Second Time Around
When a patient with acute promyelocytic leukemia shows signs of molecular relapse, a new drug therapy may offer another chance at survival.
USC/Norris hematologist Dan Douer, M.D., wants to help turn leukemia patients' early warning signs into
survival.
To follow up on his patients who have completed treatment for acute promyelocytic leukemia, Douer uses a highly sensitive molecular test that seeks out the most minute signs of cancer. If he finds malignant cells, he immediately offers patients a regimen of a newly approved arsenic-based drug-months before the patient would have suffered symptoms indicating the leukemia was back in force.
"It's best to treat a patient before the disease can return," says Douer, associate professor of medicine at the Keck School of Medicine of USC. "We want to give patients as good a second chance at cure as possible."
Acute promyelocytic leukemia, or APL, is only one of a wide variety of types of leukemia, Douer explains. APL is rare-making up only 10 percent of all acute myeloid leukemias-and Douer estimates that physicians only see about 1,500 cases in the United States every year. But its rarity makes it no less devastating for those diagnosed with it.
"In this leukemia, patients experience bleeding not only in the skin and mouth but also into organs, and this can be life-threatening. The onset can be very sudden," says Douer, a national expert on the disease. Without treatment, APL is almost always fatal.
He is quick to point out the good news, though: Within the last decade, the cure rate for APL has doubled, and it is now considered the most treatable acute leukemia in adults. Today, about 70 percent of patients are cured of the cancer. Once patients survive three years free of the cancer, they are considered safe, Douer says.
At the heart of the improved cure rate: a naturally occurring form of vitamin A, called all-trans retinoic acid. When administered before or during chemotherapy, this remedy effectively battles the cancer in many patients. Young adults and middle-aged patients, as well as those with white blood cell counts below a certain threshold, generally have a better prognosis.
After patients finish treatment, USC/ Norris lab technologist Laleh Ramezan routinely analyzes patients' bone marrow using what is called the RT-PCR test, a remarkable technology so sensitive it can find one abnormal cell among 10,000 cells. A positive result at the molecular level means a patient is highly likely to experience a clinical relapse (experiencing symptoms of leukemia or a positive blood test) within the next four to eight months-even if the patient looks and feels fine, Douer says.
In the hopes that treating such patients early might give them a better second chance at beating the leukemia, Douer is offering them the injected drug Trisenox, or arsenic trioxide, as part of a clinical trial. Hematologist Martin Tallman, M.D., of Northwestern University, is co-principal investigator.
When patients show signs of molecular relapse, Douer gives them the option of getting a five-week cycle of Trisenox, which was approved by the U.S. Food and Drug Administration in September 2001 for treating APL patients who have gone into a clinical relapse. Patients can be offered more cycles if they still test positive after such treatment, Douer says.
"If this works, and patients clearly benefit from early administration of this drug, it will be a big advance," Douer says. Today, physicians have no standard of treatment for APL when patients remain positive for leukemic cells; they may undergo further chemotherapy or undergo a bone marrow transplant, but such procedures carry their own risks. Although arsenic trioxide causes side effects in some patients, they may be managed, he says.
Douer seeks to enroll 20 patients in the trial. Patients not only may come from USC/Norris, but also from the community, he notes.
The trial may be of particular benefit to people in Southern California, where Latinos make up a sizeable part of the population.
Here is why: Over the past decade, Douer and his colleagues at LAC+USC Medical Center began noticing that APL made up more than 10 percent of the leukemia cases they saw. It seemed a statistical anomaly. But upon scrutinizing patient records, the researchers discovered that APL-while still a rare disease-accounted for about 35 percent of the acute myeloid leukemias diagnosed among Latinos at LAC+USC.
Inspired with the discovery, Douer and collaborator Susan Preston-Martin, Ph.D., professor of preventive medicine at the Keck School, studied the Los Angeles Cancer registry. They confirmed that 24 percent of Latinos with acute myeloid leukemia have APL, while APL made up only 9 percent of the acute myeloid leukemia cases in non-Latinos.
Douer set out to track down APL's roots, and soon learned that in the Andean nation of Peru, APL is the most common type of acute leukemia. Now he is collaborating with a Peruvian colleague, Sergio Santillana, M.D., at the Instituto de Enfermedades Neoplásicas in Lima to study this blood cancer.
Preliminary data looking at APL patients in Los Angeles and Lima show that there may be a particular abnormal gene arrangement accounting for many of the APL cases in Latinos, and in particular, those of mestizo, or mixed European-indigenous origin.
To understand the importance of genetics in APL is to understand the very nature of the disease.
The phenomenon of chromosome translocation, which happens within human genetic material, sets APL into motion. For reasons scientists do not entirely understand, parts of chromosomes 15 and 17 switch places. The resulting abnormal chromosomes lead to problems in the growth cycle of healthy blood cells, leading to an accumulation of immature white blood cells, uncontrolled bleeding and an inability to fight off infection.
"This unique abnormality, resulting in the rearrangement of specific genes, underlies the cause of the disease," says Douer. "This specific abnormality is not seen in any other cancer. We have no idea why people get it.
"But we do have treatments today so that most people are PCR negative-free from the malignant cells, as far as we are capable of seeing-after treatment."
Patients now being treated for APL or who completed their initial treatment within the last three years may consider asking their doctor if they are eligible to participate in RT-PCR testing or in the Trisenox trial. For information on the trial, call (323) 226-4585.
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