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Equipotent doses of daunorubicin and idarubicin for AML: a meta-analysis of clinical trials versus in vitro estimation

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Abstract

In the treatment of acute myeloid leukemia (AML), the “7 + 3”-based strategy, combining cytarabine 100–200 mg/m2 for 7 days with an anthracycline for 3 days, remains the standard of care for younger and medically fit patients. Daunorubicin (DNR) and idarubicin (IDA) are the two anthracyclines most commonly used. DNR and IDA are used interchangeably with different conversion factors, as there is no high-level evidence on the equipotency of these two agents for AML treatment. To determine the equipotent doses of DNR and IDA, we first systematically reviewed studies directly comparing the clinical outcomes of AML induction therapy utilizing DNR and IDA. We found 15 articles that met our inclusion criteria and compared time-to-event survival end points as well as complete remission rates post-induction. The DNR:IDA equipotency ratio was estimated at 5.90 with 95% confidence interval (CI) 1.7–20.7. To validate the estimate from our meta-analysis biologically, we conducted in vitro tests comparing anti-AML activity of DNR and IDA against six AML cell lines and two primary AML cells from patients with different cytogenetic and molecular characteristics. Based on these in vitro data, the equipotency dose ratio between DNR and IDA was 4.06 with 95% CI 3.64–4.49. Combining the estimates from the meta-analysis and the in vitro data using inverse-variance weighting, the current best estimate of the DNR:IDA equipotent ratio is 4.1 with 95% CI 3.9–4.3. This estimate, however, is largely driven by the in vitro chemo-sensitivity data. Given clinical studies demonstrating the safety of IDA at higher doses, our work implies that dose intensification of IDA could be investigated in future clinical trials in AML.

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References

  1. Dohner H, Estey E, Grimwade D et al (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129(4):424–447

    Article  Google Scholar 

  2. Wei AH, Tiong IS (2017) Midostaurin, enasidenib, CPX-351, gemtuzumab ozogamicin, and venetoclax bring new hope to AML. Blood 130(23):2469–2474

    Article  CAS  Google Scholar 

  3. FDA (2017) Vyxeos (daunorubicin and cytarabine) liposome label. US Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209401s209000lbl.pdf. Accessed 23 Dec 2018

  4. FDA (2017) Mylotarg (gemtuzumab ozogamicin) label. US Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761060lbl.pdf. Accessed 23 Dec 2018

  5. FDA (2017) Rydapt (midostaurin) label. US Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997Orig207991Orig207992s207000lbl.pdf. Accessed 23 Dec 2018

  6. Goozner M (2012) Drug shortages delay cancer clinical trials. J Natl Cancer Inst 104(12):891–892

    Article  Google Scholar 

  7. AML Collaborative Group (1998) A systematic collaborative overview of randomized trials comparing idarubicin with daunorubicin (or other anthracyclines) as induction therapy for acute myeloid leukaemia. Br J Haematol 103(1):100–109

    Article  Google Scholar 

  8. Berman E, McBride M (1992) Comparative cellular pharmacology of daunorubicin and idarubicin in human multidrug-resistant leukemia cells. Blood 79(12):3267–3273

    CAS  PubMed  Google Scholar 

  9. Ross DD, Doyle LA, Yang W, Tong Y, Cornblatt B (1995) Susceptibility of idarubicin, daunorubicin, and their C-13 alcohol metabolites to transport-mediated multidrug resistance. Biochem Pharmacol 50(10):1673–1683

    Article  CAS  Google Scholar 

  10. Robert J, Rigal-Huguet F, Hurteloup P (1992) Comparative pharmacokinetic study of idarubicin and daunorubicin in leukemia patients. Hematol Oncol 10(2):111–116

    Article  CAS  Google Scholar 

  11. Children’s Oncology Group (2013) Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancer 4. http://www.survivorshipguidelines.org/pdf/LTFUGuidelines_40.pdf. Accessed 22 Feb 2018

  12. Zeidner JF, Foster MC, Blackford AL et al (2015) Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7 + 3) in newly diagnosed acute myeloid leukemia. Haematologica 100(9):1172–1179

    Article  CAS  Google Scholar 

  13. Burnett AK, Russell NH, Hills RK et al (2015) A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood 125(25):3878–3885

    Article  CAS  Google Scholar 

  14. Gong Q, Zhou L, Xu S, Li X, Zou Y, Chen J (2015) High doses of daunorubicin during induction therapy of newly diagnosed acute myeloid leukemia: a systematic review and meta-analysis of prospective clinical trials. PLoS One 10(5):e0125612

    Article  Google Scholar 

  15. Luskin MR, Lee JW, Fernandez HF et al (2016) Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups. Blood 127(12):1551–1558

