Introduction:

Chimeric antigen receptor (CAR) T-cell therapy is transforming the management of patients with relapsed/refractory (R/R) B- and plasma-cell malignancies. However, a major limitation of CAR T-cell therapy is the development of severe, sometimes life-threatening, toxicities such as immune effector cell-associated neurotoxicity (ICANS) and cytokine release syndrome (CRS). While the management of CRS has dramatically improved with the early use of tocilizumab and corticosteroids, how to best predict and treat ICANS remains poorly understood, with up to 30% of patients developing severe ICANS after CD19 CAR T-cell therapy. Since we had previously observed features overlapping with hemophagocytosis lymphohistiocytosis in patients with severe CRS and ICANS, we hypothesized that the early kinetics of ferritin and soluble IL-2 receptor alpha [sIL-2Rα] post infusion could predict the development of severe ICANS.

Methods:

We retrospectively analyzed data from 195 patients with R/R B-cell malignancies previously treated on a phase I/II clinical trial (NCT01865617) of an investigational defined 1:1 CD8+:CD4+ composition CD19 CAR-T product (JCAR014; training set). CRS and ICANS severity were graded using Lee 2014 and CTCAE 4.03 criteria, respectively. Logistic regression was used to predict the occurrence of severe ICANS. Ferritin was measured using an enzyme immunoassay. sIL-2Rα was measured using Luminex®. Goodness of fit was assessed using the Akaike information criterion (AIC). Independent test set included 203 patients treated at our center with the standard-of-care CD19 CAR T-cell products axicabtagene or lisocabatagene maraleucel. Discrimination and calibration were assessed in both the training and test set.

Results:

In the training set (n=195), median age was 55 (range: 20-76). Disease type was as follows: acute lymphoblastic leukemia, n=64 (32.8%); B-cell non-Hodgkin lymphoma, n=82 (42.1%); chronic lymphocytic leukemia, n= 47 (24.1%). We observed any grade and grade ≥3 CRS in 134 (68.7%) and 27 (13.8%), respectively, and any grade and grade ≥3 ICANS in 72 (38.8%) and 37 (19.0%), respectively.

Longitudinal analyses of serum ferritin (Figure 1) and sIL-2Rα values using locally estimated scatterplot smoothing suggested that the rate of increase of both analytes was markedly higher in patients with grade ≥3 ICANS compared to grade 0-2 ICANS.

We applied univariate logistic regression to estimate the association between serum ferritin levels at early timepoints, select ratios of ferritin and sIL-2Rα values, and the occurrence of severe ICANS. The strongest association was observed between the ferritin day +3/day 0 ratio and severe ICANS (OR per log10 increase, 175; 95% CI, 19.1-2668; p < 0.001). We could further improve our model by modeling the ferritin day +3/day 0 ratio with a restricted cubic spline to allow for non-linear effects (unsplined model, AIC = 129, C-index, 0.74; splined model, AIC = 127, C-index, 0.78). Ferritin day +3/day 0 ratios of 3, 5, and 10 were associated with an 81%, 95%, and 99% probability of grade ≥3 ICANS, respectively (Figure 2). The splined model was associated with near-perfect calibration corrected for optimism using bootstrapping.

We next evaluated the predictive ability of the ferritin day +3/day 0 ratio to predict severe ICANS in our independent test set. Predictions in the test set based on our splined model retained good discriminative ability with a C-index of 0.64, although with suboptimal calibration. In a refitted logistic regression model in the test set, the ferritin day +3/day 0 ratio remained strongly associated with the development of severe ICANS (OR = 18.8 per log10 increase, 95%CI, 2.48-142.01, p = 0.004).

Conclusion:

We validated the ability of a simple point-of-care index (day +3/day 0 ferritin ratio) to predict the development of severe ICANS after CD19 CAR T-cell therapy in our training and test set. Since serum ferritin levels can be quickly measured by most clinical laboratories, the day +3/day 0 ferritin ratio could become a practical and useful tool for practitioners taking care of CAR T-cell patients. The early identification of patients at high risk of developing severe ICANS days prior to symptoms onset could enable the evaluation of targeted prophylactic interventions in future clinical trials. We plan to refine our modeling approach to further improve the calibration in test set.

