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Next-generation sequencing-based detection of minimal residual disease (NGS-MRD) was highly predictive for the risk of relapse in children or young adults with acute lymphoblastic leukemia (ALL) after treatment with the chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (Kymriah), according to a new study.

At every timepoint from 3 to 12 months after treatment, detectable disease by bone marrow NGS-MRD was highly prognostic, with 41 of 42 patients with detectable disease either relapsing or progressing to hematopoietic cell transplantation (HCT) or other therapies, reported Michael Pulsipher, MD, of Huntsman Cancer Institute at the University of Utah in Salt Lake City.

"This study demonstrates that the best biomarker described to date for determining risk of relapse at any given time throughout the first year after CAR T-cell therapy with tisagenlecleucel is NGS-MRD assessment of the marrow with a cutoff of >0 cells detected," they wrote in . "B-cell aplasia during the first year is also a strong biomarker, defining patients with possible long-term response. Those who lose B-cell aplasia prior to 6 months or develop NGS-MRD measures >0 on marrow examination are at high risk of relapse, and HCT or other cell or immune therapies should be considered."

According to the authors, second-generation CAR T-cell therapies have resulted in MRD-negative remissions by multiparametric flow cytometry (MFC) in 80% to 97% of patients. However, they also noted that some patients will lose their CAR T cells within a few months, and that one of the challenges in managing these patients is that there are no reliable markers to predict relapse.

While "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 multicenter prospective validation is needed," wrote Sara Ghorashian, BM BCh, PhD, and Jack Bartram, BM BCh, of Great Ormond Street Hospital for Children in London, in a .

They suggested that NGS-MRD should be compared with polymerase chain reaction (PCR)-MRD, "as this is the next most-sensitive methodology most widely used in Europe, with rigorous standardization and interlaboratory collaboration and quality assessment," and that "less invasive methods of MRD detection such as peripheral blood NGS-MRD should be more fully explored."

With the hypothesis that MRD measurements at various timepoints after achieving remission could identify those patients at high or low risk of relapse after CAR T-cell therapy, Pulsipher and team analyzed 1,771 MFC samples from 143 pediatric and young adult patients enrolled in the and trials, and compared MFC-MRD with NGS-MRD.

With the sampling schedule associated with this protocol (bone marrow at 1, 3, 6, 9, and 12 months), relapse was seen without previous MRD detection in:

• 50% of patients by MFC
• 31% of patients by NGS-MRD at a sensitivity of the standard cutoff of 10⁻⁶
• 0% of patients with NGS-MRD detectable below the 10⁻⁶ level

In addition to being highly predictive of relapse in ALL patients, NGS-MRD was able to identify those at risk well in advance of relapse, the authors reported. Among patients whose MRD was detected prior to relapse, the median time to relapse was 52 days from first MFC detection, 70 days from NGS-MRD detected above the cutoff of 10⁻⁶, and 168 days from NGS-MRD detected below the 10⁻⁶ cutoff.

"This shows that the more sensitive NGS measurements detect disease at levels that offer sufficient lead time prior to overt relapse to allow repeat sampling and/or coordination of therapeutic interventions," Pulsipher and colleagues observed.

They also looked at the influence of the presence or absence of B-cell aplasia and its effect on predictive models for patient outcomes, and showed that a combination of assessing B-cell aplasia along with bone marrow NGS-MRD measures is important, as patients who lose B-cell aplasia early do poorly.

Specifically, Pulsipher and colleagues found that patients who had B-cell recovery during the first year had significantly higher risk of relapse compared with those without B-cell recovery (HR 4.50, 95% CI 2.03-9.97, P<0.001), with predicted event-free survival rates at 2 years of 9% and 14% for those with B-cell recovery at 3 and 6 months, respectively.

Multivariate analysis at day 28 after treatment demonstrated independent associations of bone marrow NGS-MRD greater than 0 cells (HR 4.87, 95% CI 2.18-10.8, P<0.001) and B-cell recovery (HR 3.33, 95% CI 1.44-7.69, P=0.005) with relapse. At 3 months, patients with bone marrow NGS-MRD greater than 0 cells had extremely poor outcomes compared with those at 0 cells (HR 12.0, 95% CI 2.87-50.0, P<0.001), while B-cell recovery was not independently predictive of subsequent outcomes (HR 1.27, 95% CI 0.33-4.79, P=0.7).

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