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Continuous 72-h infusion of zosuquidar with chemotherapy in patients with newly diagnosed acute myeloid leukemia stratified for leukemic blast P-glycoprotein phenotype

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Abstract

Purpose

To evaluate the safety, tolerability, pharmacodynamics (PD), and potential efficacy of zosuquidar (Zos) in combination with daunorubicin and cytarabine in elderly patients with newly diagnosed acute myeloid leukemia (AML).

Methods

Patients with AML (N = 106) were treated with Zos as a 72-h continuous intravenous (CIV) infusion along with chemotherapy. Leukemic blasts from the patients were assessed for P-glycoprotein (P-gp) function using ex vivo bioassays for screening and PD analyses. Patient outcomes were categorized according to primary (N = 56) and secondary (N = 50) AML cohorts (pAML and sAML, respectively) and stratified into P-gp-high and P-gp-low subgroups.

Results

Patients with P-gp-high blasts exhibited comparable overall remission rates (ORR) to those with P-gp-low blasts in both the pAML and sAML cohorts. The P-gp-high and P-gp-low subgroups in the pAML cohort exhibited similar overall survival (OS). Patients with sAML and P-gp-high blasts exhibited significantly better OS than those in the P-gp-low subgroup. PD analyses revealed that Zos infusion provided 82 h of uninterrupted effective ≥ 90% inhibition of P-gp functional activity in leukemic blasts.

Conclusions

These observations provide evidence of Zos efficacy with the 72-h CIV infusion approach. The similarity of ORR in the P-gp-high and P-gp-low subgroups is consistent with Zos-mediated neutralization of P-gp as verified by PD analyses. The bioassay identified sAML patients most likely to respond favorably to Zos co-therapy indicating feasibility as a Zos companion diagnostic. A follow-up placebo-controlled trial is needed to verify these promising results.

ClinicalTrials.gov Identifier

NCT00129168; First posted on August 11, 2005.

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Data availability

De-identified individual participant data that underlines the reported results will be made available upon reasonable request. Proposals for access should be addressed to the corresponding author by email at jfmphd@yahoo.com.

References

  1. Begna KH, Ali W, Gangat N, Elliott MA, Al-Kali A, Litzow MR, Hook CC et al (2021) Mayo Clinic experience with 1123 adults with acute myeloid leukemia blood Cancer. Blood Cancer J 11:46–54. https://doi.org/10.1038/s41408-021-00435-1

    Article  PubMed  PubMed Central  Google Scholar 

  2. Premnath N, Madanat YF (2023) Paradigm shift in the management of acute myeloid leukemia—approved options in 2023. Cancers 15:1–21. https://doi.org/10.3390/cancers15113002

    Article  CAS  Google Scholar 

  3. Orvain C, Rodríguez-Arbolí E, Othus M, Sandmaier BM, Deeg HJ, Appelbaum FR et al (2023) Association between prior cytotoxic therapy, antecedent hematologic disorder, and outcome after allogeneic hematopoietic cell transplantation in adult acute myeloid leukemia. Cancers 15:352–365. https://doi.org/10.3390/cancers1502035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chen KG, Sikic BI (2012) Molecular pathways: regulation and therapeutic implications of multidrug resistance. Clin Cancer Res 18(7):1863–1869. https://doi.org/10.1158/1078-0432.CCR-11-1590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Shaffer BC, Gillet J-P, Patel C, Baer MR, Bates SE, Gottesman MM et al (2012) Drug resistance: still a daunting challenge to the successful treatment of AML. Drug Resist Update 15(1–2):62–69. https://doi.org/10.1016/j.drup.2012.02.001

    Article  CAS  Google Scholar 

  6. Arwanih EY, Louisa M, Rinaldi I, Wanandi SI (2022) Resistance mechanism of acute myeloid leukemia cells against daunorubicin and cytarabine: a literature review. Cureus 14(12):e33165. https://doi.org/10.7759/cureus.33165

