06 December 2021


Sequencing bone marrow DNA in paediatric and young adult patients with acute lymphoblastic leukaemia could help to predict those who will suffer a relapse after CAR‑T cell therapy, according to a new US study.

The study was led by Dr Michael Pulsipher, from Pediatric Hematology and Oncology at Intermountain Primary Children’s Hospital and the Huntsman Cancer Institute of the University of Utah. The team found that in those who were treated with the CAR‑T cell therapy tisagenlecleucel (Kymriah), DNA sequencing-based detection of residual disease between three and 12 months accurately identified all who would eventually relapse. Other methods, including flow cytometry and monitoring recovery of B cell aplasia, were less accurate.

“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,” Dr Pulsipher added.

More than 80% of ALL patients treated with tisagenlecleucel, a chimeric antigen receptor T-cell (CAR-T) treatment, have a complete remission. However, about half of those eventually relapse and require additional treatment, such as a bone marrow transplant, the researchers say.

Dr Pulsipher, working with Dr Stephan Grupp, chief of Cell Therapy and Transplant at Children’s Hospital of Philadelphia and the University of Pennsylvania, said accurate prediction of relapse could enable patients who need a transplant to begin the process earlier, before the disease recurs.

“Our current recommendation to centres giving tisagenlecleucel is to follow B cells in the blood monthly, using a standard test, as a way to predict patients at higher risk of relapse,” said Dr Grupp, senior author of the study. “Monitoring B-cell aplasia is not ideal because it only picks up part of the relapse risk.” This is because tisagenlecleucel targets cells producing the marker CD19, but relapse caused by cancer cells which don’t produce CD19 can occur, even if normal B cells which do produce CD19 haven’t yet recovered.

In this study, Dr Pulsipher and colleagues investigated the predictive value of flow cytometry and next-generation DNA sequencing minimal residual disease (NGS-MRD) monitoring. The team used blood and bone marrow samples collected from the ELIANA and ENSIGN phase II clinical trials at one, three, six, nine, and 12 months after tisagenlecleucel infusion.

While flow cytometry could detect approximately one cancer cell per 10,000 blood cells, NGS-MRD was more sensitive, detecting one cancer cell per 1 to 10 million blood cells, depending on the number of cells in the sample. This meant that 131% more positive samples were detected via NGS-MRD (181 samples) than with flow cytometry (51 samples).

NGS-MRD of bone marrow samples was also more accurate in predicting relapse than flow cytometry. Of patients with any detectable disease DNA at three or six months post-infusion, 100% experienced either a relapse or progression to another therapy.

NGS-MRD detection found those at risk well in advance of relapse. Those who had NGS-MRD positivity at the lowest levels relapsed a median of 168 days after the positive test, and the assay detected all the relapses. By contrast, flow cytometry was positive at a median 52 days prior to relapse and missed half of the relapses.

NGS-MRD was more accurate than B-cell aplasia at predicting relapse. However, Dr Pulsipher recommended that NGS-MRD should complement monitoring of B-cell aplasia, rather than replacing it, because for some patients 28 days may not be sufficient for CAR-T cells to rid the body of all primary disease.

Dr Pulsipher and colleagues recommended that patients who lose B-cell aplasia within six months of therapy or present with NGS-MRD-positive disease in the marrow within the first year after therapy should receive additional treatment to prevent relapse.


Pulsipher MA, Han X, Maude SL, Laetsch TW, Qayed M, Rives S, Boyer MW, Hiramatsu H, Yanik GA, Driscoll T, Myers GD, Bader P, Baruchel A, Buechner J, Stefanski HE, Kalfoglou C, Nguyen K, Waldron ER, Mueller KT, Maier HJ, Kari G, and Grupp SA. (2021) “Next-Generation Sequencing of Minimal Residual Disease for Predicting Relapse after Tisagenlecleucel in Children and Young Adults with Acute Lymphoblastic Leukaemia.” Blood Cancer Discovery, doi: 10.1158/2643-3230.BCD-21-0095

Link: https://bloodcancerdiscov.aacrjournals.org/content/early/2021/11/26/2643-3230.BCD-21-0095

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