Drug-drug interactions of newly approved small molecule inhibitors for acute myeloid leukemia


Several small molecule inhibitors (SMIs) have been recently approved for AML patients. These targeted therapies could be more tolerable than classical antineoplastics, but potential drug-drug interactions (DDI) are relatively frequent. Underestimation or lack of appropriate awareness and management of DDIs with SMIs can jeopardize therapeutic success in AML patients, which often require multiple concomitant medications in the context of prior comorbidities or for the prevention and treatment of infectious and other complications. In this systematic review, we analyze DDIs of glasdegib, venetoclax, midostaurin, quizartinib, gilteritinib, enasidenib, and ivosidenib. CYP3A4 is the main enzyme responsible for SMIs metabolism, and strong CYP3A4 inhibitors, such azoles, could increase drug exposure and toxicity; therefore dose adjustments (venetoclax, quizartinib, and ivosidenib) or alternative therapies or close monitoring (glasdegib, midostaurin, and gilteritinib) are recommended. Besides, coadministration of strong CYP3A4 inducers with SMIs should be avoided due to potential decrease of efficacy. Regarding tolerability, QTc prolongation is frequently observed for most of approved SMIs, and drugs with a potential to prolong the QTc interval and CYP3A4 inhibitors should be avoided and replaced by alternative treatments. In this study, we critically assess the DDIs of SMIs, and we summarize best management options for these new drugs and concomitant medications.

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  1. 1.

    Tallman MS, Wang ES, Altman JK, Appelbaum FR, Bhatt VR, Bixby D, Coutre SE, De Lima M, Fathi AT, Fiorella M, Foran JM, Hall AC, Jacoby M, Lancet J, LeBlanc TW, Mannis G, Marcucci G, Martin MG, Mims A, O'Donnell MR, Olin R, Peker D, Perl A, Pollyea DA, Pratz K, Prebet T, Ravandi F, Shami PJ, Stone RM, Strickland SA, Wieduwilt M, Gregory KM, OCN, Hammond L, Ogba N (2019) Acute myeloid leukemia, version 3.2019, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw 17(6):721–749

    CAS  Google Scholar 

  2. 2.

    Medeiros BC, Chan SM, Daver NG, Jonas BA, Pollyea DA (2019) Optimizing survival outcomes with post-remission therapy in acute myeloid leukemia. Am J Hematol 94(7):803–811

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Megías-Vericat JE, Ballesta-López O, Barragán E, Martínez-Cuadrón D, Montesinos P (2020) Tyrosine kinase inhibitors for acute myeloid leukemia: a step toward disease control? Blood Rev:100675 [Epub ahead of print]

  4. 4.

    Megías-Vericat JE, Ballesta-López O, Barragán E, Montesinos P (2019) IDH1-mutated relapsed or refractory AML: current challenges and future prospects. Blood Lymphat Cancer 9:19–32

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Pollyea DA, Amaya M, Strati P, Konopleva MY (2019) Venetoclax for AML: changing the treatment paradigm. Blood Adv 3(24):4326–4335

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Cortes JE, Heidel FH, Hellmann A, Fiedler W, Smith BD, Robak T, Montesinos P, Pollyea DA, DesJardins P, Ottmann O, Ma WW, Shaik MN, Laird AD, Zeremski M, O'Connell A, Chan G, Heuser M (2019) Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia 33(2):379–389

    CAS  Google Scholar 

  7. 7.

    Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Pfizer Labs (2018) DAURISMO® (glasdegib): US prescribing information. https://wwwaccessdatafdagov/drugsatfda_docs/label/2018/210656s000lblpdf Accessed 15 January 2020

  9. 9.

    Giri N, Lam LH, LaBadie RR, Krzyzaniak JF, Jiang H, Hee B, Liang Y, Shaik MN (2017) Evaluation of the effect of new formulation, food, or a proton pump inhibitor on the relative bioavailability of the smoothened inhibitor glasdegib (PF-04449913) in healthy volunteers. Cancer Chemother Pharmacol 80(6):1249–1260

    CAS  PubMed  Google Scholar 

  10. 10.

    Shaik MN, LaBadie RR, Rudin D, Levin WJ (2014) Evaluation of the effect of food and ketoconazole on the pharmacokinetics of the smoothened inhibitor PF-04449913 in healthy volunteers. Cancer Chemother Pharmacol 74(2):411–418

    CAS  PubMed  Google Scholar 

  11. 11.

