FDA Provides Final Guidance on Acute Myeloid Leukemia Drug Development

The original guidance was published as a draft 2 years ago, detailing the FDA's thoughts on the development of agents for the treatment of acute myeloid leukemia.

The FDA has issued a final guidance and 2 draft guidance’s providing information on the development of specific cancer drugs for the treatment of patients with acute myeloid leukemia (AML).

Originally, the guidance was published as a draft 2 years prior and outlined development of programs for agents for the treatment of AML and clinical trial designs assessing said agents in support of specific indications, including the maintenance setting and regimens in preparation for transplantation.

General Considerations for AML Treatments

When targeted therapeutics are developed, the FDA emphasized the necessity of also developing a companion diagnostic early in the drug development timeline, as they are sometimes necessary for the safe and efficacious use of a drug, according to the devices section of the recommendations.

The authors also indicated that after minimal residual disease (MRD) proved to be a valuable biomarker for subclinical tumor burden in patients with AML, MRD assays are recommended for selecting patients for protocols, treatment selection, or as an efficacy measure.

The clinical pharmacology section indicated that concomitant agents are frequently administered in those with AML, particularly those that are substrates, inducers, or inhibitors of cytochrome P450 enzymes. For example, triazole antifungals, which are moderate to strong CYP3A inhibitors, are frequently prescribed to patients diagnosed with AML to prevent invasive fungal infections.

It is believed that these agents could raise the systemic exposure of novel AML drugs that are also substrates of CYP3A, with a need for further research to assess the potential for harm. In the case of AML agents that are a substrate of CYP3A, the FDA recommends proactively incorporating dose modification early in clinical trial development.

The section further detailed that common supportive care agents such as antimicrobial prophylaxis and antiemetics can prolong QT interval. As such, adequate assessment early on in clinical development is needed to better examine the potential QT prolongation from AML agents. Implementation of a strategy to mitigate QT prolongation is necessary in agents with the potential to cause such effects.

This includes compiling a list of forbidden concomitant agents associated with QT prolongation with more frequent electrocardiogram and electrolytes monitoring; in particular, the guidance stated that this is important for patients experiencing nausea, vomiting, or diarrhea.

Liver or kidney function impairment may also be observed in patients diagnosed with AML, specifically in elderly populations. Before including patients with organ impairment in clinical research, the FDA recommended identifying elimination pathways of the parent agent and active metabolites.

If elimination pathways are discovered for the kidneys or liver, the impact of organ impairment on pharmacokinetics needs to be characterized early in clinical development. This will also form the basis, according to the guidance, of dose modification for those with organ impairment who are enrolled on late phase clinical trials.

In terms of special populations, the FDA recommended addressing pediatric patients with AML early in clinical development programs, such as considering adolescent patients for enrollment alongside adults. Moreover, if dosing for pediatric populations can’t be certainly determined using data from adult patients or first-in-human studies featuring those of a younger age, patients need to begin a phase 1 study with a novel monotherapy.

Although these phase 1 studies don’t need to exclusively include patients diagnosed with AML, a small cohort of pediatric patients with AML is needed to determine a recommended phase 2 dose before moving on to bigger trials, the FDA stated.

Of note, the FDA emphasized the importance of including a clinical trial population that is reflective of real-life patient populations. Older patients diagnosed with AML could have potential comorbidities related to age that may put them at a higher risk for worse outcomes with intensive treatment strategies.

Although the FDA does not require an upper limit of 75 years or older in clinical trial inclusion criteria for studies utilizing intensive chemotherapy, it encouraged using no age limit for non-intensive study regimens.

Notably, dose reductions may be necessary in patients aged 65 years or older, and safety, pharmacokinetics, and exposure data should be used to inform treatment decisions for that patient population. Use of a geriatric assessment tool to evaluate baseline physiologic function and help identify subgroups of patients who could be at risk for poor outcomes was recommended. The tool should be able to examine 1 or numerous function aspects with limited patient burden.

Appropriate Efficacy End Points in AML Research

The recommendations also detailed time-to-event end points that are appropriate to use in AML clinical trials.

Overall survival is one of the common utilized end points, defined as time from randomization to death of any cause. The guidelines also mentioned event-free survival (EFS), defined as time from randomization to induction treatment failure (ITF), relapse in those with a complete response after induction, or death from any cause. ITF was also outlined as not achieving initial interim efficacy end point within a determined period of time.

For an EFS analysis to be considered credible, the quality of data is of the utmost importance, the guidelines stated. The data quality issues that have been observed with these analyses are comparable to those observed with PFS analyses in solid tumors.

It was also stated that relapse-free survival can be considered an acceptable end point in clinical research that includes a population of patients in remission. This includes studies focused on the consolidation or maintenance settings. RFS was defined as time from randomization to relapse or death from any cause.

In terms of statistical considerations for time-to-event end points, primary analysis sets must include all randomized patients. Log-rank test has been accepted by the FDA for primary analysis method. The FDA emphasized being open to other strategies but require justification before implementation.


FDA. Acute Myeloid Leukemia: Developing Drugs and Biological Products for Treatment. Acute Myeloid Leukemia. October 17, 2022. Accessed December 13, 2022. https://bit.ly/3j2JUYv