TP53 mutations are associated with CD19- relapse and inferior outcomes after blinatumomab in adults with ALL

Despite the success of the CD19 × CD3 T-cell engager blinatumomab in B-cell acute lymphoblastic leukemia (B-ALL), treatment failure is common and can manifest with antigen loss and extramedullary disease (EMD) relapse. To understand the impact of leukemia genetics on outcomes, we reviewed 267 adult patients with B-ALL treated with blinatumomab and used next-generation sequencing to identify molecular alterations. Patients received blinatumomab for relapsed/refractory (R/R) disease (n = 150) and minimal residual disease (MRD; n = 88), upfront as induction (n = 10) or as consolidation in MRD-negative state (n = 19). In the overall cohort, 50 patients (19%) had Philadelphia chromosome (Ph)-positive ALL, 80 (30%) had Ph-like ALL, 35 (13%) had TP53 mutations (TP53m), 7 (3%) had KMT2A rearrangement, and 8 (3%) had PAX5 alterations. For patients treated for R/R ALL, the overall complete remission (CR)/CR with incomplete hematological recovery (CRi) rate was 59%. Only pretreatment high disease burden (P < .01) and active EMD (P < .01) were associated with inferior CR/CRi rate. Of 169 patients in CR/CRi after blinatumomab, 79 (47%) patients relapsed, including 22 (28%) with CD19- and 54 (68%) with CD19+ relapse. In multivariable analysis, TP53m was associated with an increased risk of CD19- relapse (hazard ratio [HR], 6.84; 95% confidence interval [CI], 2.68-17.45; P < .01). Post-blinatumomab allogeneic stem cell transplantation consolidation was associated with a lower risk of CD19- relapse (HR, 0.10; 95% CI, 0.03-0.37; P < .01) and EMD relapse (HR, 0.36; 95% CI, 0.18-0.73; P < .01). In conclusion, leukemia genetics may predict patterns of blinatumomab failure, with TP53m associated with CD19- relapse.