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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

Trump returns from Walter Reed, White House backs FDA vaccine guidelines

The White House has reportedly backed away from a battle with the U.S. Food and Drug Administration (FDA), which has been advancing a timeline for a coronavirus vaccine that suggested an approval wouldn’t happen before Election Day.

The FDA has said it will need two months of observation in late-stage trials of any coronavirus vaccine in order to consider an emergency use authorization — an objective that conflicted with President Donald Trump’s desire to have an inoculation by early November. However, the White House signed off on the new guidelines Tuesday afternoon, backing away from a potential standoff that had worried health experts.

Trump, fresh from a stint in the hospital after being diagnosed with COVID-19, re-ignited the political debate over a vaccine timeline, putting him at odds with the FDA. In a video Monday evening, Trump also said that “vaccines are coming, momentarily” — even as FDA guidelines suggest a release wouldn’t happen until well after Election Day.

Trump said as much late Tuesday on Twitter, tagging FDA Commissioner Stephen Hahn while posting, “New FDA Rules make it more difficult for them to speed up vaccines for approval before Election Day. Just another political hit job!”

The White House was previously citing pharmaceutical companies’ objections to the two-month period.

Pfizer (PFE) CEO Albert Bourla said Tuesday the company has not been in touch with the White House on the topic and “we believe (FDA)’s independence is today more important than ever as public trust in (COVID-19) vaccine development has been eroded by the politicization of the process.”

In interviews in the past 24 hours, FDA’s top vaccine official, Dr. Peter Marks said a minimum of 7 weeks would be acceptable.

“We’ve made it clear we want to see a median of two months of follow-up for any of the vaccines…while it would be nice to have much more, we have to balance the safety we get up front with the need to try to save lives,” Marks said in an interview with the Journal of the American Medical Association.

He added that an emergency use authorization of a vaccine is likely by the end of the year, since it only takes weeks to review an EUA filing, compared to months of review for a full license approval.

But even that EUA filing could remain a question. Moncef Slaoui, head of Operation. Warp Speed, said during a symposium co-hosted by Johns Hopkins University and the University of Washington that he has advised companies not to file for an EUA until they have enough vaccine to distribute.

A critical date will come on October 22, the date established by a key FDA advisory body to determine official guidelines, even though Trump could still override any decision made then.

“Data from Phase 3 studies that includes a median follow-up duration of at least two months after completion of the full vaccination regimen to help provide adequate information to assess a vaccine’s benefit-risk profile,” according to the Vaccines and Related