Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults With Acute Lymphoblastic Leukemia

Abstract

PURPOSE The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel (CTL019) has an 81% response rate in children with relapsed or chemotherapy refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is a life-threatening treatment-related toxicity that limits the full therapeutic potential in adults. We report outcomes for adults with r/r ALL treated with an optimized CTL019 dosing and CRS management strategy. METHODS Adults with r/r B-cell ALL received CTL019 in 1 of 2 trials. Patients received lymphodepletion followed by CTL019 as either a one-time infusion or fractionated infusions split over 3 days (day 1, 10%; day 2, 30%; day 3, 60%), which allowed for day 2 and day 3 doses to be held for early CRS. Total planned CTL019 dose varied with adaptive protocol modifications in response to efficacy and CRS toxicity. RESULTS Thirty-five adults with r/r ALL received CTL019 in 1 of 3 dosing cohorts. The low-dose cohort (n = 9) received single or fractionated dosing and had manageable toxicity with a 33% complete remission (CR) rate. In the high-dose single infusion cohort, 3 of 6 patients with refractory CRS concurrent with culture-positive sepsis died, and 3 achieved CR. The 20 patients in the high-dose fractionated (HDF) cohort had a 90% CR rate and manageable CRS. The HDF cohort had the highest survival, with a 2-year overall survival of 73% (95% CI, 46% to 88%) and event-free survival of 49.5% (95% CI, 21% to 73%). CONCLUSION Fractionated dosing of CTL019 with intrapatient dose modification optimizes safety without compromising efficacy in adults with r/r ALL.

Low toxicity and favorable overall survival in relapsed/refractory B-ALL following CAR T cells and CD34-selected T-cell depleted allogeneic hematopoietic cell transplant

“… 7 – 9 Several groups initiated investigation of CD19-specific CAR T cells as a potential therapeutic option for patients with R/R B-ALL. 10 – 17 This led to the approval by the Food and Drug Administration of CD19-specific CAR T cells for R/R B-ALL in patients <26 years old. 10 – 16 Despite this success, the incidence of relapse following treatment with CAR T cells in all patients with R/R B-ALL is unknown and has been reported to exceed 50% in some series, demonstrating a need to improve therapy.…”

Advances in CAR T Therapy for Hematologic Malignancies

“…Commonly used doses are within the order of magnitude of 10 6 cells/ kg (10 8 cells overall). [1][2][3] Within that dosing range, 3 day fractionated administration of tisacel in adult ALL improved the tolerability of a total dose of 5 9 10 8 cells compared to a single infusion of the same dose, 79 and a dose of 2 9 10 7 cells/kg was too toxic in early trials of liso-cel in ALL. 8 As discussed above, higher CTL019 doses increase the CR rate in patients with CLL without increasing risk of severe AE, but did not show improved OS compared to low dose.…”

“…8,80 Fractionated administration (10% of total dose on day 1, 30% on day 2, 60% on day 3) allows intra-patient dose modification in the setting of early CRS. 79 Risk adapted preemptive tocilizumab decreases the incidence of severe CRS in pediatric patients with ALL and high tumor burden (≥ 40% marrow blasts) treated with tisacel 81 ; however, prophylactic tocilizumab in adults with NHL treated with axi-cel may increase the risk of neurotoxicity. 82 Other approaches to limit CRS could include prophylaxis with a small molecule, such as the Janusassociated kinase (JAK)-1 antagonist itacitinib, currently under study to limit CAR T AE.…”

“…83 Importantly, inflammation associated with active infection has led to CRS fatalities, thus patients should be screened for infection prior to CAR-T to further limit the risk of severe CRS. 79 Comparisons of CRS severity across CAR T studies is complicated by the use of different grading systems; most commonly used are the Penn scale (tisa-cel) 13 and the Lee scale 18 (axicel). A consensus statement to standardize CRS grading was endorsed by ASTCT in 2019 and is shown in Table 2 compared to the Penn and Lee scales.…”

Chimeric Antigen Receptor T-Cells in B-Acute Lymphoblastic Leukemia: State of the Art and Future Directions

“…Some authors have suggested preemptive treatment with tocilizumab, an IL-6 inhibitor, for patients at higher risk of severe CRS due to higher disease burden, which resulted in a trend for less grade 4 CRS events in a cohort treated with this agent (40). Another study, which investigated fractionated doses of CAR-T cells, showed high CR rates with manageable toxicities in the fractionated dose cohort (41).…”