Toxicity associated with intensive postinduction therapy incorporating clofarabine in the very high-risk stratum of patients with newly diagnosed high-risk B-lymphoblastic leukemia: A report from the Children's Oncology Group study AALL1131

Wanda L. Salzer, Michael J. Burke, Meenakshi Devidas, Si Chen, Lia Gore, Eric C. Larsen, Michael Borowitz, Brent Wood, Nyla A. Heerema, Andrew J. Carroll, Joanne M. Hilden, Mignon L. Loh, Elizabeth A. Raetz, Naomi J. Winick, William L. Carroll, Stephen P. Hunger

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Children, adolescents, and young adults with very high-risk (VHR) B acute lymphoblastic leukemia (B-ALL) have poor outcomes, and novel therapies are needed for this subgroup. The AALL1131 study evaluated postinduction therapy using cyclophosphamide (CPM), etoposide (ETOP), and clofarabine (CLOF) for patients with VHR B-ALL. METHODS: Patients who were 1 to 30 years old and had VHR B-ALL received modified Berlin-Frankfurt-Münster therapy after induction and were randomized to 1) CPM, cytarabine, mercaptopurine, vincristine (VCR), and pegaspargase (control arm), 2) CPM, ETOP, VCR, and pegaspargase (experimental arm 1), or 3) CPM, ETOP, CLOF (30 mg/m2/d × 5), VCR, and pegaspargase (experimental arm 2) during the second half of consolidation and delayed intensification. RESULTS: The rates of grade 4/5 infections and grade 3/4 pancreatitis were significantly increased in experimental arm 2. The dose of CLOF was, therefore, reduced to 20 mg/m2/d × 5, and myeloid growth factor was required after CLOF administration. Despite these changes, 4 of 39 patients (10.3%) developed grade 4 infections, with 1 of these patients developing a grade 5 acute kidney injury attributed to CLOF, whereas only 1 of 46 patients (2.2%) in experimental arm 1 developed grade 4 infections, and there were no grade 4/5 infections in the control arm (n = 20). Four patients in experimental arm 2 had prolonged cytopenias for >60 days, whereas none did in the control arm or experimental arm 1. Counts failed to recover for 2 of these patients, one having a grade 5 acute kidney injury and the other removed from protocol therapy; both events occurred 92 days after the start of consolidation part 2. CONCLUSIONS: In AALL1131, CLOF, administered with CPM and ETOP, was associated with unacceptable toxicity.

Original languageEnglish (US)
JournalCancer
DOIs
StateAccepted/In press - Jan 1 2017

Fingerprint

Precursor Cell Lymphoblastic Leukemia-Lymphoma
Cyclophosphamide
Etoposide
Vincristine
Acute Kidney Injury
Therapeutics
Infection
6-Mercaptopurine
Cytarabine
Berlin
Infection Control
clofarabine
Pancreatitis
Young Adult
Intercellular Signaling Peptides and Proteins
pegaspargase

Keywords

  • Acute
  • Childhood
  • Clofarabine
  • Lymphoblastic leukemia
  • Toxicity

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Toxicity associated with intensive postinduction therapy incorporating clofarabine in the very high-risk stratum of patients with newly diagnosed high-risk B-lymphoblastic leukemia : A report from the Children's Oncology Group study AALL1131. / Salzer, Wanda L.; Burke, Michael J.; Devidas, Meenakshi; Chen, Si; Gore, Lia; Larsen, Eric C.; Borowitz, Michael; Wood, Brent; Heerema, Nyla A.; Carroll, Andrew J.; Hilden, Joanne M.; Loh, Mignon L.; Raetz, Elizabeth A.; Winick, Naomi J.; Carroll, William L.; Hunger, Stephen P.

In: Cancer, 01.01.2017.