    Shaik MN, Hee B, Wei H, LaBadie RR (2018) Evaluation of the effect of rifampin on the pharmacokinetics of the smoothened inhibitor glasdegib in healthy volunteers. Br J Clin Pharmacol 84(6):1346–1353

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    AbbVie Inc (2018) VENCLEXTA® (venetoclax): US prescribing information. https://wwwaccessdatafdagov/drugsatfda_docs/label/2018/208573s009lblpdf Accessed 15 January 2020

  13. 13.

    Salem AH, Agarwal SK, Dunbar M, Nuthalapati S, Chien D, Freise KJ, Wong SL (2016) Effect of low- and high-fat meals on the pharmacokinetics of venetoclax, a selective first-in-class BCL-2 inhibitor. J Clin Pharmacol 56(11):1355–1361

    CAS  PubMed  Google Scholar 

  14. 14.

    Agarwal SK, Hu B, Chien D, Wong SL, Salem AH (2016) Evaluation of rifampin’s transporter inhibitory and CYP3A inductive effects on the pharmacokinetics of venetoclax, a BCL-2 inhibitor: results of a single- and multiple-dose study. J Clin Pharmacol 56(11):1335–1343

    CAS  PubMed  Google Scholar 

  15. 15.

    Agarwal SK, Salem AH, Danilov AV, Hu B, Puvvada S, Gutierrez M, Chien D, Lewis LD, Wong SL (2017) Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL-2 inhibitor, in patients with non-Hodgkin lymphoma. Br J Clin Pharmacol 83(4):846–854

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Agarwal SK, DiNardo CD, Potluri J, Dunbar M, Kantarjian HM, Humerickhouse RA, Wong SL, Menon RM, Konopleva MY, Salem AH (2017) Management of venetoclax-posaconazole interaction in acute myeloid leukemia patients: evaluation of dose adjustments. Clin Ther 39(2):359–367

    CAS  PubMed  Google Scholar 

  17. 17.

    Freise KJ, Hu B, Salem AH (2018) Impact of ritonavir dose and schedule on CYP3A inhibition and venetoclax clinical pharmacokinetics. Eur J Clin Pharmacol 74(4):413–421

    CAS  PubMed  Google Scholar 

  18. 18.

    Salem AH, Hu B, Freise KJ, Agarwal SK, Sidhu DS, Wong SL (2017) Evaluation of the pharmacokinetic interaction between venetoclax, a selective BCL-2 inhibitor, and warfarin in healthy volunteers. Clin Drug Investig 37(3):303–309

    CAS  PubMed  Google Scholar 

  19. 19.

    Chiney MS, Menon RM, Bueno OF, Tong B, Salem AH (2018) Clinical evaluation of P-glycoprotein inhibition by venetoclax: a drug interaction study with digoxin. Xenobiotica 48(9):904–910

    CAS  PubMed  Google Scholar 

  20. 20.

    Agarwal SK, Tong B, Bueno OF, Menon RM, Salem AH (2018) Effect of azithromycin on venetoclax pharmacokinetics in healthy volunteers: implications for dosing venetoclax with P-gp inhibitors. Adv Ther 35(11):2015–2023

    CAS  PubMed  Google Scholar 

  21. 21.

    He H, Tran P, Gu H, Tedesco V, Zhang J, Lin W, Gatlik E, Klein K, Heimbach T (2017) Midostaurin, a novel protein kinase inhibitor for the treatment of acute myelogenous leukemia: insights from human absorption, metabolism, and excretion studies of a BDDCS II drug. Drug Metab Dispos 45(5):540–555

    CAS  PubMed  Google Scholar 

  22. 22.

    Committee for Medicinal Products for Human Use (CHMP) (2017) Assessment report. Midostaurin (Rydapt). EMEA/H/C/004095/0000. www.ema.europa.eu/contact. Accessed 15 January 2020

  23. 23.

    Novartis Pharmaceuticals Corporation (2017) RYDAPT® (midostaurin): US prescribing information. https://wwwaccessdatafdagov/drugsatfda_docs/label/2017/207997s000lblpdf Accessed 15 January 2020

  24. 24.

