Eisenmann Eric D, Swords Ronan, Huang Ying, Orwick Shelley, Buelow Daelynn, Abbott Nicole, Phelps Mitch, Zeidner Joshua, Foster Matthew C, Lin Tara L, Baer Maria R, Madanat Yazan F, Kovacsovics Tibor, Redner Robert, Al-Mansour Zeina, Bhatnagar Bhavana, Stefanos Mona, Martycz Molly, Druggan Franchesca, Chen Timothy L, Yocum Ashley O, Borate Uma, Druker Brian J, Burd Amy, Levine Ross L, Byrd John C, Baker Sharyn D, Mims Alice S
The Ohio State University, Columbus, Ohio.
Oregon Health & Science University, Portland, Oregon.
Cancer Res Commun. 2025 Jul 1;5(7):1129-1139. doi: 10.1158/2767-9764.CRC-25-0091.
Older patients who have acute myeloid leukemia (AML) with mutant TP53 and/or complex karyotype have a dismal prognosis and lack treatment options. Having previously demonstrated that TP-0903, a multikinase inhibitor, has compelling preclinical activity in drug-resistant AML, including TP53-mutated AML, we evaluated the clinical activity of TP-0903 in combination with decitabine.
This was a multicenter, open-label, phase 1b/2 substudy of Beat AML Master Trial (ClinicalTrials.gov: NCT03013998). The phase 1b portion used a 3 + 3 design, and the phase 2 portion used a Simon two-stage design. Eligible patients ages ≥60 years who had newly diagnosed AML with mutations in TP53 and/or complex karyotype (≥3 cytogenetic abnormalities) received either 37 mg (group 1) or 25 mg (group 2) TP-0903 orally on days 1 to 21 with decitabine 20 mg/m2 on days 1 to 10 for up to three 28-day induction cycles, followed by up to 30 maintenance cycles in which decitabine dosing was reduced to days 1 to 5. The primary endpoint was complete remission (CR) by the end of six cycles of treatment.
The overall composite remission rate (CR/CR with incomplete count recovery/CR with hematologic improvement) was 33.3% in group 1 and 50.0% in group 2, with CR rates of 13.3% and 25%, respectively. The median overall survival for groups 1 and 2 was 7.6 and 7.5 months, respectively.
The combination of TP-0903 and decitabine was reasonably tolerated and had activity in this patient population. Further research and novel treatment strategies are necessary to improve outcomes for patients with these high-risk subtypes of AML.
Treatment options for AML with mutant TP53 and/or complex karyotype are limited. In a phase 1b/2 clinical trial, TP-0903, a multikinase inhibitor, was well-tolerated and had activity comparable with other emerging therapies. Our results suggest that TP-0903 may offer insight and serve as a benchmark for the development of future agents leveraging similar strategies or scaffolds to improve outcomes in these intractable subtypes of AML.
患有急性髓系白血病（AML）且伴有TP53突变和/或复杂核型的老年患者预后不佳且缺乏治疗选择。此前已证明，多激酶抑制剂TP-0903在耐药AML（包括TP53突变的AML）中具有令人信服的临床前活性，我们评估了TP-0903与地西他滨联合使用的临床活性。
这是一项针对“战胜AML主试验”（ClinicalTrials.gov：NCT03013998）的多中心、开放标签的1b/2期子研究。1b期部分采用3+3设计，2期部分采用西蒙两阶段设计。年龄≥60岁、新诊断为伴有TP53突变和/或复杂核型（≥3种细胞遗传学异常）的AML患者，在第1至21天口服37mg（第1组）或25mg（第2组）TP-0903，并在第1至10天静脉注射20mg/m²地西他滨，最多进行三个28天的诱导周期，随后最多进行30个维持周期，其中地西他滨给药时间减至第1至5天。主要终点是六个治疗周期结束时的完全缓解（CR）。
第1组的总体综合缓解率（CR/伴有血细胞计数未完全恢复的CR/伴有血液学改善的CR）为33.3%，第2组为50.0%，CR率分别为13.3%和25%。第1组和第2组的中位总生存期分别为7.6个月和7.5个月。
TP-0903与地西他滨联合使用耐受性良好，且在该患者群体中具有活性。需要进一步研究和新的治疗策略来改善这些高危AML亚型患者的预后。
伴有TP53突变和/或复杂核型的AML的治疗选择有限。在一项1b/2期临床试验中，多激酶抑制剂TP-0903耐受性良好，其活性与其他新兴疗法相当。我们的结果表明，TP-0903可能为未来开发利用类似策略或支架来改善这些难治性AML亚型预后的药物提供思路并作为一个基准。
