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A phase 3 trial of inotuzumab ozogamicin for high-risk B-ALL: Second safety phase results from Children’s Oncology Group AALL1732.

Abstract

10016
Background: Inotuzumab ozogamicin (InO) is effective in adults and children with relapsed/refractory (R/R) CD22+ B-acute lymphoblastic leukemia (B-ALL). Children’s Oncology Group AALL1732 is a phase 3 randomized trial evaluating InO for newly diagnosed patients (pts) with high-risk B-ALL. Given known hepatic, hematologic, and infectious toxicities, two safety phases were completed. Methods: Pts with residual marrow disease < 0.01% by end consolidation are randomized to chemotherapy (Arm A) or chemotherapy plus 2 cycles of InO (Arm B) after consolidation and interim maintenance 1 (IM1). Modifications after safety phase 1 [SP1; McNeer et al. Blood (2021) 138 (Suppl 1):3398] included reducing InO to 1.2mg/m2/cycle, increasing hydration during IM1 on Arm B, and enhancing supportive care in delayed intensification (DI) with antimicrobials. Safety phase 2 (SP2) assessed methotrexate (MTX) clearance, treatment delays and infectious/hepatic toxicity. Planned interim analysis is reported. Results: Fifty pts were randomized and evaluable (25 Arm A, 25 Arm B). There was no difference in gr ≥3 ALT or bilirubin elevations. Sinusoidal obstruction syndrome (SOS) occurred in 4 Arm B pts during DI including 3 (1 gr 3, 2 gr 4) in DI part 2 (DI2). IM1 day 1 MTX clearance was similar 65.4 (range 52.6-154) vs 70.2 hrs (range 56.5-267) on Arm A vs B, p = 0.27. Mean duration of IM1 was 74.8 (sd 11.8) vs 84 days (sd 13.3) on Arm A vs B, p = 0.013. Arm B IM1 duration in SP2 was shorter than SP1 [90 days (sd 15.3)]. DI part 1 (DI1) duration was similar between Arms. Arm B DI2 was longer than Arm A [53.8 (sd 20.2) vs 42.6 days (sd 9.5), p = 0.025]. Sepsis occurred in DI1 in 0 Arm A and 5 Arm B pts and in DI2 in 1 Arm A and 5 Arm B pts (Table). In DI2 1 pt on each Arm had gr 5 multiorgan failure (MOF) with sepsis. In DI1 50% of Arm A and 87.5% of Arm B pts had absolute neutrophil count (ANC) < 500 (p = 0.011). In DI2 all Arm A and 92.5% of Arm B pts had ANC < 500 with longer duration on Arm B [19.3 (sd 8.1) vs 7.8 days (sd 12.4), p = 0.015]. Compliance with prophylactic antibiotics was higher on Arm B (DI1 Arm A 41.7% vs Arm B 80.9%; DI2 Arm A 52.2% vs Arm B 85%). Conclusions: While SP2 modifications improved MTX clearance and duration of IM1, SOS and infections remain concerning on Arm B, particularly during DI. Most SOS events occurred proximal to thioguanine in DI2. Neutropenia was more pronounced in DI on Arm B but compliance with antimicrobials was high. Higher sepsis rates, primarily gr 3, were observed on Arm B with no increase in gr 5 infections. Additional modifications are planned for Arm B to further mitigate toxicity during post InO chemotherapy blocks. Clinical trial information: NCT03959085.
Adverse EventBlockArm A
(N; Gr3/ Gr4/Gr5)
OrganismArm B
(N; Gr3/ Gr4/Gr5)
Organism
SepsisDI10 5; 5/0/0C parapsilosis
C albicans
R mucilaginosa
E coli
S epidermidis
 DI21; 0/1/0E coli5; 4/1/0E coli x 3
K pneumoniae
Aspergillosis & C sartagoforme
MOFDI21; 0/0/1C difficile & COVID-191; 0/0/1S Choleraesuis

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Published In

Journal of Clinical Oncology
Pages: 10016

History

Published online: May 31, 2023
Published in print: June 01, 2023

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Maureen Megan O'Brien
Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Jennifer Lynn McNeer
University of Chicago, Chicago, IL
Susan R. Rheingold
Children's Hospital of Philadelphia, Philadelphia, PA
Meenakshi Devidas
St. Jude Children's Research Hospital, Memphis, TN
Zhiguo Chen
University of Florida Department of Biostatistics, Gainesville, FL
Deepa Bhojwani
Children's Hospital Los Angeles, Los Angeles, CA
Laura B Ramsey
Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Anurag Agrawal
UCSF Benioff Children's Hospital Oakland, Oakland, CA
Brent L. Wood
Eugene Suh
Loyola University Medical Center, Maywood, IL
Sarah Alexander
The Hospital for Sick Children, Toronto, ON, Canada
Tamara P. Miller
Emory University, Atlanta, GA
Olga Militano
Children's Oncology Group, Monrovia, CA
Michael Burke
Medical College of Wisconsin, Milwaukee, WI
Wanda L. Salzer
Uniformed Services University, Bethesda, MD
Elizabeth A. Raetz
Perlmutter Cancer Center and NYU Langone, New York, NY
Mignon L. Loh
Seattle Children's Hospital, Seattle, WA
Cincinnati Children's Hospital Medical Center, Cincinnati, OH; University of Chicago, Chicago, IL; Children's Hospital of Philadelphia, Philadelphia, PA; St. Jude Children's Research Hospital, Memphis, TN; University of Florida Department of Biostatistics, Gainesville, FL; Children's Hospital Los Angeles, Los Angeles, CA; UCSF Benioff Children's Hospital Oakland, Oakland, CA; CHLA, Los Angeles, CA; Loyola University Medical Center, Maywood, IL; The Hospital for Sick Children, Toronto, ON, Canada; Emory University, Atlanta, GA; Children's Oncology Group, Monrovia, CA; Medical College of Wisconsin, Milwaukee, WI; Uniformed Services University, Bethesda, MD; Perlmutter Cancer Center and NYU Langone, New York, NY; Seattle Children's Hospital, Seattle, WA

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U.S. National Institutes of Healthgov

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Maureen Megan O'Brien, Jennifer Lynn McNeer, Susan R. Rheingold, Meenakshi Devidas, Zhiguo Chen, Deepa Bhojwani, Laura B Ramsey, Anurag Agrawal, Brent L. Wood, Eugene Suh, Sarah Alexander, Tamara P. Miller, Olga Militano, Michael Burke, Wanda L. Salzer, Elizabeth A. Raetz, Mignon L. Loh
Journal of Clinical Oncology 2023 41:16_suppl, 10016-10016

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