Better Options for Children with Difficult-to-Treat Leukemia
Some young patients with forms of acute lymphoblastic leukemia (ALL) that do not respond to current treatments may have new options, according to two clinical trials published online October 5 in the Journal of Clinical Oncology. Both trials were led by the NCI-supported Children’s Oncology Group (COG), and each yielded impressive results for patients with difficult-to-treat cancers.
In the first study, children and young adults with an uncommon type of ALL linked to a genetic mutation known as the Philadelphia chromosome (Ph chromosome) lived longer without their disease coming back when the drug imatinib (Gleevec) was added to conventional intensive chemotherapy. The Ph chromosome causes leukemia cells to produce a fusion protein called Bcr-Abl, which is blocked by imatinib, a type of drug called a tyrosine kinase inhibitor (TKI). While less than 5 percent of childhood ALL cases are linked to the Ph chromosome, only about 40 percent of patients with this form of the disease are cured by conventional therapy.
COG researchers led by Dr. Kirk Schultz of British Columbia Children’s Hospital in Vancouver, Canada, treated 92 patients aged 1 to 21 with Ph-chromosome-positive ALL in five cohorts, with each successive cohort receiving a longer period of imatinib therapy. They compared patient outcomes with those for similar patients treated with standard chemotherapy in previous COG trials. Among patients who received the most imatinib (280 continuous days), 80.5 percent were alive and had not had a relapse after 3 years. Only about 35 percent of patients who received standard therapy in previous trials achieved this outcome.
“The remarkable improvement Dr. Schultz and his colleagues saw in early outcomes for children receiving imatinib plus chemotherapy provides strong evidence that children with Ph-chromosome-positive ALL should receive treatment that includes a TKI such as imatinib,” commented Dr. Malcolm Smith, a pediatric cancer specialist in NCI’s Cancer Therapy Evaluation Program.
Longer follow-up is needed to ensure that this outcome is sustained, and the results should be confirmed in a larger group of patients, said Dr. Smith. Further research is needed, he added, to determine whether imatinib or a “second generation” TKI, such as dasatinib, is more effective when added to chemotherapy for children with Ph-chromosome-positive ALL.
Dr. Crystal Mackall, chief of NCI’s Pediatric Oncology Branch, noted that “of five dosing cohorts in this study, only patients receiving the highest exposure to imatinib experienced a benefit––yet, remarkably, this was not associated with any detectable increase in toxicity. It is an unusual occurrence in oncology to see benefit with no increase in toxicity, but this is exactly the type of outcome that is to be expected when effective targeted therapies are incorporated into treatment regimens.”
In the second study, adolescents and young adults aged 16 to 21 with ALL who were treated with an intensive multi-drug pediatric chemotherapy regimen lived longer and remained cancer-free longer than patients treated with adult therapies. Patients in this age group tend to have poorer outcomes than younger children with ALL.
Dr. James B. Nachman of the University of Chicago Children’s Hospital and his COG colleagues randomly assigned 164 adolescents and young adults with ALL who responded rapidly to induction therapy to receive a further course of either standard or intensified chemotherapy with multiple drugs, including vincristine, pegylated asparaginase, and intravenous methotrexate.
Among rapid responders to induction therapy who went on to receive intensified chemotherapy, 83 percent were alive after 5 years and 82 percent had not had a relapse. Among rapid responders treated with standard-intensity chemotherapy, 76 percent were alive after 5 years and 67 percent had not had a relapse.
These findings add to data from previous studies showing that relapse-free survival is 20 percent to 30 percent better for young adults with ALL who are treated using pediatric regimens rather than adult regimens, the authors wrote. The reason for this difference is unknown. Potential explanations include the distinctive way in which pediatric-type regimens combine specific types of leukemia agents, said Dr. Smith. An ongoing trial in which young adult patients with ALL are being treated with this COG pediatric-type regimen by medical oncologists may shed further light on this question.
Dr. Nachman and colleagues further noted that when a pediatric-type regimen is used for this patient population, routine use of stem-cell transplantation in first remission seems unwarranted.
This study, Dr. Smith said, offers convincing evidence that patients in the 16 to 21 year age range with ALL should be treated with a pediatric-type ALL regimen. “Several studies from across the world comparing outcomes for patients in this age group who are treated with adult versus pediatric regimens have uniformly shown that the pediatric ALL regimens perform better,” he added.