Shadman:Fate Therapeutics: Consultancy; Genmab: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Mustang Bio: Consultancy, Research Funding; MorphoSys/Incyte: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy; AstraZeneca: Consultancy, Research Funding; ADC therapeutics: Consultancy; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MEI Pharma: Consultancy; Janssen: Consultancy; TG Therapeutics: Research Funding; Eli Lilly: Consultancy; Vincerx: Research Funding; Regeneron: Consultancy. Hirayama:Nektar Therapeutics: Honoraria, Research Funding; Juno Therapeutics, a Bristol Myers Squibb Company: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria. Till:Proteios Technology: Consultancy, Current holder of stock options in a privately-held company; BMS/Juno Therapeutics: Research Funding; Mustang Bio: Consultancy, Patents & Royalties, Research Funding. Kimble:Juno/BMS: Research Funding. Iovino:Mustang Bio: Current equity holder in publicly-traded company. Chapuis:Juno Therapeutics: Research Funding. Cassaday:Autolus: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Servier: Research Funding; Vanda Pharmaceuticals: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; PeproMene Bio: Membership on an entity's Board of Directors or advisory committees; Seagen: Other: Spouse was employed by and owned stock in Seagen within the last 24 months.. Milano:ExCellThera Inc.: Research Funding. Turtle:Eureka Therapeutics, Caribou Biosciences, Myeloid Therapeutics, ArsenalBio, Cargo Therapeutics: Other: Stock options; Nektar Therapeutics, Century Therapeutics, Legend Biotech, Allogene, Sobi, Syncopation Life Sciences, Prescient Therapeutics: Other: Ad hoc advisory boards/consulting (last 12 months); Kyverna: Other: DSMB Member; CJT has the right to receive payment from Fred Hutch as an inventor on patents related to CAR T-cell therapy: Other: Patents; Caribou Biosciences, T-CURX, Myeloid Therapeutics, ArsenalBio, Cargo Therapeutics: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics/BMS, Nektar Therapeutics: Research Funding. Maloney:Bristol Myers Squibb: Consultancy, Honoraria, Other: Member of the JCAR017 EAP-001 Safety Review Committee and Member, CLL Strategic Council, Member of the JCAR017-BCM-03 Scientific Steering Committee under BMS, Research Funding; Amgen: Consultancy, Honoraria; A2 Biotherapeutics: Consultancy, Current holder of stock options in a privately-held company, Honoraria, Other: Member of the Scientific Advisory Board; Fred Hutch: Other: rights to royalties for patents licensed to Juno; Legend Biotech: Consultancy, Honoraria, Research Funding; Lyell Immunopharma: Other: Member, CAR T Steering Committee; Umoja: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Participation on a Data Safety Monitory Board , Research Funding; Kite, a Gilead Sciences: Consultancy, Honoraria, Research Funding; Interius: Other: Member, Clinical Advisory Board; ImmPACT Bio: Other: Member, Clinical Advisory Board, CD19/CD20 bi-specific CAR-T Cell Therapy Program; Navan Technologies: Current holder of stock options in a privately-held company; Chimeric Therapeutics: Other: Member of the Scientific Advisory Board; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Rights to royalties from Fred Hutch for patents licensed to Juno Therapeutics/BMS, Research Funding; MorphoSys: Consultancy, Honoraria; Mustang Bio: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Bioline Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participation on a Data Safety Monitory Board ; Navan Technologies: Consultancy, Honoraria, Other: Member of the Scientific Advisory Board; Genentech: Consultancy, Honoraria, Other: Chair and Member of the Lymphoma Steering Committee; Janssen: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Other: Member, Scientific Review Committee, Research Scholars Program in Hematologic Malignancies; Incyte: Consultancy, Honoraria. Gauthier:Legend Biotech: Consultancy, Honoraria; Juno Therapeutics (a Bristol Myers Squibb company): Research Funding; Celgene (a Bristol Myers Squibb company): Research Funding; Angiocrine Bioscience: Research Funding; Janssen: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; MorphoSys: Consultancy, Research Funding; Century Therapeutics: Other: Independent data review committee; Sobi: Consultancy, Honoraria, Research Funding.

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2023
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