Paper Details

ABSTRACT

Background: Despite improvements in frontline therapy for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), the outcomes of relapsed Ph+ ALL remain poor. We hypothesized that the combination of blinatumomab + asciminib, a potent allosteric inhibitor of BCR::ABL1, may lead to deep and durable remissions in patients (pts) with Ph+ ALL after failure of standard therapies. Given the established safety and clinical activity of asciminib in chronic myeloid leukemia and its unique mechanism of action compared with other BCR::ABL1 tyrosine kinase inhibitors, we also evaluated its efficacy in combination with blinatumomab in newly diagnosed pts with Ph+ ALL.

Methods: This is a phase I/II study evaluating the combination of blinatumomab + asciminib in pts ≥18 years of age with newly diagnosed Ph+ ALL and pts ≥12 years of age with R/R Ph+ ALL or CML-LBP. In the phase I portion, pts received up to 5 cycles of continuous infusion blinatumomab in a standard 4-week on/2-week off schedule, in combination with asciminib at a dose of 80mg (DL0), 120mg (DL1) or 200mg (DL2) orally daily. In the phase II portion, pts received the same regimen with asciminib given at the RP2D. Recommended CNS prophylaxis for newly diagnosed and R/R pts was 15 doses and 6-8 doses of IT chemotherapy (alternating Ara-C and MTX), respectively. For pts not proceeding with allo-HSCT or CAR T-cell therapy, asciminib is continued indefinitely as maintenance. The primary endpoint of the phase I portion is the minimum safe and biologically effective dose of asciminib in combination with blinatumomab; the primary endpoints of the phase II portion are the NGS IG/TR MRD negativity rate at sensitivity of 10^-6 (frontline pts) and the CR/CRi rate (R/R pts). For all efficacy outcomes, pts treated with different doses of asciminib were pooled for analysis.

Results: As of February 2026, 17 pts have been treated (15 in phase I and 2 in phase II). In the phase I portion of the study, 4 pts received asciminib 80mg, 5 received 120mg, and 6 received 200mg. No DLTs nor any grade ≥3 related adverse events were observed. Given the lack of drug-related toxicity and high efficacy (6/6 achieving NGS MRD negativity and 4/6 achieving CMR [i.e. PCR negativity for BCR::ABL1]), the 200mg daily dose of asciminib was chosen as the RP2D in combination with blinatumomab.

For the R/R cohort (n=11), the median age was 49 years (range, 15-70). 10 pts had Ph+ ALL and 1 had CML-LBP. Six pts (55%) had received ≥2 prior TKIs, 6 (55%) had received prior blinatumomab + ponatinib, and 1 (9%) had undergone prior allo-HSCT. All 11 pts (100%) achieved CR, all after the first cycle. 5 of 9 evaluable pts (56%) achieved NGS MRD negativity after cycle 1 and 10/11 (91%) achieved NGS MRD negativity as best response; the other pt had NGS MRD below the level of detection as best response. With a median follow-up of 14 months (range, 3-22 months), the median number of cycles received was 4 (range, 3-5). 3 pts (27%) have relapsed (1 of whom was nonadherent to therapy) and 8 are in ongoing continuous remission with a median remission duration of 12 months (range, 2-18 months). The asciminib doses in the pts who relapsed were 80mg (n=1) and 120mg (n=2). Post-protocol consolidation was allo-HSCT in 3 pts and CD19 CAR T-cell consolidation in 4 pts (1 brexu-cel and 3 obe-cel). As of last follow-up, 1 pt died (due to CNS relapse). The 1-year RFS and OS rates were 66% and 89%, respectively.

For the frontline cohort (n=6), the median age was 59 years (range, 32-81), median WBC at diagnosis was 12.6 x 10⁹/L (range, 2.7-48), and 2/5 pts with complete genomic profiling (40%) had IKZF1^plus genotype. All 6 pts (100%) achieved CR, all after the first cycle. Among 5 evaluable pts, NGS MRD negativity rates after cycle 1 and overall were 60% (3/5) and 100% (5/5). One frontline pt underwent CAR T-cell consolidation (obe-cel). None of the pts has relapsed as of last follow-up.

Conclusion: In this phase I/II study, the combination of blinatumomab and asciminib was safe and effective in both newly diagnosed and R/R pts Ph+ ALL, including those with prior exposure to blinatumomab + ponatinib. The RP2D of asciminib was 200mg daily in combination with blinatumomab. All pts achieved CR, and high rates of NGS MRD negativity have been observed in both frontline and R/R pts (100% and 91%, respectively). This study continues to accrue pts and is expanding to additional sites.