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

Ann Hematol. 2020 Sep;99(9):1989-2007. doi: 10.1007/s00277-020-04186-0. Epub 2020 Jul 18.


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.

Keywords: Acute myeloid leukemia; Enasidenib; FLT3 inhibitors; Glasdegib; Ivosidenib; Venetoclax.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / blood*
  • Benzimidazoles / adverse effects
  • Benzimidazoles / blood
  • Bridged Bicyclo Compounds, Heterocyclic / adverse effects
  • Bridged Bicyclo Compounds, Heterocyclic / blood
  • Cytochrome P-450 CYP3A Inhibitors / adverse effects
  • Cytochrome P-450 CYP3A Inhibitors / blood*
  • Drug Approval*
  • Drug Interactions / physiology*
  • Drugs, Investigational / adverse effects
  • Drugs, Investigational / metabolism
  • Humans
  • Leukemia, Myeloid, Acute / blood*
  • Leukemia, Myeloid, Acute / drug therapy*
  • Long QT Syndrome / blood
  • Long QT Syndrome / chemically induced
  • Phenylurea Compounds / adverse effects
  • Phenylurea Compounds / blood
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / blood
  • Staurosporine / adverse effects
  • Staurosporine / analogs & derivatives
  • Staurosporine / blood
  • Sulfonamides / adverse effects
  • Sulfonamides / blood


  • Antineoplastic Agents
  • Benzimidazoles
  • Bridged Bicyclo Compounds, Heterocyclic
  • Cytochrome P-450 CYP3A Inhibitors
  • Drugs, Investigational
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Sulfonamides
  • Staurosporine
  • midostaurin
  • glasdegib
  • venetoclax