Highlights on myeloproliferative neoplasms from the EHA2025 Congress

The Swiss Cancer Institute’s Young Oncology Academy (YOA) is a support and mentorship program for young oncologists. Academy participants are supervised by a renowned faculty member for almost a year and are required to write a review paper on a topic of interest. Today we present Dr. med. Emmanuel Häfligerʼs paper. He was a YOA participant in 2025 with the speciality hematology and was mentored by Prof. Dr. med. Gabriela Baerlocher.

Abstr. #S166 by Hochhaus et al.:¹ Asciminib vs. Nilotinib

Chronic myeloid leukemia (CML) has entered a new era of treatment with the introduction of tyrosine kinase inhibitors (TKIs), which have led to a near-normalization of life expectancy for most patients.² Despite their remarkable efficacy, currently available TKIs all target the ATP-binding site of BCR::ABL1 and are associated with off-target toxicity.

Asciminib represents a novel agent that targets the myristoyl pocket of BCR::ABL1, providing a new mechanism of action and the potential for an improved safety profile.³ In the ASC4FIRST trial, investigators evaluated whether asciminib achieved superior 48-week major molecular response compared with investigator-selected standard TKIs in newly diagnosed chronic-phase CML and found that asciminib demonstrated comparable – but not superior – efficacy relative to second-generation TKIs. Although a statistically significant advantage in efficacy over second-generation TKIs was not shown, asciminib appeared to offer a more favorable safety profile – an essential consideration in a chronic disease requiring lifelong therapy –, thereby paving the way for a dedicated tolerability-focused trial.

The phase IIIb trial ASC4START evaluated the safety and efficacy of asciminib versus nilotinib as first-line therapy in adults with newly diagnosed chronic-phase CML. Patients were randomized to receive either asciminib 80mg once daily or nilotinib 300mg twice daily.

The primary endpoint of the study was the time to treatment discontinuation due to adverse events – both hematologic and non-hematologic (including gastrointestinal, cardiovascular, and general symptoms such as fatigue) – or death. Key secondary endpoints included type of adverse events and molecular response rates.

The abstract presents data from an interim analysis conducted after 50 treatment discontinuations due to adverse events and/or death. At a median follow-up of 9.7 months, asciminib was associated with a significantly lower risk of treatment discontinuation due to adverse events compared with nilotinib (HR: 0.45; 95% CI: 0.25–0.81; p=0.004). Overall, asciminib seemed to demonstrate superior tolerability compared with nilotinib, leading the authors to advocate for its use as a frontline therapy for newly diagnosed chronic-phase CML.

A limitation of this analysis is that asciminib was only compared to nilotinib, rather than to all second-generation tyrosine kinase inhibitors, limiting the generalizability of the findings. As the study primarily focused on tolerability, it does not yet demonstrate an improvement in overall survival, underscoring the need for further long-term investigations to establish the full clinical benefit of asciminib in the first-line setting.

Abstr. #LB4002 by Mascarenhas etal.:⁴ INCA33989

Essential thrombocythemia (ET) is the second most common myeloproliferative neoplasm, yet its treatment remains largely non-specific and is currently limited to hydroxyurea, anagrelide, and off-label interferon.⁵ In recent years, JAK inhibitors have introduced the possibility of targeting driver pathways. Unfortunately, JAK inhibitors failed to demonstrate clinical efficacy in ET in the MAJIC-ET trial.⁶ These findings paved the way toward the search for novel therapeutic agents, including targeting alternative pathways.

In their work, Mascarenhas et al. evaluated INCA33989, a monoclonal antibody targeting mutant CALR. This first-in-human, open-label, dose-escalation study enrolled patients with high-risk CALR-mutated ET and therapy refractoriness and/or intolerance. 49 patients were included and received monoclonal antibody doses ranging from 24mg up to 2500mg intravenously every two weeks. Median treatment exposure was 22.6 weeks.

No dose-limiting toxicities were identified, and serious treatment-emergent adverse events were only reported in 6.1% of the patients (n=3). Those events were asymptomatic lipase increase (n=1), visceral venous thrombosis (n=1) and diverticulitis (n=1). Thrombocytopenia was not observed amongst the studied population.

Higher haematologic response was observed in patients receiving higher doses of treatment (doses ranging from 400mg to 2500mg). A reduction in the variant allele frequency (VAF) of mutated CALR was observed in 89% of evaluable patients with 47% of patients reaching a VAF reduction of over 20% and 21% of the patients reaching a VAF reduction of over 50%.

These early-phase data suggest a good tolerability and efficacy of this new monoclonal antibody against mutated CALR, introducing a novel mutation-targeted approach for patients with ET. Further data and longer follow-up will have to assess durability of responses, impact regarding thrombosis and cardiovascular risk, risk of transformation, and overall survival.