CTL-119

In chronic lymphocytic leukemia (CLL) patients who achieve a complete remission (CR) to anti-CD19 chimeric antigen receptor T cells (CART-19), remissions are remarkably durable. Preclinical data suggesting synergy between CART-19 and the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib prompted us to conduct a prospective single-center phase 2 trial in which we added autologous anti-CD19 humanized binding domain T cells (huCART-19) to ibrutinib in CLL patients not in CR despite at least 6 months of ibrutinib. The primary end points were safety, feasibility, and achievement of a CR within 3 months. Of 20 enrolled patients, 19 received huCART-19. The median follow-up for all infused patients was 41 months (range 0.25 - 58). Eighteen patients developed cytokine release syndrome (CRS; grade 1-2 in 15 of 18 subjects) and 5 developed neurotoxicity (grade 1-2 in 4, grade 4 in 1 patient). While the three-month CR rate among International Working Group on CLL (iwCLL)-evaluable patients was 44% (90% CI 23 to 67), at 12 months, 72% of patients tested had no measurable residual disease (MRD). The estimated overall and progression-free survival at 48 months were 84% and 70%, respectively. Of 15 patients with undetectable MRD at 3 or 6 months, 13 remain in ongoing CR at last follow-up. In CLL patients not achieving a CR despite at least 6 months of ibrutinib, adding huCART-19 mediated a high rate of deep and durable remissions. ClinicalTrials.gov number, NCT02640209.

Chimeric antigen receptor (CAR) T-cell therapy can induce durable remissions of relapsed/refractory B-acute lymphoblastic leukemia (ALL). However, case reports suggested differential outcomes mediated by leukemia cytogenetics. We identified children and young adults with relapsed/refractory CD19+ ALL/lymphoblastic lymphoma treated on 5 CD19-directed CAR T-cell (CTL019 or humanized CART19) clinical trials or with commercial tisagenlecleucel from April 2012 to April 2019. Patients were hierarchically categorized according to leukemia cytogenetics: High-risk lesions were defined as KMT2A (MLL) rearrangements, Philadelphia-chromosome (Ph+), Ph-like, hypodiploidy, or TCF3/HLF; favorable as hyperdiploidy or ETV6/RUNX1; and intermediate as iAMP21, IKZF1 deletion, or TCF3/PBX1. Of 231 patients aged 1-29, 74 (32%) were categorized as high-risk, 28 (12%) as intermediate, 43 (19%) as favorable, and 86 (37%) as uninformative. Overall CR rate was 94%, with no difference between strata. There was no difference in relapse free survival (RFS, p=0.8112), with 2-year RFS for the high-risk group of 63% (95%CI 52-77). There was similarly no difference seen in OS (p=0.5488) with 2-year OS for the high-risk group of 70% (95%CI 60-82). For patients with KMT2A-rearranged infant ALL (n=13), 2-year RFS was 67% (95%CI 45-99), and OS was 62% (95%CI 40-95), with multivariable analysis demonstrating no increased risk of relapse (HR 0.70, 95%CI 0.21-2.90, p=0.7040), but a higher proportion of relapses associated with myeloid lineage switch, and a 3.6-fold increased risk of all-cause death (95%CI 1.04-12.75, p=0.0434). CTL019/huCART19/tisagenlecleucel are effective at achieving durable remissions across cytogenetic categories. Relapsed/refractory patients with high-risk cytogenetics, including KMT2A-rearranged infant ALL, demonstrated high RFS and OS probabilities at 2 years.