Contributions
Abstract: EP508
Type: E-Poster Presentation
Session title: Aggressive Non-Hodgkin lymphoma - Clinical
Background
CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cells can achieve high response rates in patients (pts) with relapsed or refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (NHL). Despite its promising efficacy, CD19 CAR T-cell therapy remains limited by two significant toxicities: cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Varying incidence and severity of CRS and ICANS have been reported across distinct CD19 CAR T-cell products, but these observations could have been confounded by differences in pt and disease characteristics.
Aims
To estimate the independent effect of 3 CD19 CAR T-cell products (axicabtagene ciloleucel[axicel], tisagenlecleucel [tisacel], and JCAR014) on CRS and ICANS severity in pts with R/R aggressive NHL.
Methods
We retrospectively analyzed 136 aggressive NHL pts treated with cyclophosphamide and fludarabine lymphodepletion (LD) followed by CD19 CAR T-cell therapy. Axicel and tisacel pts were treated off trial using commercial products. JCAR014 (defined-composition 4-1BB-costimulated CD19 CAR T cells) was administered in all pts at the dose of 2x106/kg on a phase I/II clinical trial (NCT01865617). CRS and ICANS were graded according to the ASTCT criteria and CTCAE 4.03, respectively. We used multivariable proportional odds logistic regression to model CRS and ICANS grade. We used propensity score estimation to reduce confounding based on age, hematopoietic cell transplantation comorbidity (HCT-CI), preLD LDH, preLD albumin, lymphoma type.
Results
Lymphoma type was diffuse large B cell lymphoma non-otherwise specified in 74%, large B cell lymphoma transformed from indolent histologies in 15%, and other aggressive lymphoma types in 11% of pts. Pts received axicel, tisacel, or JCAR014 in 50%, 28%, and 22% of cases, respectively. Compared to axicel pts, we observed higher preLD LDH levels in tisacel and JCAR014 pts, and lower preLD albumin with tisacel (p < 0.001) with comparable age and HCT-CI across CAR T-cell products. Higher day-28 overall response rates by Lugano criteria were observed after axicel (71%) compared to tisacel (56%) and JCAR014 (53%).
Adjusting for age, HCT-CI, preLD LDH, preLD albumin, CAR T-cell product type remained associated with CRS severity (tisacel versus [vs] axicel, OR = 0.45, p = 0.05; JCAR014 vs axicel, OR = 0.29, p = 0.005;). Age had limited or no impact on CRS severity (OR 95%CI, 0.97-1.02), while the effect of HCT-CI was undetermined (OR 95%CI, 0.85-1.27).
In a multivariable model including the same covariates as above, CAR T-cell product type (tisacel vs axicel, OR = .14, p < .001; JCAR014 vs axicel, OR = 0.31, p = 0.009), preLD LDH (OR = 3.96 per log10 increase; p = 0.04) and age (OR =1.32 per 10-year increase; p = .06) were associated with ICANS severity. Interaction effect testing suggested effect modification of age by the CAR T-cell product type (tisacel/JCAR014 versus axicel, p = 0.06). Predictions of ICANS severity according to age and the CAR T-cell product type are shown in the Figure.
The independent impact of CAR T-cell product type on CRS and ICANS severity was confirmed after propensity score adjustment.
Conclusion
CAR T-cell product type was independently associated with CRS and ICANS severity in NHL pts. We observed higher ICANS severity in older patients treated with axicel; in contrast, age had limited impact on ICANS severity in those receiving tisacel or JCAR014. While further analyses comparing efficacy are warranted, our findings provide insights to guide CAR T-cell product selection in older patients.
Keyword(s): CAR-T, DLBCL, Lymphoma, Toxicity
Abstract: EP508
Type: E-Poster Presentation
Session title: Aggressive Non-Hodgkin lymphoma - Clinical
Background
CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cells can achieve high response rates in patients (pts) with relapsed or refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (NHL). Despite its promising efficacy, CD19 CAR T-cell therapy remains limited by two significant toxicities: cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Varying incidence and severity of CRS and ICANS have been reported across distinct CD19 CAR T-cell products, but these observations could have been confounded by differences in pt and disease characteristics.
Aims
To estimate the independent effect of 3 CD19 CAR T-cell products (axicabtagene ciloleucel[axicel], tisagenlecleucel [tisacel], and JCAR014) on CRS and ICANS severity in pts with R/R aggressive NHL.
Methods
We retrospectively analyzed 136 aggressive NHL pts treated with cyclophosphamide and fludarabine lymphodepletion (LD) followed by CD19 CAR T-cell therapy. Axicel and tisacel pts were treated off trial using commercial products. JCAR014 (defined-composition 4-1BB-costimulated CD19 CAR T cells) was administered in all pts at the dose of 2x106/kg on a phase I/II clinical trial (NCT01865617). CRS and ICANS were graded according to the ASTCT criteria and CTCAE 4.03, respectively. We used multivariable proportional odds logistic regression to model CRS and ICANS grade. We used propensity score estimation to reduce confounding based on age, hematopoietic cell transplantation comorbidity (HCT-CI), preLD LDH, preLD albumin, lymphoma type.
Results
Lymphoma type was diffuse large B cell lymphoma non-otherwise specified in 74%, large B cell lymphoma transformed from indolent histologies in 15%, and other aggressive lymphoma types in 11% of pts. Pts received axicel, tisacel, or JCAR014 in 50%, 28%, and 22% of cases, respectively. Compared to axicel pts, we observed higher preLD LDH levels in tisacel and JCAR014 pts, and lower preLD albumin with tisacel (p < 0.001) with comparable age and HCT-CI across CAR T-cell products. Higher day-28 overall response rates by Lugano criteria were observed after axicel (71%) compared to tisacel (56%) and JCAR014 (53%).
Adjusting for age, HCT-CI, preLD LDH, preLD albumin, CAR T-cell product type remained associated with CRS severity (tisacel versus [vs] axicel, OR = 0.45, p = 0.05; JCAR014 vs axicel, OR = 0.29, p = 0.005;). Age had limited or no impact on CRS severity (OR 95%CI, 0.97-1.02), while the effect of HCT-CI was undetermined (OR 95%CI, 0.85-1.27).
In a multivariable model including the same covariates as above, CAR T-cell product type (tisacel vs axicel, OR = .14, p < .001; JCAR014 vs axicel, OR = 0.31, p = 0.009), preLD LDH (OR = 3.96 per log10 increase; p = 0.04) and age (OR =1.32 per 10-year increase; p = .06) were associated with ICANS severity. Interaction effect testing suggested effect modification of age by the CAR T-cell product type (tisacel/JCAR014 versus axicel, p = 0.06). Predictions of ICANS severity according to age and the CAR T-cell product type are shown in the Figure.
The independent impact of CAR T-cell product type on CRS and ICANS severity was confirmed after propensity score adjustment.
Conclusion
CAR T-cell product type was independently associated with CRS and ICANS severity in NHL pts. We observed higher ICANS severity in older patients treated with axicel; in contrast, age had limited impact on ICANS severity in those receiving tisacel or JCAR014. While further analyses comparing efficacy are warranted, our findings provide insights to guide CAR T-cell product selection in older patients.
Keyword(s): CAR-T, DLBCL, Lymphoma, Toxicity