocytic, B-cells and sometimes T-cell proof that CML derived from pluripotent stem cell
· Molecular consequence of the t(9;22) is the fusion protein BCR–ABL, which has increased in tyrosine kinase activity
· BCR-ABL protein transform hematopoietic cells so that their growth and survival become independent of cytokines
· It protects hematopoietic cells from programmed cell death (apoptosis)
Clinical Features
o Disease is biphasic, sometimes triphasic
o 40% asymptomatic
o Chronic phase
o Splenomegaly often massive
o Symptoms related to hypermetabolism
o Weight loss
o Anorexia
o Lassitude
o Night sweats
o Features of anaemia
o Pallor, dyspnoea, tachycardia
o Abnormal platelet function
o Bruising, epistaxis, menorrhagia
o Hyperleukocytosis
o thrombosis
o Increased purine breakdown : gout
o Visual disturbances
o Priapism
o Lab features
o Peripheral blood film
o Anaemia
o Leukocytosis (usu >25 x 109/L, freq> 100 x 109/L
o WBC differential shows granulocytes in all stages of maturation
o Basophilia
o thrombocytosis
o Bone marrow
o Hypercellular (reduced fat spaces)
o Myeloid:erythroid ratio – 10:1 to 30:1 (N : 2:1)
o Myelocyte predominant cell, blasts less 10%
o Megakaryocytes increased & dysplastic
o Increase reticulin fibrosis in 30-40%
o Other lab features :
o NAP reduced
o Serum B12 and transcobalamin increased
o Serum uric acid increased
o Lactate dehydrogenase increased
o Cytogenetic : Philadelphia chromosome
Laboratory- summary
Lab investigation to confirm diagnosis
Full blood picture
Neutrophil alkaline phosphatase
Bone marrow cytogenetic
Phases
Accelerated phase
Median duration is 3.5 – 5 yrs before evolving to more aggressive phases
Clinical features
Increasing splenomegaly refractory to chemo
Increasing chemotherapy requirement
Lab features
Blasts>15% in blood
Blast & promyelocyte > 30% in blood
Basophil 20% in blood
Thrombocytopenia
Cytogenetic: clonal evolution
Phases
Blastic phase
Resembles acute leukaemia
Diagnosis requires > 30% blast in marrow
2/3 transform to myeloid blastic phase and 1/3 to lymphoid blastic phase
Survival : 9 mos vs 3 mos (lym vs myeloid)
General Management
o Discussion with family
o The disease & diagnosis
o Prognosis
o Choices of treatment
§ Cytotoxic drug vs bone marrow transplant
§ Side effect
o CML - principles of treatment
o Relieve symptoms of hyperleukocytosis, splenomegaly and thrombocytosis
o Hydration
o Chemotherapy (bulsuphan, Hydoxyurea)
o Control and prolong chronic phase (non-curative)
o alpha interferon+chemotherapy
o imatinib mesylate
o chemotherapy (hydroxyurea)
o CML - principles of treatment
o Treatment cont…
o Eradicate malignant clone (curative)
o allogeneic transplantation
o alpha interferon ?
o imatinib mesylate/STI 571 ?(Thyrosine kinase inhibitor)
o Chemotherapy
o Busulphan
o Alkylating agent
o Preferred in older pts (not candidate for transplant)
o Side effect :
§ prolonged myelosuppression
§ Pulmonary fibrosis
§ Skin pigmentation
§ infertility
o Chemotherapy
o Hydoxyures
o Fewer side effect
o Acts by inhibiting the enzyme ribonucleotide reductase
o Haematological remissions obtain in 80% for both drugs
o However disease progression not altered and persistence of Ph chromosome containing clone
o Chemotherapy
o Recombinant human α- Interferon
o Prolong chronic phase and increase survival
o Haematogical and cytogenetic remission
o Side effect
§ Flu like symptoms
§ Fever and chills
§ Anorexia
§ Depression
o CML - prognosis
o Median survival 3.5 yrs (range 2-8 yrs)
o Interferon + chemotherapy :6 years
o Transplant : 5+ years
o imatinib mesylate ?
Because CML develops slowly, it is difficult to detect in its early stages. Sometimes it is discovered only when a blood test is done for another reason.
The symptoms of CML are often vague and non-specific and are caused by the increased number of abnormal white blood cells in the bone marrow and the reduced number of normal blood cells:
- a feeling of fullness or a tender lump on the left side of the abdomen. This is because, in CML, the spleen can become enlarged. The spleen is an organ which lies just below the ribs on the left side of the abdomen. It filters the blood and removes worn-out red blood cells. The swelling of the spleen may also cause pressure on the stomach, which can lead to indigestion and poor appetite
- some people feel tired and look pale, due to a lack of red blood cells (anaemia)
- due to a lower number of platelets in the blood some people may notice that they bleed or bruise more easily. As well as bruising more easily than normal, a special type of bruising can be seen. This consists of small blood-like spots usually seen on the legs or in the mouth and is called petechiae. Women may find that their periods become very much heavier. However, these symptoms and signs are rare
- some people may notice a generalised itching.