    Article  CAS  Google Scholar 

  16. Lee JH, Joo YD, Kim H et al (2011) A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia. Blood 118(14):3832–3841

    Article  CAS  Google Scholar 

  17. Fernandez HF, Sun Z, Yao X et al (2009) Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 361(13):1249–1259

    Article  CAS  Google Scholar 

  18. Lowenberg B, Ossenkoppele GJ, van Putten W et al (2009) High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med 361(13):1235–1248

    Article  Google Scholar 

  19. Parmar MK, Torri V, Stewart L (1998) Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 17(24):2815–2834

    Article  CAS  Google Scholar 

  20. Diez P, Vogelius IS, Bentzen SM (2010) A new method for synthesizing radiation dose-response data from multiple trials applied to prostate cancer. Int J Radiat Oncol Biol Phys 77(4):1066–1071

    Article  Google Scholar 

  21. Eridani S, Singh AK, Slater NGP et al (1989) A phase II study of idarubicin versus daunorubicin in the treatment of acute non-lymphocytic leukaemia. Cancer J 2:296–299

    Google Scholar 

  22. Berman E, Heller G, Santorsa J et al (1991) Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood 77(8):1666–1674

    CAS  PubMed  Google Scholar 

  23. Mandelli F, Petti MC, Ardia A et al (1991) A randomised clinical trial comparing idarubicin and cytarabine to daunorubicin and cytarabine in the treatment of acute non-lymphoid leukaemia. A multicentric study from the Italian Co-operative Group GIMEMA. Eur J Cancer 27(6):750–755

    Article  CAS  Google Scholar 

  24. Vogler WR, Velez-Garcia E, Weiner RS et al (1992) A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study. J Clin Oncol 10(7):1103–1111

    Article  CAS  Google Scholar 

  25. Wiernik PH, Banks PL, Case DC Jr et al (1992) Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood 79(2):313–319

    CAS  PubMed  Google Scholar 

  26. Masaoka T, Ogawa M, Yamada K, Kimura K, Ohashi Y (1996) A phase II comparative study of idarubicin plus cytarabine versus daunorubicin plus cytarabine in adult acute myeloid leukemia. Semin Hematol 33(4 Suppl 3):12–17

    CAS  PubMed  Google Scholar 

  27. Reiffers J, Huguet F, Stoppa AM et al (1996) A prospective randomized trial of idarubicin vs daunorubicin in combination chemotherapy for acute myelogenous leukemia of the age group 55 to 75. Leukemia 10(3):389–395

    CAS  PubMed  Google Scholar 

  28. Creutzig U, Ritter J, Zimmermann M et al (2001) Idarubicin improves blast cell clearance during induction therapy in children with AML: results of study AML-BFM 93. AML-BFM Study Group. Leukemia 15(3):348–354

    Article  CAS  Google Scholar 

  29. Mandelli F, Vignetti M, Suciu S et al (2009) Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10. J Clin Oncol 27(32):5397–5403

    Article  CAS  Google Scholar 

  30. Pautas C, Merabet F, Thomas X et al (2010) Randomized study of intensified anthracycline doses for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study. J Clin Oncol 28(5):808–814

    Article  CAS  Google Scholar 

  31. Ohtake S, Miyawaki S, Fujita H et al (2011) Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study. Blood 117(8):2358–2365

    Article  CAS  Google Scholar 

  32. Creutzig U, Zimmermann M, Bourquin JP et al (2013) Randomized trial comparing liposomal daunorubicin with idarubicin as induction for pediatric acute myeloid leukemia: results from Study AML-BFM 2004. Blood 122(1):37–43

    Article  CAS  Google Scholar 

  33. Trifilio S, Zhou Z, Mehta J et al (2013) Idarubicin appears equivalent to dose-intense daunorubicin for remission induction in patients with acute myeloid leukemia. Leuk Res 37(8):868–871

    Article  CAS  Google Scholar 

  34. Lee JH, Kim H, Joo YD et al (2017) Prospective randomized comparison of idarubicin and high-dose daunorubicin in induction chemotherapy for newly diagnosed acute myeloid leukemia. J Clin Oncol 35(24):2754–2763

    Article  CAS  Google Scholar 

  35. Yates J, Glidewell O, Wiernik P et al (1982) Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood 60(2):454–462

    CAS  PubMed  Google Scholar 

  36. Burnett AK, Russell NH, Hills RK et al (2016) Higher daunorubicin exposure benefits FLT3 mutated acute myeloid leukemia. Blood 128(3):449–452

    Article  CAS  Google Scholar 

  37. Owattanapanich W, Owattanapanich N, Kungwankiattichai S, Ungprasert P, Ruchutrakool T (2018) Efficacy and toxicity of idarubicin versus high-dose daunorubicin for induction chemotherapy in adult acute myeloid leukemia: a systematic review and meta-analysis. Clin Lymphoma Myeloma Leuk 18(12):814–821e813

