Bortezomib reinduction chemotherapy in high-risk ALL in first relapse: a report from the Children's Oncology Group

Terzah M. Horton, James A. Whitlock, Xiaomin Lu, Maureen M. O'Brien, Michael J Borowitz, Meenakshi Devidas, Elizabeth A. Raetz, Patrick A Brown, William L. Carroll, Stephen P. Hunger

Research output: Contribution to journalArticle

Abstract

While survival in paediatric acute lymphoblastic leukaemia (ALL) is excellent, survival following relapse is poor. Previous studies suggest proteasome inhibition with chemotherapy improves relapse ALL response rates. This phase 2 Children's Oncology Group study tested the hypothesis that adding the proteasome inhibitor bortezomib to chemotherapy increases complete response rates (CR2). Evaluable patients (n = 135, 103 B-ALL, 22 T-ALL, 10 T-lymphoblastic lymphoma) were treated with reinduction chemotherapy plus bortezomib. Overall CR2 rates were 68 ± 5% for precursor B-ALL patients (<21 years of age), 63 ± 7% for very early relapse (<18 months from diagnosis) and 72 ± 6% for early relapse (18–36 months from diagnosis). Relapsed T-ALL patients had an encouraging CR2 rate of 68 ± 10%. End of induction minimal residual disease (MRD) significantly predicted survival. MRD negative (MRDneg; MRD <0·01%) rates increased from 29% (post-cycle 1) to 64% following cycle 3. Very early relapse, end-of-induction MRDneg precursor B-ALL patients had 70 ± 14% 3-year event-free (EFS) and overall survival (OS) rates, vs. 3-year EFS/OS of 0–3% (P = 0·0001) for MRDpos (MRD ≥0·01) patients. Early relapse patients had similar outcomes (MRDneg 3-year EFS/OS 58–65% vs. MRDpos 10–19%, EFS P = 0·0014). These data suggest that adding bortezomib to chemotherapy in certain ALL subgroups, such as T-cell ALL, is worthy of further investigation. This study is registered at http://www.clinical.trials.gov as NCT00873093.

Original languageEnglish (US)
JournalBritish journal of haematology
DOIs
StatePublished - Jan 1 2019

Fingerprint

Precursor Cell Lymphoblastic Leukemia-Lymphoma
Recurrence
Drug Therapy
Residual Neoplasm
Survival
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Bortezomib
Proteasome Inhibitors
Proteasome Endopeptidase Complex
Survival Rate
Pediatrics

Keywords

  • acute lymphoblastic leukaemia
  • acute lymphocytic leukaemia
  • minimal residual disease
  • paediatric leukaemia
  • proteasome inhibition

ASJC Scopus subject areas

  • Hematology

Cite this

Bortezomib reinduction chemotherapy in high-risk ALL in first relapse : a report from the Children's Oncology Group. / Horton, Terzah M.; Whitlock, James A.; Lu, Xiaomin; O'Brien, Maureen M.; Borowitz, Michael J; Devidas, Meenakshi; Raetz, Elizabeth A.; Brown, Patrick A; Carroll, William L.; Hunger, Stephen P.

In: British journal of haematology, 01.01.2019.

Research output: Contribution to journalArticle

Horton, Terzah M. ; Whitlock, James A. ; Lu, Xiaomin ; O'Brien, Maureen M. ; Borowitz, Michael J ; Devidas, Meenakshi ; Raetz, Elizabeth A. ; Brown, Patrick A ; Carroll, William L. ; Hunger, Stephen P. / Bortezomib reinduction chemotherapy in high-risk ALL in first relapse : a report from the Children's Oncology Group. In: British journal of haematology. 2019.
@article{cf9ca07571844639b0e85219313709cc,
title = "Bortezomib reinduction chemotherapy in high-risk ALL in first relapse: a report from the Children's Oncology Group",
abstract = "While survival in paediatric acute lymphoblastic leukaemia (ALL) is excellent, survival following relapse is poor. Previous studies suggest proteasome inhibition with chemotherapy improves relapse ALL response rates. This phase 2 Children's Oncology Group study tested the hypothesis that adding the proteasome inhibitor bortezomib to chemotherapy increases complete response rates (CR2). Evaluable patients (n = 135, 103 B-ALL, 22 T-ALL, 10 T-lymphoblastic lymphoma) were treated with reinduction chemotherapy plus bortezomib. Overall CR2 rates were 68 ± 5{\%} for precursor B-ALL patients (<21 years of age), 63 ± 7{\%} for very early relapse (<18 months from diagnosis) and 72 ± 6{\%} for early relapse (18–36 months from diagnosis). Relapsed T-ALL patients had an encouraging CR2 rate of 68 ± 10{\%}. End of induction minimal residual disease (MRD) significantly predicted survival. MRD negative (MRDneg; MRD <0·01{\%}) rates increased from 29{\%} (post-cycle 1) to 64{\%} following cycle 3. Very early relapse, end-of-induction MRDneg precursor B-ALL patients had 70 ± 14{\%} 3-year event-free (EFS) and overall survival (OS) rates, vs. 3-year EFS/OS of 0–3{\%} (P = 0·0001) for MRDpos (MRD ≥0·01) patients. Early relapse patients had similar outcomes (MRDneg 3-year EFS/OS 58–65{\%} vs. MRDpos 10–19{\%}, EFS P = 0·0014). These data suggest that adding bortezomib to chemotherapy in certain ALL subgroups, such as T-cell ALL, is worthy of further investigation. This study is registered at http://www.clinical.trials.gov as NCT00873093.",
keywords = "acute lymphoblastic leukaemia, acute lymphocytic leukaemia, minimal residual disease, paediatric leukaemia, proteasome inhibition",
author = "Horton, {Terzah M.} and Whitlock, {James A.} and Xiaomin Lu and O'Brien, {Maureen M.} and Borowitz, {Michael J} and Meenakshi Devidas and Raetz, {Elizabeth A.} and Brown, {Patrick A} and Carroll, {William L.} and Hunger, {Stephen P.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1111/bjh.15919",
language = "English (US)",
journal = "British Journal of Haematology",
issn = "0007-1048",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - Bortezomib reinduction chemotherapy in high-risk ALL in first relapse

