[ICKSH 2025] CML therapy moves toward precision with asciminib and genomic profiling

Chronic myeloid leukemia (CML) treatment is entering a new phase of precision-tailored strategies, with the rise of asciminib and genomic profiling marking a turning point in frontline therapy and long-term disease control.

Speaking with Korea Biomedical Review during the International Congress of the Korean Society of Hematology (ICKSH) 2025 held at Grand Walkerhill Seoul, Professor Timothy Hughes of the South Australian Health and Medical Research Institute (SAHMRI) introduced emerging data positioning asciminib as a safer and more effective first-line option, while also highlighting the growing role of genomic mutations such as ASXL1 in shaping individualized treatment plans.

“Asciminib really is the start of a new era in CML therapy,” Hughes said, referring to the first-in-class STAMP inhibitor that selectively targets the myristoyl pocket of BCR::ABL1. “We’ve had 25 years of effective TKIs, but toxicity has always been a major limitation.”

Asciminib allows physicians to get very effective kinase inhibition without hitting other kinases, which gives much better tolerability, Hughes added.

The ASC4FIRST study, which supported the U.S. FDA’s 2024 approval of asciminib for newly diagnosed CML-CP, showed superior outcomes in efficacy and safety compared to investigator-selected TKIs.

Patients treated with asciminib achieved higher rates of major molecular response (72 percent vs. 56.9 percent), MR4 (45.0 percent vs. 31.4 percent), and MR4.5 (26.0 percent vs. 23.5 percent), while also experiencing fewer grade 3 or higher adverse events and lower treatment discontinuation.

“Everything from efficacy to tolerability favored asciminib,” Hughes noted. “These findings suggest that asciminib is not only a viable option but could be considered a preferred frontline therapy for many patients.”

Hughes also emphasized the importance of identifying patients for whom asciminib may not be suitable as a standalone first-line therapy. He pointed to four key populations -- those with ASXL1 mutations, elderly patients with significant cardiovascular comorbidities, individuals with atypical BCR::ABL1 transcripts, and patients facing high out-of-pocket costs.

“ASXL1 mutation carriers are a clear high-risk group,” he said. “We’re seeing resistance mutations emerging specifically in these patients, particularly in the drug’s binding site—the myristoyl pocket. That makes early genomic profiling crucial in selecting the right treatment.”

In later-line settings, Hughes described a rational role-sharing approach between asciminib and ponatinib.

While ponatinib remains the drug of choice for overcoming T315I mutations, he cautioned against its cardiovascular risks at high doses.

Data from the OPTIC study showed a stepwise dose-reduction strategy could mitigate these risks, whereas asciminib demonstrated a much lower incidence of vascular events—just two events per 100 patient years.

“For patients with intolerance, asciminib is a clear choice,” he said. “For those with moderate resistance and low cardiovascular risk, ponatinib is an option.”

But for high-resistance, low-cardiovascular-risk patients, starting ponatinib at a higher dose and de-escalating might still be the most effective strategy, he added.

Another key focus of the lecture was the evolving strategy for treatment-free remission (TFR), which has become a central goal in CML care. While most relapses occur within the first six months of stopping therapy, Hughes warned that late molecular relapses—over five years post-cessation—can still occur.

“We continue to monitor patients every three months until 10 years off the drug, and then every six months,” he said. “The kinetics of relapse are very different between early and late cases, which suggests different biological mechanisms—possibly immune-related factors.”

Hughes introduced new data linking clonal hematopoiesis of indeterminate potential (CHIP) to relapse patterns. Among 153 patients attempting TFR, CHIP-positive patients showed higher 12-month TFR success rates (88 percent vs. 52 percent for CHIP-negative), but a more gradual trend toward late relapse.

“This tells us that we may need to tailor our monitoring intensity based on CHIP status,” he said.

In sum, Hughes’s presentation offered a comprehensive vision for the future of CML treatment—one grounded in molecular precision, safety-conscious sequencing, and individualized remission strategies.

“We’re no longer in the era of one-size-fits-all,” he said. “With agents like asciminib and a deeper understanding of genomic risk, we are now able to offer our patients a much more refined and hopeful treatment journey.”