    Article  Google Scholar 

  38. Teuffel O, Leibundgut K, Lehrnbecher T, Alonzo TA, Beyene J, Sung L (2013) Anthracyclines during induction therapy in acute myeloid leukaemia: a systematic review and meta-analysis. Br J Haematol 161(2):192–203

    Article  CAS  Google Scholar 

  39. Recher C, Bene MC, Lioure B et al (2014) Long-term results of a randomized phase 3 trial comparing idarubicin and daunorubicin in younger patients with acute myeloid leukaemia. Leukemia 28(2):440–443

    Article  CAS  Google Scholar 

  40. Vail DM, Husbands BD, Kamerling SG et al (2012) Phase I study to determine the maximal tolerated doseand dose-limiting toxicities of orally administered idarubicin in dogs with lymphoma. J Vet Intern Med 26(3):608–613

    Article  CAS  Google Scholar 

  41. Case DC Jr, Gerber MC, Gams RA et al (1993) Phase II study of intravenous idarubicin in unfavorable non-Hodgkin’s lymphoma. Leuk Lymphoma 10(Suppl):73–79

    Article  Google Scholar 

  42. Tamura K (1996) A phase I study of idarubicin hydrochloride in patients with acute leukemia. The Idarubicin Study Group of Japan. Semin Hematol 33(4 Suppl 3):2–11

    CAS  PubMed  Google Scholar 

  43. Lee MH, Kim SY (2016) Phase I study of idarubicin dose escalation for remission induction therapy in acutemyeloid leukemia. Leuk Lymphoma 57(10):2268–2274

    Article  CAS  Google Scholar 

  44. Anderlini P, Benjamin RS, Wong FC et al (1995) Idarubicin cardiotoxicity: a retrospective study in acute myeloid leukemia and myelodysplasia. J Clin Oncol 13(11):2827–2834

    Article  CAS  Google Scholar 

  45. Li X, Xu S, Tan Y, Chen J (2015) The effects of idarubicin versus other anthracyclines for induction therapy of patients with newly diagnosed leukaemia. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD010432.pub2

    Article  PubMed  PubMed Central  Google Scholar 

  46. Danesi R, Fogli S, Gennari A, Conte P, Del Tacca M (2002) Pharmacokinetic-pharmacodynamic relationships of the anthracycline anticancer drugs. Clin Pharmacokinet 41(6):431–444

    Article  CAS  Google Scholar 

  47. Gallois L, Fiallo M, Garnier-Suillerot A (1998) Comparison of the interaction of doxorubicin, daunorubicin, idarubicin and idarubicinol with large unilamellar vesicles. Circular dichroism study. Biochim Biophys Acta 1370(1):31–40

    Article  CAS  Google Scholar 

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Acknowledgements

The work was partially funded by the NCI Grant P30CA134274 to the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center.

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Authors and Affiliations

  1. School of Medicine, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, 22 S. Greene St., Room N9E24, Baltimore, MD, 21201, USA

    Sunil Adige, Rena G. Lapidus, Brandon A. Carter-Cooper, Alison Duffy, Ciera Patzke, Jennie Y. Law, Maria R. Baer, Nicholas P. Ambulos, Ying Zou, Søren M. Bentzen & Ashkan Emadi

  2. Department of Medicine, University of Maryland, Baltimore, USA

    Sunil Adige, Rena G. Lapidus, Brandon A. Carter-Cooper, Jennie Y. Law, Maria R. Baer & Ashkan Emadi

  3. Department of Pharmacology, University of Maryland, Baltimore, USA

    Ashkan Emadi

  4. Department of Pathology, University of Maryland, Baltimore, USA

    Ying Zou

  5. Department of Pharmacy Practice and Science, School of Pharmacy, University of Maryland, Baltimore, USA

    Alison Duffy & Ciera Patzke

  6. Department of Epidemiology and Public Health, University of Maryland, Baltimore, MD, USA

    Søren M. Bentzen

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  1. Sunil Adige
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Contributions

SA performed the literature search, designed, created Supplementary Table 1 and Figure 1, and helped to write the manuscript. RGL and BACC performed in vitro studies and helped to write the manuscript. AD and CP provided consultation on pharmacy-related issues and helped to write the manuscript. JYL developed the second draft of the manuscript under the direction of AE. MRB helped to write the manuscript. YZ and NPA performed cytogenetic and molecular analyses. SMB developed the statistical design and performed statistical analysis and co-authored the final result section with AE. AE developed the study design, supervised data collection and all aspects of the study, helped with data analysis, coordinated different sections of the project, and wrote and revised the manuscript.

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Correspondence to Ashkan Emadi.

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Adige, S., Lapidus, R.G., Carter-Cooper, B.A. et al. Equipotent doses of daunorubicin and idarubicin for AML: a meta-analysis of clinical trials versus in vitro estimation. Cancer Chemother Pharmacol 83, 1105–1112 (2019). https://doi.org/10.1007/s00280-019-03825-2

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