    Filppula AM, Mustonen TM, Backman JT (2018) In vitro screening of six protein kinase inhibitors for time-dependent inhibition of CYP2C8 and CYP3A4: possible implications with regard to drug-drug interactions. Basic Clin Pharmacol Toxicol 123(6):739–748

    CAS  PubMed  Google Scholar 

  25. 25.

    Dutreix C, Munarini F, Lorenzo S, Roesel J, Wang Y (2013) Investigation into CYP3A4-mediated drug–drug interactions on midostaurin in healthy volunteers. Cancer Chemother Pharmacol 72(6):1223–1234

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Ouatas T, Duval V, Sinclair K, Berkowitz N (2017) Concomitant use of midostaurin with strong CYP3A4 inhibitors: an analysis from the Ratify trial. Blood 130(suppl 1):3814–3814

    Google Scholar 

  27. 27.

    Tollkuci E (2019) Isavuconazole therapy in an FLT3 mutated acute myeloid leukemia patient receiving midostaurin: a case report. J Oncol Pharm Pract 25(4):987–989

    PubMed  Google Scholar 

  28. 28.

    Schlafer D (2019) Management of midostaurin-CYP3A4 drug-drug interactions in patients with acute myeloid leukemia. Oncology (Williston Park) 33(7):629381

  29. 29.

    Schlenk RF, Fiedler W, Salih HR, Wulf G, Thol F, Kündgen A, Kindler T, Salwender HJ, Lübbert M, Brossart P, Westermann J, Kraemer D, Goetze K, Horst HA, Krauter J, Girschikofsky M, Ringhoffer M, Südhoff T, Held G, Kirchner HH, Schmiegel W, Greil R, Griesshammer M, Lange E, Martens U, Hertenstein B, de Wit M, Koller E, Petzer AL, Hesse T, Runde V, Reimer P, Schultheis BS, Kirchen H, Griesinger F, Hebart H, Heil G, Kremers S, Nachbaur D, Basara N, Schwänen C, Schöndube D, Greiner J, Münnich A, Weber D, Gaidzik VI, Teleanu MV, Paschka P, Theis F, Benner A, Heuser M, Döhner K, Ganser A, Döhner H (2016) Impact of age and midostaurin-dose on response and outcome in acute myeloid leukemia with FLT3-ITD: interim-analyses of the AMLSG 16-10 trial. Blood 128(22):449

    Google Scholar 

  30. 30.

    Schlenk RF, Weber D, Fiedler W, Salih HR, Wulf G, Salwender H, Schroeder T, Kindler T, Lübbert M, Wolf D, Westermann J, Kraemer D, Götze KS, Horst HA, Krauter J, Girschikofsky M, Ringhoffer M, Südhoff T, Held G, Derigs HG, Schroers R, Greil R, Grießhammer M, Lange E, Burchardt A, Martens U, Hertenstein B, Marretta L, Heuser M, Thol F, Gaidzik VI, Herr W, Krzykalla J, Benner A, Döhner K, Ganser A, Paschka P, Döhner H, German-Austrian AML Study Group (2019) Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood 133(8):840–851

    CAS  PubMed  Google Scholar 

  31. 31.

    Hsiao S-H, Lusvarghi S, Huang Y-H, Ambudkar SV, Hsu S-C, Wu C-P (2019) The FLT3 inhibitor midostaurin selectively resensitizes ABCB1-overexpressing multidrug-resistant cancer cells to conventional chemotherapeutic agents. Cancer Lett 445:34–44

    CAS  PubMed  Google Scholar 

  32. 32.

    Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA (2017) Döhner H (2017) Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 377:454–464

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Tisdale JE (2016) Drug-induced QT interval prolongation and torsades de pointes: role of the pharmacist in risk assessment, prevention and management. Can Pharm J (Ott) 149(3):139–152

    Google Scholar 

  34. 34.

    Li J, Kankam M, Trone D, Gammon G (2019) Effects of CYP3A inhibitors on the pharmacokinetics of quizartinib, a potent and selective FLT3 inhibitor, and its active metabolite. Br J Clin Pharmacol 85(9):2108–2117

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Committee for Medicinal Products for Human Use (CHMP) (2019) Assessment report. Quizartinib (Vanflyta) EMEA/H/C/004468/0000 wwwemaeuropaeu/contact Accessed 15 January 2020

  36. 36.

