Impact of late immune effector cell associated hematotoxicity (ICAHT) and prolonged neutropenia after CAR-T therapy on infection and survival outcomes.
Authors: Morgan Zenner, Spencer Lessans, Kai Rejeski, Miguel-Angel Perales, Richard T. Maziarz, Andy I. Chen, David L. Porter, Stephen J. Schuster, Joseph McGuirk, Michael Russell Bishop, Veronika Bachanova, Loretta J. Nastoupil, Peter A. Riedell, Olalekan O. Oluwole, Shakthi Bhaskar, Vivek Patel
Journal: Journal of Clinical Oncology (2024)

7041 Background: Prolonged hematologic toxicity is a common side effect of chimeric antigen receptor T-cell (CART) therapy. The EHA/EBMT panel developed the late ICAHT grading which incorporates depth of neutropenia after Day 30. Recently, the early ICAHT grade (D 0-30) was associated with infection (infx) and survival outcomes. Here, we evaluate the impact of late ICAHT and neutropenia on survival and infx outcomes after CD19 CART. Methods: We included two cohorts of adult patients (pts) with large B cell lymphoma (LBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL) who received commercial CD19 CART. Late was graded based on depth of neutropenia after D30 (G1 ≤ 1.5; G2 ≤ 1.0; G3 ≤ 0.5; G4 ≤ 0.1 G/L) and pts were censored for relapse, progression, or loss of follow up. Infxs after D30 were graded per CTCAE as mild G ≤ 2 or severe G ≥ 3. Cohort 1 included pts from 8 US medical centers for survival outcomes. Only data for severe infx was collected from D30-D100 and longer term infx data was not available. Landmark survival analysis at D+100 was performed using the Kaplan-Meier method and multivariate cox proportional hazards. To assess long term late infx outcomes, cohort 2 included pts at Vanderbilt with granular cytopenia and infx data (D30-365). Results: Cohort 1 included 277 pts with LBCL of whom 143 received axi-cel, 61 tisa-cel, and 72 liso-cel with median follow up 395 days (range 30-1763). By D100, there were 111 (40%) without, 89 (41%) with mild to moderate (G1-G2), and 53 (19%) with severe (G3-G4) late ICAHT. There were 13 pts (6%) with severe infx which was not associated with severe ICAHT (p=0.68). In multivariate landmark survival analysis using previously published covariates, severe late ICAHT was not associated with PFS (HR 1.64, p=0.11) or OS (HR 1.54, p=0.17); however, D100 neutropenia (ANC ≤ 1000) was associated with inferior PFS (HR 2.00, p=0.002) and OS (HR 1.95, p=0.003). NRM was 11% and associated with D100 neutropenia (p=0.015) but not late ICAHT (p=0.15). Cohort 2 had 43 pts (35 LBCL, 7 MCL, 1 FL) with median follow up 483 days (range 233-2133). 34 pts received axi-cel, 2 tisa-cel, and 7 brexu-cel. By 1 yr, there were 10 (23%) without, 27 (63%) with mild to moderate, and 6 (14%) with severe late ICAHT. There were 52 infxs by 1 yr and 16 pts (37%) had no infx. Median time to first infx after D30 was 165 days (range 31-365). There were 31 (60%) mild and 21 (40%) severe infx. IVIG was used in 28 (65%) and G-CSF in 27 (62%). Only 1 pt with severe ICAHT had severe infx. Late ICAHT and neutropenia were not associated with severe infection in logistic regression. Conclusions: These data did not show an association between EHA/EBMT late ICAHT grading and infx after D30 or survival. A detailed reporting of T and B cell reconstitution data may provide clues to better predict late infx. Persistent neutropenia at D100 was associated with inferior PFS and OS which needs validation in future studies.