Personal Health - Living With C.M.L, a Formerly Fatal Blood Cell Cancer - NYTimes.com

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MUTATE Leukemia white blood cells, through a scanning electron microscope.


Personal Health
Living With a Formerly Fatal Blood Cancer
By JANE E. BRODY
Published: January 18, 2010

In December 2005, a series of mysterious symptoms — night sweats, easy bruising, swollen ankles and breathlessness upon exertion — prompted Barry to see his doctor. Only six months earlier, a physical exam had found nothing abnormal. But now Barry’s white blood cell count was through the roof.

A bone marrow test the next day revealed a genetic abnormality called the Philadelphia chromosome that is the signature of chronic myelogenous leukemia, or C.M.L., a blood cell cancer that in the last decade has been transformed from ultimately fatal to nearly always treatable, usually until something else claims the patient’s life.

Despite his illness, Barry, a lawyer who for privacy reasons asked that his last name not be used, is living a normal life. “I go to the gym, go to work, travel, play with my grandson — that’s the best,” he said in an interview. “In some of my support groups, people have been living with the disease now for 10 or 12 years.”

Before 2000, fewer than half of C.M.L. patients survived seven years; now nearly 90 percent are alive seven years after diagnosis and, like Barry, lead relatively normal lives. (The basketball star Kareem Abdul-Jabbar announced in November that he had been living with the disease for nearly a year.)

“C.M.L. has become a chronic disease leading to a normal life span in the majority of patients,” Dr. Elias Jabbour of the University of Texas M.D. Anderson Cancer Center said last month in a teleconference 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 identification of the genetic marker of the disease and development of a drug called Gleevec (imatinib), which attacks the leukemia-promoting protein, tyrosine kinase, found in 95 percent of C.M.L. patients.

Since the approval in 2001 of Gleevec, a drug that inhibits activity of this protein, two other even more powerful tyrosine kinase inhibitors have been approved by the Food and Drug Administration to treat the disease.

Barry, for example, is now on the third generation of anti-C.M.L. drugs, Tasigna (nilotinib), after his cancer became resistant to control by Gleevec and he developed an uncontrollable side effect to its successor, Sprycel (dasatinib).

A Model of Complexity

But while the success to date with C.M.L. has been nothing short of inspirational, the experience over the past decade with this genetically relatively 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 C.M.L., all it takes for a cancer to escape the stranglehold of modern therapies is for one cancer cell to develop a treatment-resistant mutation and take over.

“C.M.L. 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 in an interview. “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.”

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

“And in those with a mutation,” he continued, “the presence of mutated cells seems to affect the nonmutated 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 last June, 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 — $98,000 a year, Barry said. He is now on Medicare, and in just one month he reached the “doughnut hole” in the program’s drug benefit, during which he must pay the full cost of treatment before the insurance resumes.

Still, Barry remains very encouraged. As he learned from the latest conference of the American Society of Hematology, “they’re working on vaccines and drug combinations, as well as additional drugs for C.M.L., to address a mutation that current drugs don’t handle.”

Stages of the Disease

C.M.L. was diagnosed in about 5,050 new patients last year in the United States, most of them, like Barry, in midlife or older. And, like Barry, about 95 percent of patients have the distinctive Philadelphia chromosome in their leukemic cells. Those missing this genetic trait have 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 ionizing radiation, like what occurred in the bombings of Hiroshima and Nagasaki. The disease occasionally occurs in patients who were heavily treated with radiation for previous cancers.

C.M.L. has three stages: chronic, accelerated and blastic. At diagnosis, Barry, like 85 percent 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.

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. 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

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Personal Health - Living With C.M.L, a Formerly Fatal Blood Cell Cancer - NYTimes.com

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