Investigators sought to discover if ABL blockade with catalytic domain and allosteric inhibitors would be discovered as tolerable and effective in adult patients with BCR-ABL1+ ALL, to be presented at the 2021 Annual ASH Meeting.

This phase 1 study enrolled 12 patients, with a median age of 66 years, with untreated BCR-ABL1+ ALL, all having discontinued therapy previously. Investigators administered ABL001 in combination with DAS plus prednisone in BCR-ABL1+ ALL, employing a 3+3 dose escalation design with an expansion cohort with the primary objective to determine the maximum tolerated dose (MTD)/recommended phase 2 dose.

Patients were treated with DAS 140 mg daily and prednisone 60 mg/m2 days (d) 1-24 (max 120 mg daily, tapered d 25-32) with escalating doses of ABL001 once/d administered fasting. DAS plus ABL001 are given in 28-day cycles. Furthermore, patients receive CNS prophylaxis with intrathecal ctx.

“The study remains open to accrual and patients will be assessed by CTCAEv5 under a new amendment. Of note, all DLTs to date would be <gr 3 under CTCAEv5 (all asymptomatic amylase/lipase <5xULN without clinical sequalae). All patients remain alive”, Marlise R. Luskin, MD, Dana-Farber Cancer Institute, explained, alongside co-investigators.

To note, pre-treatment tumor genotyping and serial on-treatment, single-cell profiling of tumor and microenvironment fractions have been performed in all patients to date, highlighting extensive biophysical, transcriptional, and genetic inter-tumor heterogeneity. Researchers are interrogating the linked biophysical and transcriptomic data to develop predictive biomarkers and illuminate MRD biology.

To conclude, “ Dual ABL1 kinase inhibition with asciminib and DAS plus prednisone in BCR-ABL1+ ALL is feasible. Primary toxicity is asymptomatic amylase and lipase elevation. Enrollment continues at DL2 under CTCAEv5 to further define safety profile and determine MTD. An expansion cohort of 10 pts (age ≥18 yrs) at the RP2D is planned,” Dr Luskin, et al. -Alexis Hyams