Chronic myeloid leukaemia

Haematologist, Dr Michael Cass, educates us on chronic myeloid leukaemia.

What is chronic myeloid leukaemia?

Chronic myeloid leukaemia (CML), also called chronic myelogenous leukaemia, is a chronic (long-term and slow-growing) type of leukaemia. Leukaemia is a cancer of white blood cells which originates in the bone marrow (blood-forming organ of the body).

CML results in an increase in the number of immature blood cells in the bone marrow. These cells also spill out of the bone marrow into the blood and accumulate in the spleen. 

CML is sometimes discovered incidentally in an asymptomatic patient who has a blood test done for an unrelated reason. 

Symptoms

When it is symptomatic, CML can cause a sensation of abdominal fullness or discomfort (due to enlargement of the spleen). Fatigue, loss of energy and shortness of breath with exertion may result from anaemia (in this case a decrease in red cell production by the bone marrow is due to the bone marrow being filled with leukaemia cells); and constitutional symptoms, like fever, loss of weight or night sweats can also occur. 

Symptoms usually develop gradually over the course of a few months. In a small proportion of patients, CML may transform into an aggressive form of acute leukaemia with severe symptoms and a rapidly rising white cell count. 

What causes CML?

CML arises because of a genetic abnormality. This is not something which is inherited or can be passed on to children. It develops only in cells in the bone marrow of the patient with CML. 

Chromosomes are the tightly packaged form that DNA takes during the division of cells. CML develops when one of the very immature cells in the bone marrow undergoes a break in two chromosomes (chromosome 9 and chromosome 22). These chromosomes re-fuse to form a new, abnormal chromosome, called the Philadelphia chromosome (so named because this is the city where it was first identified). 

At the site of the fusion, a new (abnormal) gene is formed, called BCR-ABL1. This gene causes an abnormal protein, called BCR-ABL1 tyrosine kinase, to be made by affected cells. 

This is what stimulates the leukaemia cells to grow rapidly and prevents them from undergoing programmed cell suicide (apoptosis). These leukaemia cells with this abnormal gene therefore grow faster and survive longer than normal white blood cells. 

Phases of CML

• Chronic phase: Most patients (around 85%) are in chronic phase at diagnosis. There are fewer than 5% immature leukaemic cells (aka leukaemic blasts) in the bone marrow, though (because the leukaemic cells are not highly abnormal and are still able to undergo normal maturation to a degree) the total white cell count in the blood may be very high. A normal white cell count is 4 – 10 billion cells per litre of blood. A patient with newly diagnosed CML may have many hundreds of billions of white cells per litre of blood. Chronic phase CML can be well-controlled with oral medications in nearly every case.
• Accelerated phase: During this phase, the leukaemic blasts become increasingly abnormal and begin to lose their ability to mature into adult white cells. Leukaemic blasts make  up between 5 and 19% of all bone marrow cells. Accelerated phase is often more difficult, though often possible, to control with oral medications. This is probably due to additional mutations that have developed in the leukaemic cells during acceleration of the disease.
• Blast phase: This phase is also known as blast crisis; essentially a form of acute leukaemia. Leukaemic blasts now constitute more than 20% of bone marrow cells. This phase can evolve from previously diagnosed chronic- or accelerated phase but occasionally patients are already in blast crisis at the time the disease is diagnosed. Blast phase is an aggressive disease and oral medications alone are insufficient to control the disease. Patients require urgent, intensive intravenous chemotherapy (of the variety that is used to treat acute leukaemia). Once patients are in complete remission, they require allogeneic bone marrow transplantation to prevent relapse of the blast crisis. Without this intensive treatment, blast phase CML is rapidly fatal.

Treatment of CML

• Tyrosine kinase inhibitors (TKIs): These drugs are targeted therapies and inhibit the effects of the abnormal protein, BCR-ABL1 tyrosine kinase, in the leukaemic cells in CML. TKIs, therefore, eliminate the leukaemic cells ability to grow rapidly and allow them to undergo programmed cell death. They provide excellent control of the disease in majority of cases and produce fewer and more tolerable side effects than traditional chemotherapy. TKIs currently available in South Africa include imatinib, nilotinib and dasatinib. These medications are indicated in the treatment of all phases of CML. Dasatinib is the treatment of choice for blast phase CML, but is usually used in combination with intensive chemotherapy. These targeted drugs are often required as chronic treatment; the disease is likely to relapse if the treatment is discontinued. There is emerging evidence that for patients whose tests for minute traces of BCR/ABL1 remain negative for a protracted period of time (two to five years in different research studies), there is the possibility that the TKI has in fact cured the disease and treatment discontinuation can be considered.
• Chemotherapy: Intensive chemotherapy is required for the treatment of blast phase CML and is used in conjunction with a TKI. 
• Allogeneic bone marrow transplantation: These are required for patients who fail to respond to TKIs, and for those in blast phase once they have achieved a complete remission with intensive chemotherapy combined with a TKI. 

This transplantation is also often performed for patients who are diagnosed in accelerated phase once they have achieved a response to treatment. Bone marrow transplantation is often curative in this scenario but is not considered for all patients with CML as there is a high risk of complications with this treatment.

Goals of treatment

The first goal of treatment is a complete haematological response. This implies the disappearance of leukaemic white blood cells from the blood and normalisation of spleen size. 

The next goal is a complete cytogenetic response. This means the disappearance of the Philadelphia chromosome from the bone marrow. 

The most important goal of treatment is a major molecular response. This is achieved when highly sensitive blood tests, called real-time quantitative polymerase chain reaction (RT-QPCR), are negative. These tests are specifically designed to detect the presence of the BCR-ABL1 gene, to show that the percentage of cells containing the abnormal gene are below a level of 0,1% of all white blood cells. 

Patients who achieve a major molecular response within 12 months of starting treatment with a TKI have an excellent prognosis and are likely to live normal lives and have a very low risk of progressing to accelerated- or blast phase CML. 

Modern RT-QPCR tests have become extremely sensitive and some are able to detect levels as low as 0.0001% and lower. It is when these tests become completely negative and BCR-ABL1 has become undetectable and remained so for a period of two to five years that the disease may be cured and treatment discontinuation can be considered. CML is thus a highly treatable disease in the era of these modern therapies. Most patients with this disease can lead normal lives. 

“Life doesn’t have to stop when you’ve been diagnosed with blood cancer. Those battling against leukaemia can recover and be fitter and healthier than they ever were. It’s all about showing people that it’s possible to get over it and do these mad things.” – John Applebee, chronic myeloid leukaemia patient.

MEET OUR EXPERT  – Dr Michael Cass

Dr Michael Cass is a clinical haematologist and stem cell transplant physician at Alberts Cellular Therapy (Dr Brittain and Partners Inc, affiliated to ABJ Oncology) based at Netcare Pretoria East Hospital. He also consults at the ABJ Benoni Oncology Unit and Life Glynnwood Hospital.