Pediatric patients with acute lymphocytic leukemia (ALL) often receive induction therapy that includes the glucocorticoid prednisone; however, research has shown that dexamethasone may have higher anti-leukemic potency compared with prednisone, potentially leading to fewer relapses and improved survival.
In a recent Blood article, Anja MÃ¶ricke, from the Department of Pediatrics at the Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, in Germany, and colleagues reported results from the open-label AIEOP-BFM ALL 2000 trial, which compared induction therapy with dexamethasone versus prednisone in 3,720 pediatric ALL patients.
Patients (age range = 1-17 years) who were diagnosed with ALL at one of the 127 participating centers in Austria, Germany, Italy, and Switzerland were included in this collaborative trial and stratified into risk cohorts:
- High risk, meaning patients met at least one of the following criteria:
- Prednisone poor-response
- No complete response (CR) on day 33
- Evidence of t(9;22) or t(4;11)
- Minimal residual disease (MRD) load of 5×10-4 or more on day 78
- Medium risk, meaning patients met at least one of the following criteria:
- Absence of high-risk designation
- Positive MRD on day 33 and/or day 78 but at a level less than 5×10-4 on day 78
- Not classifiable by MRD
- Standard risk, meaning patients had negative MRD status on day 33 and day 78
After a seven-day prednisone pre-phase, patients were randomized to receive either dexamethasone 10 mg/m2 per day (experimental therapy; n=1,853) or prednisone 60 mg/m2 per day for three weeks followed by tapering doses (standard therapy; n=1,867) as part of their induction therapy.
After a median follow-up of 8.8 years, rates of event-free survival (EFS; the study's primary endpoint) were significantly higher for patients receiving dexamethasone compared with prednisone (hazard ratio [HR] = 0.85; 95% CI 0.73-0.98; p=0.024), though no difference was seen between the two cohorts in overall survival (OS) rates (HR=1.05; 95% CI 0.87-1.27).
Five-year cumulative incidences of relapse were 10.8 percent in the dexamethasone cohort and 15.6 percent in the prednisone cohort (p<0.0001), leading to a five-year EFS rate of 83.9 percent for patients treated with dexamethasone and 80.8 percent for those treated with prednisone (p=0.024; TABLE). However, the dexamethasone cohort also experienced a significantly higher induction-related death rate compared with the prednisone cohort (2.5% vs. 0.9%; p=0.00013).
"Despite treatment with a protocol that results in better EFS despite similar OS, it is counterbalanced by a large proportion of patients who do not benefit from the intensified first-line treatment, but are subjected to the risk of more toxicity," Dr. MÃ¶ricke and colleagues wrote.
The majority of the life-threatening and fatal adverse events (AEs) were related to infection (64% and 69%, respectively). The incidence of these infections was also significantly higher in dexamethasone-treated patients than in prednisone-treated patients: 124 (7.0%) versus 53 (2.7%) for life-threatening AEs (p<0.0001) and 42 (2.4%) versus 19 (1.0%) for fatal AEs (p=0.0011).
The researchers also performed a retrospective analysis of the clinical risk subgroups finding that, among patients with T-ALL, dexamethasone provided a significant survival benefit over prednisone. In patients with B-ALL who had good responses in the prednisone pre-phase stage, dexamethasone reduced the incidence of salvageable relapses, resulting in inferior survival after relapse.
Limitations of this analysis include using EFS as a primary endpoint to evaluate front-line treatments; using OS as the only endpoint, the researchers noted, would introduce risk that success or failure of treatments used for relapsed disease might distort the effect of the tested therapy.
"Dexamethasone in induction was clearly more effective than prednisone in terms of relapse reduction if given in the treatment schedule," Dr. MÃ¶ricke told ASH Clinical News. "And, in context of the AIEOP-BFM ALL 2000 trial, it was also much more toxic, leading to a higher rate of induction-related severe and fatal toxic events."
The results indicate that dexamethasone should not be used in the childhood ALL population and should only be used with caution in adult patients with ALL, according to Dr. MÃ¶ricke.
"Since chemotherapy tolerance is lower in adult and adolescent patients – who generally experience more toxic effects compared with pediatric patients – we would be cautious with a general recommendation to treat adult patients with dexamethasone instead of prednisone in induction," she said. However, the potential benefit of dexamethasone for adult ALL patients may depend on a number of other factors including the underlying chemotherapy regimen, the biologic ALL subset or clinical features."
MÃ¶ricke A, Zimmermann M, Valsecchi MG, et al. Dexamethasone vs. prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood. 2016 February 17. [Epub ahead of print]
|TABLE. Events in Each Treatment Cohort|
|Dexamethasone||Prednisone||p Value||HR (95% CI)|
|Death before CR||37 (2%)||15 (0.8%)||0.0019||2.49 (1.36-4.53)|
|Non-response||3 (0.2%)||6 (0.3%)||0.51||0.5 (0.13-2.02)|
|Death in first CR||42 (2.3%)||32 (1.7%)||0.24||1.33 (0.84-2.11)|
|All relapses||229 (10.8%)||323 (15.6%)||<0.0001||0.7 (0.59-0.83)|
|158 (7.6%)||204 (9.7%)||0.013||0.77 (0.62-0.95)|
|19 (0.9%)||37 (1.9%)||0.019||0.51 (0.3-0.9)|
|9 (0.4%)||23 (1.1%)||0.016||0.39 (0.18-0.84)|
Combined CNS/BM involved
|15 (0.7%)||30 (1.5%)||0.027||0.5 (0.27-0.92)|
Combined BM/other (without CNS)
|17 (0.8%)||21 (1%)||0.52||0.8 (0.42-1.52)|
|11 (0.4%)||8 (0.4%)||0.47||1.37 (0.55-3.41)|
|Secondary neoplasms||30 (1%)||25 (0.8%)||0.47||1.18 (0.7-2.01)|
|All events||341 (16.1%)||401 (19.2%)||0.024||0.85 (0.73-0.98)|
|BM = bone marrow; CNS = central nervous system|