Table 1.
Select strategies to prevent severe CRS and ICANS
| Strategy | Disease/product | Outcome | Comparison∗ | Comments | Reference |
|---|---|---|---|---|---|
| Fractionated CAR T-cell dosing | |||||
| Fractionated dosing: day 1 (10% dose), day 2 (30%), and day 3 (60%), with day 2 and day 3 doses allowed to be held for early CRS. | Adult B-ALL treated with CD19 CAR T cells. | Fractionated dose: grade ≥4 CRS, 5% (Penn grading scale) Grade ≥3 neurotoxicity, 6%. |
High fixed dose: grade ≥4 CRS, 50%; 3 of 6 patients died. | Difficult to implement with fixed-dose commercial CAR T-cell products. | Frey et al25 NCT02030847 |
| Prophylaxis | |||||
| Prophylactic tocilizumab given on day 2. | Adult DLBCL treated with axi-cel. | Prophy toci: grade ≥3 CRS, 3%. Grade ≥3 ICANS, 41%. One case of cerebral edema. |
No prophy toci (ZUMA-1 cohorts 1-2)26: grade ≥3 CRS, 13%. Grade ≥3 ICANS, 28%. | Peak IL-6 levels were higher in the prophy toci group, possibly because IL-6R antagonists increase free IL-6. | Locke et al (ZUMA-1 cohort 3)27 NCT02348216 |
| Prophylactic dexamethasone 10 mg on days 0, 1, and 2. | Adult DLBCL treated with axi-cel. | Prophy dex: grade ≥3 CRS, 0%. Grade ≥3 ICANS, 13%. | No prophy dex (ZUMA-1 cohorts 1-2): grade ≥3 CRS, 13%. Grade ≥3 ICANS, 28%. | Lower baseline tumor burden than ZUMA-1 cohorts 1-2. | Oluwole et al (ZUMA-1 cohort 6)28 NCT02348216 |
| Prophylactic anakinra given on days 0-7. | Adult DLBCL treated with axi-cel. | Prophy anakinra: grade ≥2 CRS, 40%. Grade ≥3 ICANS, 20% | No prophy anakinra, tumor burden–matched retrospective cohort: grade ≥2 CRS, 70%. Grade ≥3 ICANS, 50%. | Early follow-up suggests efficacy preserved. | Strati et al29 NCT04432506 |
| Prophylactic anakinra. Started at first fever, or day 2 if no fever. Continued for a minimum of 10 days. | Adult DLBCL and MCL treated with axi-cel, tisa-cel, and brexu-cel. | Prophy anakinra: grade ≥3 CRS, 6%. Grade ≥3 ICANS, 6%. | No specific comparison cohort. | Early follow-up suggests efficacy preserved. | Park et al30 NCT04148430 |
| Early intervention during low-grade CRS | |||||
| Intervention with tocilizumab and/or corticosteroids for persistent grade 1 or any grade 2 CRS/ICANS. | Adult DLBCL treated with axi-cel. | Early intervention: grade ≥3 CRS, 2%. Grade ≥3 ICANS, 17%. | No early intervention (ZUMA-1 cohorts 1-2): grade ≥3 CRS, 13%. Grade ≥3 ICANS, 28%. | Lower baseline tumor burden than ZUMA-1 cohorts 1-2. | Topp et al (ZUMA-1 cohort 4)31 NCT02348216 |
| Tocilizumab at CRS onset in patients with high tumor burdens. | Children and young adults with >40% bone marrow involvement of B-ALL treated with CD19 CAR T cells. | Early toci: grade ≥4 CRS, 27% (Penn grading scale). Grade ≥4 neurotoxicity, 7%. | No early toci prior phase 1 trial, high tumor burden: grade ≥4 CRS, 50%. Grade ≥4 neurotoxicity, 4%. | Efficacy similar to prior cohorts. | Kadauke et al3 NCT02906371 |
| Tocilizumab and/or corticosteroids if persistent CRS. | Children and young adults with B-ALL treated with CD19 CAR T cells. | Early intervention: severe CRS, 15%. Grade ≥3 neurotoxicity, 22%. | No early intervention, cohort on same trial treated in DLT phase: severe CRS, 30%. Grade ≥3 neurotoxicity, 25%. | Used a study-specific definition of severe CRS. Efficacy appeared preserved. | Gardner et al4 NCT02028455 |
| Concurrent BTK inhibition | |||||
| Ibrutinib + CAR T cells. | Adult CLL treated with CD19 CAR T cells. | Concurrent ibrutinib: grade ≥3 CRS, 0%. Grade ≥3 ICANS, 26%. | No concurrent ibrutinib, earlier cohort of same trial: grade ≥3 CRS, 11%. Grade ≥3 ICANS, NA. | Better CAR T-cell expansion with concurrent ibrutinib, no difference in efficacy. | Gauthier et al32 NCT01865617 |
| Concurrent JAK inhibition | |||||
| Itacitinib + CAR T cells. | Adult DLBCL or MCL (90% of patients) treated with axi-cel, tisa-cel, or brexu-cel. | Concurrent itacitinib: grade ≥3 CRS 2%. Grade ≥3 ICANS, 13%. | No specific comparison cohort. | Randomized phase 2 (itacitinib vs placebo) underway, treating DLBCL/FL with axi-cel. | Pratta et al33 NCT04071366 |
axi-cel, axicabtagene ciloleucel; brexu-cel, brexucabtagene autoleucel; BTK, Bruton tyrosine kinase; CLL, chronic lymphocytic leukemia; CRS, cytokine release syndrome; DLBCL, diffuse large B-cell lymphoma; DLT, dose-limiting toxicity; FL, follicular lymphoma; MCL, mantle cell lymphoma; NA, not available; prophy, prophylactic; toci, tocilizumab; tisa-cel, tisagenlecleucel.
∗
None of the comparisons are randomized and instead provide information as compared with nonrandomized cohorts, cross-trial comparisons, and retrospective cohorts.