Pulmonary function tests performed prior to CAR-T cell administration could be instrumental in predicting post-treatment pulmonary toxicity: A single-arm prospective study Free

Introduction: Chimeric antigen receptor T (CAR-T) cells, a novel anticancer treatment introduced less than a decade ago, have demonstrated high efficacy in eliciting early and durable anti-tumor response in patients with certain hematological malignancies. However, the established benefits of these therapies are offset by significant associated toxicities, the most common of these being the cytokine release syndrome (CRS), observed in 40-100% of patients, with pulmonary toxicity occurring in approximately 30% of cases. While grades I-II CRS are manageable, grades III-IV disease may be associated with major morbidity. Pulmonary toxicity, either related to or independent of CRS, could manifest as hypoxia, respiratory failure, pleural effusions, or interstitial pneumonitis, with various degrees of severity. Although pulmonary function tests (PFTs) are routinely applied in the assessment of candidates for stem cell transplantation, they are currently not included in the workup test battery used prior to CAR-T cell administration. This study has aimed to investigate the value of PFTs in predicting CAR-T cell-related pulmonary toxicity.

Methods: All consecutive patients referred for commercial anti-CD19 CAR-T cell therapy to the Rambam Health Care Campus between January 2023 and May 2025 were recruited to this prospective trial. Patients underwent PFTs, which included spirometry [forced expiratory volume in 1 second (FEV1) and (FVC)] for the measurement of lung volumes, as well as diffusion capacity of the lungs to carbon monoxide (DLCO) 2-4 weeks prior to and one-month post-CAR-T cell infusion. During CAR-T cell therapy hospitalization, patients were monitored for any sign of CRS and pulmonary deterioration. CRS was diagnosed and graded according to the EBMT and JACIE guidelines. The variable termed “respiratory failure” was defined as the presence of any of the following indications during hospitalization: oxygen saturation on room air below 90%, requirement for supplemental oxygen, mechanical ventilation, or use of Bilevel Positive Airway Pressure. PFT results were compared between patients with low- versus high-grade CRS, and between patients who did and did not experience respiratory failure during hospitalization. A logistic regression model was used in the assessments.

Results:Ninety-four patients [55 males, 39 females, median age 65 (range 19-86) years] were recruited and received anti-CD19 CAR-T cells (axicabtagene ciloleucel: n=68, tisagenlecleucel: n=17, brexucabtagene autoleucel: n=9). The distribution of disease types was as follows: diffuse large B-cell lymphoma accounted for 67 cases, high-grade lymphoma for 4 cases, primary mediastinal B-cell lymphoma for 3 cases, follicular lymphoma for 8 cases, mantle cell lymphoma for 7 cases, Burkett lymphoma for 2 cases, and B-cell acute lymphoblastic leukemia for 3 cases.

The majority of patients experienced CRS (98%), with grades I-II and grades III- IV occurring in 82% (n=75) and 18% (n=17) of patients, respectively. Twenty-three patients (24%) required supplemental oxygen during hospitalization, and three patients (3%) required positive pressure respiratory support.

Baseline PFT results were consistent with normal spirometry and normal lung volumes, but mildly reduced DLCO (72±15% of the predicted rate). During post-treatment hospitalization following CAR-T cell administration, no statistically significant differences in lung volume values were found between patients who developed grades I-II CRS and grades III-IV CRS (FEV1/FVC ratio: 83.5 and 65.1, respectively; p=0.134), or between patients who did and did not develop respiratory failure. However, DLCO was found to be significantly associated with respiratory failure, with each 1-unit increase in DLCO corresponding to a decreased odds of respiratory failure (OR 0.94, [95% CI 0.9-0.99], p=0.02) in a logistic regression model. Conclusions: The findings of the current study demonstrate that low baseline DLCO confers a significantly increased risk of respiratory failure development in patients hospitalized following CAR-T cell infusion. Pre-hospitalization PFTs could aid in respiratory risk assessment preceding the administration of this therapy. Further studies are required to strengthen the findings of this study. If confirmed, these data could serve as a platform for the inclusion of PFTs in routine protocols for the evaluation of patients planned to receive CAR-T cell therapy.