Real-Life Use of Asciminib in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Results of the Turkish Managed Access Program
Authors: Özmen Deniz , Kürekçi Derya Deniz , Özkocaman Vildan , Altındağ Avcı Burcu , Bozer Denis Sabriye , Kasar Mutlu , Şahin Osman , Korkmaz Akat Gülten , Can Ferda , Pepeler Mehmet Sezgin , Erkut Nergiz , Kırkızlar Onur , Yel Uygun Kübra , Bulduk Tuba , Yıldırım Murat , Aslaner Ak Müzeyyen , Altındal Şermin , Arıkan Fatma , Dal Mehmet Sinan , Deveci Burak , Güler Nil , Güneş Ahmet Kürşad , Gürkan Emel , Özbalcı Demircan , Öztürk Osman Can , Ülküden Burcu , Yılmaz Hüseyin , Yüksel Meltem Kurt , Aylı Meltem , Demir Ahmet Muzaffer , Özatlı Düzgün , Özkalemkaş Fahir , Saydam Güray , Sönmez Mehmet , Turgut Burhan , Turgut Mehmet , Ünal Ali , Eskazan Ahmet Emre 
Published: December 2024

Introduction: Asciminib (ASC), a first-in-class BCR::ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP), differs from other tyrosine kinase inhibitors (TKIs) with its unique mechanism of action and it has the potential to overcome failure to approved TKIs. It is active against both wild-type and mutated BCR::ABL1, including the T315I. Clinical trials show the high potency and a relatively favorable safety profile of ASC in patients (pts) with CML-CP. In Turkey, ASC has been available through Managed Access Program for CML-CP pts who failed at least two previous TKIs and/or with T315I mutation since May, 2023. The aim of this study is to demonstrate the real-life efficacy and safety of ASC.
Methods: All information on demographics, previous treatments, TKI responses and toxicities, and follow-up data were gathered retrospectively. Early molecular response (EMR) was defined as a BCR::ABL1IS transcript level &lt;10% at 3 months. Major molecular response (MMR) and deep molecular response (DMR) were defined as BCR::ABL1IS transcript levels ≤0.1% and ≤0.01% (MR4.0) or deeper, respectively.
Results: We included 49 pts from 25 centers, of which 25 (51%) were female and the median age was 61 years (range, 26-80 years). All patients received ASC at recommended doses (200 mg BID for cases harboring T315I and 40 mg BID or 80 mg QD for the rest). The most common comorbidities were hypertension (29%), cardiovascular diseases (20%), and diabetes mellitus (6%). The median number of previous TKIs was 4 (range, 2-6), and median follow-up until ASC start was 78 months (range, 14-322 months). Twenty-three (47%), 10 (20%), and 10 (20%) pts received ASC due to resistance, intolerance, or both resistance and intolerance to previous TKIs, respectively. The remaining 6 pts were switched to ASC due to inaccessibility to ponatinib (PON). Eighteen pts (37%) had previous PON exposure, and PON was the latest TKI in 15 (31%). Of these 15 pts, three and 2 pts were switched to ASC due to resistance or intolerance, respectively, and four pts received ASC both due to resistance and intolerance. Seven of 49 pts (14%) had T315I, and one had G250E. With a median ASC therapy of 8 months (range, 2-13 months), seven pts (14%) experienced all grades hematological adverse events (AEs), of which four (8%) were grade 3-4. Non-hematological AEs were observed in 11 pts (22%), and four (8%) were grade 3-4 toxicities. No pts discontinued ASC for AEs. ASC dose was reduced in 10 pts (20%) due to AEs, and subsequently in five pts, daily dose could be increased to the standard dose. Eight of 49 pts did not have a molecular testing at 3 months, and EMR rate was 80%. EMR rate in pts who were switched to ASC due to intolerance were higher when compared to pts receiving ASC due to resistance (90% vs. 74%, p=0.311). EMR rate in PON-pretreated pts was higher than those achieved in PON-naïve group (94% vs. 72%, p=0.090). For all pts, cumulative MMR and DMR rates were 20% and 35%, respectively. Cumulative MMR rates under ASC in pts with resistance and intolerance to prior TKIs were 26% and 20%, respectively (p=0.712). Cumulative DMR rate in pts who were intolerant to previous TKIs were significantly higher than those who received ASC due to resistance (80% vs. 22%, p=0.02). In PON-naïve group, cumulative MMR and DMR rates were 23% and 26%, respectively, and these were 17% and 50% among PON-pretreated pts, respectively (p=0.624 for MMR and p=0.090 for DMR). Forty-one pts (83.6%) maintained or deepened their responses under ASC, and eight pts who lost their molecular responses and/or experienced progression were all receiving ASC due to resistance. Four pts (8%) discontinued ASC permanently (3 due to progression to advanced-phase disease and one due to unresponsiveness), and two harbored T315I. Among four pts who quit ASC, two died of blast crisis (none had T315I).
Conclusion: Although the follow-up is relatively short, we showed that ASC is an effective and safe treatment option in a heavily pretreated population in the real-life setting. Pts with intolerance to previous TKIs had superior molecular responses than those who received ASC for resistance. Nearly 85% of the pts maintained or deepened their responses during ASC therapy. It was expected to observe better response rates under ASC in PON-naïve pts than in PON-pretreated cases, and this is most probably due to the high percentage of pts with optimal responses under PON needing to quit the drug due to the inaccessibility of PON in Turkey.