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Meta-Analysis Backs MRD as AML Trial Endpoint

Reaching measurable residual disease (MRD) negativity in acute myeloid leukemia (AML) was associated with improved survival outcomes and could be used as an endpoint to speed up trials of novel therapies, according to findings from a systematic review and meta-analysis.

In more than 11,000 patients across over 80 studies, those who achieved MRD-negative status following treatment had superior disease-free survival (DFS) compared to those who were MRD-positive (average HR 0.37, 95% bayesian credible interval [CrI] 0.34-0.40), and better overall survival (OS) as well (average HR 0.36, 95% CrI 0.33-0.39), reported Farhad Ravandi, MD, of MD Anderson Cancer Center in Houston, and colleagues.

Writing in JAMA Oncology, the team showed that the MRD-negative group had an estimated 5-year DFS of 64%, as compared to 25% for the MRD-positive group. Estimated 5-year OS was 68% versus 34%, respectively.

The association “was observed across ages, disease subtypes, time of assessment, specimen source, and most MRD detection methods,” the researchers wrote, with the exception being cytogenetics/fluorescence in situ hybridization (though only two studies used this method).

“Assessment of MRD in AML in cytomorphologic remission provides important prognostic information,” Ravandi and co-authors argued. “Given the robustness of the association of MRD with long-term outcomes across studies, use of MRD status as an eligibility criterion and/or an endpoint in clinical trial design could lead to more efficient assessment of the efficacy of new drugs and combination therapies in AML.”

Comparing the MRD-negative versus MRD-positive groups, the 5-year restricted mean survival time difference for OS was 15.37 months (95% CrI 13.58-17.19), and was 19.61 months for DFS (95% CrI 17.33-21.92).

“Given that the standard of care therapy for AML of ‘3+7’ has not changed in over 40 years and yet cures only a minority of adults with AML, more rapid drug development of therapies for AML is needed,” wrote Deepa Jeyakumar, MD, and Susan O’Brien, MD, both of the University of California-Irvine in Orange, in an accompanying editorial. “A lesson learned from the RATIFY trial is that it took over a decade from study conception to U.S. Food and Drug Administration approval of midostaurin based on using overall survival as a primary endpoint.”

Jeyakumar and O’Brien noted that the “suboptimal outcomes” for patients who fail to achieve MRD negativity support novel treatment approaches, with hypomethylating agents having shown potential benefit in clinical trials in this population so far.

MRD status is routinely used to guide treatment in acute lymphoblastic leukemia, Ravandi and co-authors noted, but while numerous publications have suggested its clinical value in AML, the optimal use either as a risk stratification tool or for clinical decision-making has been ill-defined, in part due to the heterogeneity of these earlier reports.

To further evaluate the role of MRD status in AML, the group performed a systematic review and meta-analysis that ultimately examined 81 studies and included a total of 11,151 patients, with MRD evaluated using various methods, including next-generation sequencing, polymerase chain reaction (PCR), and multiparameter flow cytometry (MFC).

The DFS analysis included 64 studies while

Endpoint Health and Vanderbilt University Medical Center to Create World’s First Precision Medicine Trial Network Focused on Critical Illness

Late-stage interventional trials will evaluate personalized approaches to existing care and novel targeted therapies

Endpoint Health, the first targeted therapeutics company focused on integrated solutions for critical illnesses, today announced a new strategic partnership with Vanderbilt University Medical Center (VUMC) to create the first precision medicine clinical trial network focused on late-stage clinical trials in critical illness. The network will combine leading critical illness researchers, trialists and premier medical centers from across the country to create a sustained system for conducting phase II and III interventional trials intended to validate precision medicine technologies, therapies, and deployable patient-centric care approaches. It will prioritize trials investigating promising precision-driven interventions to prevent or treat critical illnesses such as sepsis and acute respiratory distress syndrome (ARDS), which are the most expensive conditions to treat in the hospital setting and are associated with half of U.S. hospital mortality.

“Endpoint Health envisions a future where clinicians are empowered with an array of targeted therapies and personalized approaches to improve the outcomes of their sickest patients,” said Jason Springs, co-founder and CEO of Endpoint Health. “Our partnership with VUMC will establish a foundational piece of the ecosystem necessary to make this vision real for the critical care community.”

VUMC will serve as the trial network coordinating center with Endpoint Health providing the underlying technology that leverages digital and molecular patient data to predict likely therapeutic response. The goal of the network is to conduct an ongoing series of trials that study multiple precision-driven interventions to treat or prevent critical illness. Endpoint’s technology is already being piloted in a phase II randomized controlled trial at VUMC, which started enrolling patients this month. Endpoint will also sponsor the first precision interventional trial, which will evaluate one of the company’s investigational products.

“Precision medicine in critical care has long been a goal that healthcare has struggled to attain due to the complex and fast-moving nature of critical illnesses,” said Dr. Todd Rice, Director of the Medical Intensive Care Unit at VUMC. “Our partnership with Endpoint Health will help turn that vision into a reality. Together, we are building the infrastructure needed to run efficient and effective precision clinical trials that use advanced technologies to guide patient enrollment and treatment selection that ultimately improve patient outcomes.”

“COVID-19 has put a spotlight on the need for better, more personalized care that addresses critically ill patients in both the ED and ICU,” said Dr. Wesley Self, Vice Chair of Research in the Department of Emergency Medicine at VUMC. “Our ability to validate new treatments in a manner that can be translated into actual clinical practice quickly and effectively is an essential step to bringing life-saving targeted therapies to some of the sickest patients. This is an exciting development for the medical community, and ultimately patients, as it will facilitate significant new research and therapy discovery opportunities.”

About Endpoint Health

Endpoint Health combines therapeutics, companion diagnostics, and artificial intelligence (AI) into an integrated platform designed to improve outcomes of patients with critical