Prophylactic Anakinra to Prevent Neurotoxicity After CAR T-Cell Therapy in Aggressive B-Cell Lymphomas: A Single-Center Real-World Experience

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This retrospective, single-center study evaluates prophylactic anakinra after CD19 CAR T-cell therapy in patients with relapsed/refractory DLBCL or aggressive B-cell lymphoma. The authors compare 40 patients who received anakinra with 40 patients managed without anakinra. The topic is clinically relevant and the real-world dataset is valuable. However, the manuscript requires revision because the endpoint framing, cohort imbalance, statistical analysis, and interpretation of hospitalization outcomes need strengthening.

1. The manuscript is framed as a study of ICANS prevention, but the Methods define OS and PFS as the primary endpoint, with toxicity as a secondary endpoint. This is inconsistent with the title, abstract, and rationale.

2. The two groups differ in several clinically meaningful variables, including B-symptoms, LDH before lymphodepletion, CAR T-cell product distribution, and follow-up duration. These factors may influence toxicity, hospitalization, and survival outcomes.

   Consider to add multivariable or propensity-adjusted analyses if feasible. At minimum, clearly state that unadjusted comparisons limit causal interpretation.

3. Hospitalization among ICANS patients was shorter with anakinra, but this was not statistically significant and involved a small subgroup: 27 vs. 40 days, p = 0.077. Consider to present this as exploratory and hypothesis-generating rather than evidence of clinical benefit.
4. The title specifies DLBCL, but the cohort includes HGBL, PMBL, and Burkitt-like lymphoma. Consider changing the title to “aggressive B-cell lymphoma” or clarifying the population.
5. Correct typographical and formatting issues, including “recieving,” “targetet,” “p=>0.999,” and p=<0.001. Standardize terminology, such as CAR T, CAR-T, CAR T-cell, axi-cel, tisa-cel, and liso-cel.

Author Response

This retrospective, single-center study evaluates prophylactic anakinra after CD19 CAR T-cell therapy in patients with relapsed/refractory DLBCL or aggressive B-cell lymphoma. The authors compare 40 patients who received anakinra with 40 patients managed without anakinra. The topic is clinically relevant and the real-world dataset is valuable. However, the manuscript requires revision because the endpoint framing, cohort imbalance, statistical analysis, and interpretation of hospitalization outcomes need strengthening.

1. The manuscript is framed as a study of ICANS prevention, but the Methods define OS and PFS as the primary endpoint, with toxicity as a secondary endpoint. This is inconsistent with the title, abstract, and rationale.

Authors: We thank the reviewer for this important comment. We modified our methods part and included the incidence of ICANS as primary endpoints and PFS and OS as secondary endpoints.

2. The two groups differ in several clinically meaningful variables, including B-symptoms, LDH before lymphodepletion, CAR T-cell product distribution, and follow-up duration. These factors may influence toxicity, hospitalization, and survival outcomes. Consider to add multivariable or propensity-adjusted analyses if feasible. At minimum, clearly state that unadjusted comparisons limit causal interpretation.

Authors: We are grateful for this important comment. Due to the relatively small number of patients included in the study, we believe that multivariable or propensity-adjusted analyses would be difficult to interpret reliably. Therefore, instead of performing adjusted analyses, we revised the limitations section in the discussion to more clearly acknowledge that the observed differences between the groups may have been influenced by baseline imbalances, including differences in B-symptoms, LDH levels before lymphodepletion, CAR T-cell product distribution, and follow-up duration. We also explicitly state that these unadjusted comparisons limit causal interpretation of our findings.

3. Hospitalization among ICANS patients was shorter with anakinra, but this was not statistically significant and involved a small subgroup: 27 vs. 40 days, p = 0.077. Consider to present this as exploratory and hypothesis-generating rather than evidence of clinical benefit.

Authors: We thank the reviewer for this important comment. We revised the Discussion and now present the shorter hospitalization in the anakinra group as an exploratory, hypothesis-generating finding rather than evidence of clinical benefit.

 

4. The title specifies DLBCL, but the cohort includes HGBL, PMBL, and Burkitt-like lymphoma. Consider changing the title to “aggressive B-cell lymphoma” or clarifying the population.

