Emily R Finch1, Laura J Janke2, Lie Li1, Monique A Payton1, David A Jenkins1, Kristine R Crews1, Mary V Relling1, Seth E Karol3. 1. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. 2. Department of Pathology, Division of Comparative Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. 3. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Abstract
INTRODUCTION: There are clinical reports that the incorporation of dasatinib may increase the frequency of osteonecrosis in acute lymphoblastic leukemia (ALL) treatment regimens. No rigorous testing of this hypothesis is available to guide clinicians. METHODS: We tested whether oral dasatinib increased the frequency of dexamethasone-induced osteonecrosis in a murine model and tested its effects on dexamethasone's antileukemic efficacy in a murine BCR-ABL+ model of ALL. RESULTS: Dasatinib did not change the frequency of osteonecrosis (p = .99) nor of arteriopathy (p = .36) in dexamethasone-treated mice when given at dosages that achieved clinically relevant steady-state dasatinib plasma concentrations of 53.1 ng/ml (95% CI: 43.5-57.3 ng/ml). These dasatinib exposures were not associated with increased dexamethasone plasma exposure in nonleukemia-bearing mice. These same dosages were not associated with any decrement in antileukemic efficacy of dexamethasone in a responsive BCR-ABL+ model of ALL. CONCLUSIONS: Based on the results of our preclinical murine studies, we conclude that dasatinib is unlikely to increase the osteonecrotic effects of dexamethasone in ALL regimens.
INTRODUCTION: There are clinical reports that the incorporation of dasatinib may increase the frequency of osteonecrosis in acute lymphoblastic leukemia (ALL) treatment regimens. No rigorous testing of this hypothesis is available to guide clinicians. METHODS: We tested whether oral dasatinib increased the frequency of dexamethasone-induced osteonecrosis in a murine model and tested its effects on dexamethasone's antileukemic efficacy in a murine BCR-ABL+ model of ALL. RESULTS: Dasatinib did not change the frequency of osteonecrosis (p = .99) nor of arteriopathy (p = .36) in dexamethasone-treated mice when given at dosages that achieved clinically relevant steady-state dasatinib plasma concentrations of 53.1 ng/ml (95% CI: 43.5-57.3 ng/ml). These dasatinib exposures were not associated with increased dexamethasone plasma exposure in nonleukemia-bearing mice. These same dosages were not associated with any decrement in antileukemic efficacy of dexamethasone in a responsive BCR-ABL+ model of ALL. CONCLUSIONS: Based on the results of our preclinical murine studies, we conclude that dasatinib is unlikely to increase the osteonecrotic effects of dexamethasone in ALL regimens.
Authors: Kathryn G Roberts; Yung-Li Yang; Debbie Payne-Turner; Wenwei Lin; Jacob K Files; Kirsten Dickerson; Zhaohui Gu; Jack Taunton; Laura J Janke; Taosheng Chen; Mignon L Loh; Stephen P Hunger; Charles G Mullighan Journal: Blood Adv Date: 2017-08-30
Authors: William B Slayton; Kirk R Schultz; John A Kairalla; Meenakshi Devidas; Xinlei Mi; Michael A Pulsipher; Bill H Chang; Charles Mullighan; Ilaria Iacobucci; Lewis B Silverman; Michael J Borowitz; Andrew J Carroll; Nyla A Heerema; Julie M Gastier-Foster; Brent L Wood; Sherri L Mizrahy; Thomas Merchant; Valerie I Brown; Lance Sieger; Marilyn J Siegel; Elizabeth A Raetz; Naomi J Winick; Mignon L Loh; William L Carroll; Stephen P Hunger Journal: J Clin Oncol Date: 2018-05-29 Impact factor: 44.544
Authors: Richard Aplenc; Susan M Blaney; Lewis C Strauss; Frank M Balis; Suzanne Shusterman; Ashish Mark Ingle; Shruti Agrawal; Junfeng Sun; John J Wright; Peter C Adamson Journal: J Clin Oncol Date: 2011-01-24 Impact factor: 44.544
Authors: Nidal Boulos; Heather L Mulder; Christopher R Calabrese; Jeffrey B Morrison; Jerold E Rehg; Mary V Relling; Charles J Sherr; Richard T Williams Journal: Blood Date: 2011-01-24 Impact factor: 22.113
Authors: Neil P Shah; Dong-Wook Kim; Hagop Kantarjian; Philippe Rousselot; Pedro Enrique Dorlhiac Llacer; Alicia Enrico; Jorge Vela-Ojeda; Richard T Silver; Hanna Jean Khoury; Martin C Müller; Alexandre Lambert; Yousif Matloub; Andreas Hochhaus Journal: Haematologica Date: 2010-02 Impact factor: 9.941
Authors: Lisa J Christopher; Donghui Cui; Chiyuan Wu; Roger Luo; James A Manning; Samuel J Bonacorsi; Michael Lago; Alban Allentoff; Francis Y F Lee; Betty McCann; Susan Galbraith; Donald P Reitberg; Kan He; Anthony Barros; Anne Blackwood-Chirchir; W Griffith Humphreys; Ramaswamy A Iyer Journal: Drug Metab Dispos Date: 2008-04-17 Impact factor: 3.922
Authors: Kimmo Porkka; Perttu Koskenvesa; Tuija Lundán; Johanna Rimpiläinen; Satu Mustjoki; Richard Smykla; Robert Wild; Roger Luo; Montserrat Arnan; Benoit Brethon; Lydia Eccersley; Henrik Hjorth-Hansen; Martin Höglund; Hana Klamova; Håvar Knutsen; Suhag Parikh; Emmanuel Raffoux; Franz Gruber; Finella Brito-Babapulle; Hervé Dombret; Rafael F Duarte; Erkki Elonen; Ron Paquette; C Michel Zwaan; Francis Y F Lee Journal: Blood Date: 2008-05-13 Impact factor: 22.113
Authors: Emily R Finch; Monique A Payton; David A Jenkins; Xiangjun Cai; Lie Li; Seth E Karol; Mary V Relling; Laura J Janke Journal: Haematologica Date: 2021-08-01 Impact factor: 9.941