Living with a formerly fatal blood cancer

Despite his illness,Barry,a lawyer,is living a normal life. Before 2000,less than half of CML patients survived seven years; now nearly 90 per cent are alive seven years after diagnosis and,like Barry,lead relatively normal lives.

“CML has become a chronic disease leading to a normal life span in a majority of patients,” Dr Elias Jabbour of the University of Texas M D Anderson Cancer Center said in a workshop sponsored by CancerCare.

“As for quality of life,among more than 3,000 patients who have been followed now for almost 10 years,there’s been no significant increase in the incidence of infection,other cancers or other causes of death when compared to the normal population.”

What led to this turnaround was the identification of the genetic marker of the disease and the development of a drug called Gleevec (imatinib),which attacks the leukemia-promoting protein,tyrosine kinase,found in 95 per cent of CML patients.

After Gleevec,a drug that inhibits the activity of this protein,in 2001,two other even more powerful tyrosine kinase inhibitors came into the picture.

A model of complexity

But while the success with CML has been nothing short of inspirational,the experience over the past decade with this genetically relative simple cancer has demonstrated why it is so challenging to find cures for other cancers,most of which are much more complex.

As sometimes happens with CML,all it takes for cancer to escape the stranglehold of modern therapies is for one cancer cell to develop a treatment-resistant mutation and take over.

“CML is a disease we always considered to be a model of genetic abnormality,” Dr Jorge E Cortes,a leukemia specialist at M D Anderson,said. “All one needed to do is design a drug directed at that abnormality and get a great response. Then we started to uncover just how heterogeneous this ‘homogeneous’ disease really is.”

“The expression of certain genes is very different in different patients. While the majority of patients respond well to Gleevec,some don’t,some respond initially and then lose the response,and some develop mutations that may or may not be sensitive to the drugs,” said Dr Cortes.

Among patients who develop resistance to the treatment,Dr Cortes said,“only about half have a mutation that we can detect.”

“And in those with a mutation,” he added,“the presence of mutated cells seems to affect the non-mutated cells and make them more resistant to treatment. Even in a disease that is genetically simple,these leukemic cells don’t just roll over and die,even if attacked by very effective weapons. They find ways to survive.”

In the M D Anderson publication,OncoLog,Dr Cortes said: “We’ve clearly changed the natural history of this disease with imatinib,but it doesn’t work for everybody. We still need to improve therapy,in both newly diagnosed and resistant disease.”

Another problem is an inability to know for certain if and when the disease has been cured. For as long as a drug is working,patients must now continue to take it every day to keep the disease suppressed. And the cost is astronomical.

In the latest conference of the American Society of Hematology,it was realised that researchers are working on vaccines and drug combinations,as well as additional drugs for CML,to address a mutation that current drugs don’t handle.

CML was diagnosed in about 5,050 new patients last year in US,most of them,like Barry,in midlife or older. And about 95 per cent of patients have the distinctive philadelphia chromosome in their leukemic cells. Those missing this genetic trait show a poorer response to treatment.

The philadelphia chromosome results from a gene exchange between chromosomes 9 and 22. The resulting new “fusion” gene,called Bcr-Abl,dictates the production of the leukemia-promoting enzyme,tyrosine kinase.

The disease,however,is not inherited. The only known risk factor is exposure to high doses of ionising radiation. The disease occasionally occurs in patients who were heavily treated with radiation for previous cancers.

CML has three stages

Stage 1: Chronic

When diagnosed,Barry,like 85 per cent of new patients,was in the chronic phase,the earliest and easiest stage to control. There are relatively few abnormal “blast” cells in the blood and bone marrow. Some patients at this stage have no symptoms or only mild vague ones like fatigue and a feeling of abdominal fullness,and they learn of their disease through a routine blood test.

Stage 2: Accelerated

In the accelerated phase,which develops over years and signals imminent progression to uncontrollable disease,symptoms are prominent and blast cell numbers in the blood and bone marrow are higher.

Stage 3: Blastic

Once patients develop the final phase,a blast crisis,the spleen can become dangerously enlarged,and the disease,which more closely resembles acute leukemia,progresses rapidly.

Dr Cortes cautioned patients against stopping therapy when they appeared to be perfectly healthy. Those who fail to stick with continuous daily treatment are more likely to relapse.