Optimization of a clofarabine-based drug combination regimen for the preclinical evaluation of pediatric acute lymphoblastic leukemia
Xie, Jinhan; Span, Miriam; van Maarseveen, Erik; Langenhorst, Jurgen; Boddy, Alan V; Sia, Keith C S; Sutton, Rosemary; Venn, Nicola; Punt, Arjen M; Tyrrell, Vanessa; Haber, Michelle; Trahair, Toby; Lau, Loretta; Marshall, Glenn M; Lock, Richard B
(2020) Pediatric Blood & Cancer, volume 67, issue 4, pp. 1 - 10
(Article)
Abstract
BACKGROUND: The aim of this study was to improve the predictive power of patient-derived xenografts (PDXs, also known as mouse avatars) to more accurately reflect outcomes of clofarabine-based treatment in pediatric acute lymphoblastic leukemia (ALL) patients. PROCEDURE: Pharmacokinetic (PK) studies were conducted using clofarabine at 3.5 to 15 mg/kg in
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mice. PDXs were established from relapsed/refractory ALL patients who exhibited good or poor responses to clofarabine. PDX engraftment and response to clofarabine (either as a single agent or in combinations) were assessed based on stringent objective response measures modeled after the clinical setting. RESULTS: In naïve immune-deficient NSG mice, we determined that a clofarabine dose of 3.5 mg/kg resulted in systemic exposures equivalent to those achieved in pediatric ALL patients treated with clofarabine-based regimens. This dose was markedly lower than the doses of clofarabine used in previously reported preclinical studies (typically 30-60 mg/kg) and, when scheduled consistent with the clinical regimen (daily × 5), resulted in 34-fold lower clofarabine exposures. Using a well-tolerated clofarabine/etoposide/cyclophosphamide combination regimen, we then found that the responses of PDXs better reflected the clinical responses of the patients from whom the PDXs were derived. CONCLUSIONS: This study has identified an in vivo clofarabine treatment regimen that reflects the clinical responses of relapsed/refractory pediatric ALL patients. This regimen could be used prospectively to identify patients who might benefit from clofarabine-based treatment. Our findings are an important step toward individualizing prospective patient selection for the use of clofarabine in relapsed/refractory pediatric ALL patients and highlight the need for detailed PK evaluation in murine PDX models.
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Keywords: acute lymphoblastic leukemia, clofarabine, combination chemotherapy, xenograft, Hematology, Oncology, Pediatrics, Perinatology, and Child Health, Journal Article
ISSN: 1545-5009
Publisher: Wiley-Liss Inc.
Note: Funding Information: This research was funded by Australian Federal Government Department of Health funding awarded to Zero Childhood Cancer, a joint initiative of Children's Cancer Institute Australia and The Kids Cancer Centre, Sydney Children's Hospitals Network, as well as grants from the National Health and Medical Research Council of Australia (NHMRC Fellowships APP1059804 and APP1157871 to RBL, NHMRC Program Grant 1091261). The authors thank Ms Georgina Eden and Ms Kathryn Evans for technical assistance, and the Children's Cancer Institute Tumour Bank for providing samples and related clinical information for this study. Children's Cancer Institute Australia is affiliated with UNSW Sydney and The Sydney Children's Hospitals Network. Funding Information: This research was funded by Australian Federal Government Department of Health funding awarded to Zero Childhood Cancer, a joint initiative of Children's Cancer Institute Australia and The Kids Cancer Centre, Sydney Children's Hospitals Network, as well as grants from the National Health and Medical Research Council of Australia (NHMRC Fellowships APP1059804 and APP1157871 to RBL, NHMRC Program Grant 1091261). The authors thank Ms Georgina Eden and Ms Kathryn Evans for technical assistance, and the Children's Cancer Institute Tumour Bank for providing samples and related clinical information for this study. Children's Cancer Institute Australia is affiliated with UNSW Sydney and The Sydney Children's Hospitals Network. Publisher Copyright: © 2019 Wiley Periodicals, Inc.
(Peer reviewed)