<i>TP53</i> mutations are associated with CD19− relapse and inferior outcomes after blinatumomab in adults with ALL
Ibrahim Aldoss, Shanpeng Li, Jianying Zhang, Mary C. Clark, Vaibhav Agrawal, Hoda Pourhassan, Paul Koller, Ahmed Aribi, Haris Ali, Amanda Blackmon, Salman Otoukesh, Karamjeet Sandhu, Brian Ball, Shukaib Arslan, Andrew Artz, Idoroenyi Amanam, Monzr M. Al Malki, Amandeep Salhotra, Tibor Kovacsovics, Lindsey Murphy, Michelle Afkhami, Dat Ngo, Jose Tinajero, Zhaohui Gu, Pamela S. Becker, Ryotaro Nakamura, Anthony S. Stein, Guido Marcucci, Stephen J. Forman, Vinod Pullarkat
Abstract
ABSTRACT: 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.