Recent drug approvals for newly diagnosed acute myeloid leukemia: gifts or a Trojan horse?

Leukemia. 2020 Mar;34(3):671-681. doi: 10.1038/s41375-019-0704-5. Epub 2020 Jan 8.


Since 2017 the US Food and Drug Administration (FDA) has approved glasdegib, venetoclax, ivosidenib, midostaurin, CPX- 351, and gemtuzumab ozogamicin (GO) to treat persons with newly diagnosed acute myeloid leukemia. The European Medicines Agency (EMA) has done likewise for midostaurin, CPX-351, and GO. While increasing options for persons, particularly older ones, for whom current therapy is unsatisfactory, or simply not given, these approvals raise several concerns. Although the venetoclax and glasdegib approvals were for persons considered "unfit" for intensive induction, the criteria for fitness were not well defined (age ≥75 per se being insufficient) and are frequently subjective, making it likely that many subjects in the venetoclax and glasdegib registration trials were fit for intensive induction; for example, none had performance status 3-4. Fitness must be assessed together with the potential efficacy of a proposed therapy. We note the modest complete remission rates and durations in the venetoclax + hypomethylating agent trial. Although these formed the basis for FDA approval, it is unclear that better results might not have obtained with more intense induction, as several studies, with considerably longer-follow up, have suggested. Hence, we question the venetoclax (and glasdegib) approvals absent randomized comparisons with intense induction. Given the uncertain relation in older individuals between survival and complete remission (CR), much less responses less than CR, we are skeptical of the sole use of these responses in the ivosidenib and venetoclax approvals; we also question the use of survival, without event-free survival, in the glasdegib approval. Noting the midostaurin and CPX-351 approvals included populations not participating in the registration studies we suggest means to address this issue as well as those involving fitness, randomization, and endpoints.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Benzimidazoles / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cytarabine / pharmacology
  • Daunorubicin / pharmacology
  • Drug Approval*
  • Gemtuzumab / pharmacology
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Phenylurea Compounds / pharmacology
  • Pyridines / pharmacology
  • Randomized Controlled Trials as Topic
  • Staurosporine / analogs & derivatives
  • Staurosporine / pharmacology
  • Sulfonamides / pharmacology
  • United States
  • United States Food and Drug Administration


  • Antineoplastic Agents
  • Benzimidazoles
  • Bridged Bicyclo Compounds, Heterocyclic
  • CPX-351
  • Phenylurea Compounds
  • Pyridines
  • Sulfonamides
  • Cytarabine
  • Gemtuzumab
  • Staurosporine
  • midostaurin
  • glasdegib
  • venetoclax
  • ivosidenib
  • Glycine
  • Daunorubicin