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.
N1 - Funding Information:
NIH-R01-CA193776, Texas Children’s Cancer Center, and Hyundai Hope on Wheels Research Award. JAW is the Women’s Auxiliary Millennium Chair in Haematology/Oncology, The Hospital for Sick Children; EAR is a KiDS of NYU Foundation Professor at NYU Langone Health. SPH is the Jeffrey E. Perelman Distinguished Chair in the Department of Pediatrics, Children’s Hospital of Philadelphia and the St. Baldrick’s Foundation. Research reported in this publication was supported by grants U10 CA98543, U10 CA98413, U10 CA180886, 1U24-CA196173 and U10 CA180899 from the National Institutes of Health, and by St. Baldrick’s Foundation. Bortezomib was kindly supplied by Millennium Pharmaceuticals (now Takeda) through a CRADA with the NIH NCI Cancer Therapy Evaluation Program (CTEP). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
Gaye Jenkins provided technical research support. TMH was funded in part by NIH-K12-CA90433, NIH K23-CA113775,
Publisher Copyright:
© 2019 British Society for Haematology and John Wiley & Sons Ltd
PY - 2019/7
Y1 - 2019/7
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
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U2 - 10.1111/bjh.15919
DO - 10.1111/bjh.15919
M3 - Article
C2 - 30957229
AN - SCOPUS:85063997609
SN - 0007-1048
VL - 186
SP - 274
EP - 285
JO - British journal of haematology
JF - British journal of haematology
IS - 2
ER -