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Validation of Minimal Residual Disease as Surrogate Endpoint for Event-Free Survival in Childhood Acute Lymphoblastic Leukemia

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...

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Autores principales: Galimberti, Stefania, Devidas, Meenakshi, Lucenti, Ausiliatrice, Cazzaniga, Giovanni, Möricke, Anja, Bartram, Claus R, Mann, Georg, Carroll, William, Winick, Naomi, Borowitz, Michael, Wood, Brent, Basso, Giuseppe, Conter, Valentino, Zimmermann, Martin, Suciu, Stefan, Biondi, Andrea, Schrappe, Martin, Hunger, Stephen P, Valsecchi, Maria Grazia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649800/
https://www.ncbi.nlm.nih.gov/pubmed/31360884
http://dx.doi.org/10.1093/jncics/pky069
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author Galimberti, Stefania
Devidas, Meenakshi
Lucenti, Ausiliatrice
Cazzaniga, Giovanni
Möricke, Anja
Bartram, Claus R
Mann, Georg
Carroll, William
Winick, Naomi
Borowitz, Michael
Wood, Brent
Basso, Giuseppe
Conter, Valentino
Zimmermann, Martin
Suciu, Stefan
Biondi, Andrea
Schrappe, Martin
Hunger, Stephen P
Valsecchi, Maria Grazia
author_facet Galimberti, Stefania
Devidas, Meenakshi
Lucenti, Ausiliatrice
Cazzaniga, Giovanni
Möricke, Anja
Bartram, Claus R
Mann, Georg
Carroll, William
Winick, Naomi
Borowitz, Michael
Wood, Brent
Basso, Giuseppe
Conter, Valentino
Zimmermann, Martin
Suciu, Stefan
Biondi, Andrea
Schrappe, Martin
Hunger, Stephen P
Valsecchi, Maria Grazia
author_sort Galimberti, Stefania
collection PubMed
description 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 [Formula: see text] = 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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spelling pubmed-66498002019-07-29 Validation of Minimal Residual Disease as Surrogate Endpoint for Event-Free Survival in Childhood Acute Lymphoblastic Leukemia Galimberti, Stefania Devidas, Meenakshi Lucenti, Ausiliatrice Cazzaniga, Giovanni Möricke, Anja Bartram, Claus R Mann, Georg Carroll, William Winick, Naomi Borowitz, Michael Wood, Brent Basso, Giuseppe Conter, Valentino Zimmermann, Martin Suciu, Stefan Biondi, Andrea Schrappe, Martin Hunger, Stephen P Valsecchi, Maria Grazia JNCI Cancer Spectr Article 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 [Formula: see text] = 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. Oxford University Press 2018-12-19 /pmc/articles/PMC6649800/ /pubmed/31360884 http://dx.doi.org/10.1093/jncics/pky069 Text en © The Author(s) 2018. Published by Oxford University Press. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Article
Galimberti, Stefania
Devidas, Meenakshi
Lucenti, Ausiliatrice
Cazzaniga, Giovanni
Möricke, Anja
Bartram, Claus R
Mann, Georg
Carroll, William
Winick, Naomi
Borowitz, Michael
Wood, Brent
Basso, Giuseppe
Conter, Valentino
Zimmermann, Martin
Suciu, Stefan
Biondi, Andrea
Schrappe, Martin
Hunger, Stephen P
Valsecchi, Maria Grazia
Validation of Minimal Residual Disease as Surrogate Endpoint for Event-Free Survival in Childhood Acute Lymphoblastic Leukemia
title Validation of Minimal Residual Disease as Surrogate Endpoint for Event-Free Survival in Childhood Acute Lymphoblastic Leukemia
title_full Validation of Minimal Residual Disease as Surrogate Endpoint for Event-Free Survival in Childhood Acute Lymphoblastic Leukemia
title_fullStr Validation of Minimal Residual Disease as Surrogate Endpoint for Event-Free Survival in Childhood Acute Lymphoblastic Leukemia
title_full_unstemmed Validation of Minimal Residual Disease as Surrogate Endpoint for Event-Free Survival in Childhood Acute Lymphoblastic Leukemia
title_short Validation of Minimal Residual Disease as Surrogate Endpoint for Event-Free Survival in Childhood Acute Lymphoblastic Leukemia
title_sort validation of minimal residual disease as surrogate endpoint for event-free survival in childhood acute lymphoblastic leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649800/
https://www.ncbi.nlm.nih.gov/pubmed/31360884
http://dx.doi.org/10.1093/jncics/pky069
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