TOPLINE:

Germline genetic variations in myeloid cell biology genes predict toxicity and efficacy of Chimeric Antigen Receptor T-cell therapy (CAR T) in large B-cell lymphoma (LBCL). Increasing Polygenic Risk Score (PRS) for monocyte count was linked to 2.5 times higher risk for cytokine release syndrome.

METHODOLOGY:

• Researchers analyzed genome-wide genotyping data from 170 patients with LBCL treated with standard-of-care axicabtagene ciloleucel between January 2018 and October 2021.
• Analysis included PRS instruments for blood cell traits and inflammatory markers, with exploratory gene-based and genome-wide association studies performed using PRSice-2.
• Patients received conditioning chemotherapy with cyclophosphamide (500 mg/m²) and fludarabine (30 mg/m²) on days -5 to -3, followed by axicabtagene ciloleucel infusion (2 × 10⁶ cells/kg) on day 0.

TAKEAWAY:

• Increased PRS for monocyte count was associated with 2.49-fold higher risk for cytokine release syndrome of any grade (odds ratio [OR], 2.49; 95% CI, 1.18-5.25; P = .016).
• Genetically predicted interleukin-1 receptor antagonist levels were decreased (P = .002) and interleukin-27 levels were increased (P = .012) in patients with grade 3-4 day 30 cytopenia.
• Genome-wide significant variants (P < 5 × 10^-8) were identified in SPOCK1, SLC28A2-AS1, and DUOX1 genes, associated with progression-free and overall survival.
• European ancestry was associated with decreased risk for day 30 grade 3-4 cytopenia (OR, 0.23; 95% CI, 0.06-0.84; P = .026).

IN PRACTICE:

“Elucidating such intrinsic determinants may help improve patient selection and develop strategies to enhance the therapeutic index of CART,” the authors of the study wrote.

SOURCE:

This study was led by Paolo Strati, PhD, MD Anderson Cancer Center in Houston. It was published online in Journal for ImmunoTherapy of Cancer.

LIMITATIONS:

According to the authors, the study’s limitations included its single-center and retrospective nature, the lack of a validation cohort, and limited statistical power to assess PRS associations in cases of low-incidence toxicities or to perform robust genome-wide analysis. The researchers also noted that causality implications of observed associations remain to be confirmed.

DISCLOSURES:

This study was supported by the University of Texas MD Anderson Cancer Center B-cell Lymphoma Moonshot and the MD Anderson Cancer Center Support Grant from National Institutes of Health. Strati disclosed receiving a Kite Gilead Scholar in Clinical Research Award and a Leukemia Lymphoma Society Career Development Program Award. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.