Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment

Abstract

This long-term follow-up analysis evaluated overall survival (OS) and relapse-free survival (RFS) in a phase 2 study of the bispecific T-cell engager antibody construct blinatumomab in 36 adults with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). In the primary analysis, 25 (69%) patients with relapsed/refractory ALL achieved complete remission with full (CR) or partial (CRh) hematologic recovery of peripheral blood counts within the first 2 cycles. Twenty-five patients (69%) had a minimal residual disease (MRD) response (<10(-4) blasts), including 22 CR/CRh responders, 2 patients with hypocellular bone marrow, and 1 patient with normocellular bone marrow but low peripheral counts. Ten of the 36 patients (28%) were long-term survivors (OS ≥30 months). Median OS was 13.0 months (median follow-up, 32.6 months). MRD response was associated with significantly longer OS (Mantel-Byar P = .009). All 10 long-term survivors had an MRD response. Median RFS was 8.8 months (median follow-up, 28.9 months). A plateau for RFS was reached after ∼18 months. Six of the 10 long-term survivors remained relapse-free, including 4 who received allogeneic stem cell transplantation (allo-SCT) as consolidation for blinatumomab and 2 who received 3 additional cycles of blinatumomab instead of allo-SCT. Three long-term survivors had neurologic events or cytokine release syndrome, resulting in temporary blinatumomab discontinuation; all restarted blinatumomab successfully. Long-term survivors had more pronounced T-cell expansion than patients with OS <30 months.

Figure 1

Patient disposition. Of the 36 patients in the study, 25 achieved CR or CRh and 11 patients did not achieve CR/CRh. Furthermore, 25 patients achieved an MRD response and 11 patients did not achieve an MRD response. Although numerically identical, the MRD response subgroups overlapped but were not the same as the CR/CRh response subgroups.

Figure 2

Probability of OS. (A) OS in the entire patient population (N = 36) at a median follow-up of 32.6 months. *Two patients who were alive at the last follow-up at 29.7 and >29.9 months were censored at these visits and were considered to have an OS of ≥30 months after rounding to the nearest whole number. (B) Simon-Makuch analysis of OS in patients with and without MRD response. (C) OS with and without prior allo-SCT in the entire patient population (N = 36) at a median follow-up of 32.6 months. HSCT, hematopoietic stem cell transplantation.

Figure 3

Probability of RFS. RFS among responders (n = 25) at a median follow-up of 28.9 months.

Figure 4

T-cell and B-cell kinetics during cycle 1 (day 1 to 29) and cycle 2 (day 43 to 71) of blinatumomab treatment. (A) CD3⁺ T-cell expansion. (B) CD3⁺ T_EM-cell expansion. (C) CD19⁺ B-cell depletion. Patients were grouped according to MRD response and duration of OS (<30 vs ≥30 months). Data shown are median cell values (interquartile range) with numbers of evaluable data points per patient subgroup at each time point given below. For clarity, initial T-cell redistribution during the first treatment week of cycles 1 and 2 is not shown.