Maureen M O'Brien1, Lingyun Ji2, Nirali N Shah3, Susan R Rheingold4, Deepa Bhojwani5, Constance M Yuan6, Xinxin Xu7, Joanna S Yi8, Andrew C Harris9, Patrick A Brown10, Michael J Borowitz11, Olga Militano7, John Kairalla12, Meenakshi Devidas13, Elizabeth A Raetz14, Lia Gore15, Mignon L Loh16. 1. University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati OH. 2. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA. 3. Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD. 4. Perelman School of Medicine, Division of Oncology at the Children's Hospital of Philadelphia, Philadelphia, PA. 5. Division of Pediatric Hematology and Oncology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA. 6. Flow Cytometry Unit, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD. 7. Children's Oncology Group, Monrovia, CA. 8. Pediatric Hematology/Oncology, Baylor College of Medicine/Texas Children's Hospital, Houston, TX. 9. Pediatric Blood and Marrow Transplantation, University of Utah/Primary Children's Hospital, Salt Lake City, UT. 10. Division of Pediatric Oncology, Johns Hopkins Kimmel Cancer Center, Baltimore, MD. 11. Departments of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD. 12. Department of Biostatistics, Colleges of Medicine, Public Health and Health Professions, University of Florida, Gainesville, FL. 13. Department of Global Pediatric Medicine, St Jude Children's Research Hospital, Memphis, TN. 14. Department of Pediatrics, NYU Langone Health, New York, NY. 15. University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO. 16. Department of Pediatrics, Benioff Children's Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA.
Abstract
PURPOSE: Children's Oncology Group trial AALL1621 was conducted to prospectively determine the safety and efficacy of inotuzumab ozogamicin (InO) in pediatric and adolescent patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). PATIENTS AND METHODS: This single-arm phase II trial enrolled patients age 1-21 years with R/R CD22-positive B-ALL. In cycle 1, InO dosing was 0.8 mg/m2 intravenously on day 1 and 0.5 mg/m2 on days 8 and 15 of a 28-day cycle with response evaluation at day 28. Using a two-stage design, the trial was continuously monitored for dose-limiting toxicities and sinusoidal obstruction syndrome (SOS). CD22 expression was retrospectively evaluated by central flow cytometry. RESULTS: Forty-eight patients were evaluable for response and toxicity; 19 had complete response (CR) and nine CR with incomplete count recovery (CRi) after cycle 1 (CR/CRi rate: 58.3%; two-sided 90% CI, 46.5 to 69.3). Twenty-seven of 28 patients with CR or CRi had minimal residual disease measured by flow cytometry; 18 (66.7%) had minimal residual disease < 0.01%. Seven of 28 patients (25%) with CR or CRi had delayed count recovery past day 42 in cycle 1. Three (6.3%) patients had grade 3 ALT elevation and one patient had grade 3 hyperbilirubinemia in cycle 1. Of 21 patients undergoing hematopoietic stem-cell transplantation after InO, 6 (28.6%) developed grade 3 SOS. Partial CD22 expression and lower CD22 site density were associated with lower likelihood of response to InO. CONCLUSION: InO is effective and well tolerated in heavily pretreated children and adolescents with R/R CD22-positive B-ALL. SOS after hematopoietic stem-cell transplantation and prolonged cytopenias were notable. CD22 modulation was identified as a mechanism of resistance. Expanded study of InO combined with chemotherapy is underway.
PURPOSE: Children's Oncology Group trial AALL1621 was conducted to prospectively determine the safety and efficacy of inotuzumab ozogamicin (InO) in pediatric and adolescent patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). PATIENTS AND METHODS: This single-arm phase II trial enrolled patients age 1-21 years with R/R CD22-positive B-ALL. In cycle 1, InO dosing was 0.8 mg/m2 intravenously on day 1 and 0.5 mg/m2 on days 8 and 15 of a 28-day cycle with response evaluation at day 28. Using a two-stage design, the trial was continuously monitored for dose-limiting toxicities and sinusoidal obstruction syndrome (SOS). CD22 expression was retrospectively evaluated by central flow cytometry. RESULTS: Forty-eight patients were evaluable for response and toxicity; 19 had complete response (CR) and nine CR with incomplete count recovery (CRi) after cycle 1 (CR/CRi rate: 58.3%; two-sided 90% CI, 46.5 to 69.3). Twenty-seven of 28 patients with CR or CRi had minimal residual disease measured by flow cytometry; 18 (66.7%) had minimal residual disease < 0.01%. Seven of 28 patients (25%) with CR or CRi had delayed count recovery past day 42 in cycle 1. Three (6.3%) patients had grade 3 ALT elevation and one patient had grade 3 hyperbilirubinemia in cycle 1. Of 21 patients undergoing hematopoietic stem-cell transplantation after InO, 6 (28.6%) developed grade 3 SOS. Partial CD22 expression and lower CD22 site density were associated with lower likelihood of response to InO. CONCLUSION: InO is effective and well tolerated in heavily pretreated children and adolescents with R/R CD22-positive B-ALL. SOS after hematopoietic stem-cell transplantation and prolonged cytopenias were notable. CD22 modulation was identified as a mechanism of resistance. Expanded study of InO combined with chemotherapy is underway.
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