TY - JOUR
T1 - Validation of Minimal Residual Disease as Surrogate Endpoint for Event-Free Survival in Childhood Acute Lymphoblastic Leukemia
AU - Galimberti, Stefania
AU - Devidas, Meenakshi
AU - Lucenti, Ausiliatrice
AU - Cazzaniga, Giovanni
AU - Möricke, Anja
AU - Bartram, Claus R.
AU - Mann, Georg
AU - Carroll, William
AU - Winick, Naomi
AU - Borowitz, Michael
AU - Wood, Brent
AU - Basso, Giuseppe
AU - Conter, Valentino
AU - Zimmermann, Martin
AU - Suciu, Stefan
AU - Biondi, Andrea
AU - Schrappe, Martin
AU - Hunger, Stephen P.
AU - Valsecchi, Maria Grazia
N1 - Funding Information:
This work was partially supported by the Associazione Italiana Ricerca sul Cancro AIRC Investigator Grant (grant no. 2013-14634 to MGV).
Publisher Copyright:
© The Author(s) 2018.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - Background: The aim of this study was to assess whether minimal residual disease (MRD) at the end of induction front-line treatment can serve as a surrogate endpoint for event-free survival (EFS) in childhood B-lineage acute lymphoblastic leukemia. Methods: The analysis was based on individual data of 4830 patients from two large phase III trials that asked a randomized question on the effect of different corticosteroids (dexamethasone vs prednisone) during induction chemotherapy on EFS. The association between MRD classified in three ordered categories [negative = 0, low positive = (>0 and <5 × 10-4), and positive = (≥5 × 10-4)] and EFS at the individual and trial levels was evaluated with the meta-analytic approach based on the Plackett copula model. Centers within trial were grouped according to geographical area, and a total of 28 units were identified for the analysis. Results: MRD at the end of induction was a poor surrogate for treatment effect on EFS at the trial level, with R2trial = 0.09 (95% confidence interval [CI] = 0.00 to 0.29), whereas at the individual level it was strongly associated with EFS, with an odds ratio of 3.90 (95% CI = 3.35 to 4.44) of failure for patients with higher compared with lower MRD levels. Additional sensitivity and relevant subgroup analyses confirmed these findings at both trial- and patient-level association. Conclusions: Although MRD is a robust biomarker highly predictive of outcome for individual patients, clinicians and regulatory bodies should be cautious in using early MRD response in the context of complex multiagent acute lymphoblastic leukemia therapy as an early surrogate endpoint to predict the effect of a randomized treatment intervention on long-term EFS.
AB - Background: The aim of this study was to assess whether minimal residual disease (MRD) at the end of induction front-line treatment can serve as a surrogate endpoint for event-free survival (EFS) in childhood B-lineage acute lymphoblastic leukemia. Methods: The analysis was based on individual data of 4830 patients from two large phase III trials that asked a randomized question on the effect of different corticosteroids (dexamethasone vs prednisone) during induction chemotherapy on EFS. The association between MRD classified in three ordered categories [negative = 0, low positive = (>0 and <5 × 10-4), and positive = (≥5 × 10-4)] and EFS at the individual and trial levels was evaluated with the meta-analytic approach based on the Plackett copula model. Centers within trial were grouped according to geographical area, and a total of 28 units were identified for the analysis. Results: MRD at the end of induction was a poor surrogate for treatment effect on EFS at the trial level, with R2trial = 0.09 (95% confidence interval [CI] = 0.00 to 0.29), whereas at the individual level it was strongly associated with EFS, with an odds ratio of 3.90 (95% CI = 3.35 to 4.44) of failure for patients with higher compared with lower MRD levels. Additional sensitivity and relevant subgroup analyses confirmed these findings at both trial- and patient-level association. Conclusions: Although MRD is a robust biomarker highly predictive of outcome for individual patients, clinicians and regulatory bodies should be cautious in using early MRD response in the context of complex multiagent acute lymphoblastic leukemia therapy as an early surrogate endpoint to predict the effect of a randomized treatment intervention on long-term EFS.
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U2 - 10.1093/JNCICS/PKY069
DO - 10.1093/JNCICS/PKY069
M3 - Article
C2 - 31360884
AN - SCOPUS:85103191777
SN - 2515-5091
VL - 2
JO - JNCI Cancer Spectrum
JF - JNCI Cancer Spectrum
IS - 4
M1 - pky069
ER -