Authors: We thank the reviewer for this comment and have revised the title, summary, abstract and the manuscript text to ‘aggressive B-cell lymphoma’ to better describe the study cohort.

5. Correct typographical and formatting issues, including “recieving,” “targetet,” “p=>0.999,” and p=<0.001. Standardize terminology, such as CAR T, CAR-T, CAR T-cell, axi-cel, tisa-cel, and liso-cel.

Authors: We thank the reviewer for this important comment. We have revised the manuscript to correct all typographical and formatting errors and to standardize terminology, including CAR T nomenclature and p-value formatting.

Reviewer 2 Report

Comments and Suggestions for Authors

Schmid et al., evaluates whether prophylactic anakinra, an IL-1 receptor antagonist, can reduce the incidence or severity of immune effector cell-associated neurotoxicity syndrome (ICANS) in patients with relapsed/refractory DLBCL receiving CD19-directed CAR T-cell therapy. A total of 80 patients treated with different CAR T products were analyzed, comparing those who received short-course prophylactic anakinra (days 0–6) with a matched standard-of-care cohort. Overall, prophylactic anakinra did not significantly reduce the incidence or severity of ICANS. CAR T-related neurotoxicity rates, including grade ≥3 ICANS, were comparable between groups. Survival outcomes (PFS and OS) and CAR T-cell expansion were also unaffected by anakinra administration, suggesting no impairment of therapeutic efficacy. A trend toward shorter hospitalization was observed in patients who developed ICANS in the anakinra group, although this did not reach statistical significance. In summary, the study suggests that prophylactic anakinra does not prevent ICANS in this setting but may potentially influence clinical management once toxicity occurs. However, conclusions are limited by the retrospective design, sample size, and heterogeneity of CAR T products. Prospective controlled studies are needed to define the role of IL-1 blockade in ICANS prevention and management. Please find my concerns below.

 

Major Comments

-The study is retrospective and includes patients treated with three different CAR T products (tisagenlecleucel, axicabtagene ciloleucel, and lisocabtagene maraleucel). Given the known differences in ICANS incidence across these products, more detailed stratification or adjustment is needed to avoid confounding.

-The anakinra regimen (100 mg subcutaneously days 0–6) appears somewhat arbitrary. Please clarify the rationale for dose selection, timing, and duration, and whether alternative schedules were considered.

-The groups may differ in baseline disease burden, inflammatory status, or bridging therapy. These potential confounders should be better described and adjusted for the analysis.

-The primary endpoint (ICANS incidence) shows no difference; however, the study may be underpowered to detect clinically meaningful effects. A power calculation or discussion of effect size would strengthen the interpretation.

-The observed trend toward shorter hospitalization in the anakinra group (p = 0.077) should be interpreted cautiously. Additional analysis is needed to determine whether this reflects toxicity mitigation or differences in supportive care practices.

-It remains unclear whether cytokine profiles (e.g., IL-1, IL-6 levels) were assessed. Such mechanistic data would strengthen the biological interpretation of anakinra’s role.

 

Minor Comments

-Please ensure consistency in reporting p-values (e.g., “p > 0.999” formatting).

-Clarify whether ICANS grading was performed prospectively or retrospectively and whether standardized criteria (e.g., ASTCT) were used uniformly.

-Consider adding a figure summarizing ICANS onset timing and severity distribution between groups.

Author Response

Schmid et al., evaluates whether prophylactic anakinra, an IL-1 receptor antagonist, can reduce the incidence or severity of immune effector cell-associated neurotoxicity syndrome (ICANS) in patients with relapsed/refractory DLBCL receiving CD19-directed CAR T-cell therapy. A total of 80 patients treated with different CAR T products were analyzed, comparing those who received short-course prophylactic anakinra (days 0–6) with a matched standard-of-care cohort. Overall, prophylactic anakinra did not significantly reduce the incidence or severity of ICANS. CAR T-related neurotoxicity rates, including grade ≥3 ICANS, were comparable between groups. Survival outcomes (PFS and OS) and CAR T-cell expansion were also unaffected by anakinra administration, suggesting no impairment of therapeutic efficacy. A trend toward shorter hospitalization was observed in patients who developed ICANS in the anakinra group, although this did not reach statistical significance. In summary, the study suggests that prophylactic anakinra does not prevent ICANS in this setting but may potentially influence clinical management once toxicity occurs. However, conclusions are limited by the retrospective design, sample size, and heterogeneity of CAR T products. Prospective controlled studies are needed to define the role of IL-1 blockade in ICANS prevention and management. Please find my concerns below.

