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Sequencing-Based MRD Detection in Bone Marrow May Predict ALL Relapse After CAR T-Cell Therapy

NEW YORK – Minimal residual disease detection in bone marrow in the months after treatment appears to predict relapse in pediatric and young adult acute lymphoblastic leukemia patients who have received chimeric antigen receptor T-cell treatment tisagenlecleucel (Novartis' Kymriah; tisa-cel), according to research by investigators at the Children's Hospital of Philadelphia, the University of Pennsylvania, and other institutions.

"A key goal for our patients and families is not only to define which patients are at increased relapse risk and need further therapy, but also to identify patients heading toward longer-term benefit who might not need further therapies such as transplant," senior author Stephan Grupp, a pediatrics professor and chief of the Children's Hospital of Philadelphia and University of Pennsylvania Cell Therapy and Transplant, said in a statement.

In a study funded by Novartis and published in Blood Cancer Discovery on Wednesday, he and his colleagues used next-generation sequencing-based MRD detection (NGS-MRD) and multiparameter flow cytometry focused on more than a dozen cell surface proteins to search for traces of ALL in blood and bone marrow samples collected over time after tisa-cel treatment in 143 patients from two international, multicenter Phase II clinical trials.

Tisa-cel is an autologous CAR T-cell treatment that involves tuning a patient's own T cells to target CD19, a protein commonly found on the surface of ALL cells. While more than half of pediatric or young adult patients with relapsed or treatment-resistant ALL are able to reach long-term remission with tisa-cel treatment, the team explained, a significant proportion of patients who experience early remission eventually relapse.

In some cases, that relapse has been linked to the early reappearance of normal CD19-expressing immune B cells, which are typically depleted by CD19-targeting CAR T-cell treatments in a process known as B-cell aplasia, the researchers noted. But other resistance mechanisms have been identified as well.

"Our current recommendation to centers giving tisa-cel is to follow B cells in the blood monthly, using a standard test, as a way to predict patients at higher risk of relapse," Grupp said, cautioning B-cell aplasia monitoring would miss forms of relapse that involve CAR T-cell evasion due to muted tumor cell expression of CD19 in the absence of B-cell recovery.

Based on analyses on more than 1,700 bone marrow or blood samples taken at time points one, three, six, nine, and 12 months after treatment, the team found that NGS-MRD was more sensitive than flow cytometry for finding tumor cells in the blood or bone marrow. In addition, bone marrow NGS-MRD appeared to be a particularly promising method for picking up impending recurrence over a median follow-up time of more than 38 months.

"Our data show that [bone marrow NGS-MRD] measurements are the most sensitive biomarkers to date for defining risk of relapse after CAR T-cell therapy," the authors reported, adding that by three months and up to a year, "any detectable disease by [bone marrow NGS-MRD] was highly prognostic."

Disease progression or relapse was reported in all 41 of the patients available for follow-up who had MRD in their bone marrow at the three-month or six-month time points, the team noted, and the NGS-MRD approach identified signs of returning disease in the bone marrow samples much earlier than they could be spotted by flow cytometry.

The analyses also provided a look at B-cell aplasia dynamics in relation to relapse, demonstrating that B-cell recovery in the six months after CAR T-cell treatment is linked to enhanced relapse risk, though ties to relapse are less pronounced for B-cell aplasia measurements taken a year after treatment.

Given such results, the investigators suggested that clinicians consider intensifying treatment for ALL patients with early B-cell recovery after CAR T-cell treatment, as well as for those with bone marrow MRD detected by sequencing in the year after treatment — an approach that will reportedly be tested in an upcoming clinical trial.

"This is the first paper to show an approach that identifies markers of relapse that are very specific, allowing clinicians to add additional therapy prior to relapse that will prevent it," first author Michael Pulsipher, a transplantation and cellular therapy researcher with the Children's Hospital Los Angeles Cancer and Blood Disease Institute, said in a statement.

In a related commentary in Blood Cancer Discovery, Sara Ghorashian from the University College London's Great Ormond Street Institute of Child Health and Jack Bartram with the Great Ormond Street Hospital for Children, noted that the findings offer new insights into the significance of B-cell recovery at several points post-CAR T-cell treatment and demonstrate the additional role that NGS-MRD may have as a relapse risk marker over time.

Still, they cautioned against relying too heavily on individual NGS-MRD results and called for additional analyses in larger prospective studies. They also encouraged sampling from noninvasive peripheral blood sources rather than bone marrow, when possible.

"Whilst it is clear from these data that NGS-MRD has the potential to be a powerful predictor of relapse post infusion of tisagenlecleucel, to take these data forward, the wider applicability of this approach in a multi-center prospective validation is needed," Ghorashian and Bartram wrote, adding that "NGS-MRD should be compared to PCR-MRD as this is the next-most sensitive methodology most widely used in Europe."

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