    USA’s Food and Drug Administration (2019) FDA briefing document. Oncologic Drugs Advisory Committee (ODAC) Meeting Quizartinib Accessed 15 January 2020

  37. 37.

    Li J, Kumar P, Anreddy N, Zhang Y-K, Wang Y-J, Chen Y, Talele TT, Gupta K, Trombetta LD, Chen ZS (2017) Quizartinib (AC220) reverses ABCG2-mediated multidrug resistance: in vitro and in vivo studies. Oncotarget 8(55):93785–93799

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Bhullar J, Natarajan K, Shukla S, Mathias TJ, Sadowska M, Ambudkar SV, Baer MR (2013) The FLT3 inhibitor quizartinib inhibits ABCG2 at pharmacologically relevant concentrations, with implications for both chemosensitization and adverse drug interactions. PLoS One 8(8):e71266

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Li J, Trone D, Mendell J, O’Donnell P, Cook N (2019) A drug–drug interaction study to assess the potential effect of acid-reducing agent, lansoprazole, on quizartinib pharmacokinetics. Cancer Chemother Pharmacol 84(4):799–807

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Cortes JE, Kantarjian H, Foran JM, Ghirdaladze D, Zodelava M, Borthakur G, Gammon G, Trone D, Armstrong RC, James J, Levis M (2013) Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol 31(29):3681–3687

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Cortes JE, Tallman MS, Schiller GJ, Trone D, Gammon G, Goldberg SL, Perl AE, Marie JP, Martinelli G, Kantarjian HM, Levis MJ (2018) Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD–mutated, relapsed or refractory AML. Blood 132(6):598–607

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ (2019) Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol 20(7):984–997

    CAS  PubMed  Google Scholar 

  43. 43.

    Astellas Pharma US, Inc (2018) XOSPATA® (gilteritinib): US prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211349s000lbl.pdf Accessed 15 January 2020

  44. 44.

    Levis M, Smith C, Litzow M, Perl A, Altman J, James A, Kadokura T, Sargent B, Yuen G, Lu Z, Liu C, Nagase I, Bahceci E (2017) Drug-drug interaction potential of gilteritinib in healthy subjects and patients with relapsed/refractory acute myeloid leukemia. Haematologica 102:386

    Google Scholar 

  45. 45.

    Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ (2019) Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med 381(18):1728–1740

    CAS  PubMed  Google Scholar 

  46. 46.

    Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ et al (2017) Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 130(6):722–731

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Stein EM, DiNardo CD, Fathi AT, Pollyea DA, Stone RM, Altman JK, Roboz GJ, Patel MR, Collins R, Flinn IW, Sekeres MA, Stein AS, Kantarjian HM, Levine RL, Vyas P, MacBeth KJ, Tosolini A, VanOostendorp J, Xu Q, Gupta I, Lila T, Risueno A, Yen KE, Wu B, Attar EC, Tallman MS, de Botton S (2019) Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib. Blood 133(7):676–687

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Tong Z, Atsriku C, Yerramilli U, Wang X, Li Y, Reyes J, Fan B, Yang H, Hoffmann M, Surapaneni S (2019) Absorption, distribution, metabolism and excretion of an isocitrate dehydrogenase-2 inhibitor enasidenib in rats and humans. Xenobiotica 49(2):200–210

    CAS  PubMed  Google Scholar 

  49. 49.

    Li Y, Liu L, Gomez D, Chen J, Tong Z, Palmisano M, Zhou S (2018) Pharmacokinetics and safety of Enasidenib following single oral doses in Japanese and Caucasian subjects. Pharmacol Res Perspect 6(6):e00436

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Agios Pharmaceuticals. IDHIFA® (enasidenib): US prescribing Information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209606s000lbl.pdf Accessed 15 January 2020

  51. 51.

    Li Y, Connarn JN, Chen J, Tong Z, Palmisano M, Zhou S (2019) Modeling and simulation of the endogenous CYP3A induction marker 4β-hydroxycholesterol during enasidenib treatment. Clin Pharmacol 11:39–50

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Tong Z, Yerramilli U, Yao S, Young JD, Hoffmann M, Surapaneni S (2019) In vitro inhibition of human nucleoside transporters and uptake of azacitidine by an isocitrate dehydrogenase-2 inhibitor enasidenib and its metabolite AGI-16903. Xenobiotica 49(10):1229–1236

    CAS  PubMed  Google Scholar 

  53. 53.

