Despite the success of the CD19xCD3 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), minimal residual disease (MRD+) (n=88), upfront as induction (n=10), or as consolidation in MRD- state (n=19). In the overall cohort, 50 (19%) patients 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<0.01) and active EMD (p<0.01) were associated with inferior CR/CRi rate. Of 169 patients in CR/CRi post-blinatumomab, 79 (47%) patients relapsed, including 22 (28%) with CD19- and 54 (68%) with CD19+ relapse. In multivariable analysis, TP53m was associated with increased risk of CD19- relapse (HR=6.84; 95%CI: 2.68-17.45, p<0.01). Post blinatumomab allogenic stem cell transplantation consolidation was associated with lower risk of CD19- relapse (HR=0.10; 95%CI: 0.03-0.37, p<0.01) and EMD relapse (HR=0.36; 95%CI: 0.18-0.73, p<0.01). In conclusion, leukemia genetics may predict patterns of blinatumomab failure, with TP53m associated with CD19- relapse.
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