Next-generation sequencing of bone marrow samples from pediatric and young adult patients with acute lymphoblastic leukemia (ALL) treated with tisagenlecleucel was more accurate in predicting relapse than flow cytometry and monitoring of B-cell aplasia, according to the results from a study by Pulsipher et al published in Blood Cancer Discovery.

Studies show that treatment with tisagenlecleucel has produced high remission rates and durable remissions without additional therapy in high-risk pediatric and young adult patients with relapsed or refractory B-cell ALL. However, about half of the patients who experience remission will eventually relapse and require additional treatment, such as hematopoietic cell transplantation.

Accurately predicting which patients are likely to relapse could allow those patients who need a transplant to begin the process before the disease actually recurs. Bone marrow next-generation DNA sequencing (NGS)-based measurable residual disease (MRD) monitoring reliably predicts risk of relapse with sufficient time to consider approaches for relapse prevention, including bone marrow transplant or a second chimeric antigen receptor (CAR) T-cell infusion. 

Study Methodology

The researchers analyzed a total of 1,771 blood and bone marrow samples from 143 patients enrolled in the ENSIGN and ELIANA studies to assess the predictive value of flow cytometry and next-generation DNA sequencing measurable residual disease (NGS-MRD) monitoring at 1, 3, 6, 9, and 12 months after tisagenlecleucel infusion. For flow cytometry, cells were analyzed for the presence of CD9, CD10, CD13,  D19, CE20, CD22, CD33, CD34, CD38, CD45, CD58, CD58, CD66c, and CD123. For next-generation sequencing, the researchers analyzed the gene sequences of lgH, LgK, and lgL for rearrangements and translocations.

Results

The researchers found that NGS-MRD detection > 0 in bone marrow was highly associated with relapse. B-cell recovery (signifying loss of functional CAR-T cells) within the first year of treatment was associated with a hazard ratio for relapse of 4.5 (95% confidence interval [CI] = 2.03–9.97, P < .001).

Multivariate analysis at day 28 showed independent associations of bone marrow NGS-MRD > 0 (hazard ratio [HR] = 4.87, 95% CI = 2.18–10.8, P < .001) and B-cell recovery (HR = 3.33, 95% CI = 1.44–7.69, P = .005) with relapse. By 3 months, the bone marrow NGS-MRD hazard ratio increased to 12 (95% CI = 2.87–50, P < .001), whereas B-cell recovery was not independently predictive (HR = 1.27, 95% CI = 0.33–4.79, P = .7). Relapses occurring with persistence of B-cell aplasia were largely CD19-negative (23/25; 88%).

“Detectable bone marrow NGS-MRD reliably predicts risk with sufficient time to consider approaches to relapse prevention such as hematopoietic cell transplantation or second CAR T-cell infusion,” concluded the study authors.

Clinical Significance

“Detectable disease by bone marrow NGS-MRD with or without B-cell aplasia is highly predictive of relapse after tisagenlecleucel therapy for ALL. Clonotypic rearrangements used to follow NGS-MRD did not change after loss of CD19 or lineage switch. High-risk patients identified by these biomarkers may benefit from hematopoietic cell transplantation or investigational cell therapies,” according to the study authors.

“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,” said the lead author of this study Michael Pulsipher, MD, Professor of Pediatrics and Division Chief of Pediatric Hematology and Oncology at Intermountain Primary Children’s Hospital and the University of Utah Huntsman Cancer Institute, in a statement.

Disclosure: Funding for this study was provided by Novartis Pharmaceuticals Corporation. For full disclosures of the study authors, visit bloodcancerdiscov.aacrjournals.org.