S1636 fractionated dosing of ari-0001 cells (a3b1:cd8:4–1bb:cd3z car19) and early tocilizumab administration may reduce the incidence of severe cytokine release syndrome in patients with cd19+ malignancies

Background: Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) are major adverse events in patients receiving CART cell therapy. Forecasting the in vivo toxicity of “living drugs” like CART cells is complex and multifactorial. Some of these factors might be disease burden and CART cell dose, so adjusting dose to disease burden might be a plausible strategy to minimize toxicity. Nevertheless, reliably assessing disease burden is a tricky task due to technical issues and even hour‐changing disease dynamics. Aims: To characterize the impact of ARI‐0001 cell dose fractioning on CRS and ICANS in two cohorts (fractioned vs single‐full dose) of adult and pediatric patients with relapsed/refractory (R/R) CD19+ malignancies. Methods: Eligibility criteria included patients with R/R CD19+ acute lymphoblastic leukemia (ALL), non‐Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) who had failed standard available therapy. All patients were conditioned with fludarabine (90 mg/m 2 ) and cyclophosphamide (900 mg/m 2 ) before receiving ARI‐0001 cells (0.5–5 x10 6 cells/kg). Originally, patients received the entire ARI‐0001 cell dose in a single infusion (day 0) (single dose [SD] cohort), but after 3 fatal toxic events (two of them CRS) a major amendment to the protocol was implemented. After the amendment, patients received 10%, 30% and 60% of the total ARI‐0001 cell dose on days 0, +1 and +2 (fractionated dose [FC] cohort), with administration of fractions 2 and 3 contingent on the absence of CRS signs or symptoms. Also, before the amendment tocilizumab was administered to patients with grade ≥ 3 CRS and after amendment to patients with grade ≥ 2 CRS. Results: As of February 2019, a total of 30 patients (23 adults/7 pediatrics) have received ARI‐0001 cells (19 SD and 11 FD). 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. At screening, active disease (≥ 5% lymphoblasts in the bone marrow, or tumor masses by PET‐CT) was documented in 62% of SD patients and 33% in FD patients. The remaining patients were in complete remission at screening. CRS was observed in 16/19 (84%) of SD patients and 5/11 (45%) of FD patients. Indeed, fraction 3 was omitted in 2/11 (18%) FD patients due to early onset of CRS. Moreover, grade ≥ 3 CRS occurred in 5/19 (26%) of SD patients, including 2 fatal events, whilst 0/11 (0%) cases of grade ≥ 3 CRS were observed in FD patients. Finally, tocilizumab was administered to 26% (5/19) of SD patients and to 18% (2/11) of FD patients. Grade 1–2 ICANS was documented in 3/19 (16%) of SD patients and in 3/11 (27%) of FD patients. The only 2 cases of grade 2 ICANS occurred in patients with known active CSF infiltration at the time of ARI‐0001 cell infusion. No cases of grade ≥ 3 ICANS were seen neither in SD nor FD patients, and no specific treatment was required. Summary/Conclusion: The fractionated administration of ARI‐0001 cells may improve their safety profile by reducing the incidence of grade ≥ 3 CRS. The incidence of ICANS appeared equally low with both approaches. Based on these preliminary results, FD has been selected for a phase 2 multicenter trial on the use of ARI‐0001 cells in patients with R/R ALL.