Blinatumomab maintenance after allogeneic hematopoietic cell transplantation for B-lineage acute lymphoblastic leukemia

Abstract

Patients with B-lineage acute lymphoblastic leukemia (ALL) are at high-risk for relapse after allogeneic hematopoietic cell transplantation (HCT). We conducted a single-center phase 2 study evaluating the feasibility of 4 cycles of blinatumomab administered every 3 months during the first year after HCT in an effort to mitigate relapse in high-risk ALL patients. Twenty-one of 23 enrolled patients received at least 1 cycle of blinatumomab and were included in the analysis. The median time from HCT to the first cycle of blinatumomab was 78 days (range, 44 to 105). Twelve patients (57%) completed all 4 treatment cycles. Neutropenia was the only grade 4 adverse event (19%). Rates of cytokine release (5% G1) and neurotoxicity (5% G2) were minimal. The cumulative incidence of acute graft-versus-host disease (GVHD) grades 2 to 4 and 3 to 4 were 33% and 5%, respectively; 2 cases of mild (10%) and 1 case of moderate (5%) chronic GVHD were noted. With a median follow-up of 14.3 months, the 1-year overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM) rates were 85%, 71%, and 0%, respectively. In a matched analysis with a contemporary cohort of 57 patients, we found no significant difference between groups regarding blinatumomab's efficacy. Correlative studies of baseline and posttreatment samples identified patients with specific T-cell profiles as "responders" or "nonresponders" to therapy. Responders had higher proportions of effector memory CD8 T-cell subsets. Nonresponders were T-cell deficient and expressed more inhibitory checkpoint molecules, including T-cell immunoglobulin and mucin domain 3 (TIM3). We found that blinatumomab postallogeneic HCT is feasible, and its benefit is dependent on the immune milieu at time of treatment. This paper is posted on ClinicalTrials.gov, study ID: NCT02807883.

Graphical abstract

Figure 1.

Heatmap of surface marker expression of T cells in nonresponders and responders. Hyperbolic arcsin transformed fluorochrome expression for 14 markers were averaged for baseline samples taken from nonresponders (n = 3) and responders (n = 10), and posttreatment samples from nonresponders (n = 4) and responders (n = 11).

Figure 2.

Subpopulations identified via viSNE analysis of 14 surface markers in all 56 samples. (A) viSNE map for nonresponders and responders color-coded according to PhenoGraph cluster annotation. viSNE maps were separated to baseline and posttreatment in both nonresponders and responders groups. (B) Heatmap of mean surface marker expression in each cluster. Percentage in parentheses denotes the size of each cluster.

Figure 3.

Study outcomes for patients treated with blinatumomab. At 1 year, the rate of relapse was 29% (95% CI, 11%-49%) (A), progression-free survival (PFS) 71% (95% CI, 47%-86%) (B), and overall survival (OS) 85% (95% CI, 61%-95%) (C).

Figure 4.

Comparison of PFS and OS between patients treated with blinatumomab maintenance and no posttransplant maintenance (matched-case cohort). At 1 year, the rates of PFS for the blinatumomab vs the control group were 71% vs 68%, P = .44 (A), and the rates for OS for the blinatumomab vs the control group were 85% vs 76%, P = .23 (B).