The CAR-Hematotox Identifies Patients at High Risk of Infectious/Inflammatory Complications in a Cohort of Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) Treated with ARI-0001 (Varnimcabtagene Autoleucel)
Authors: Arbelaez Monroy Maria Isabel , Albiol Nil , Martínez-Roca Alexandra , Martínez-Cibrián Nuria , Arnaldos Cristina , Español-Rego Marta , Navarro-Velazquez Sergio , Brillembourg Helena , Merchan Beatriz , Alserawan Leticia , Castella Maria , Benitez-Ribas Daniel , Montoro-Lorite Mercedes , Ayora Pilar , Ramos Carla , Fernández de Larrea Carlos , González-Navarro E. Azucena , Urbano-Ispizua Alvaro , Esteve Reyner Jordi , Juan Manel , Delgado Julio , Rodríguez-Lobato Luis Gerardo , Ortiz-Maldonado Valentin 
Published: December 2024

Introduction
Chimeric antigen receptor T cells (CART) have improved outcomes in many hematologic malignancies. Cytopenia or ICAHT (immune effector cell-associated hematotoxicity) are common and pose a direct impact on procedure-related mortality. They raise a challenge in the short and long-term follow-up. The CAR-HEMATOTOX score (HT) uses ferritin, CRP, hemoglobin, platelet, and neutrophil count to predict the risk of hematological toxicities in CART receptors. It is validated in follicular, mantle-cell lymphoma, and large B-cell lymphoma. However, its usefulness remains unclear in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients treated with CAR T cells.
Methods
This is a single-center, retrospective, and observational study that includes R/R BCP-ALL adult patients treated with varnimcabtagene autoleucel (var-cel, ARI-0001), an autologous, second-generation, 4-1BB-based CD19-targeted CART product. This includes patients treated in the CART19-BE-01 trial and the consecutive compassionate use and hospital exemption program between July 2017 and November 2023. All patients were treated at Hospital Clínic (Barcelona, Spain). We retrospectively calculated CAR-HEMATOTOX at lymphodepletion for each patient and explored its association with several outcomes. Statistical analyses were performed with R v 4.3.2 and Graphpad Prism v 10.2.
Results
The first ten were excluded from 68 patients with BCP-ALL infused with var-cel, as they received the total dose in a single infusion (var-cel current label consists of a fractionated infusion in three consecutive days). A total of 58 BCP-ALL patients were analyzed. The median age at infusions was 38.5 years (range 20-73), 28 (43.3%) patients were female and 54 (93.1%) presented an ECOG between 0-1. Patients median lines of treatment were 3 (range 1-6), forty-seven (81%) of the patients had received at least 2 lines of treatment (median 3.7, 1-6) and 47 (81%) had also undergone allogeneic stem cell transplant. Twenty-three (48.9%) patients presented any infection during the admission period (8.6% two or more infections), 25 patients (44.6%) had CRS (only 1 grade ³3), and only 2 (3.6%) patients presented ICANS. The median follow-up of the whole cohort was 15 months (1.7-67.4).
A high HT score was observed in 38 (68%) subjects. Patient characteristics (age, sex, ECOG) were equally distributed between groups, All patients in the low-HT group received the 3 fractionated doses, while 3 and 4 patients in the high-HT received one and two doses, respectively. The high-HT group presented a higher incidence of fever (64% vs 21%; p=0.01) and CRS (55% vs 22%; p=0.02) as well as infections (61% vs 21% p=0.02), bacterial mainly (55%) in contrast with the low-HT group. Early ICAHT occurred in 82.6% and late in 91.3% of patients, though not statistically significant, high-HT patients presented grades 3 or 4 of ICAHT compared to those with low-HT (28% vs 7%). Hence, the aplastic phenotype was more frequent in high-HT patients (39.4% vs 14.3%, p=ns). The requirement for blood products was more frequent in the high-HT group as expected (45% vs 7%; p=0.02). No differences were observed in DOR, PFS, or OS (p=0.6). Finally, we did not find differences between high and low HT either in the expansion peak (median 6.66 cells/µl vs 3.53 cells/µl, p=0.3) or AUC at 30d (median 81.82 μl/l vs 61.59 μl/l, p=0.2).
Conclusion:
The CAR-HEMATOTOX score at lymphodepletion predicts inflammatory complications and transfusion dependence by identification of a high-risk group in our R/R BCP-ALL cohort, that can help us design individual prophylaxis and support strategies, as well as select patients for outpatient infusion and follow-up.