    Article  PubMed  PubMed Central  Google Scholar 

  7. Boyer T, Gonzales F, Barthélémy, Marceau-Renaut A, Marceau-Renaut A, Peyrouze P, Guihard S et al (2019) Clinical significance of ABCB1 in acute myeloid leukemia: a comprehensive study. Cancers 11:1–15. https://doi.org/10.3390/cancers11091323

    Article  CAS  Google Scholar 

  8. Markus Schaich S, Soucek C, Thiede, Ehninger G, Illmer T, SHG AML96 Study Group (2005) MDR1 and MRP1 gene expression are independent predictors for treatment outcome in adult acute myeloid leukaemia. Br J Haematol 128:324–332. https://doi.org/10.1111/j.1365-2141.2004.05319.x

    Article  CAS  PubMed  Google Scholar 

  9. Dantzig AH, Law KL, Cao J, Starling JJ (2001) Reversal of multidrug resistance by the P-glycoprotein modulator, LY335979, from the bench to the clinic. Curr Med Chem 8(1):39–50

    Article  CAS  PubMed  Google Scholar 

  10. Goebel J, Chmielewski J, Hrycyna CA (2021) The roles of the human ATP-binding cassette transporters P-glycoprotein and ABCG2 in multidrug resistance in cancer and at endogenous sites: future opportunities for structure-based drug design of inhibitors. Cancer Drug Resist 4:784–804. https://doi.org/10.20517/cdr.2021.19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Robey RW, Pluchino KM, Hall MD, Fojo AT, Bates SE, Gottesman MM (2018) Revisiting the role of efflux pumps in multidrug-resistant cancer. Nat Rev Cancer 18(7):452–464. https://doi.org/10.1038/s41568-018-0005-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lancet JE, Baer MR, Duran GE, List AF, Fielding R, Marcelletti JF et al (2009) A phase I trial of continuous infusion of the multidrug resistance inhibitor zosuquidar with daunorubicin and cytarabine in acute myeloid leukemia. Leuk Res 33:1055–1061. https://doi.org/10.1016/j.leukres.2008.09.015

    Article  CAS  PubMed  Google Scholar 

  13. Callies S, de Alwis DP, Mehta A, Burgess M, Aarons L (2004) Population pharmacokinetic model for daunorubicin and daunorubicinol coadministered with zosuquidar.3HCl (LY335979). Cancer Chemo Pharmacol 54:39–48. https://doi.org/10.1007/s00280-004-0775-4

    Article  CAS  Google Scholar 

  14. Gerrard G, Payne E, Baker RJ, Jones DT, Potter M, Prentice HG et al (2004) Clinical effects and P-glycoprotein inhibition in patients with acute myeloid leukemia treated with zosuquidar trihydrochloride, daunorubicin and cytarabine. Haematologica 89(7):782–790

    CAS  PubMed  Google Scholar 

  15. Sandler A, Gordon M, De Alwis DP, Pouliquen I, Green L, Marder P et al (2004) A phase I trial of a potent P-glycoprotein inhibitor, zosuquidar trihydrochloride (LY335979), administered intravenously in combination with doxorubicin in patients with advanced malignancy. Clin Cancer Res 10:3265–3272. https://doi.org/10.1158/1078-0432.CCR-03-0644

    Article  CAS  PubMed  Google Scholar 

  16. Marcelletti JF, Sikic BI (2023) A clinical trial of zosuquidar plus gemtuzumab ozogamicin (GO) in relapsed or refractory acute myeloid leukemia (RR AML): evidence of efficacy based on leukemic blast P-glycoprotein functional phenotype. Cancer Chemother Pharmacol 92(5):369–380. https://doi.org/10.1007/s00280-023-04578-9

