EASIX-guided risk stratification for complications and outcome after CAR T-cell therapy with ide-cel in relapsed/refractory multiple myeloma

Abstract

Background: Chimeric antigen receptor (CAR) T-cell therapy has demonstrated significant benefits in the treatment of relapsed/refractory multiple myeloma (RRMM). However, these outcomes can be compromised by severe complications, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS) and immune effector cell-associated hematotoxicity (ICAHT), predisposing for life-threatening infections.

Methods: This retrospective observational study examined a total of 129 patients with RRMM who had received idecabtagene vicleucel (ide-cel) at two major myeloma centers in Germany and one center in the USA to assess the Endothelial Activation and Stress Index (EASIX) as a risk marker for an unfavorable clinical course and outcome after CAR T-cell therapy. EASIX is calculated by lactate dehydrogenase (U/L) × creatinine (mg/dL) / platelets (10⁹ cells/L) and was determined before lymphodepletion (baseline) and at the day of CAR T-cell infusion (day 0). The analysis was extended to EASIX derivatives and the CAR-HEMATOTOX score.

Results: An elevated baseline EASIX (>median) was identified as a risk marker for severe late ICAHT, manifesting with an impaired hematopoietic reconstitution and pronounced cytopenias during the late post-CAR-T period. Patients with high EASIX levels (>upper quartile) were particularly at risk, as evidenced by an increased rate of an aplastic phenotype of neutrophil recovery, severe late-onset infections and ICANS. Finally, we found associations between baseline EASIX and an inferior progression-free and overall survival. Moreover, the EASIX at day 0 also demonstrated potential to serve as a risk marker for post-CAR-T complications and adverse outcomes.

Conclusions: In conclusion, EASIX aids in risk stratification at clinically relevant time points prior to CAR T-cell therapy with ide-cel. Increased EASIX levels might help clinicians to identify vulnerable patients to adapt peri-CAR-T management at an early stage.

Keywords: chimeric antigen receptor - CAR; cytopenia; immunotherapy; multiple myeloma; treatment related adverse event - trAE.

Figure 1. Frequency and severity of toxicities after CAR T-cell therapy in the total cohort. (A) CRS; (B) ICANS; (C) Late ICAHT. (D–F) Median absolute neutrophil count (D), platelet count (E) and hemoglobin levels (F) over time depending on late ICAHT grade. The filled area illustrates the corresponding 95% CIs. Measured events per group and time point are provided in the table below. P values are shown to the right of the table and refer to pairwise group comparisons across time points. Further statistical analyses using a linear mixed model are summarized in online supplemental table S6. Baseline, prior to lymphodepletion. Day 0, day of CAR T-cell infusion. CAR, chimeric antigen receptor; CRS, Cytokine-release syndrome; ICAHT, immune effector cell-associated hematotoxicity; ICANS, immune effector cell-associated neurotoxicity syndrome.

Figure 2. EASIX is associated with severe late cytopenias. (A–C) Graph showing the association between baseline log₂(EASIX) (prior to lymphodepletion) and late ANC (A), platelet count (B) and hemoglobin (C) nadir values. Best-fit line and 95% confidence bands were obtained by simple linear regression. Coefficient (r) and p values are based on Spearman correlation analysis. (D) Baseline log₂(EASIX) values depending on late ICAHT grade. Median (left to right): −0.03 vs 0.63 vs 0.83. P values of the group comparisons are shown at the top. The dashed lines indicate the median and the upper quartile of the baseline EASIX. (E) ROC curves to assess the potential of the baseline (bl) EASIX (prior to lymphodepletion (LD)) (red) and the EASIX at day 0 (day of CAR T-cell infusion) (blue) to identify patients at risk for severe late ICAHT (grade ≥3). AUC values, p values and sensitivity/specificity for selected baseline EASIX cut-off values (median, upper quartile [Q₃], optimal cut-off) are provided below. (F) Frequency and severity of late ICAHT depending on baseline EASIX group (≤median [≤1.26] vs >median [>1.26]). (G–I) Blood cell count nadir values during the late post-CAR-T period depending on baseline EASIX group (≤median [≤1.26] vs >median [>1.26]). P values of the group comparisons are shown at the top. Late ANC nadir values (G), median (left to right): 1.71/nL vs 0.96/nL. Late platelet count nadir values (H), median (left to right): 135.5/nL vs 51.5/nL. Late hemoglobin nadir values (I), median (left to right): 10.85 g/dL vs 9.90 g/dL. ANC, absolute neutrophil count; AUC, area under the curve; CAR, chimeric antigen receptor; EASIX, Endothelial Activation and Stress Index; ICAHT, immune effector cell-associated hematotoxicity; ROC, receiver operating characteristic.