 Major Comments

1. The study is retrospective and includes patients treated with three different CAR T products (tisagenlecleucel, axicabtagene ciloleucel, and lisocabtagene maraleucel). Given the known differences in ICANS incidence across these products, more detailed stratification or adjustment is needed to avoid confounding.

Authors. We agree with the reviewer that CAR T-cell product may confound ICANS risk. However, due to small subgroup sizes, stratified or adjusted analyses were not feasible. We have clarified this limitation in the Discussion.

2. The anakinra regimen (100 mg subcutaneously days 0–6) appears somewhat arbitrary. Please clarify the rationale for dose selection, timing, and duration, and whether alternative schedules were considered.

Authors. We are grateful for this important comment. The rationale for the selected anakinra dose (100 mg subcutaneously once daily for 7 days) was based on two previous studies (Park et al. and Nath et al.). The regimen was chosen in a pragmatic manner, primarily based on the known time to onset of ICANS rather than pharmacokinetic data. We have added this clarification to the Methods section.

3. The groups may differ in baseline disease burden, inflammatory status, or bridging therapy. These potential confounders should be better described and adjusted for the analysis.

Authors. We thank the reviewer for this important comment. In our analysis, no significant differences in baseline disease burden or bridging therapy were observed between the two groups. Inflammatory parameters were not systematically assessed as part of this study. We have clarified these points in the Results section.

4. The primary endpoint (ICANS incidence) shows no difference; however, the study may be underpowered to detect clinically meaningful effects. A power calculation or discussion of effect size would strengthen the interpretation.

Authors. We thank the reviewer for this comment. Indeed, due to the limited sample size, the study may have been underpowered to detect moderate clinically meaningful differences in ICANS incidence. We have added this point to the Discussion section

5. The observed trend toward shorter hospitalization in the anakinra group (p = 0.077) should be interpreted cautiously. Additional analysis is needed to determine whether this reflects toxicity mitigation or differences in supportive care practices.

Authors. We agree with the reviewer. We have revised the Discussion section and have presented the shorter hospitalization in the anakinra group as an exploratory, hypothesis-generating finding rather than evidence of clinical benefit. We also acknowledge that differences in supportive care practices may have contributed to this observation

6. It remains unclear whether cytokine profiles (e.g., IL-1, IL-6 levels) were assessed. Such mechanistic data would strengthen the biological interpretation of anakinra’s role.

 Authors. We thank the reviewer for this valuable comment. Unfortunately, cytokine profiling (including IL-1 and IL-6 levels) was not performed as part of this study. Therefore, mechanistic insights into the biological effects of anakinra cannot be provided and should be addressed in future prospective studies.

Minor Comments

1. Please ensure consistency in reporting p-values (e.g., “p > 0.999” formatting).

Authors. We thank the reviewer for this point and have standardized p-value reporting throughout the manuscript.

2. Clarify whether ICANS grading was performed prospectively or retrospectively and whether standardized criteria (e.g., ASTCT) were used uniformly.

Authors. We thank the reviewer for this important point. ICANS grading was performed retrospectively using standardized and uniformly applied ASTCT criteria, and this has been clarified in the Methods section.

3. Consider adding a figure summarizing ICANS onset timing and severity distribution between groups.

Authors. We thank the reviewer for this helpful suggestion. Due to the limited sample size and the descriptive nature of the analysis, we believe that an additional figure summarizing ICANS onset timing and severity distribution would provide limited additional information beyond the data already presented in the tables and text

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors addressed all of my previous comments. 

Reviewer 2 Report

Comments and Suggestions for Authors

okay