    Article  CAS  PubMed  Google Scholar 

  17. Cripe LD, Uno H, Paietta EM, Litzow MR, Ketterling RP, Bennett JM et al (2010) Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: a randomized, placebo-controlled, trial of the Eastern Cooperative Oncology Group (ECOG 3999). Blood 116(20):4077–4085. https://doi.org/10.1182/blood-2010-04-277269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Marcelletti JF, Paietta E, Cripe LD, Sikic BI (2019) Evidence of a role for functional heterogeneity in multidrug resistance (MDR) transporters in clinical trials of P-glycoprotein modulation in acute myeloid leukemia. Cytometry B Clin Cytom 96(1):57–66. https://doi.org/10.1002/cyto.b.21737

    Article  CAS  PubMed  Google Scholar 

  19. Green LJ, Marder P, Slapak CA (2001) Modulation by LY335979 of P-glycoprotein function in multidrug-resistant cell lines and human natural killer cells. Biochem Pharmacol 61:1393–1399

    Article  CAS  PubMed  Google Scholar 

  20. Marcelletti JF, Multani PS, Lancet JE, Baer MR, Sikic BI (2009) Leukemic blast and natural killer cell P-glycoprotein function and inhibition in a clinical trial of zosuquidar infusion in acute myeloid leukemia. Leuk Res 33:769–774. https://doi.org/10.1016/j.leukres.2008.09.020

    Article  CAS  PubMed  Google Scholar 

  21. Polley M-YC, Dignam JJ (2021) Statistical considerations in the evaluation of continuous biomarkers. J Nucl Med 62:605–611. https://doi.org/10.2967/jnumed.120.251520

    Article  PubMed  PubMed Central  Google Scholar 

  22. Wang Q, Tardi P, Sadowski N (2020) Pharmacokinetics, drug metabolism, and tissue distribution of CPX-351 in animals. Nanomedicine: NBM 30:1–12. https://doi.org/10.1016/j.nano.2020.102275

    Article  CAS  Google Scholar 

  23. Libby E, Hromas R (2010) Dismounting the MDR horse. Blood 116(20):4037–4038. https://doi.org/10.1182/blood-2010-09-304311

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thankfully acknowledge the participation of the following investigators (shown are institutional associations at the time of the study) and their respective teams in the conduct of this trial, including investigator (1) Jeff Lancet, MD., H. Lee Moffitt Cancer Center (Tampa, FL), (2) Larry Cripe, MD., Indiana Univ. (Indianapolis, IN), (3) Steve Petersdorf, MD, Univ. of Washington (Seattle WA), (4) Selina Luger, MD, Univ. of Pennsylvania (Philadelphia, PA), (5) Meir Wetzler, MD, Roswell Park Cancer Institute (Buffalo, NY), (6) Ivana Gojo, MD, Univ. of Maryland Medical System (Baltimore, MD), (7) Martin Tallman, MD, Northwestern Univ. (Chicago, IL), and (8) Jason Gotlib, MD, Stanford Cancer Center, Stanford Univ. School of Medicine (Stanford, CA).

Funding

This study was funded by Kanisa Pharmaceuticals, San Diego, CA, USA. Additional funding was provided by the NIH to the laboratories of Branimir I. Sikic, R01 CA114037, and R01 CA184968. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. All authors had direct access to all raw data and calculations used for figures and tables presented herein.

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Authors and Affiliations

  1. Marcelletti Consulting, San Diego, CA, USA

    John F. Marcelletti

  2. Clinical and Translational Research Unit, Stanford Cancer Institute, Stanford, CA, USA

    Branimir I. Sikic

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  1. John F. Marcelletti
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Contributions

BIS designed and oversaw the conduct of the clinical trial. JFM oversaw conduct of the bioassays and conducted the statistical analyses. JFM and BIS prepared the manuscript.

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Correspondence to John F. Marcelletti.

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Marcelletti, J.F., Sikic, B.I. Continuous 72-h infusion of zosuquidar with chemotherapy in patients with newly diagnosed acute myeloid leukemia stratified for leukemic blast P-glycoprotein phenotype. Cancer Chemother Pharmacol (2024). https://doi.org/10.1007/s00280-024-04656-6

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