PS1214 INFECTIOUS COMPLICATIONS FOLLOWING ARI‐0001 CELL (A3B1:CD8:4–1BB:CD3Z CART19) TREATMENT IN ADULT AND PEDIATRIC PATIENTS WITH CD19+ RELAPSED / REFRACTORY MALIGNANCIES
Authors: Ortiz‐Maldonado V. , Alonso‐Saladrigues A. , Cardozo C. , Baumann T. , Díaz‐Beyá M. , Torrebadell M. , Català A. , Caballero‐Baños M. , Castro P. , Fernández S. , Jordan Y. , Esteve J. , Yagüe J. , Rovira M. , Urbano‐Ispizua A. , Juan M. , Noguera A. , Puerta‐Alcalde P. , Soriano A. , García‐Vidal C. , Rives S. , Delgado J. 
Published: June 2019

Background:Several chimeric antigen receptor products targeting CD19 are either approved or in development for the treatment of acute lymphoblastic leukemia (ALL) and non‐Hodgkin's lymphoma (NHL). Nevertheless, information on infections and immune impairment caused by this procedure (lymphodepletion chemotherapy, neutropenia, B‐cell aplasia and hypogammaglobulinemia) remains scarce.Aims:To characterize the immune impairment, fever episodes and epidemiology of proven infections in a cohort of adult and pediatric patients with relapsed/refractory (R/R) CD19+ malignancies treated with ARI‐0001 cells.Methods:Eligibility criteria included patients with R/R CD19+ malignancies who had failed standard available therapy. All patients were conditioned with fludarabine (90 mg/m2) and cyclophosphamide (900 mg/m2) before receiving 0.4–5 x106 ARI‐0001 cells/kg. We report all infections with positive microbiological results from the start of lymphodepletion chemotherapy to day +120, and its association with fever (≥ 38°C), cytokine release syndrome (CRS), neutropenia, B‐cell aplasia and hypogammaglobulinemia (IgG < 6.8 g/L [adults], ≤ 8.0 g/L [pediatrics]). Antimicrobial prophylaxis included trimethoprim/sulfamethoxazole or pentamidine (until >200 CD4+ cells/ml), acyclovir for 3–6 months in all pediatric patients and in adults if VZV or HSV+, plus levofloxacin and fluconazol or voriconazol (during grade 4 neutropenia [<0.5 neutrophils x109/L]).Results:A total of 30 patients (23 adults/7 pediatrics) received ARI‐0001 cells. Diagnoses were ALL (25), NHL (4) and CLL (1). Median age was 24 years (3–54), and 56% were men. 21/25 of ALL patients relapsed after alloHCT, and 3/4 of NHL patients relapsed after autoHCT. Hypogammaglobulinemia was detected at screening in 73% (22/30) of patients (72% in LLA, and 80% NHL/CLL) with median IgG levels of 5.6 g/L (adults) and 7.49 g/L (pediatrics). After therapy, B‐cell aplasia occurred in all patients with a median duration of 84 days (42–371), while hypogammaglobulinemia persisted in 61.5% (8/13) of evaluable patients at day +120. Grade 4 neutropenia was observed in 90% (27/30) of all patients, with a median duration of 10.5 days (1–85) in patients with ≥ 0.5 neutrophils x109/L prior lymphodepletion. 13 patients (43%) had 17 episodes of infection (7 bacterial and 10 viral; see Table 1): 9 from lymphodepletion to day +30 post‐infusion (4 bacterial and 5 viral), and 8 from day +31 to day +120 (3 bacterial and 5 viral). No fungal infections were documented. We observed 2 severe infections: a C. difficile‐positive pseudomembranous colitis that caused the patient's death on day +6, and a respiratory syncytial virus tracheobronchitis that required ICU on day +10. Median neutrophil count at time of infection was 0.6 (0.1–3.8) x109/L for bacterial and 1.4 (0.0–3.3) x109/L for viral infections. Median IgG levels at screening and at day +120 was 4.8 and 5.95 g/L (with infections), and 6.54 and 7.16 g/L (without infections), respectively. Median B‐cell aplasia lasted 101.5 (70–287) days (with infections), and 70 (42–371) days (without infections). 66% of patients (20/30) had a total of 24 febrile episodes: 18/24 (75%) were attributed to CRS, 3/24 (12.5%) had a proven infection, and the remaining 12.5% (3/24) did not have CRS or proven infection.Summary/Conclusion:Immune impairment was extensive due to lymphodepleting chemotherapy, neutropenia, B‐cell aplasia and hypogammaglobulinemia. Febrile episodes were mostly attributed to CRS, with few proven infections. Infections occurred but were mostly mild, with an infection‐related mortality of 3.3%.image