Blinatumomab Therapy for Low Level Minimal Residual Disease Detected By Next-Generation Sequencing in Adult B-Cell Acute Lymphoblastic Leukemia

Blinatumomab, a bi-specific T-cell engager, has shown clinical benefit in minimal residual disease (MRD)-positive (≥0.1%) Acute Lymphoblastic Leukemia (ALL) with the BLAST trial (Gökbuget N et al., Blood. 2018) demonstrating improved overall survival (OS) and disease-free survival (DFS). We evaluated the utility of Blinatumomab in low level MRD (<0.1%) using Next Generation Sequencing (NGS, sensitivity 0.0001%). We included adult (18+) B- cell ALL patients (pts) treated at Norris Comprehensive Cancer Center between 2016 and 2022 who received Blinatumomab for MRD positivity tracked using the NGS-based clonoSEQ assay (Adaptive Biotechnologies, Seattle, WA). Pts who didn't receive Blinatumomab were included if they were MRD-positive with clonoSEQ. All patients were in first complete remission. Cumulative incidence of relapse (CIR) was evaluated using competing risk regression (Fine-Gray method), while OS and DFS were analyzed using Cox proportional hazards. Confounder-adjusted KM curves were calculated using direct standardization. Forty-seven pts were included with a median age of 45 (range: 21-70) and follow-up of 12 months. The 3-year OS, DFS, and CIR were 95.4% (95% CI 89.3-100%), 75.1% (95% CI 60.4-93.5%), and 20.3% (95% CI 7.2-38.0%). Twenty-six pts were treated with Blinatumomab (median 2 cycles, range 1-9), most (N= 14, 53.8%) with low levels of MRD (<0.1%). Fourteen pts (53.8%) achieved MRD negativity within a median time of 3.1 months. There were no relapses or death in pts who achieved MRD negativity in the treated group. However, Blinatumomab non-responders had one death and two relapses. Pts who received Blinatumomab were more likely to be MRD positive on multiparameter flow cytometry (MFC) (60.0% vs. 28.6%, P = 0.042) but had a similar distribution of patient age, treatment type, and receipt of transplant. Additionally, there was a trend toward increased median percent residual cells on clonoSEQ (0.018% vs. 0.003% P =0.244) and flow (0.02% vs 0% P =0.066) in the Blinatumomab treatment group. On univariate analysis, significant predictors of CIR and DFS were flow percent (DFS: HR = 1.54; 95% CI 1.07-2.23; P = 0.019; CIR: HR = 1.83; 95% CI 1.38-2.41; P<0.001) and clonoSEQ residual cell count(DFS: HR = 1.58; 95% CI 1.04-2.41; P = 0.031, CIR: HR = 1.88; 95% CI 1.18-2.97 P=0.008). When controlling for the number of residual cells on clonoseq, pts who received Blinatumomab had significantly better CIR(HR = 0.11; 95% CI 0.02-0.69; P = 0.019) and a trend towards improved DFS(HR = 0.21; 95% CI 0.04-1.28; P = 0.092), but no difference in OS. On subgroup analysis of the 31 pts with low levels of MRD (<0.1%), DFS did not improve with Blinatumomab (HR = 0.41; 95% CI 0.04-3.91; P = 0.44). Of those with low levels of MRD two relapsed and both did not receive Blinatumomab. In B cell ALL, Blinatumomab may offer a CIR benefit to pts with low levels of MRD detected on clonoSEQ.