Background Asciminib is a Specifically Targeting the ABL1 Myristoyl Pocket (STAMP) inhibitor that demonstrated its safety and efficacy in the frontline and salvage settings of patients with chronic myeloid leukemia (CML). Here, we report the results of the interim analysis of an investigator-initiated phase II trial of asciminib in patients with newly diagnosed (ND) CML.

Methods This is a phase II trial of asciminib given at 80 mg/day in patients with ND CML in chronic phase or accelerated phase as defined by clonal evolution only. The primary endpoint was the rate of major molecular response (MMR) by 12 months of therapy. Patients were monitored by serial BCR::ABL1 assessments using RT-PCR every 3 months during the first year then every 3-6 months thereafter. Adverse events were recorded according to the CTCAE version 5.0 criteria. The data cutoff was July 21, 2025.

Results Fifty patients were treated. The median age was 49 years (range, 21-79); 29 (58%) were males, 48 (96%) were in CP and 2 (4%) in AP. Sokal score was low in 23 patients (46%), intermediate in 18 (36%), and high in 9 (18%). With a median follow-up of 7.7 months (95% CI, 5.5-9.9), the cumulative best overall response was MCyR in 40 patients (80%), CCyR in 36 (72%), MMR in 24 (48%), MR4 in 15 (30%), and MR4.5 in 11 (22%); 10 patients were still early during the course of therapy and hence not evaluable for efficacy. The MMR rate by 12 months was 57%.

By 3 months, among 40 evaluable patients, 38 (95%) achieved MCyR or transcript levels below 10% on the international scale (IS), 27 (68%) CCyR or transcript levels below 1% IS, 14 (35%) MMR, 5 (13%) MR4, and 2 (5%) MR4.5. Two patients (5%) had a complete hematologic response (CHR) with transcript levels above 10%. Of these 2 patients, one achieved CCyR at 6 months and the other remains on therapy but has not yet reached the 6-month landmark. By 6 months, among 33 evaluable patients, the CCyR rate was 100% (33/33), MMR rate 64% (21/33), MR4 rate 42% (14/33), and MR4.5 rate 30% (10/33). By 12 months, the best response achieved among 14 evaluable patients was CCyR in all (100%), MMR in 8 (57%), MR4 in 5 (35%), and MR4.5 in 3 (21%).

The most frequent adverse events that were possibly related to asciminib included elevated lipase (Grade[G]2, n=8), myalgia (G1, n=6; G2, n=1), and abdominal pain (G1, n=3; G2, n=3). Two patients developed pancreatitis (G2, n=1; G3, n=1) and one patient developed G2 pericardial effusion and later a G3 brain stroke leading to asciminib discontinuation. The latter is a 79-year-old patient with a previous medical history of coronary artery disease and a subacute brain stroke prior to asciminib. A 71-year-old patient with a previous medical history of hypertension developed G5 acute coronary syndrome after 2.5 months of asciminib therapy.

Overall, 5 of 50 patients (10%) discontinued asciminib after a median of 7.6 months (range, 0.5-16.6) due to 1) a G3 subacute brain stroke, switched to bosutinib; 2) a G2 and G3 pancreatitis in one patient each, both switched to dasatinib; 3) a G5 acute coronary syndrome (NSTEMI) with cardiogenic shock in a 71-year-old male w; 4) a loss of CCyR after 11.4 months of therapy with the emergence of A337T and F497L mutations with subsequent switch to ponatinib. The 6-month rates of FFS, EFS, and OS were 93%, 97%, and 97%, respectively.

Conclusion This interim analysis showed very good response rates with asciminib in ND CML after a short follow-up with MMR and deep molecular response rates of 64% and 42% by 6 months, respectively. Adverse events, including gastrointestinal, as well as one fatal cardiovascular event, were observed.

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2025
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