Population Pharmacokinetics of Inotuzumab Ozogamicin (InO) As Single Agent in Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia - Results from the ITCC-059 Phase IA and Phase II Trial

Pennesi, Edoardo; Brivio, Erica; Pelletier, Kathleen; Chen, Ying; Huitema, Alwin D. R.; Jiang, Yilin; Ammerlaan, Anneke C.J.; Sleight, Barbara; Locatelli, Franco; Sluis, Inge M. van der; Chen-Santel, Christiane; Bielorai, Bella; Petit, Arnaud; Starý, Jan; Sramkova, Lucie; Rubio, C. Díaz de Heredia; Rives, Susana; O’Marcaigh, Aengus; Rizzari, Carmelo; Engstler, Gernot; Nysom, Karsten; Rubio‐San‐Simón, Alba; Sirvent, Francisco José Bautista; Bruno, Bénédicte; Bertrand, Yives; Brethon, Benoît; Rialland, Fanny; Plat, Geneviève; Dirksen, Uta; Garrett, May; Zwaan, C. Michel

doi:10.1182/blood-2022-165954

Cited by 2 publications

(1 citation statement)

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“…Additionally, other demographic factors (e.g., age, race, and sex) and measures of renal and hepatic function did not impact InO PK. In a study applying this model to samples from 53 pediatric patient with BCP-ALL treated with InO, the same covariates were identified (28). Of note, ADCs in general, including InO, do not cross the blood-brain barrier and there is no available data to support its use for central nervous system ALL (29,30).…”

Section: Pharmacologymentioning

confidence: 99%

Inotuzumab ozogamicin in B-cell precursor acute lymphoblastic leukemia: efficacy, toxicity, and practical considerations

Rubinstein

O’Brien

2023

Front. Immunol.

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Inotuzumab ozogamicin (InO) is an antibody drug conjugate composed of a humanized monoclonal antibody targeting the cell surface receptor CD22 coupled to a cytotoxic calicheamicin payload via an acid labile linker. InO has shown significant activity in relapsed and refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in both single agent and combination chemotherapy regimens in adult and pediatric trials. Its use in newly diagnosed elderly patients has also been established while clinical trials investigating its use in newly diagnosed pediatric patients and fit adults are ongoing. Notable toxicities include sinusoidal obstruction syndrome (SOS), particularly in patients who undergo hematopoietic stem cell transplantation (HSCT) after InO as well as myelosuppression and B-cell aplasia which confer increased infection risk, particularly in combination with cytotoxic chemotherapy. In the relapsed/refractory (R/R) setting, the planned subsequent curative therapy modality must be considered when using InO to mitigate SOS risk if proceeding to HSCT and account for potential B-cell aplasia if proceeding to chimeric antigen receptor CAR-T therapy. Studies exploring mechanisms of resistance or failure of InO are ongoing but modulation or loss CD22 expression, alternative CD22 splicing, and high Bcl-2 expression have been implicated. In this review, we will summarize the currently available data on InO, with an emphasis on pediatric trials, and explore future directions including combinatorial therapy.

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Section: Pharmacologymentioning

confidence: 99%