Gilteritinib: The Story of a Proceeding Success into Hard-to-Treat FLT3-Mutated AML Patients

Abstract

The traditionally dismal outcome of acute myeloid leukemia (AML) patients carrying the FMS-related tyrosine kinase 3 (FLT3) mutations has been mitigated by the recent introduction of tyrosine kinase inhibitors (TKI) into clinics, such as midostaurin and gilteritinib. The present work summarizes the clinical data that led to the use of gilteritinib in clinical practice. Gilteritinib is a second-generation TKI with deeper single-agent activity than first-generation drugs against both FLT3FLT3–ITD and TKD mutations in human studies. Moreover, the phase I/II dose-escalation, dose-expansion Chrysalis trial showed an acceptable safety profile of gilteritinib (diarrhea, elevated aspartate aminotransferase, febrile neutropenia, anemia, thrombocytopenia, sepsis, and pneumonia) and a 49% overall response rate (ORR) in 191 FLT3FLT3-mutated relapsed/refractory (R/R) AML patients. In 2019, the pivotal ADMIRAL trial showed that the median overall survival was significantly longer in patients treated with gilteritinib than among those receiving chemotherapy (9.3 vs. 5.6 months, respectively) and the ORR to gilteritinib was 67.6%, outperforming the 25.8% for chemotherapy arm and leading to the license for its clinical use by the US Food and Drug Administration. Since then, several real-world experiences have confirmed the positive results in the R/R AML setting. Finally, gilteritinib-based combinations currently under investigation, with several compounds (venetoclax, azacitidine, conventional chemotherapy, etc.) and some practical tips (maintenance after allogeneic transplantation, interaction with antifungal drugs, extramedullary disease, and onset of resistance), will be analyzed in detail in this review.

AML under the Scope: Current Strategies and Treatment Involving FLT3 Inhibitors and Venetoclax-Based Regimens

“…Second-Generation FLT3 Inhibitors 2.5.1. Gilteritinib Gilteritinib is a second-generation type 1 tyrosine kinase inhibitor (TKI) that primarily targets FLT3 and AXL (an oncogenic tyrosine kinase) receptors [61,76]. In September 2018, it was approved in Japan for the treatment of R/R FLT3-mutated AML, and 2 months later, it was approved in the same indications by the FDA [76].…”

Protective effect of borneol on the cutaneous toxicity of gilteritinib

“…在接受TKI治疗的患者中，皮疹、毛发和指甲变化、黏膜炎、光敏性等皮肤毒性发生率很高 ［ 21 - 22 ］ 。目前，相较于其他脏器的毒性，临床上对皮肤毒性关注度不高。然而，皮肤作为人体最大的器官，是人体防御外界刺激的第一道屏障，具有调节体温、代谢、呼吸等多种生理功能 ［ 23 ］ 。药物性皮肤毒性的发生会极大地改变外表，给患者带来身心困扰，降低生活质量。严重的药物性皮肤毒性不仅会影响治疗效果，甚至会导致死亡 ［ 24 ］ 。吉列替尼是一种多靶点激酶抑制剂，应用于 FLT3 突变的复发性或难治性（药物难治）急性髓性白血病成人患者的一线治疗，但在其治疗期间约36%的患者出现了皮肤毒性 ［ 3 ］ ，吉列替尼皮肤毒性机制不明以及干预策略的缺乏极大限制了其临床应用。因此，研究吉列替尼引起皮肤毒性的机制并制订相应的干预策略至关重要。但在目前药物的皮肤毒性研究中，会存在实验造模表型与临床毒性表型不一致的问题，导致结果的可靠性与可复制性较低 ［ 25 - 26 ］ 。…”

“…吉列替尼（Gilteritinib）属于第二代FLT3新型分子靶向抑制剂，目前已在多个国家和地区被批准应用于 FLT3 突变的复发性或难治性（药物难治）急性髓性白血病成人患者的标准化治疗 ［ 1 ］ 。与接受化疗的患者比较，接受吉列替尼治疗的患者无进展生存期显著延长，白细胞数全部或部分恢复正常水平的患者显著增多，展现出极好的治疗效果 ［ 2 ］ 。然而，临床研究结果显示，约36%的患者在吉列替尼治疗期间出现了皮疹 ［ 3 ］ ，虽多数患者表现较轻，但仍有部分患者会发展为较为严重的急性发热性嗜中性皮肤病（Sweet综合征） ［ 4 - 6 ］ ，影响患者的生活质量，甚至不得不中止治疗，最终导致肿瘤进展。目前对吉列替尼皮肤毒性的治疗策略和管理手段十分有限，只能通过局部或全身应用类固醇等手段加以缓解，无法从根本上解决问题。…”

Potentiating Gilteritinib Efficacy Using Nanocomplexation with a Hyaluronic Acid–Epigallocatechin Gallate Conjugate

“…Although several FLT3 inhibitors have been discovered and tested in clinical trials, gilteritinib (GLT) is currently the only medication approved by the U.S. Food and Drug Administration (FDA) as a monotherapy for the treatment of AML patients harboring FLT3 mutations [ 3 ]. In the randomized phase III trial, GLT treatment greatly extended the median overall survival (9.3 months) compared to conventional salvage chemotherapy (5.6 months) in patients with refractory/relapsed FLT3-mutated AML [ 4 ]; however, nearly one-fourth of GLT-treated patients showed no response, and only 20.6% of them survived for more than 2 years, highlighting the unmet clinical need [ 5 ]. In this perspective, it is desirable to develop advanced nanoparticle formulations capable of enhancing the anti-leukemic activity of GLT for more effective AML treatment.…”