Population-based validation of the CAR-HEMATOTOX for hematotoxicity, infections, and survival after CART in R/R LBCL

Abstract

Early identification of patients at risk of immune effector cell-associated hematotoxicity (ICAHT) is essential to minimize nonrelapse mortality. The CAR-HEMATOTOX (HT) score is an implemented risk-stratification tool for ICAHT, infections, and survival in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL) receiving chimeric antigen receptor T-cell therapy (CART). Although validated in its defining study, the HT score was developed in a small cohort, necessitating independent external validation. This study externally validates the HT score in a real-world population-based cohort of adults with R/R LBCL receiving CART. The HT score, based on absolute neutrophil count (ANC), hemoglobin, platelets, C-reactive protein, and ferritin, was calculated before lymphodepleting chemotherapy. Of 245 consecutive patients, 171 (70%) had an HT score of ≥2 (HThigh). The initial end point, clinically significant neutropenia (ANC of <500/μL for ≥14 days), occurred in 21% of patients. The binary HT score was associated with clinically significant neutropenia (odds ratio [OR], 2.94; 95% confidence interval [CI], 1.27-6.80; P = .012) with a good predictive performance (area under the curve = 0.73). Similar results were achieved for early and late ICAHT grade ≥3 (OR, 2.92; 95% CI, 1.19-7.14; P = .019; and OR, 2.42; 95% CI, 1.31-4.47; P = .005). A trend toward an association with severe infections was observed (OR, 2.02; 95% CI, 0.91-4.48; P = .085). HThigh patients had a lower progression-free and overall survival (hazard ratio [HR], 1.84; 95% CI, 1.15-2.93; P = .011; and HR, 2.83; 95% CI, 1.64-4.87; P < .001, respectively). The HT score identified CART-treated patients with R/R LBCL at risk of clinically significant neutropenia, poor survival outcomes, and potentially severe infections.

Graphical abstract

Figure 1.

The HT score stratifies patients with severe neutropenia after CART. (A) Aggregate ANC over time (day −6 until 120) per neutrophil recovery phenotype: quick recovery (n = 134 [55%]), intermittent recovery (n = 56 [23%]), and aplastic (n = 55 [22%]). (B) Relative incidences of neutrophil recovery phenotypes (quick recovery, intermittent recovery, and aplastic), split for HT^low and HT^high patients. (C) Percentages of patients receiving G-CSF after CAR T-cell infusion, split for HT^low and HT^high patients. (D) Relative incidences of early and late ICAHT severity, split for HT^low and HT^high patients. (E) Aggregate ANC over time (day −6 until 120), split for HT^low and HT^high patients. (F) Total duration of neutropenia between days 0 and 60 divided by a low vs high HT score. (G) ROC curve of the continuous HT score for the end point clinically significant neutropenia (ANC of ≤500/uL for ≥14 days). ROC, receiver operating characteristic.

Figure 2.

Association of the continuous and binary HT scores with clinically significant neutropenia, early ICAHT, late ICAHT, severe infections, PFS, and OS. Continuous HT score ranged from 1 to 7. Binary HT score is presented using a cutoff of ≥2. ORs/HRs are presented with squares and 95% CI with whiskers. HR, hazard ratio.

Figure 3.

Distribution of infection grades by HT score. (A) Distribution of infection grades and infection type in patients with a low HT score. (B) Distribution of infection grades and infection type in patients with a high HT score. (C) Infection severity according to a low and high HT score. Low-grade infection represents infection grades 1 to 2. Severe infection is defined as an infection grade ≥3. Upper P value describes the difference between HT^high and HT^low patients in the incidence of infection grade ≥3, and lower P value in the incidence of infection grade ≥2.

Figure 4.

Discriminatory capacity of the HT score for OS, PFS, NRM, and the CAR T-cell–related toxicities CRS and ICANS. (A) Kaplan-Meier estimates of OS by the HT score. (B) Kaplan-Meier estimates of PFS by the HT score. (C) Cumulative incidence of NRM by the HT score. (D) Relative distribution of CRS severity by HT score. (E) Relative distribution of ICANS severity by HT score. The black line describes the difference between HT^high and HT^low patients.