    Dai D, Yang H, Nabhan S, Liu H, Hickman D, Liu G, Zacher J, Vutikullird A, Prakash C, Agresta S, Bowden C, Fan B (2019) Effect of itraconazole, food, and ethnic origin on the pharmacokinetics of ivosidenib in healthy subjects. Eur J Clin Pharmacol 75(8):1099–1108

    CAS  PubMed  Google Scholar 

  54. 54.

    Agios Pharmaceuticals. TIBSOVO® (Ivosidenib): US prescribing information. 2018 https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211192s001lbl.pdf Accessed 15 January 2020

  55. 55.

    Le K, Wada R, Dai D, Fan B, Liu G, Liu H, Attar EC, Agresta SV, Yang H (2018) Population pharmacokinetics of ivosidenib (AG-120) in patients with IDH1-mutant advanced hematologic malignancies [abstract]. Blood 132(Suppl 1):1394

    Google Scholar 

  56. 56.

    Fan B, Mellinghoff IK, Wen PY, Lowery MA, Goyal L, Tap WD, Pandya SS, Manyak E, Jiang L, Liu G, Nimkar T, Gliser C, Prahl Judge M, Agresta S, Yang H, Dai D (2020) Clinical pharmacokinetics and pharmacodynamics of ivosidenib, an oral, targeted inhibitor of mutant IDH1, in patients with advanced solid tumors. Investig New Drugs 38(2):433–444

    CAS  Google Scholar 

  57. 57.

    DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Swords R, Collins RH, Mannis GN, Pollyea DA, Donnellan W, Fathi AT, Pigneux A, Erba HP, Prince GT, Stein AS, Uy GL, Foran JM, Traer E, Stuart RK, Arellano ML, Slack JL, Sekeres MA, Willekens C, Choe S, Wang H, Zhang V, Yen KE, Kapsalis SM, Yang H, Dai D, Fan B, Goldwasser M, Liu H, Agresta S, Wu B, Attar EC, Tallman MS, Stone RM, Kantarjian HM (2018) Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med 378(25):2386–2398

    CAS  PubMed  Google Scholar 

  58. 58.

    Cuyàs E, Fernández-Arroyo S, Corominas-Faja B, Rodríguez-Gallego E, Bosch-Barrera J, Martin-Castillo B, De Llorens R, Joven J, Menendez JA (2015) Oncometabolic mutation IDH1 R132H confers a metformin-hypersensitive phenotype. Oncotarget 6(14):12279–12296

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Pagano L, Akova M, Dimopoulos G, Herbrecht R, Drgona L, Blijlevens N (2011) Risk assessment and prognostic factors for mould-related diseases in immunocompromised patients. J Antimicrob Chemother 66(Suppl 1):i5–i14

    CAS  PubMed  Google Scholar 

  60. 60.

    Pagano L, Busca A, Candoni A, Cattaneo C, Cesaro S, Fanci R, Nadali G, Potenza L, Russo D, Tumbarello M, Nosari A, Aversa F, SEIFEM (Sorveglianza Epidemiologica Infezioni Fungine nelle Emopatie Maligne) Group (2017) Risk stratification for invasive fungal infections in patients with hematological malignancies: SEIFEM recommendations. Blood Rev 31:17–29

    PubMed  Google Scholar 

  61. 61.

    Rambaldi B, Russo D, Pagano L (2016) Defining invasive fungal infection risk in hematological malignancies: a new tool for clinical practice. Mediterr J Hematol Infect Dis 9:e2017012

    Google Scholar 

  62. 62.

    Patel HP, Perissinotti AJ, Patel TS, Bixby DL, Marshall VD, Marini BL (2019) Incidence and risk factors for breakthrough invasive mold infections in acute myeloid leukemia patients receiving remission induction chemotherapy. Open Forum Infect Dis 6(5):ofz176

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Nucci M, Anaissie E (2014) How we treat invasive fungal diseases in patients with acute leukemia: the importance of an individualized approach. Blood 124:3858–3869

    CAS  PubMed  Google Scholar 

  64. 64.

