Acute lymphocytic leukemia in children is the first common cancer to be cured by chemotherapy, “but we’re still losing half of our patients because of the disease’s resistance to treatment,” Donald Pinkel said this week when he delivered the annual David A. Karnofsky Memorial Lecture at the meeting of the American Society of Clinical Oncology in Washington.
The half who are being cured are those who receive the optimal treatment in the most advanced facilities. “Most children with the disease around the world do not benefit from these advances,” said Pinkel, now at Milwaukee Children’s Hospital. “The treatment is too complex and is not accessible to them.
“The challenge we face is to solve the problem of resistant leukemia by investigating the biology of leukemia as it occurs in children, and then develop effective treatment that is simple and safe.”
Pinkel, who for several years was medical director of St. Jude Children’s Hospital, discussed studies at St. Jude’s which involved attempts to improve on treatment that is producing long term remissions in 50% or more of ALL patients. Complete remission is the initial treatment objective, through chemotherapy. Prophylatic irradiation of the. central nervous system is then administered, followed by remission maintenance chemotherapy.
The fact that this regimen, in various combinations of drugs, produces 50% long term remissions suggests “there is one group of children in which we can’t control the disease, another group in which control is achieved but relapse occurs, and another group in which we can eradicate the disease,” Pinkel said.
“What about the other half? Why can’t we save them?” Pinkel asked. The major reason, he suggested, is the acquired resistance of leukemia to treatment. “There are several classical ways to try to overcome this resistance:”
1. Increase dosage. He cited studies which demonstrated that acquired resistance cannot be overcome by higher doses.
2. Administration of high doses of drugs in the early weeks of remission. But again, studies indicated there is no significant benefit with this method compared with standard doses.
3. Intensive chemotherapy early in remission with agents not used to induce remission. This also did not offer any advantage.
4. Addition of more drugs to the regimen. Comparing single drug with two, three and four drug combinations, the results turned out to be the same, Pinkel said. “You can’t assume that more drugs are
better, or that higher doses are better.”
So what is next?
“We must restudy the disease, learn more about the biology of leukemia. If we gain a better understanding of it, we can improve the treatment.”
As examples, Pinkel said that studies of the biology of ALL in the last five years reveal that there is a relationship between the types of cell surface markers and responsiveness to therapy-“one type will be responsive to cyclophosphamide, another to methotrexate. One type of cell might have more receptors for certain drugs, with better absorption.”