T2 - a report from the Children's Oncology Group

AU - Horton, Terzah M.

AU - Whitlock, James A.

AU - Lu, Xiaomin

AU - O'Brien, Maureen M.

AU - Borowitz, Michael J

AU - Devidas, Meenakshi

AU - Raetz, Elizabeth A.

AU - Brown, Patrick A

AU - Carroll, William L.

AU - Hunger, Stephen P.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - While survival in paediatric acute lymphoblastic leukaemia (ALL) is excellent, survival following relapse is poor. Previous studies suggest proteasome inhibition with chemotherapy improves relapse ALL response rates. This phase 2 Children's Oncology Group study tested the hypothesis that adding the proteasome inhibitor bortezomib to chemotherapy increases complete response rates (CR2). Evaluable patients (n = 135, 103 B-ALL, 22 T-ALL, 10 T-lymphoblastic lymphoma) were treated with reinduction chemotherapy plus bortezomib. Overall CR2 rates were 68 ± 5% for precursor B-ALL patients (<21 years of age), 63 ± 7% for very early relapse (<18 months from diagnosis) and 72 ± 6% for early relapse (18–36 months from diagnosis). Relapsed T-ALL patients had an encouraging CR2 rate of 68 ± 10%. End of induction minimal residual disease (MRD) significantly predicted survival. MRD negative (MRDneg; MRD <0·01%) rates increased from 29% (post-cycle 1) to 64% following cycle 3. Very early relapse, end-of-induction MRDneg precursor B-ALL patients had 70 ± 14% 3-year event-free (EFS) and overall survival (OS) rates, vs. 3-year EFS/OS of 0–3% (P = 0·0001) for MRDpos (MRD ≥0·01) patients. Early relapse patients had similar outcomes (MRDneg 3-year EFS/OS 58–65% vs. MRDpos 10–19%, EFS P = 0·0014). These data suggest that adding bortezomib to chemotherapy in certain ALL subgroups, such as T-cell ALL, is worthy of further investigation. This study is registered at http://www.clinical.trials.gov as NCT00873093.

AB - While survival in paediatric acute lymphoblastic leukaemia (ALL) is excellent, survival following relapse is poor. Previous studies suggest proteasome inhibition with chemotherapy improves relapse ALL response rates. This phase 2 Children's Oncology Group study tested the hypothesis that adding the proteasome inhibitor bortezomib to chemotherapy increases complete response rates (CR2). Evaluable patients (n = 135, 103 B-ALL, 22 T-ALL, 10 T-lymphoblastic lymphoma) were treated with reinduction chemotherapy plus bortezomib. Overall CR2 rates were 68 ± 5% for precursor B-ALL patients (<21 years of age), 63 ± 7% for very early relapse (<18 months from diagnosis) and 72 ± 6% for early relapse (18–36 months from diagnosis). Relapsed T-ALL patients had an encouraging CR2 rate of 68 ± 10%. End of induction minimal residual disease (MRD) significantly predicted survival. MRD negative (MRDneg; MRD <0·01%) rates increased from 29% (post-cycle 1) to 64% following cycle 3. Very early relapse, end-of-induction MRDneg precursor B-ALL patients had 70 ± 14% 3-year event-free (EFS) and overall survival (OS) rates, vs. 3-year EFS/OS of 0–3% (P = 0·0001) for MRDpos (MRD ≥0·01) patients. Early relapse patients had similar outcomes (MRDneg 3-year EFS/OS 58–65% vs. MRDpos 10–19%, EFS P = 0·0014). These data suggest that adding bortezomib to chemotherapy in certain ALL subgroups, such as T-cell ALL, is worthy of further investigation. This study is registered at http://www.clinical.trials.gov as NCT00873093.

KW - acute lymphoblastic leukaemia

KW - acute lymphocytic leukaemia

KW - minimal residual disease

KW - paediatric leukaemia

KW - proteasome inhibition

UR - http://www.scopus.com/inward/record.url?scp=85063997609&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85063997609&partnerID=8YFLogxK

U2 - 10.1111/bjh.15919

DO - 10.1111/bjh.15919

M3 - Article

C2 - 30957229

AN - SCOPUS:85063997609

JO - British Journal of Haematology

JF - British Journal of Haematology

SN - 0007-1048

ER -