The CAR-HEMATOTOX risk-stratifies patients for severe infections and disease progression after CD19 CAR-T in R/R LBCL.

Background: CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) represents a promising treatment modality for an increasing number of B-cell malignancies. However, prolonged cytopenias and infections substantially contribute to the toxicity burden of CAR-T. The recently developed CAR-HEMATOTOX (HT) score-composed of five pre-lymphodepletion variables (eg, absolute neutrophil count, platelet count, hemoglobin, C-reactive protein, ferritin)-enables risk stratification of hematological toxicity.
Methods: In this multicenter retrospective analysis, we characterized early infection events (days 0-90) and clinical outcomes in 248 patients receiving standard-of-care CD19 CAR-T for relapsed/refractory large B-cell lymphoma. This included a derivation cohort (cohort A, 179 patients) and a second independent validation cohort (cohort B, 69 patients). Cumulative incidence curves were calculated for all-grade, grade ≥3, and specific infection subtypes. Clinical outcomes were studied via Kaplan-Meier estimates.
Results: In a multivariate analysis adjusted for other baseline features, the HT score identified patients at high risk for severe infections (adjusted HR 6.4, 95% CI 3.1 to 13.1). HT ^high patients more frequently developed severe infections (40% vs 8%, p<0.0001)-particularly severe bacterial infections (27% vs 0.9%, p<0.0001). Additionally, multivariate analysis of post-CAR-T factors revealed that infection risk was increased by prolonged neutropenia (≥14 days) and corticosteroid use (≥9 days), and decreased with fluoroquinolone prophylaxis. Antibacterial prophylaxis significantly reduced the likelihood of severe bacterial infections in HT ^high (16% vs 46%, p<0.001), but not HT ^low patients (0% vs 2%, p=n.s.). Collectively, HT ^high patients experienced worse median progression-free (3.4 vs 12.6 months) and overall survival (9.1 months vs not-reached), and were hospitalized longer (median 20 vs 16 days). Severe infections represented the most common cause of non-relapse mortality after CAR-T and were associated with poor survival outcomes. A trend toward increased non-relapse mortality in HT ^high patients was observed (8.0% vs 3.7%, p=0.09).
Conclusions: These data demonstrate the utility of the HT score to risk-stratify patients for infectious complications and poor survival outcomes prior to CD19 CAR-T. High-risk patients likely benefit from anti-infective prophylaxis and should be closely monitored for potential infections and relapse.
Competing Interests: Competing interests: KR: Kite/Gilead: Research Funding and travel support. Novartis: Honoraria. GI: Consultancy and Honoraria: Novartis, Roche, Kite/Gilead, Bristol-Myers Squibb, Abbvie, Janssen, Sandoz, Miltenyi. OP: has received honoraria or travel support from Astellas, Gilead, Jazz, MSD, Neovii Biotech, Novartis, Pfizer and Therakos. He has received research support from Gilead, Incyte, Jazz, Neovii Biotech and Takeda. He is member of advisory boards to Jazz, Gilead, MSD, Omeros, Priothera, Shionogi and SOBI. VeB: AMGEN: Honoraria; Celgene: Research Funding; Pfizer: Honoraria; Kite/Gilead: Research Funding, Honoraria; Novaritis: Honoraria. DM: Abbvie: Consultancy, Honoraria, Novartis: Consultancy; Janssen: Consultancy; AMGEN: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Research Funding; Roche AG: Consultancy; Takeda: Consultancy. CC: Takeda: Honoraria, Consultancy/Advisory; Novartis: Honoraria, Consultancy/Advisory. ViB: Novartis: Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Janssen: Research Funding. LB: Advisory role or expert testimony-Abbvie, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Hexal, Janssen, Jazz Pharmaceuticals, Menarini, Novartis, Pfizer; Honoraria-Abbvie, Amgen, Astellas, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Janssen, Jazz Pharmaceuticals, Novartis, Pfizer, Sanofi, Seattle Genetics; Financing of scientific research-Bayer, Jazz Pharmaceuticals. FLL: has a scientific advisory role with Kite, a Gilead Company, Novartis, Celgene/Bristol-Myers Squibb, GammaDelta Therapeutics, Wugen, Amgen, Calibr, and Allogene; is a consultant with grant options for Cellular Biomedicine Group, Inc.; and receives research support from Kite, a Gilead Company, Novartis, and Allogene; and reports that his institution holds unlicensed patents in his name in the field of cellular immunotherapy. MvB-B: Consultancy, Research Funding and Honoraria: MSD Sharp & Dohme, Novartis, Roche, Kite/Gilead, Bristol-Myers Squibb, Astellas, Mologen, and Miltenyi. AM: Advisory, Speaking Engagement: Gilead, Novartis. WAB: Novartis: Consultancy, Honoraria Gilead: Consultancy, Honoraria, Miltenyi: Consultancy, Research Funding. PB: declares having received honoraria from Amgen, BMS, Gilead, Incyte, Miltenyi Biotec, Novartis and Pfizer not related with the present article. MJ: Kite/Gilead: Consultancy/Advisory, Novartis: Consultancy/Advisory, BMS: Consultancy/Advisory, Takeda: Consultancy/Advisory. MS: Morphosys: Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Seattle Genetics: Research Funding; AMGEN: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Research Funding; Roche AG: Consultancy, Research Funding. The remaining authors have nothing to declare. None of the mentioned conflicts of interest were related to financing of the content of this manuscript.
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