Detecting blasts
The ability to perform certain diagnostic tests has helped dramatically increase the survival rate of acute lymphoblastic leukaemia patients in Malaysia.
TREATING cancer is a delicate process, involving treading a very fine line in terms of treatment doses. Overdose on the chemotherapy and/or radiotherapy, and you will kill off too many healthy cells, causing the patient to develop other health problems.
Underdose on the drugs and/or radiation, then you face the high probability of the cancer returning.
This, of course, also applies in acute lymphoblastic leukaemia (ALL), the most common cancer in those below 18. Also called acute lymphocytic leukaemia, ALL is a cancer of the bone marrow and blood.
The bone marrow is the factory in which all our blood cells are produced. This includes our red blood cells, platelets and white blood cells, which all develop from the same blood stem cell.
While we use the general term “white blood cells” to cover all the blood cells tasked with protecting our body against infections and diseases, there are actually a few different types of such cells.
Among them are the lymphoblasts, which develop into the B- and T-lymphocytes, as well as natural killer cells. (See Birth of ALL)
In ALL, it is these lymphoblasts and lymphocytes that are abnormal. Not only are too many of them produced – resulting in the crowding out of other blood cells, but they are also immature and unable to function properly.
All about ALL
According to University Malaya Medical Centre (UMMC) senior consultant paediatric oncologist Prof Dr Hany Ariffin, ALL comprises a quarter of all child cancer cases.
In Malaysia, she shares that a rough count among her colleagues nationwide indicate that there are around 800 new leukaemia patients every year.
The problem with diagnosing leukaemia is that its symptoms are quite general.
Typical symptoms include feeling weak or tired, frequent infections and fevers, bruising and bleeding easily, loss of appetite and weight, as well as paleness.
Along with taking the child’s history and conducting a physical examination, the attending doctor will also arrange for a series of tests to confirm the diagnosis, and check the type of leukaemia.
These tests would usually include a full blood count, a bone marrow biopsy or aspiration, and a lumbar puncture, among others.
Treatment usually invariably involves chemotherapy.
The first stage of treatment is usually induction chemotherapy, where the aim is to bring the disease into remission.
A patient is considered in remission once their blood counts are back to normal, and there are no signs of leukaemic cells in their bone marrow samples.
However, this does not mean that all the leukaemic cells have been killed as these samples are examined visually via the microscope.
Because of this, patients still need to undergo consolidation chemotherapy, which aims to further reduce the number of cancer cells in the body.
If the patient still remains in remission after these two phases of chemotherapy, they will then continue on maintenance chemotherapy.
This stage aims to kill off all the leukaemic cells once and for all.
Many patients also receive intrathecal chemotherapy to their central nervous system in order to destroy any leukaemic cells that might have spread to their brains or spinal cords.
Some may undergo radiation therapy to the brain for the same purpose.
Due to the many complications associated with a bone marrow transplant, this is usually the final option for treatment in patients for whom chemotherapy does not work well.
Surviving ALL
However, the good news is that over the years, ALL patients have come to have very good overall survival rates.
Says Prof Hany: “In the year 2010, survival rates had increased to 80%.”
Unfortunately, this was not the case in Malaysia.
“In UMMC, we were not able to achieve that number because of many reasons.
“Among them: we were unable to fully understand the workings of the disease; patients are scattered all over Malaysia, so they might eventually return to their home state where there is no paediatric oncologist (to follow them up); and patient awareness (about the disease) is not very good.”
She shares the results of a study published in the journal Cancer in 1978, by a team of paediatricians led by Dr D. Sinniah from UMMC, then known as University Hospital, Kuala Lumpur.
The paper, entitled Acute leukaemia in Malaysian children, said that 40% of patients with good prognostic factors, and one-third of patients with poor indicators, survived up to three years with proper treatment.
Fast-forward a couple of decades, and another study looking at the outcome of young ALL patients treated at the hospital between 1995 to 2002 showed that at five years after diagnosis, 65% of those with good prognostic factors were still alive, along with only a quarter of those in the highest-risk group. The average overall survival rate was 56%.
Prof Hany shares that the then-head of UMMC’s Paediatric Department Prof Dr Lin Hai Peng decided that something had to be done to address the dismal survival rates of their ALL patients.
Two-nation collaboration
“In 2002, we decided to embark on a collaboration with Singapore,” says Prof Hany.
“We formed an entity called Maspore (the Malaysia-Singapore Acute Lymphoblastic Leukaemia Study Group), whereby Singapore would do certain special diagnostic tests only available there, and they would teach us certain diagnostic tests, so that we could determine the biology of the cells very, very accurately.”
Research in recent decades has shown that there are several genetic and biological factors that indicate the potential response of an ALL patient to treatment.
Some factors can be obtained easily, like age and white blood cell count. (Patients aged one to 10, and those with a count below 50,000 at diagnosis, fare the best.)
Others require more sophisticated laboratory equipment, which were not then available at UMMC.
These factors include the number of chromosomes the patient has, and whether or not genes on certain chromosomes have moved or translocated to other chromosomes.
Those with hyperdiploidy – more than the normal 46 chromosomes in humans, and no translocation of certain genes like the BCRABL1 and MLL, have a better prognosis.
Another factor includes tracking the patient’s initial response to therapy via detection of their minimal residual disease (MRD) burden.
The lower the MRD at any point, the better the patient’s chances of being cured.
As several studies have shown that leukaemic cells in approximately 90% of ALL patients have certain rearranged or translocated genes, a patient’s MRD can be detected through genetic tools like polymerase chain reaction (PCR) amplification, with a sensitivity of up to one in 10,000 or more cells.
Those with the above factors against them