Abnormal bone marrow findings post CAR-T cell therapy help uncover responses to treatment

From the Yeung and Naresh labs, Translational Sciences and Therapeutics Division

Chimeric antigen receptor-T cell (CAR-T cell) therapies have been a significant advance in the field of cancer immunotherapeutics in recent years, particularly for B-cell malignancies. Yet, this innovative treatment, where patients’ own T cells engineered to target tumor cells, doesn’t come without its own risks. Cytokine-release syndrome (CRS), in which immune cells release very large and potentially deadly quantities of inflammatory cytokines, cytopenia, a reduction in cell numbers, and macrophage activation syndrome (MAS) are some common adverse events seen in CAR-T cell patients. Despite the high incidence of morbidities tied to cellular responses, there has been a significant lack of studies on bone marrow of patients experiencing adverse effects. But why, you might ask? Almost certainly upstream contributions to cytopenia, for instance, stem from the bone marrow, noted Dr. Cecilia Yeung, a Professor in the Translational Sciences and Therapeutics Division.

The initial observation that led to this study recently published in the European Journal of Haematology by Dr. Yeung and Dr. Kikkeri Naresh, was made here at the Hutch more than 7 years ago. Looking at slides of bone marrow samples from some of the earliest CAR-T cell patients, they observed some unexpected findings: there were features consistent with dysplasia, or abnormal presentation of cells, where they were not expecting to see such a phenomenon. As more and more CAR-T cell patients were seen in the Fred Hutch clinic, bone marrow samples were routinely collected, something almost no other institution had the foresight to do. With nearly all Fred Hutch CAR-T cell patients represented with samples at timepoints from before and after the start of treatment, this collection of samples was the ideal resource to help better characterize the cell abnormalities seen in the early CAR-T patients.

Flow plot of patient bone marrow findings showcasing changes in bone marrow morphology and high prevalence of abnormal findings.
Flow plot of patient bone marrow findings showcasing changes in bone marrow morphology and high prevalence of abnormal findings. Image taken from original article.

Due to the impressive sample collection, the research team was able to observe and characterize bone marrow samples from 259 patients. They noted a variation in bone marrow findings pre- and post-CAR-T cell infusion. Some patients had evident disease which persisted, while others went into remission. For patients with abnormal bone marrow morphology prior to the infusion, the same abnormalities were observed at later follow ups as well. What was particularly interesting to the research team, was a group of 188 patients with initially normal bone marrow morphology, who later developed abnormalities post-infusion, most within the first 100 days. Of these patients, some eventually did revert to normal bone marrow morphology, which is consistent with many reports of transient cytopenia or dysplasia post CAR-T infusion. However, some patients’ abnormal bone marrow morphology persisted long-term. Of the many cellular alterations and observations in the abnormal bone marrow samples, few primary trends with these phenotypes and patient outcomes emerged. The presence of lymphoid aggregates was associated with a reduction in residual disease (a larger change in residual disease pre- and post- CAR-T). Dr. Yeung added that she and her colleagues are excited to see whether these cells were the CAR-T cells that had infiltrated the bone marrow. They also observed that increased lymphocytes, lymphocyte aggregates, and histiocytes were all associated with lack of residual disease, possibly signaling remission for these patients. However, increased histiocytes, as well as bone marrow fibrosis, was associated with worse overall survival. Dr. Yeung explained that this potential contradiction with histiocytes may be due to the interaction between CAR-T cells and macrophages, as macrophage-activation syndrome is already recognized as a common adverse event for this treatment. Additionally, they observed that there was an increase of abnormal bone marrow findings in patients who presented with neutrophil-based cytopenia by day 28, potentially highlighting a biomarker for higher-risk patients.

Overall, the research team was excited about their finding, as it represented a first-of-its-kind look at bone marrow changes for patients receiving CAR-T cell therapy. The authors highlight that because transient changes are so common, it is incredibly important to recognize specific alterations that may be a real concern. Dr. Yeung explained that defining what is normal and abnormal is crucial, and “finding where to draw those lines” will facilitate appropriate treatment for the patients who would actually need it. She was excited to see whether these findings could represent surrogate markers indicative of effective CAR-T infusions, such as the increased lymphocytes, lymphocyte aggregates, and possibly increased histiocytes, since methods for recognizing successful treatment in patients are still lacking as well. Dr. Yeung also emphasized that such work would not have been possible without the efforts of Fred Hutch to collect hundreds bone marrow samples to build their repository and are thankful to work at a cancer center that helped make this research possible. However, this work also highlights the importance for institutions to assess bone marrow in CAR-T-treated patients to improve patient outcomes.

This study was funded by the Fred Hutch Cancer Center Support Grant.

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Cecilia Yeung, Alexandre Hirayama and Kikkeri Naresh.

Yeung CCS, Woolston DW, Wu V, Voutsinas JM, Basom R, Davis C, Hirayama AV, Naresh KN. Abnormal bone marrow findings in patients following treatment with chimeric antigen receptor-T cell therapy. Eur J Haematol. 2023 Aug 1. doi: 10.1111/ejh.14068. Epub ahead of print. PMID: 37526606.