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-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. Cancer 2018;124:1150-9. © 2017 American Cancer Society.

• Authors: 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
• Journal: Cancer (Cancer) Vol. 124 Issue 6 Pg. 1150-1159 (03 15 2018) ISSN: 1097-0142 [Electronic] United States
• PMID: 29266189 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 American Cancer Society.

Chemical References

• Clofarabine

Topics

• Acute Kidney Injury (chemically induced, diagnosis, epidemiology)
• Adolescent
• Adult
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Bacterial Infections (chemically induced, epidemiology)
• Child
• Child, Preschool
• Clofarabine (administration & dosage, adverse effects)
• Disease-Free Survival
• Dose-Response Relationship, Drug
• Female
• Humans
• Infant
• Male
• Pancreatitis (chemically induced, diagnosis, epidemiology)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, mortality, pathology)
• Remission Induction (methods)
• Severity of Illness Index
• Young Adult