Almost 90 percent of children with acute lymphoblastic leukemia (ALL) can be cured today with the use of glucocorticoids as induction therapy. The glucocorticoids prednisone and dexamethasone have been compared directly as induction therapy in several randomized clinical trials, but it has not been clear whether one is superior to the other.
The answer may depend, according to a recent report from the AIEOP-BFM ALL 2000 trial (Associazione Italiana di Ematologia e Oncologia Pediatrica–Berlin-Frankfurt-Munster (AIEOP-BFM), on which part of “superior” one means.
In efficacy, the use of dexamethasone in the induction phase of treatment for pediatric ALL in AIEOP-BFM ALL 2000, rather than standard prednisone, led to a one-third reduction in the relapse rate—the 5-year cumulative incidence of relapse was 15.6 percent for prednisone versus 10.8 percent for dexamethasone. But in terms of safety, dexamethasone also increased mortality before complete response plus mortality in first complete response related to treatment, a total of 2.5 percent versus 0.9 percent for prednisone. And 5-year overall survival was virtually identical: 90.3 percent for dexamethasone versus 90.5 percent for prednisone. The data were published recently in Blood (127;2101-2112).
First author Anja Möricke, MD, Department of Pediatrics at the University Medical Center Schleswig-Holstein, Kiel, Germany, reported that the only overall survival benefit seen with dexamethasone was in the subset of patients with T-cell ALL and good early treatment response.
The study included 3,720 children and adolescent patients from age 1 to 17 years diagnosed with ALL in one of the 127 participating study centers in Austria, Germany, Italy, and Switzerland.
Patients in this open-label study were randomly assigned to receive standard glucocorticoid therapy with prednisone (60 mg/m2 per day) or dexamethasone (10 mg/m2 per day) as part of a four-drug induction therapy. Between July 1, 2000 and July 31, 2006, 1,853 patients were randomly assigned to the dexamethasone arm and 1,867 patients to the prednisone arm. The primary outcome was event-free survival.
ALL Study Results
Relapse Rates: The 5-year cumulative incidence of relapse was 10.8 percent in the dexamethasone study arm versus 15.6 percent in the prednisone arm group, with the largest effect on extramedullary relapses.
Event-Free Survival: The benefit of dexamethasone was partially counterbalanced by a significantly higher induction-related death rate, resulting in 5-year event-free survival rates of 83.9 percent for dexamethasone and 80.8 percent for prednisone.
Overall Survival: No difference was seen in 5-year overall survival—dexamethasone 90.3 percent versus prednisone 90.5 percent.
However, there was a significant overall survival benefit from dexamethasone in patients with T-cell ALL who had a good response to the prednisone pre-phase, 91.4 percent for dexamethasone versus 82.6 percent for prednisone.
“In patients with precursor B-cell ALL and good response to the prednisone pre-phase, survival after relapse was significantly worse if patients were previously assigned to the dexamethasone arm,” the researchers reported.
The study's senior author, Martin Schrappe, MD, Chair of General Pediatrics at the University Medical Center Schleswig-Holstein, noted that prednisone was used in pre-phase because its prognostic value has been prospectively determined in earlier trials of the ALL-BFM group. Such data are not available for dexamethasone, he said; therefore, it would be a major mistake to replace prednisone with dexamethasone without such data.
“We had hoped that patients who did not respond adequately to prednisone in the pre-phase would have a benefit from dexamethasone, but this was not the case.”
Life-threatening events in the dexamethasone arm included bacterial (primarily gram-negative rods) as well as fungal (primarily molds) infections. There was also a higher incidence of life-threatening neurologic and gastrointestinal complications in dexamethasone-treated patients.
Primary Endpoint Choice
The researchers said their data suggest trials using event-free survival as the primary endpoint to evaluate front-line treatments may be influenced by survival after relapse.
“However, using overall survival as the only endpoint bears the risk that success or failure of the relapse treatment might distort the effect of the tested therapy,” they added. An overall-survival endpoint would also require higher patient numbers to reach sufficient statistical power, and many pediatric ALL trials would be underpowered—“as is the case in our trial.”
The authors acknowledge using event-free survival as a primary endpoint to evaluate a front-line treatment is a limitation of this study, but they also point out using overall survival as the only endpoint would mean that efficacy of treatments used for relapse might have biased the effect of dexamethasone.
In a commentary in Blood accompanying the study (2016;127:2049-2051) by Stephen P. Hunger, MD, Chief of the Division of Oncology at the University of Pennsylvania and Director of the Center for Childhood Cancer Research, Children's Hospital of Philadelphia, noted that the one-third reduction in relapse risk with use of dexamethasone is the greatest reduction seen in BFM trials in the past 40 years.
“On balance, dexamethasone is the drug of choice...right?” Hunger wrote. “Not so fast—the devil is in the details, and the results of this study have complex implications for how we think about ALL therapy in the 21st century.”
Hunger speculates dexamethasone improved event-free survival but not overall survival because more patients treated initially with prednisone were salvaged following relapse.
“This makes sense for two reasons—first, dexamethasone had its greatest effect on preventing extramedullary relapses, which are much more salvageable than marrow relapses. And second, many of the relapses prevented by dexamethasone were those that occurred after completion of therapy, and [it is known that] children with relapsed ALL are much more curable when relapse, even marrow relapse, occurs after completion of therapy than when relapse occurs during primary therapy.”
The relapses prevented were the ones that could not be salvaged easily with current therapeutic approaches, Hunger wrote. “For this group, dexamethasone is clearly better than prednisone.”
So although questions still remain concerning how to optimally use glucocorticoids in pediatric ALL therapy, Hunger said, “a fundamental lesson of this trial is the need to identify interventions that prevent early bone marrow relapses. Such interventions will likely improve survival, which is the ultimate goal of ALL therapy.”
Robert H. Carlson is a contributing writer.