Representation of Older Adults in FDA and EMA Registrational Trials for Acute Myeloid Leukemia (AML)

Introduction: AML is predominantly a disease of older adults with the median age at diagnosis of 69 years and over 60% patients diagnosed above the age of 65 years. The U.S. Food and Drug Administration (FDA) has published a guidance document on including adequate representation of older adults in cancer clinical trials that particularly emphasizes the importance of including adults older than age 75 (Inclusion of Older Adults, 2022). Differences may exist in drug response and toxicity due to age-related physiologic changes and comorbidities. This study evaluates the percent enrollment of older adults and age subgroup reporting in clinical trials that led to therapeutic approvals for AML from 2017 to 2023.

Methods: Therapeutic approvals in AML and associated clinical evidence were collected from the FDA and European Medicines Agency (EMA) websites. Data from each trial was searched in public databases using drug name, trial name, and/or registration number. Details regarding total number of participants, median age, age range, and proportion of patients >60 years of age, >65 years of age, and >75 years of age if reported were recorded.

Results: There were 11 new FDA and EMA drug approvals between 2017-2023 based on 12 trials. Eight trials focused on newly diagnosed (ND) and four on relapsed or refractory (R/R) AML. Four drugs were approved in 2017: midostaurin (ND FLT3-ITD/-TKD+ AML), enasidenib (R/R IDH2-mutated AML), CPX-351 (ND secondary-AML), and gemtuzumab ozogamicin (ND or R/R CD33+ AML). Gilteritinib (R/R FLT3-ITD/-TKD+), ivosidinib (R/R IDH1-mutated AML), and glasdegib+low-dose cytarabine (LDAC) [newly diagnosed AML ≥75 years or unfit for intensive chemotherapy (IC)] were approved in 2018. Venetoclax combinations with decitabine/azacitidine/LDAC (newly diagnosed AML ≥75 years or unfit for IC) were approved between 2018-2020. Ivosidinib was approved for ND AML ≥75 years or unfit for IC in 2019. In 2022, ivosidinib with azacitidine was approved in ND IDH1-mutated AML ≥75 years or unfit for IC. Olutasidinib was approved in 2022 for R/R AML with IDH1 mutation. Quizartinib was approved in 2023 in ND FLT3-ITD+ AML.

The median age in these trials ranged from 48-77 years. Four trials had an upper age limit of less than 75 years reflective of the eligibility criteria for these trials. The RATIFY trial for midostaurin did not enroll any patients older than 65 years. The registrational trials for quizartinib, CPX-351, and gemtuzumab ozogamicin did not enroll any patients older than 75 years. Five trials (ivosidinib in ND, ivosidinib with azacitidine, glasdegib+LDAC, and venetoclax combined with azacitidine or LDAC) had a median age of >75 years and these trials were designed as specific to patients ≥75 years or those ineligible for IC. Four trials reported subgroup percentages for patients >60 years, 6 reported >65 years, and 9 reported >75 years (including if there were no patients in the subgroup). Two trials (olutasidinib and ivosidinib for R/R AML) did not report any subgroup analyses based on age although the age range for these trials were 32-87 years with 153 participants and 18-89 years with 125 participants, respectively. Trials assessing FLT3 inhibitors had a lower median age than other therapies with median ages of 48 (midostaurin), 56 (quizartinib), and 62 (gilteritinib) years on these trials.

Conclusions: Most registrational trials for AML do report a subgroup for older adults. However, the ages of subgroup reporting are variable. This may be since some trials restricted older adult enrollment while others are designed for older adults ineligible for IC. In the future, reporting of trials should include and distinguish patients both older than 65 and older than 75 for subgroup analyses. Standardization of age subgroup reporting with subpopulation analysis will better enable benefit-risk profile of new agents for older adults with AML.