Figure 3. EASIX is associated with the neutrophil recovery phenotype and the CAR-HEMATOTOX (CAR-HTX) score. (A) Baseline log₂(EASIX) values (prior to lymphodepletion) depending on the phenotype of neutrophil recovery (quick, intermittent or aplastic). Median (left to right): −0.03 vs 0.43 vs 1.24. P values of the group comparisons are shown at the top. The dashed lines indicate the median and the upper quartile of the baseline EASIX. (B) ROC curves to assess the potential of the baseline (bl) EASIX (prior to lymphodepletion (LD)) (red) and the EASIX at day 0 (day of CAR T-cell infusion) (blue) to identify patients at risk for an aplastic phenotype of neutrophil recovery. AUC values, p values and sensitivity/specificity for selected baseline EASIX cut-off values (median, upper quartile [Q₃], optimal cut-off) are provided below. (C) Distribution of the quick, intermittent and aplastic phenotype of neutrophil recovery depending on baseline EASIX group (≤upper quartile [≤2.15] vs >upper quartile [>2.15]). (D) Comparison of patients with a low (<2) and a high (≥2) CAR-HTX regarding baseline log₂(EASIX) values in the German cohort (G) and the US cohort (US). Median (left to right): 0.24 vs 1.05 vs 1.65. P values of the group comparisons are shown at the top. The dashed lines indicate the median and the upper quartile of the baseline EASIX. (E) Graph showing the association between baseline log₂(EASIX) (prior to lymphodepletion) and exact CAR-HTX score for all patients with available data in the German cohort. (G) Best-fit line and 95% confidence bands were obtained by simple linear regression. Coefficient (r) and p values are based on Spearman correlation analysis. (F) Alluvial plot showing the individual patient distribution and associations regarding (left to right) baseline EASIX group>median (>1.26) (yes (orange) vs no (gray)), baseline EASIX group>upper quartile (>Q₃; >2.15) (yes vs no) and baseline CAR-HTX (high vs low) in the German cohort (G) for all patients with available CAR-HTX. AUC, area under the curve; CAR, chimeric antigen receptor; EASIX, Endothelial Activation and Stress Index; ROC, receiver operating characteristic.

Figure 4. EASIX is associated with severe late-onset infections, ICANS and medical interventions. (A) Comparison of patients with and without late-onset severe infection (Common Terminology Criteria (CTC) grade ≥3) regarding baseline log₂(EASIX) values (prior to lymphodepletion). Median (left to right): 0.26 vs 1.14. P value of the group comparison is shown at the top. The dashed lines indicate the median and the upper quartile of the baseline EASIX. (B.) ROC curves to assess the potential of the baseline (bl) EASIX (prior to lymphodepletion (LD)) (red) and the EASIX at day 0 (day of CAR T-cell infusion) (blue) to identify patients at risk for a severe late-onset infection. AUC values, p values and sensitivity/specificity for selected baseline EASIX cut-off values (median, upper quartile [Q₃], optimal cut-off) are provided below. (C) Frequency of late-onset severe infections depending on baseline EASIX group (≤ upper quartile [≤2.15] vs >upper quartile [>2.15]). (D) Comparison of patients with and without ICANS regarding baseline log₂(EASIX) values. Median (left to right): 0.33 vs 1.38. P value of the group comparison is shown at the top. The dashed lines indicate the median and the upper quartile of the baseline EASIX. (E) ROC curves to assess the potential of the baseline EASIX (prior to LD) (red) and the EASIX at day 0 (day of CAR T-cell infusion) (blue) to identify patients at risk for ICANS (any grade). AUC values, p values and sensitivity/specificity for selected baseline EASIX cut-off values (median, Q₃, optimal cut-off) are provided below. (F) Frequency and severity of ICANS depending on baseline EASIX group (≤upper quartile [≤2.15] vs >upper quartile [>2.15]). (G–I) Comparison of patients with and without CRS grade ≥2, tocilizumab and dexamethasone treatment due to CAR T-cell associated toxicities regarding baseline log₂(EASIX) values. P values of the group comparisons are shown at the top. The dashed lines indicate the median and the upper quartile of the baseline EASIX. CRS grade ≥2 (G), median (left to right): 0.24 vs 0.61. Tocilizumab (H), median (left to right): 0.14 vs 0.63. Dexamethasone (I),median (left to right): 0.17 vs 0.64. AUC, area under the curve; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; EASIX, Endothelial Activation and Stress Index; ICANS, immune effector cell-associated neurotoxicity syndrome; ROC, Receiver operating characteristic.

Figure 5. EASIX is associated with inferior outcomes after CAR T-cell therapy. (A) Forest plot showing the results of the univariate Cox regression analysis of PFS in the total cohort. The plot shows the respective HR and 95% CI. Included continuous and binary variables: age (continuous), age ≥70 years, female sex, ISS stage 3, R-ISS 3, high risk cytogenetics, extraosseous disease, penta-drug refractoriness, prior BCMA-TT, eGFR <60 mL/min, log₂(EASIX) prior to lymphodepletion (LD) (continuous), EASIX prior to LD>upper quartile (Q₃) and log₂(EASIX) at day 0 (day of CAR T-cell infusion) (continuous). (B) Kaplan-Meier estimates of the probability of PFS in days since ide-cel infusion for the baseline EASIX (prior to LD) ≤ Q₃ (≤2.15) group (green) (median PFS 344 days; 95% CI: 225 to 515) and the baseline EASIX>Q₃ (>2.15) group (violet) (median PFS 126 days; 95% CI: 79 to 323) in the total cohort. (C) Forest plot showing the results of the univariate Cox regression analysis of OS. The plot shows the respective HR and 95% CI. Included continuous and binary variables are shown above. (D) Kaplan-Meier estimates of the probability of OS in days since ide-cel infusion for the baseline EASIX (prior to LD) ≤ Q₃ (≤2.15) group (green) (median OS NR) and the baseline EASIX>Q₃ (>2.15) group (violet) (median OS 463 days; 95% CI: 188 to NR) in the total cohort. BCMA-TT, B-cell maturation antigen-targeted therapy; CAR, chimeric antigen receptor; EASIX, Endothelial Activation and Stress Index; eGFR, estimated glomerular filtration rate; ide-cel, idecabtagene vicleucel; ISS, International Staging System; NR, not reached; OS, overall survival; PFS, progression-free survival; R-ISS Revised International Staging System stage.