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The following is a summary of “Vodobatinib for patients with Philadelphia chromosome-positive chronic myeloid leukaemia resistant or intolerant to multiple lines of previous therapy: an open-label, multicentre, phase 1/2 trial,” published in the March 2025 issue of Lancet Hematology by Cortes et al. 

Resistance or intolerance to tyrosine kinase inhibitors (TKIs) limits treatment options for chronic myeloid leukemia, requiring effective alternatives. 

Researchers conducted a retrospective study on vodobatinib, a selective BCR::ABL1 TKI, in patients with Philadelphia chromosome-positive (Ph-positive) chronic myeloid leukemia resistant or intolerant to at least 3 TKIs, including ponatinib and asciminib. 

They conducted this open-label, multicenter, phase 1/2 trial at 28 sites across 10 countries. Patients (≥18 years) with Ph-positive chronic myeloid leukemia or acute lymphoblastic leukemia (phase 1 only) and an Eastern Cooperative Oncology Group performance status of ≤2 were eligible. Phase 1 included patients with ≥3 prior TKIs or no other options, while phase 2 required resistance or intolerance to ≥3 TKIs, including ponatinib. They excluded patients with the Thr315Ile mutation. Patients self-administered vodobatinib (12–240 mg) daily in 28-day cycles for up to 60 months. Primary endpoints were maximum tolerated dose (phase 1) and antileukemic activity (phase 2). They assessed safety, activity, and pharmacokinetics through pooled analysis.  

The results showed that 78 patients received vodobatinib. Phase 1 enrolled 58 patients, and phase 2 enrolled 20. Chronic-phase was in 66 (85%), accelerated-phase in 8 (10%), and blast-phase in four (5%). The median age was 59·0 years (IQR 47·0–66·0), and median follow-up was 22·3 months (IQR 11·1–43·9). The maximum tolerated dose was 204 mg. Treatment-emergent adverse events occurred in 73 (94%), with grade 3 or higher in 47 (60%). About 7 (9%) died, 1 treatment related. Major cytogenetic response occurred in 44 (70%) of 63 chronic-phase patients, including 12 (75%) of 16 in phase 2. Major hematological response was seen in six (86%) of seven accelerated-phase and two (50%) of four blast-phase patients. 

Investigators found vodobatinib had clinically meaningful antileukemic activity and a tolerable safety profile in advanced chronic myeloid leukemia. They noted that the phase 2 study was underpowered and required further phase 3 investigation. 

Source: thelancet.com/journals/lanhae/article/PIIS2352-3026(24)00354-5/abstract