Research output: Contribution to journalArticle

Salzer, Wanda L. ; Burke, Michael J. ; Devidas, Meenakshi ; Chen, Si ; Gore, Lia ; Larsen, Eric C. ; Borowitz, Michael ; Wood, Brent ; Heerema, Nyla A. ; Carroll, Andrew J. ; Hilden, Joanne M. ; Loh, Mignon L. ; Raetz, Elizabeth A. ; Winick, Naomi J. ; Carroll, William L. ; Hunger, Stephen P. / Toxicity associated with intensive postinduction therapy incorporating clofarabine in the very high-risk stratum of patients with newly diagnosed high-risk B-lymphoblastic leukemia : A report from the Children's Oncology Group study AALL1131. In: Cancer. 2017.
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title = "Toxicity associated with intensive postinduction therapy incorporating clofarabine in the very high-risk stratum of patients with newly diagnosed high-risk B-lymphoblastic leukemia: A report from the Children's Oncology Group study AALL1131",
abstract = "BACKGROUND: Children, adolescents, and young adults with very high-risk (VHR) B acute lymphoblastic leukemia (B-ALL) have poor outcomes, and novel therapies are needed for this subgroup. The AALL1131 study evaluated postinduction therapy using cyclophosphamide (CPM), etoposide (ETOP), and clofarabine (CLOF) for patients with VHR B-ALL. METHODS: Patients who were 1 to 30 years old and had VHR B-ALL received modified Berlin-Frankfurt-M{\"u}nster therapy after induction and were randomized to 1) CPM, cytarabine, mercaptopurine, vincristine (VCR), and pegaspargase (control arm), 2) CPM, ETOP, VCR, and pegaspargase (experimental arm 1), or 3) CPM, ETOP, CLOF (30 mg/m2/d × 5), VCR, and pegaspargase (experimental arm 2) during the second half of consolidation and delayed intensification. RESULTS: The rates of grade 4/5 infections and grade 3/4 pancreatitis were significantly increased in experimental arm 2. The dose of CLOF was, therefore, reduced to 20 mg/m2/d × 5, and myeloid growth factor was required after CLOF administration. Despite these changes, 4 of 39 patients (10.3{\%}) developed grade 4 infections, with 1 of these patients developing a grade 5 acute kidney injury attributed to CLOF, whereas only 1 of 46 patients (2.2{\%}) in experimental arm 1 developed grade 4 infections, and there were no grade 4/5 infections in the control arm (n = 20). Four patients in experimental arm 2 had prolonged cytopenias for >60 days, whereas none did in the control arm or experimental arm 1. Counts failed to recover for 2 of these patients, one having a grade 5 acute kidney injury and the other removed from protocol therapy; both events occurred 92 days after the start of consolidation part 2. CONCLUSIONS: In AALL1131, CLOF, administered with CPM and ETOP, was associated with unacceptable toxicity.",
keywords = "Acute, Childhood, Clofarabine, Lymphoblastic leukemia, Toxicity",
author = "Salzer, {Wanda L.} and Burke, {Michael J.} and Meenakshi Devidas and Si Chen and Lia Gore and Larsen, {Eric C.} and Michael Borowitz and Brent Wood and Heerema, {Nyla A.} and Carroll, {Andrew J.} and Hilden, {Joanne M.} and Loh, {Mignon L.} and Raetz, {Elizabeth A.} and Winick, {Naomi J.} and Carroll, {William L.} and Hunger, {Stephen P.}",
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T1 - Toxicity associated with intensive postinduction therapy incorporating clofarabine in the very high-risk stratum of patients with newly diagnosed high-risk B-lymphoblastic leukemia

T2 - A report from the Children's Oncology Group study AALL1131

AU - Salzer, Wanda L.

AU - Burke, Michael J.

AU - Devidas, Meenakshi

AU - Chen, Si

AU - Gore, Lia

AU - Larsen, Eric C.

AU - Borowitz, Michael

AU - Wood, Brent

AU - Heerema, Nyla A.

AU - Carroll, Andrew J.

AU - Hilden, Joanne M.

AU - Loh, Mignon L.

AU - Raetz, Elizabeth A.

