By Deborah Borfitz

December 7, 2020 | Four years ago, most patients with acute myeloid leukemia (AML) over the age of 60 faced the double whammy of a five-year survival rate below 5% as well as no FDA-approved targeted therapy available for their particular disease subtype to improve treatment outcomes. Physicians were also understandably reluctant to wait for results of molecular testing to make more personalized treatment decisions, so they typically default to the same chemotherapy regimen that has been used for the past 40 years, says John C. Byrd, M.D. chair of leukemia research at The Ohio State University and one of the clinical leads on the ongoing Beat AML Master Clinical Trial.

FDA-approved targeted therapy drugs for AML have since emerged that are specific to about 40% of all AML cases, Byrd says. The groundbreaking Beat AML umbrella study, sponsored by The Leukemia & Lymphoma Society's (LLS), has also been testing a variety of treatment approaches that are providing glimmers of hope against the devastating disease. 

As recently reported in Nature Medicine (DOI: 10.1038/s41591-020-1089-8), patients in the Beat AML study treated based on their cancer-driving genetic mutations fared better than those who opted for the one-size-fits-all approach with a net gain of about nine additional months of life, says Byrd.

Importantly, the prospective study demonstrated that it was safe and feasible to wait seven days on sequencing results to identify a potentially good treatment match, says Amy Burd, Ph.D., vice president of research strategy at the LLS and first author on the paper. The unprecedentedly fast turnaround time by Foundation Medicine, which had co-authors on the study, was a “really big deal” given that genomic analysis typically takes two to four weeks.

Master clinical trials are themselves notoriously hard to launch because of the level of collaboration involved. The “secret sauce” here is the convening power of the Leukemia & Lymphoma Society that enabled all parties to align on a common focus and mission, says Burd, noting that the LLS is the first nonprofit healthcare organization to sponsor a trial and hold the investigational new drug (IND) application from the FDA. “Once you convince people to put the patient first it is really easy to pull everybody together.” 

All enrollees in the Beat AML study have access to investigational treatment, including some FDA-approved targeted therapies never before tried in newly diagnosed patients, says Burd. Since its launch in 2016, the study has generally had between seven and 11 research arms and the involvement of about seven pharmaceutical companies.

The personalized approach was shown to improve outcomes for individuals in some molecular groups and confirmed the hypothesis that certain agents are particularly active. One of the initial treatment arms was dropped due to a lack of efficacy and another has been so effective that the LLS is now working with the manufacturer to “expand to something more registrational,” Burd says. Data from Beat AML is already being used for a randomized phase 3 study of one other targeted therapeutic.

The roughly 20% of patients who don’t have a molecular marker for AML that can be directly or indirectly targeted by one of the personalized therapies get assigned to standard therapy for the disease, says Byrd, which is either infusion of a combination of two chemotherapies (cytarabine and daunorubicin) or treatment with a hypomethylating agent. Three-quarters of all AML patients are over the age of 60 (68 is the average) and they often don’t respond well to the chemotherapy given to younger patients, he adds. The regimens used in Beat AML are the ones customarily used in both younger and older cancer patients. 

Currently, 12 prominent subtypes of AML have a known molecular marker but about 100 AML-related mutations have been identified and not all of them have a drug targeting them, says Byrd. But some drugs might work for that molecular group by targeting the signaling pathway.

Time To Decide

The data presented in the recently published study represents the 487 patients who were enrolled between Nov. 17, 2016 and Jan. 30, 2018. Of these, 395 were found to be eligible and screening and analysis was successfully completed within the seven-day timeline for 374 (94.7%) of them. Ultimately, 224 patients opted to participate on one of the 11 study arms that were active during that period.

Patients are all seen at one of 16 cancer centers designated by the National Cancer Institute (NCI) and, if stable, are allowed to go home during the weeklong wait for test results to ponder the decision about whether to participate in the trial, Byrd notes. In typical real-world practice, patients would immediately face a four- to five-week hospital stay and the grim news that the standard treatment has a 10% to 20% chance of killing them as well as a 30% to 50% chance of putting them in remission. 

Patients in Beat AML may or may not be hospitalized, depending on which type of therapy they receive, according to a LLS spokesperson. Some of the treatments are oral and can be taken at home and others are infusions given in a clinic. 

“Giving patients time to think about what they want to do is really important and something we have underappreciated,” says Burd, and “allows them to make different decisions than what was expected.”

Indeed, about 10% of patients in the study who would otherwise have been automatically rushed into therapy opted for supportive care, says Byrd. “They truly could make an informed decision.” 

The most common reasons individuals have opted out of Beat AML is the inconvenience of travel to the study site or a better trial was available to them, he adds. Misconceptions and suspicions about clinical trials among people of color and certain ethnicities may also play a role, as suggested by an entire body of literature on the topic.

The primary hypothesis of the Beat AML study—that older, newly diagnosed AML patients given a precision medicine assignment within seven days would do better than those emergently started on standard care—has effectively been proven out, says Byrd. The finding will be practice-changing for physicians treating patients outside of a clinical trial by making them more comfortable waiting on the molecular marker information and deciding on targeted therapies unless immediate action is “absolutely essential.”

The Beat AML trial, which will run indefinitely, has to date screened more than 1,000 patients, says Burd. Enrollment was until recently suspended due to COVID-19—initially out of concern for patients and later due to an inability to get genetic testing done as quickly as required across all study sites. Since opening back up in August, between 25 and 30 new patients are signing up monthly versus a pre-pandemic level of close to 35. 

But operation of the trial with the previously enrolled patients was unaffected because it was “set up in such a way that allowed us to do remote monitoring and oversight of all of our clinical sites,” she adds. Drugs could also be directly shipped to patients. 

More Studies, Same Platform

The same team and infrastructure used for Beat AML was to be tapped for a Beat COVID trial testing FDA-approved acalubrutinib (AstraZeneca’s Calquence) to see if it can help improve the grim survival odds among people suffering from both blood cancer and COVID-19, says Byrd, who wrote the protocol. Studies have shown blood cancer patients face a 30% to 60% risk of death if infected with SARS-CoV-2, and acalubrutinib previously showed promise is addressing deadly symptoms of COVID-19.

The FDA recently approved the Investigational New Drug application for the Beat COVID study, but enrollment has yet to begin, reports an LLS spokesperson. The holdup is due to results of a study of acalubrutinib in noncancer COVID-19 patients which, as recently announced by AstraZeneca, did not meet the primary efficacy endpoint. The company is now in discussions with LLS about next steps since the patient populations are different.

The Beat AML study has also helped paved the way for next year’s planned launch of a new master protocol, MyeloMATCH, an NCI-sponsored umbrella trial that will test treatments for AML and myelodysplastic syndromes (MDS, a blood cancer that frequently progresses to AML), Byrd adds. 

The LLS has just filed an IND for its own Stop MDS trial, using the same platform as Beat AML but targeting specific disease subtypes with few good therapeutic options, Byrd says. The study will initially have four arms—a combination of experimental agents and approved FDA-approved therapies—and enrollment is expected to begin in the second quarter of 2021. An additional three or four drugs are likely to be added to the study later on, he adds.

The LLS has also announced that an LLS PedALL study is being planned, primarily for pediatric AML patients who have relapsed, and that the IND will likely be submitted next spring. The study will be international and could begin enrolling patients next summer, says Burd.