CHILDREN WITH ALL FAILING INDUCTION CHEMOTHERAPY

A "remarkable collaborative effort" has provided insight into a rare group of patients — children with acute lymphoblastic leukemia (ALL) who fail induction chemotherapy. Because they comprise only 2% to 3% of the total patient population, 14 centers on 3 continents pooled their data, in the largest study to date, to analyze outcomes.

The results, which appear in the April 12 issue of the New England Journal of Medicine,show a high degree of heterogeneity. The researchers offer a rather surprising conclusion that could lead to a change in clinical practice.

"In the past, when patients did not respond to induction therapy, we thought that they wouldn't respond to any other therapy, so we would go on to stem cell transplants," said corresponding author Ching-Hon Pui, MD, chair of the Department of Oncology at St. Jude Children's Research Hospital in Memphis, Tennessee. "But we have been pleasantly surprised by these results."

The results show that one subgroup of patients who fail induction therapy — children younger than 6 years who have B precursor leukemia (about 25% of the total) — respond better to further chemotherapy than to transplantation.

"I believe that the evidence is strong enough to use this new approach to therapy," Dr. Pui told Medscape Medical News.

"This may substantially affect current practice," writes Karen Rabin, MD, PhD, from the Texas Children's Cancer Center, Baylor College of Medicine, in Houston, in an accompanying editorial.

"Until now, children with ALL with induction failure have generally been considered to be an extremely high-risk group, and most pediatric oncologists have viewed stem cell transplantation as the best treatment option," Dr. Rabin told Medscape Medical News.

This study "demonstrates a range of outcomes among children with induction failure, and suggests that treatment with chemotherapy without stem cell transplantation may be appropriate in some cases," she said.

International Collaboration

"Induction failure is rare, occurring in only 2% to 3% of all patients, but it constitutes one of the most unfavorable outcomes in pediatric ALL," write the researchers, headed by Martin Schrappe, MD, from the Department of Pediatrics at the Christian-Albrechts University Kiel in Germany.

They collaborated with other centers in Europe, the United States, and Japan to collect sufficient data on this rare patient population.

In total, 14 centers collaborated and pooled data on 44,017 patients (age, 0 to 18 years) with newly diagnosed ALL who were treated from 1985 to 2000. From this group, the team identified 1014 patients (2.4%) who failed induction therapy.

Induction treatment is usually carried out with 3 or 4 drugs, Dr. Pui explained, including steroids, vincristine, asparaginase, and usually danorubicin.

The analysis found that overall, patients who failed induction therapy had poor outcomes, with a 10-year survival rate estimated to be only 32%.

In contrast, children who respond to induction therapy and then go on to transplant or continuation chemotherapy have a very high chance of cure — around 80% to 90% in developed countries, Dr. Pui told Medscape Medical News. At St. Jude, the 10-year survival for the overall ALL population (which includes induction failures) is now 91%, he said.

These results show that the patients who failed induction were a very heterogeneous group, some patients fared better than others, and outcomes depended on subsequent treatment.

The team found that pediatric ALL patients who have T cell leukemia and who fail induction therapy (about 38% of all the induction-failure patients in this study) appear to have a better outcome with allogeneic stem cell transplantation than with chemotherapy. Conversely, patients with precursor B-cell leukemia without other adverse features (about 25% of the total) appear to have a better outcome with chemotherapy.

Another 13% of patients who failed induction therapy had the Philadelphia chromosome. They were not included in this analysis because targeted drugs such as imatinib (Gleevec) have led to dramatic improvements in their outcome.

Subgroup With Best Outcome

The patients with the best outcomes were those with precursor B-cell leukemia who were either younger than 6 years or had high hyperdiploidy, the researchers report. This subgroup had a 10-year survival rate of 72% when treated with chemotherapy alone.

This is starting to approach the 80% to 90% cure rate for ALL overall, said Dr. Pui, and is strikingly better than the 32% rate seen for the total induction-failure population.

"Our analysis showed no benefit of allogeneic transplantation in patients younger than 6 years of age who had precursor B-cell ALL and induction failure and no high-risk cytogenetic features," the researchers write.

This observation has "considerable clinical implications, since transplantation is generally considered to be the standard of care for such patients," they add.

"Given this result, I would not automatically recommend transplantation for children 1 to 6 years of age with precursor B-cell leukemia and no other high-risk features, as we have done in the past," Dr. Pui explained. "I would give these patients consolidation treatment with high-dose methotrexate and mercaptopurine to evaluate the response. For patients who respond well to this treatment, I would continue with intensive chemotherapy, and would reserve transplantation for patients who do not respond well."

Dr. Schrappe added in a statement that "these results tell us that induction failure should no longer be considered an automatic indication for a transplant."