Imatinib Added to Chemotherapy Keeps Disease in Check for Longer in Children with Rare Form of Acute Lymphoblastic Leukemia
The addition of the targeted drug imatinib to chemotherapy for children with an uncommon form of acute lymphoblastic leukemia (ALL) dramatically improved the length of time the disease remained in remission, compared with that in children who received standard chemotherapy in previous clinical trials. The finding provides strong evidence for adding a targeted drug like imatinib to the treatment of children with this form of ALL.
Journal of Clinical Oncology, published online ahead of print, October 5, 2009 (see the journal abstract).
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. In about one in 20 patients, an abnormal chromosome is found in the blood-forming cells of the bone marrow. Called the Philadelphia (Ph) chromosome, it produces an abnormal protein that leads to the overproduction of immature, poorly functioning white blood cells. This form of ALL is known as Ph-positive ALL. Children with Ph-positive ALL tend to have a poorer long-term outlook than do other children with ALL.
The drug imatinib (Gleevec) is a targeted therapy that blocks the abnormal protein produced by the Ph chromosome and has limited effects on normal cells.
Ninety-two children and young adults, ages 1 to 21, who had Ph-positive ALL participated in the study. All of the patients received at least two rounds of multi-drug chemotherapy. After two rounds of chemotherapy, patients who had a matched sibling donor received bone marrow transplants.
For those without matched sibling donors, doctors gave imatinib to five successive groups of patients, with each group getting the drug for a longer period of time. Doctors assessed the patients in each group for adverse effects before giving the drug for a longer time to the next group. The fifth group took imatinib for 280 days. Patients who had bone marrow transplants took imatinib for six months after the transplant.
Doctors compared the outcomes in each group of patients with those for similar patients with Ph-positive ALL who received standard chemotherapy in previous clinical trials. The study was conducted by investigators with the Children's Oncology Group, one of 12 clinical trials cooperative groups supported by the National Cancer Institute. The lead investigator was Kirk R. Schultz, M.D., of British Columbia Children's Hospital in Vancouver, Canada.
Among patients who received imatinib for 280 days, 80.5 percent were alive and had not had a relapse after three years. In previous trials, only about 35 percent of patients who received standard chemotherapy achieved this outcome. The addition of imatinib to chemotherapy caused no serious side effects.
Longer follow-up is needed to be sure that the addition of imatinib to chemotherapy not only postpones relapse but also leads to long-term disease-free survival, said Malcolm Smith, M.D., Ph.D., a pediatric cancer specialist with NCI's Cancer Therapy Evaluation Program. The study's findings should also be confirmed in a larger group of patients, Dr. Smith continued.
"The remarkable improvement in early outcomes for children receiving imatinib plus chemotherapy provides strong evidence that all children with Ph-positive ALL should receive treatment that includes a targeted drug like imatinib," said Dr. Smith. He added that a trial is now underway to test the effectiveness of another targeted drug, dasatinib, in children with Ph-positive ALL. Dasatinib is a newer, potentially more powerful drug that blocks the same abnormal protein blocked by imatinib.
Dr. Crystal Mackall, chief of NCI's Pediatric Oncology Branch, noted that, of the five groups of patients treated with imatinib in this study, only those who took imatinib for the longest time benefited from the drug. "Yet, remarkably, there was no increase in adverse effects," she said. "In cancer treatment it's unusual to see benefit with no increase in adverse effects. But this is exactly the type of outcome that is to be expected when effective targeted therapies are added to standard chemotherapy."