Acute myeloid leukemia (AML) is one of the most difficult cancers to treat. It has a poor prognosis, with a 20% rate of overall survival (OS) at 5 years in people older than 20 years and a 67% rate of OS at 5 years in patients younger than 20 years. For several decades, no significant advances were made in the treatment of AML, and induction treatment with cytotoxic therapy remained the standard of care in young, fit patients.

However, recent breakthroughs in AML research and the development of targeted drugs directed at specific mutations have led to an explosion of novel treatments with different mechanisms of action and fewer toxicities, such as IDH and FTL3 inhibitors.

Related Articles

In an editorial published in the American Journal of Hematology, Daniel A Pollyea, MD, MS, of the University of Colorado in Aurora, argued that the approval of venetoclax by the US Food and Drug Administration (FDA) should prompt researchers to investigate new drug development strategies for the treatment of AML. He questioned the current standard of care for AML treatment in the initial and relapse settings, the rationale underscoring research about and design and approval of new treatments, the clinical end points used in clinicial research, and the standards against which new drugs are measured.

Questioning the Current Standard of Care

The only induction treatment currently available for fit patients with AML is a combination regimen that includes 7 days of standard-dose cytarabine and 3 days of daunorubicin, doxorubicin, idarubicin, or mitoxantrone (7 + 3). The 7 + 3 induction regimen is known to lead to toxicity, lack effectiveness in most patients, and yield a worse prognosis in patients who relapse.

In the relapse setting, patients with AML have different biological profiles, and there is no consensus regarding a standard of care. Similarly, for older patients unfit to receive chemotherapy, there is no approved therapy in the upfront setting, yet the assumed standard of care is the 7 + 3 regimen even though it may only provide a marginal OS benefit. Treatment is individualized according to the patient’s tolerance of risk and chemotherapy.

Additionally, there is an ongoing debate about clinical end points and the standard of care in AML, both in induction and in the relapse setting. Although improved OS over the standard of care has been the accepted metric for determining the efficacy of new therapeutic agents, several new drugs have received approval without yielding a benefit in OS. In the absence of a standard of care in these settings, Dr Pollyea suggested that OS should not be considered a reference for FDA approval of new therapies, especially when new options show superior response rates and tolerability whereas it might take years of research to show superior OS.

However, response rate may not be an adequate clinical end point either, especially in the induction treatment setting. In this setting, novel products are typically tested in combination with established therapies such as 7 + 3 based on the assumption that the combination will demonstrate synergy. However, response rates following induction are already high, so novel treatment strategies may not lead to a significant change in response. As for OS, “the nuances of transplantation and the variety of treatments given in the relapsed setting could mask [the observation of an OS benefit],” Dr Pollyea wrote.

This practice perpetuates the 7 + 3 regimen as a standard of care. However, Dr Pollyea explained, these methods for determining induction treatment efficacy do not apply to current standards of treatment and have not led to any new discoveries in AML treatment.

Instead, Dr Pollyea proposed revising the traditional methods for assessment of response, assessment of fitness, and prognostication in AML to facilitate approval of effective and safe therapies.

“We should unhitch our wagons and not look back,” he wrote.