If you have any of the above symptoms, it is important to see your doctor, but remember, they are common to many illnesses other than chronic myeloid leukaemia.
Phases of CML
Chronic myeloid leukaemia is a blood and bone marrow disease that develops slowly. It has three phases. The phase is determined by the number of blast cells in the blood and bone marrow and the severity of symptoms.
The chronic phase
Most people are diagnosed when the CML is in the chronic phase. At this time CML progresses very slowly and is often stable for long periods. It is sometimes called the ‘stable phase’. There may be few symptoms and most people find they can lead a normal life. It is rare to need to go into hospital. Treatment can be given as an outpatient and usually does not cause many side effects. You will have regular appointments to check your condition and to have your blood tested. Although it varies from person to person this phase lasts on average about 4–5 years but can be longer.
In chronic phase CML there are 5% or fewer blast cells in the blood and bone marrow.
The accelerated phase
After some time, the leukaemia may gradually move into an accelerated phase, during which the disease is developing more quickly. In this phase there are 6–30% blast cells in the blood and bone marrow. Sometimes this change may be picked up from your blood tests, in which blast cells can be seen, or from symptoms you may have. These may include feeling very tired (due to anaemia), infections, bruising or bleeding. If you notice any of these symptoms, let your doctor know straight away. The treatment for the accelerated phase is often more intensive than in the stable phase and you may need to spend some time in hospital as an in-patient.
The blast phase
After some time in the accelerated phase, usually months, the leukaemia ‘transforms’ into a ‘blast phase’, which is more like an acute leukaemia. In this phase much of the bone marrow has been replaced by many very immature (blast) cells. In this phase there are more than 30% blast cells in the blood and bone marrow.
In some people chronic myeloid leukaemia changes quickly from the chronic phase to the blast phase without going through the accelerated phase. If tiredness, a high temperature and an enlarged spleen occur during the blast phase this is known as blast crisis.
Rarely, CML develops into a condition called myelofibrosis. This means that the bone marrow cannot make red cells, white cells or platelets because it is replaced by scar tissue (fibrosis).
Relapsed chronic myeloid leukaemia
A relapse is when the number of blast cells increases after a period of remission. Remission is when the number of blast cells in the blood and bone marrow goes back to normal following treatment.
Complete remission means that all of the blood and bone marrow tests are normal. A molecular remissionis when the Philadelphia chromosome cannot be found even by a very sensitive test called PCR.
How it is diagnosed?
Usually you will begin by seeing your family doctor (GP) who will examine you and take a blood test. If the results of the test are found to be abnormal your GP will refer you to hospital for specialist advice and treatment. In CML the blood test will generally show a high number of white blood cells.The doctor at the hospital will take your full medical history before doing a full physical examination and a blood test which checks the number and stage of development of all the different types of blood cell.
If the blood test shows that leukaemia cells are present, your doctor will want to take a sample of your bone marrow. This is to confirm the diagnosis so that the best treatment can be planned.
- Bone marrow sample
- Philadelphia chromosome
Bone marrow sample
A small sample of bone marrow is taken from the back of the hip bone (pelvis) or occasionally the breast bone (sternum). It is looked at under the microscope by a pathologist to see if it contains any abnormal white blood cells. The pathologist will be able to tell which type of leukaemia it is by identifying the type of abnormal white cell.
The bone marrow sample is normally taken under a local anaesthetic. You are given a small injection to numb the area and a needle is passed through the skin into the bone. A small sample of the bone marrow is then drawn into a syringe for examination under a microscope.
The test can be done on the ward or in the outpatients department. The whole procedure lasts about 15–20 minutes. It may be painful, but this only lasts a short time as the marrow is drawn into the syringe. You may be offered a sedative to reduce any pain or discomfort during the test.
Sometimes a small core of marrow is needed (a trephine biopsy) and this procedure takes a few minutes longer. You may feel bruised after the test and have an ache for a few days. This can be eased with mild painkillers.
The sample of bone marrow is examined to find out if the Philadelphia chromosome is present. This information helps the doctors to make decisions about treatment. It can take about a week to get the results of a bone marrow biopsy.
Philadelphia chromosome
Most people with CML have a genetic abnormality known as a Philadelphia chromosome which can be detected by laboratory tests. Every cell in the body has a nucleus that contains chromosomes. Chromosomes are long structures made up of DNA. DNA determines how the cell looks and acts. The Philadelphia chromosome develops when part of chromosome 9 (the ABL gene) wrongly attaches to chromosome 22 (the BCR gene) during cell division. This creates a new gene, known as BCR-ABL which produces a specific new protein. The protein causes the production of an enzyme called tyrosine kinase, which leads to the chronic phase of CML by stimulating the production of abnormal blood cells by the bone marrow.
The Philadelphia chromosome is not inherited and cannot be passed on to your children.
Philadelphia chromosome. A piece of chromosome 9 and a piece of chromosome 22 break off and trade places. The bcr-abl gene is formed on chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called the Philadelphia chromosome.
Philadelphia chromosome. A piece of chromosome 9 and a piece of chromosome 22 break off and trade places. The bcr-abl gene is formed on chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called the Philadelphia chromosome.
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