AU - Winick, Naomi J.

AU - Carroll, William L.

AU - Hunger, Stephen P.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - BACKGROUND: Children, adolescents, and young adults with very high-risk (VHR) B acute lymphoblastic leukemia (B-ALL) have poor outcomes, and novel therapies are needed for this subgroup. The AALL1131 study evaluated postinduction therapy using cyclophosphamide (CPM), etoposide (ETOP), and clofarabine (CLOF) for patients with VHR B-ALL. METHODS: Patients who were 1 to 30 years old and had VHR B-ALL received modified Berlin-Frankfurt-Münster therapy after induction and were randomized to 1) CPM, cytarabine, mercaptopurine, vincristine (VCR), and pegaspargase (control arm), 2) CPM, ETOP, VCR, and pegaspargase (experimental arm 1), or 3) CPM, ETOP, CLOF (30 mg/m2/d × 5), VCR, and pegaspargase (experimental arm 2) during the second half of consolidation and delayed intensification. RESULTS: The rates of grade 4/5 infections and grade 3/4 pancreatitis were significantly increased in experimental arm 2. The dose of CLOF was, therefore, reduced to 20 mg/m2/d × 5, and myeloid growth factor was required after CLOF administration. Despite these changes, 4 of 39 patients (10.3%) developed grade 4 infections, with 1 of these patients developing a grade 5 acute kidney injury attributed to CLOF, whereas only 1 of 46 patients (2.2%) in experimental arm 1 developed grade 4 infections, and there were no grade 4/5 infections in the control arm (n = 20). Four patients in experimental arm 2 had prolonged cytopenias for >60 days, whereas none did in the control arm or experimental arm 1. Counts failed to recover for 2 of these patients, one having a grade 5 acute kidney injury and the other removed from protocol therapy; both events occurred 92 days after the start of consolidation part 2. CONCLUSIONS: In AALL1131, CLOF, administered with CPM and ETOP, was associated with unacceptable toxicity.

AB - BACKGROUND: Children, adolescents, and young adults with very high-risk (VHR) B acute lymphoblastic leukemia (B-ALL) have poor outcomes, and novel therapies are needed for this subgroup. The AALL1131 study evaluated postinduction therapy using cyclophosphamide (CPM), etoposide (ETOP), and clofarabine (CLOF) for patients with VHR B-ALL. METHODS: Patients who were 1 to 30 years old and had VHR B-ALL received modified Berlin-Frankfurt-Münster therapy after induction and were randomized to 1) CPM, cytarabine, mercaptopurine, vincristine (VCR), and pegaspargase (control arm), 2) CPM, ETOP, VCR, and pegaspargase (experimental arm 1), or 3) CPM, ETOP, CLOF (30 mg/m2/d × 5), VCR, and pegaspargase (experimental arm 2) during the second half of consolidation and delayed intensification. RESULTS: The rates of grade 4/5 infections and grade 3/4 pancreatitis were significantly increased in experimental arm 2. The dose of CLOF was, therefore, reduced to 20 mg/m2/d × 5, and myeloid growth factor was required after CLOF administration. Despite these changes, 4 of 39 patients (10.3%) developed grade 4 infections, with 1 of these patients developing a grade 5 acute kidney injury attributed to CLOF, whereas only 1 of 46 patients (2.2%) in experimental arm 1 developed grade 4 infections, and there were no grade 4/5 infections in the control arm (n = 20). Four patients in experimental arm 2 had prolonged cytopenias for >60 days, whereas none did in the control arm or experimental arm 1. Counts failed to recover for 2 of these patients, one having a grade 5 acute kidney injury and the other removed from protocol therapy; both events occurred 92 days after the start of consolidation part 2. CONCLUSIONS: In AALL1131, CLOF, administered with CPM and ETOP, was associated with unacceptable toxicity.

KW - Acute

KW - Childhood

KW - Clofarabine

KW - Lymphoblastic leukemia

KW - Toxicity

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