The CAR-Hematotox Score Identifies Patients at High Risk for Hematological Toxicity, Infections and Poor Clinical Outcomes Following Brexucabtagene Autoleucel in Relapsed/Refractory Mantle Cell Lymphoma

Background: Hematological toxicity and infectious complications drive the toxicity burden of CD19 CAR-T. We recently developed the CAR-HEMATOTOX (HT) score - a validated risk-stratification system of hematotoxicity, infections, and clinical outcomes in LBCL patients (Rejeski et al. Blood 2021/JITC 2022). The score integrates parameters associated with pre-CAR-T hematopoietic reserve (e.g. ANC, hemoglobin, platelet count) and inflammation (e.g. CRP, ferritin). Whether the HT score is of prognostic utility in relapsed/refractory mantle cell lymphoma (R/R MCL) remains unstudied.

Methods: In this multicenter retrospective study, we characterized the influence of the HT score on toxicity and survival in 78 patients receiving standard-of-care brexucabtagene autoleucel (brexu-cel) across seven international sites. Patterns of hematopoietic recovery were defined as quick recovery vs. intermittent recovery vs. aplastic as previously described (Rejeski et al. Blood 2021). The duration of severe neutropenia was assessed as the total cumulative days with an ANC<500/µl between days 0-60. Early infection events (day 0-90) were defined as bacterial, viral or fungal based on microbiologic data or as a clinical syndrome of infection (e.g. pneumonia, cellulitis, cystitis) based on retrospective chart review. Severe (Grade ≥3) infections were defined as requiring intravenous anti-infectives and/or hospitalization. Kaplan-Meier estimates of progression-free (PFS) and overall survival (OS) were compared using the log-rank test.

Results: The study cohort comprised a representative cohort of R/R MCL patients treated in a real-world setting: median age was 68 (range 49-89), median ECOG PS was 1, median LDH was 217 U/L (interquartile range 171-289 U/L), and patients had received a median of 3 prior treatment lines (IQR 2-4). Of note, 28% of patients had received a prior autologous stem cell transplant (ASCT) and >90% were BTKi exposed. The rate of severe (grade ≥3) CRS and ICANS was 2.6% and 27%, respectively. Tocilizumab was applied in 82% of patients, while glucocorticoids were used in 64% of all cases. Across all patients, the median duration of severe neutropenia was 8 days (IQR 5-15). The distribution of neutrophil recovery phenotypes was: 30% quick, 46% intermittent, and 24% aplastic. The cumulative 90-day incidence of any-grade and severe infections was 37% and 17%, respectively.

The median CAR-HEMATOTOX score was 1 (IQR 1-3), including 42 HT^low (Score 0-1) and 36 HT^high (Score ≥2) patients. When comparing risk groups, we noted higher serum LDH levels in HT^high patients(median 261 vs. 209 U/L, p=0.07).In terms of toxicity, the incidence of severe CRS and ICANS was comparable between both groups. However, the duration of neutropenia was significantly increased in HT^high patients compared to their HT^low counterparts (15 vs. 7 days, p<0.001). Moreover, the proportion of patients displaying an aplastic phenotype of neutrophil recovery, defined by continuous severe neutropenia ≥14 days, was markedly increased in the HT^high group (53 vs. 0%, p<0.0001, Fig. 1A). This translated into a higher rate of severe infectious complications in the HT^highgroup (28% vs. 7%, p=0.03), including 3 life-threatening (all bacterial), and 2 fatal infections (1 bacterial, 1 fungal).Notably, a high HT score was associated with markedly inferior PFS (median 7.5 months vs. not-reached, p=0.0006, Fig. 1B) and OS (median 15.3 months vs. not-reached, p=0.0004). Comparing the HT^high vs. HT^low groups, we observed 1-year PFS of 73% vs. 38% and 1-year OS of 88% vs. 51%.

Conclusions: Taken together, these findings underline the importance of pre-CAR-T bone marrow reserve and systemic inflammation in driving immunotoxicity after CD19 CAR-T therapy. Importantly, they validate the utility of the HT score to risk-stratify patients for hematotoxicity, severe infections and poor survival outcomes prior to brexu-cel infusion. The score can be used to aid clinical decision-making concerning anti-infective prophylaxis and early or prophylactic G-CSF use. Considering that ASCT represents a mainstay of frontline MCL therapy, the HT score may also guide the use of stem cell rescue (obtained at time of remission) for the patients developing severe CAR-T-related aplasia.