    Maertens JA, Girmenia C, Brüggemann RJ, Duarte RF, Kibbler CC, Ljungman P, Racil Z, Ribaud P, Slavin MA, Cornely OA, Peter Donnelly J, Cordonnier C (2018) European guidelines for primary antifungal prophylaxis in adult haematology patients: summary of the updated recommendations from the European Conference on Infections in Leukaemia. J Antimicrob Chemother 73(12):3221–3230

    CAS  PubMed  Google Scholar 

  65. 65.

    Mellinghoff SC, Panse J, Alakel N, Behre G, Buchheidt D, Christopeit M, Hasenkamp J, Kiehl M, Koldehoff M, Krause SW, Lehners N, von Lilienfeld-Toal M, Löhnert AY, Maschmeyer G, Teschner D, Ullmann AJ, Penack O, Ruhnke M, Mayer K, Ostermann H, Wolf HH, Cornely OA (2018) Primary prophylaxis of invasive fungal infections in patients with haematological malignancies: 2017 update of the recommendations of the infectious diseases working party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO). Ann Hematol 97(2):197–207

    PubMed  Google Scholar 

  66. 66.

    Astellas Pharma US, Inc (2015) CRESEMBA® (isavuconazole): US prescribing information. https://wwwaccessdatafdagov/drugsatfda_docs/label/2015/207500Orig1s000lblpdf Accessed 15 January 2020

  67. 67.

    DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, Arellano M, Frattini MG, Kantarjian H, Popovic R, Chyla B, Xu T, Dunbar M, Agarwal SK, Humerickhouse R, Mabry M, Potluri J, Konopleva M, Pollyea DA (2018) Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol 19(2):216–228

    CAS  PubMed  Google Scholar 

  68. 68.

    DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, Frankfurt O, Konopleva M, Wei AH, Kantarjian HM, Xu T, Hong WJ, Chyla B, Potluri J, Pollyea DA, Letai A (2019) Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 133(1):7–17

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Rausch CR, DiNardo CD, Maiti A, Jammal N, Kadia TM, Marx K, Borthakur GM, Savoy JM, Pemmaraju N, Dipippo A, Daver NG, Chew S, Sasaki K, Issa GC, Naqvi K, Ravandi F, Kantarjian HM, Konopleva MY (2019) Venetoclax dosing in combination with antifungal agents: real world experience in patients with acute myeloid leukemia. Blood 134(Supplement_1):2640

    Google Scholar 

  70. 70.

    Stone RM, DeAngelo DJ, Klimek V, Galinsky I, Estey E, Nimer SD, Grandin W, Lebwohl D, Wang Y, Cohen P, Fox EA, Neuberg D, Clark J, Gilliland DG, Griffin JD (2005) Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 105:54–60

    CAS  PubMed  Google Scholar 

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This study was supported in part by a grant from the “Instituto Carlos III” (PI16/00665) and the “Instituto Investigacion Sanitaria La Fe” (2019/052-1) assigned to the Pharmacy and Hematology Departments.

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Correspondence to Pau Montesinos.

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Pau Montesinos reports these potential conflicts of interest, AbbVie: advisory board, speakers bureau, research support; Astellas: research support, consultant, speakers bureau, advisory board; Agios: consultant; Tolero Pharmaceutical: consultant; Glycomimetics: consultant; Forma Therapeutics: consultant; Celgene: research support, consultant, speakers bureau, advisory board; Daiichi Sankyo: research support, consultant, speakers bureau, advisory board; Incyte: speakers bureau, advisory board; Janssen: research support, speakers bureau, advisory board; Karyopharm: research support, advisory board; Novartis: research support, speakers bureau, advisory board; Pfizer: research support, speakers bureau, advisory board; Teva: research support, speakers bureau, advisory board. The rest of authors declare that there are no competing financial interests in relation to the work described.

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Megías-Vericat, J.E., Solana-Altabella, A., Ballesta-López, O. et al. Drug-drug interactions of newly approved small molecule inhibitors for acute myeloid leukemia. Ann Hematol 99, 1989–2007 (2020). https://doi.org/10.1007/s00277-020-04186-0

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  • Acute myeloid leukemia
  • Glasdegib
  • FLT3 inhibitors
  • Ivosidenib
  • Enasidenib
  • Venetoclax