Expanding Clinical Trial Networks in Pediatric Acute Lymphoblastic Leukemia

Treatment of pediatric acute lymphoblastic leukemia (ALL) is one of the major successes in cancer medicine. Fifty years ago, this disease was incurable. Today, a child diagnosed with ALL in highincome countries in North America, Western Europe, Australia, New Zealand or Japan has a better than 90% chance of surviving 5 years, with expected cure rates above 85%. However, most children who develop ALL do not live in one of these countries, all of which have highly developed health care systems; they live in countries with fewer resources. A major challenge is thus to improve cure rates for children with ALL throughout the world. Although difficult, this challenge is feasible because the gains in childhood ALL survival in high-income countries have occurred mostly through optimizing use of an existing panel of drugs. Except for the pegylated asparaginase products now used in treatment regimens of the major North American and European cooperative groups, these drugs are readily available worldwide and not particularly expensive. In addition, effective ALL treatment can be provided with relatively simple diagnostic tests and does not involve surgery. Because of this, many but certainly not all countries have access to the tools necessary to deliver highly effective ALL therapy. However, ALL chemotherapy regimens are complex, require meticulous supportive care to minimize the risk of treatment-related mortality, and typically last 2 to 3 years. Thus, highly trained medical specialists and a dedicated team of nurses and other health care professionals are needed to implement effective ALL treatment programs. The gains in ALL survival observed in high-income countries have been possible because of high (in some cases nearly populationbased) enrollment in clinical trials by cooperative groups and large institutions, with the two largest being the Children’s Oncology Group (COG) based in North America and the International BerlinFrankfurt-Munster (BFM) group based in Western Europe. In the article that accompanies this editorial, Stary et al describe results of more than 5,000 children with ALL enrolled onto the International BFM Intercontinental trial (ALL IC-BFM) between 2002 and 2007. Fifteen countries participated in the ALL IC-BFM 2002 trial, contributing from 36 to 1,270 patients, each. Using World Bank definitions almost all of the 15 are classified as high-income countries, on the basis of gross national income (GNI) per capita of more than $12,616 US, although several countries (Cuba, Serbia, Ukraine) are classified as upper middle–income countries (GNI per capita $4,086-$12,615). However, the GNI per capita for most of these countries is less than $20,000 as compared with $35,000 to $50,000 (or more) for the United States, Canada, Japan, Australia, and most countries in Western Europe, and the medical care systems and medical research infrastructure generally have fewer resources. Countries were selected for participation in the ALL IC-BFM 2002 trial if they were part of the BFM network, had achieved ALL event-free survival (EFS) rates greater than 65% in recent years, and did not have access to the technology to consistently perform the minimal residual disease studies required for participation in the Associazione Italiana Ematologia Oncologia Pediatrica (AEIOP) BFM ALL 2000 trial. The IC-BFM investigators report 5-year EFS and overall survival (OS) rates of 74% and 82%, respectively. These outcomes are impressive, although not quite as good as rates seen in contemporaneous BFM and COG trials that had risks of death about half that observed in the ALL IC-BFM 2002 trial. Importantly, the cumulative incidence of relapse was relatively similar to that seen in the ALL-BFM 95 and AIEOP-ALL 95 trials, which served as the basis for the regimens used in this study. In contrast, the toxic mortality rate (induction deaths and deaths in remission) was higher than that observed in BFM and COG trials, suggesting that a main focus of future research efforts for this network should be on implementing changes to reduce treatment-related deaths. Given the higher rate of treatment-related mortality, the fact that approximately 10% of patients met criteria to undergo hematopoietic stem-cell transplantation in first remission (although only approximately 3% actually did so) is worrisome and suggests that those criteria might be reconsidered. There was countryspecific variability in EFS, OS, relapse rates, and toxic mortality rates, but the authors indicate that the results were generally better in each country than prior EFS/OS rates. This means that many lives were saved through participation in this trial. More data on the outcomes by country and comparisons to prior results would have been a useful addition to this report. Equally important to the survival improvements, this group has demonstrated how a clinical trial network with outstanding rates of timely data collection can be established in 15 countries located on three continents. A critical feature of the ALL IC-BFM 2002 trial was that it included randomized questions in three different risk groups defined on the basis of clinical features and conventional measures of early treatment response. The trial explored variations on the protocol II (delayed intensification) phase, first developed by Hansjorg Riehm (one of the authors of the report by Stary et al) and his colleagues in the BFM in the 1970s, which is now a critical component of BFM and COG ALL therapy. None of the variations improved EFS, but the fact that this group undertook and completed a large randomized clinical JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 3 JANUARY 2