Real-Life Outcomes of Bosutinib in Patients with Chronic Myeloid Leukemia: A Multicenter Nationwide Study from Turkey
Authors: Guven Serkan , Özmen Deniz , Çatma Yunus , Güllü Koca Tuba , Kırkızlar Onur , Şeker Ömer , Ünal Sercan , Salim Seçil , Tüzün Betül Kübra , Öztürkmen Aslı Yüksel , Erkut Nergiz , Kiriktir Esra , Kanat Nesibe Taşer , Patır Püsem , Karışmaz Abdülkadir , Akpınar Seval , Gürkan Emel , Kürkçü Nurcan Özçelik , Aydın Öznur , Çağlıyan Gülsüm , Gedük Ayfer , Arslan Süleyman , Narlı Özdemir Zehra , Çiftçiler Rafiye , Uysal Ayşe , Aydoğan Merve , İpek Yıldız , Erdoğan Yön Merve Ecem , Karabulut Zeynep Tuğba , Bostan Emel , Mersin Sinan , Tiryaki Tarık Onur , Gürsoy Vildan , Yavaşoğlu İrfan , Doğan Ali , Alanoğlu Güchan , Baysal Mehmet , Arslan Davulcu Eren , Kaya Ayşe , Pınar İbrahim Ethem , Yıldız Abdülkerim , Akyol Gülşah , Alacacıoğlu İnci , Arat Mutlu , Ayer Mesut , Aylı Meltem , Berber İlhami , Demir Ahmet Muzaffer , Haznedaroğlu İbrahim , Hindilerden Fehmi , Kurtoğlu Erdal , Nalçacı Meliha , Özkalemkaş Fahir , Özkocaman Vildan , Saydam Güray , Sönmez Mehmet , Toprak Selami Koçak , Tuğlular Tülin , Turgut Burhan , Turgut Mehmet , Eskazan Ahmet Emre 
Published: December 2024

Introduction: Although the prognosis of chronic myeloid leukemia (CML) changed dramatically with the introduction of imatinib (IM), some patients (pts) still need further BCR::ABL1 tyrosine kinase inhibitor (TKI) therapies due to resistance and/or intolerance to IM. 2nd-generation TKIs (2GTKIs) including bosutinib (BOS) can be utilized in those pts. In Turkey, IM is the only BCR::ABL1 TKI reimbursed in newly diagnosed pts, and BOS can be utilized in the 2nd and later lines of therapy. Real-life data of BOS in pts with CML failing previous lines of TKI therapy is still limited in the literature and the aim of this multicenter study is to evaluate the efficacy and safety of BOS therapy in pts with CML beyond first-line TKI therapy in the real-life setting.
Methods: All information on demographics, previous treatments, TKI responses and toxicities, and follow-up data were gathered from the files of the pts 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. between BCR::ABL1IS transcript levels between 0.1-1% were considered as complete cytogenetic response (CCyR).
Results: Two hundred eighty-three pts from 40 centers were included. The median age was 58 years (range, 20-86 years), and 58% of the pts (n=167) were male. At diagnosis, 260 pts were in chronic phase (CML-CP) (91.3%), and 15 (5.3%) and 8 (2.8%) pts were in accelerated and blastic phases, respectively. Prior to BOS therapy, the median follow-up was 45.5 months (range, 0-288 months) and 5 pts (1.8%) received an allograft. The median number of prior TKIs was 2 (range, 0-4), and BOS was used as 1st-, 2nd-, 3rd-, and &gt;3rd-lines of therapy in 2 (0.7%), 74 (26.1%), 98 (34.6%), and 109 (38.6%) pts, respectively. Of the CML-CP pts, 123 (47.3%) were switched to BOS due to resistance and 108 (40.4%) due to intolerance to prior TKI therapy and in 29 (11.2%), both due to intolerance and resistance. One hundred and eighty-three pts (64.6%) had at least one comorbidity, and the most common comorbidities were hypertension (39.9%), cardiovascular diseases (29%), and diabetes (23.3%). The initial daily dose was 500 mg in 194 pts (68.6%), 400 mg in 50 pts (17.7%), 300 mg in 28 pts (9.9%), 200 mg in 7 pts (2.5%), and 100 mg in 4 pts (1.4%). The mean BOS dose intensity was 449.47 mg/day (range, 100-500 mg/day). With a median duration of 17 months of BOS therapy (range, 3-178 months), 75.6% of 281 pts (n=214) experienced at least one AE, and the most common non-hematological adverse event (AE) was diarrhea, observed in 144 pts (43.8%). Of these, 130 (90.3%) and 14 (9.7%) pts experienced grade 1-2 and grade 3-4 diarrhea, respectively. The percentages of grade 3-4 anemia, neutropenia, and thrombocytopenia were 7.1% (20/282), 3.2% (9/282), and 3.2% (9/282), respectively. Dose reduction was required in 75 pts (26.5%) due to any AEs. In 58 pts (20.5%), BOS was interrupted and 92 pts (32.5%) discontinued BOS therapy permanently. Main reasons for permanent discontinuation were AEs (47.8%) and loss of response and/or progression (39.1%). The incidences of any AEs were comparable across treatment lines; 70.3% (52/74) in 2nd-line, 78.6% (77/98) in 3rd-line, and 77.1% (84/109) in &gt;3rd-line (p=0.420). At time of BOS start, rates of any response less than CCyR, CCyR, MMR, and DMR were 53.7%, 11.7%, 15.9%, and 17.7%, respectively. Under BOS therapy, CCyR, MMR, and DMR rates were 4.6%, 23%, and 43.1%, respectively and 63 pts (22.3%) achieved a response level less than CCyR. The percentage of pts with optimal responses were significantly higher with BOS when compared to those achieved prior to BOS therapy (p&lt;0.001). EMR rates were significantly higher in pts receiving 500 mg/day BOS than those with a daily dose &lt;500 mg (34.2% vs. 64.8%, p=0.023).
Conclusion: Our multicenter, nationwide study among pts with CML in the real world setting demonstrated that BOS is an effective 2GTKI in pts who failed at least one TKI therapy with a generally manageable toxicity profile.