Abstract
Blinatumomab (BLIN), a CD19xCD3 bispecific T-cell engager, improves outcomes in relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), with a median overall survival (OS) of 7.7 months and complete remission (CR) rate of 34%, but efficacy is limited in high disease burden and T-cell dysfunction. Bruton's tyrosine kinase (BTK) signaling plays a pathogenic role in B-ALL, and inhibition of this pathway by the BTK inhibitor, ibrutinib (IBR), shows activity in pre-clinical models. IBR, through off-target interleukin-2-inducible T-cell kinase (ITK) inhibition, may enhance Th1 responses, and preclinical studies support IBR's role in enhancing T-cell–mediated cytotoxicity. We hypothesized that IBR would synergize with BLIN through immunomodulatory effects and that combining IBR with BLIN would improve CR rates in R/R B-ALL.
This multicenter, single-arm, Phase 2 trial (NCT02997761) evaluated IBR + BLIN in adults with R/R B-ALL. Eligibility included age ≥18 years and R/R disease (including MRD ≥0.1%), and failure of ≥1 second-generation TKI for Ph+ patients. Prior transplant (HSCT) was permitted, and BLIN was excluded. The induction consisted of two cycles of IBR and BLIN. Cycles were 6 weeks long and consisted of 4 weeks of combined IBR (560mg daily) and BLIN (28 mcg/day continuous infusion, with ramp-up during cycle 1), followed by 2 weeks of IBR 560mg daily monotherapy. During cycle 1 only, patients were treated with a 1-week IBR 560mg daily monotherapy lead-in to prime the Th1 response prior to starting combined IBR and BLIN. Responders could receive up to 3 consolidation cycles and optional IBR maintenance. The primary endpoint was CR rate. The study used Simon's minimax two-stage design, with a safety lead-in of 6–9 patients and 18 response-evaluable patients required in total. CR in ≥10/18 would reject the null hypothesis of a 33% CR rate. The secondary and exploratory objectives were to further evaluate safety and efficacy and pharmacodynamics, respectively.
Between 2019–2024, 19 patients were enrolled at two centers. One withdrew consent early and was replaced. Median age was 48 (range 26–73); the majority (58%) were male and 63% were Hispanic or Latino. B-ALL subtypes included Ph-negative (53%), Ph-like (37%), and Ph+ (10%). Median bone marrow blasts at baseline were 56% (range 1–95%). Most (63%) had relapsed disease. Median number of prior therapies was 1 (range 1–3), and 2 had prior HSCT.
In the safety lead-in, 2/9 patients had DLTs (arthralgia, back pain, and hypophosphatemia; elevated AST/ALT). The study met criteria to proceed to full accrual. Among 18 evaluable patients, CR rate was 50% (n=9), and CR/CR with incomplete count recovery was 55.6% (n=10). All responses were MRD-negative by flow cytometry (<0.01%). Six patients (33%) were bridged to HSCT or CAR-T. All patients discontinued study therapy (8 for treatment failure, 6 for HSCT/CAR-T, and 1 each for relapse, MRD relapse, investigator decision, and withdrawal of consent). With median follow-up of 9.1 months, median OS was 12.3 months (95% confidence interval, 7.8–15.6).
Median number of cycles was 2 (range 1–6). There were no treatment-related deaths. Related grade 3+ treatment-emergent adverse events (TEAEs) occurring in 20% or more patients included anemia (32%), febrile neutropenia (32%), elevated ALT (21%), and elevated AST (21%). Related CRS occurred in 47%, neurotoxicity in 16%, and headaches in 26%. Related atrial fibrillation and grade 3+ hemorrhagic events were not seen. Serious TEAEs included febrile neutropenia (n=2), and arthralgia, myalgia, gum infection, and neurotoxicity (each n=1).
The combination of IBR and BLIN demonstrated encouraging efficacy with a high MRD-negative CR rate in R/R B-ALL and was generally well-tolerated. Although the primary endpoint was not met, observed outcomes compare favorably to historical data (e.g. TOWER trial and patients with high baseline disease burden), supporting further evaluation. These results suggest immunomodulatory synergy between BTKi and T-cell engagers in B-ALL, warranting randomized trials.