Rejeski:Novartis: Honoraria; Kite/Gilead: Other: Travel Support, Research Funding. Wang:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Loxo@Lilly: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; MorphoSys: Research Funding; Genentech: Research Funding; Genmab: Research Funding; Eli Lilly and Company: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; InnoCare: Membership on an entity's Board of Directors or advisory committees, Research Funding. Munoz:Gilead/Kite Pharma, Kyowa, Bayer, Pharmacyclics/Janssen, Seattle Genetics, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche: Speakers Bureau; Targeted Oncology, OncView, Curio, Kyowa, Physicians' Education Resource, Dava, Global clinical insights, MJH, Shanghai Youyao, and Seattle Genetics: Honoraria; Bayer, Gilead/Kite Pharma, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, Millennium: Research Funding; Pharmacyclics/Abbvie, Bayer, Gilead/Kite Pharma, Pfizer, Janssen, Juno/Celgene, BMS, Kyowa, Alexion, Fosunkite, Innovent, Seattle Genetics, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, Beigene, Servier, Novartis, Morphosys/Incyte, Mei pharma: Consultancy. Sesques:Chugai, Novartis, and Kite/Gilead: Research Funding. Iacoboni:NOVARTIS, KITE/GILEAD, BMS/CELGENE, ASTRAZENECA, ROCHE, ABBVIE, JANSSEN, MILTENYI: Honoraria; NOVARTIS, KITE/GILEAD, BMS/CELGENE: Consultancy. Dreyling:Astra Zeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, Roche: Consultancy; Amgen, Astra Zeneca, Gilead/Kite, Janssen, Lilly, Novartis, Roche: Honoraria; Abbvie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Roche: Research Funding. Locke:CAREducation: Other: Education or editorial activity; Clinical Care Options Oncology: Other: Education or editorial activity; Sana: Consultancy; Society for Immunotherapy of Cancer: Other: Education or editorial activity; Takeda: Consultancy; BioPharm Communications: Other: Education or editorial activity; ASH: Other: Education or editorial activity; Aptitude Health: Other: Education or editorial activity; CERo Therapeutics: Research Funding; ), National Cancer Institute: Research Funding; Leukemia and Lymphoma Society: Research Funding; Imedex: Other: Education or editorial activity; Daiichi Sankyo: Consultancy; BMS: Research Funding; A2: Consultancy; Celgene: Consultancy; Other: Patents & Royalties: patents, royalties, other intellectual property from several patents held by the institution in my name (unlicensed) in the field of cellular immunotherapy.; Wugen: Consultancy; Umoja: Consultancy; Novartis: Consultancy, Research Funding; Legend Biotech: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy; Iovance: Consultancy; GammaDelta Therapeutics: Consultancy; Emerging Therapy Solutions Gerson Lehrman Group: Consultancy; EcoR1: Consultancy; Cowen: Consultancy; Calibr: Consultancy; Cellular Biomedicine Group: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Bluebird Bio: Consultancy, Research Funding; Allogene: Consultancy, Research Funding; Amgen: Consultancy. Barba:Allogene, Amgen, BMS, Gilead, Incyte, Jazz Pharmaceuticals, Miltenyi Biomedicine, Nektar and Novartis: Consultancy. Bachy:Kite, Gilead, Novartis, Roche, Incyte, Miltenyi Biotech, Takeda, Sanofi: Honoraria; Roche, Gilead, ADC Therapeutics, Takeda, Novartis, Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen, BMS: Research Funding; Hospices Civils de Lyon: Current Employment. Lin:Merck: Research Funding; Novartis: Consultancy; Bluebird Bio: Consultancy, Research Funding; Gamida Cell: Consultancy; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Legend: Consultancy; Juno: Consultancy; Takeda: Research Funding; Vineti: Consultancy; Sorrento: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Subklewe:Pfizer: Consultancy; Seattle Genetics: Research Funding; Miltenyi Biotech: Research Funding; Novartis: Consultancy, Speakers Bureau; Seagen: Research Funding; Morphosys: Research Funding; Roche: Consultancy, Research Funding; Janssen: Consultancy, Speakers Bureau; Takeda: Other: Travel support; Gilead: Consultancy, Research Funding, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding. Jain:MyeloidTx: Consultancy; Novartis: Consultancy; BMS: Consultancy; Incyte: Research Funding; Kite Pharma: Consultancy, Research Funding.