Background Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) in pediatric patients remains a high-risk subtype with limited treatment options after tyrosine kinase inhibitor (TKI) failure. Olverembatinib is a potent third-generation TKI with activity against BCR::ABL1 genetic variants, including T315I. Lisaftoclax, a selective BCL-2 inhibitor, has shown encouraging activity in hematologic malignancies. This ongoing phase 1b study evaluates the safety, tolerability, preliminary efficacy, and pharmacokinetics of olverembatinib combined with lisaftoclax in pediatric patients with relapsed/refractory (R/R) Ph+ ALL.

Methods This open-label, dose-escalation and expansion study (NCT05495035) enrolled pediatric patients aged <18 years with R/R Ph+ALL resistant or intolerant to ≥ 1 prior TKI. Patients received olverembatinib monotherapy (40 mg adult-equivalent dose [AED], every other day, days 1–14), followed by combination therapy with lisaftoclax (200, 400, or 600 mg AED daily, with 3-day dose ramp-up) and dexamethasone (6 mg/m²/day, days 15–42). Primary endpoints included safety, overall response rate (ORR), measurable residual disease (MRD) negativity, and pharmacokinetics. A dose-expansion cohort was initiated with lisaftoclax 600 mg AED combined with olverembatinib 40 mg AED.

Results As of the data cutoff date of June 26, 2025, 15 patients(median age 13.0 years, range 9–15) were enrolled. All had R/R Ph+ ALL; 33.3% (5/15) harbored BCR::ABL1 genetic variants, including baseline T315I (n = 4) and F317L (c.951C>A) (n = 1). Median body weight was 44.3 kg (range 22.8–86.0). Fourteen patients (93.3%) had the p190 transcript and one (6.7%) had the p210 transcript. One patient discontinued on cycle 1 day 1 (C1D1) because of a seizure. Fourteen eligible patients (8/14, R/R; 5/14, intolerant, 1 both R/R and intolerant) received lisaftoclax at AEDs of 200 (n = 3), 400 (n = 3), or 600 mg (n = 8). These patients completed two treatment cycles and were assessed for the primary endpoints. Twelve of 15 patients (80%) experienced grade ≥ 3 hematologic treatment-emergent adverse events (TEAEs), including neutropenia (46.7%, n = 7), anemia (26.7%, n = 4), thrombocytopenia (20.0%, n = 3), and elevated hepatic transaminases (6.7%, n = 1). Two patients (13.3%) discontinued because of adverse events (one seizure on C1D1, one hepatic toxicity).

Among 8 patients evaluable for morphologic response, the ORR (complete remission [CR] + CR with incomplete count recovery [CRi]) improved substantially from prior analysis. At the end of olverembatinib monotherapy (EOM), the ORR was 50% (4/8; 2 CR, 2 CRi). By C2D15 (mid-cycle) and end of combination therapy (EOC; C2D27), the ORR increased to 87.5% (7/8; all CR). These response rates represent marked improvements from the interim analysis (ORR, 33.3% [2/6] at EOM, 83.3% [5/6] at EOC). Among 11 evaluable patients, MRD negativity was observed in 7 (63.6%) by C2D15 and C2D27. MRD-negative responses occurred across all dose levels, including in patients with baseline BCR::ABL1 genetic variants.

Pharmacokinetic data demonstrated comparable exposure to adult profiles for both agents, with no significant drug accumulation or drug-drug interactions, supporting the feasibility of this regimen in pediatric patients.

Conclusions This updated analysis further supports the safety, tolerability, and promising antileukemic activity of olverembatinib combined with lisaftoclax in pediatric patients with R/R Ph+ ALL. The regimen demonstrated rapid and deep remissions with high MRD negativity rates and favorable pharmacokinetics. Importantly, these outcomes were achieved without intensive chemotherapy or immunotherapy, highlighting this novel combination as an effective orally active and chemotherapy-free treatment option for this high-risk pediatric population. The study is ongoing for further efficacy and safety assessments and regimen optimization.

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2025
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