Pemmaraju Naveen, Carter Bing Z, Bose Prithviraj, Jain Nitin, Kadia Tapan M, Garcia-Manero Guillermo, Bueso-Ramos Carlos E, DiNardo Courtney D, Bledsoe Sharon, Daver Naval G, Popat Uday, Konopleva Marina Y, Zhou Lingsha, Pierce Sherry, Estrov Zeev E, Borthakur Gautam M, Ohanian Maro, Qiao Wei, Masarova Lucia, Wang Xuemei, Mak Po Yee, Cortes Jorge, Jabbour Elias, Verstovsek Srdan
Department of Leukemia.
Department of Hematopathology.
Blood Adv. 2021 Aug 24;5(16):3163-3173. doi: 10.1182/bloodadvances.2020003829.
Outcomes in patients with high-risk and treatment-resistant myelofibrosis (MF) post-JAK inhibitor therapy remain poor, with no approved drug therapies beyond the JAK inhibitor class. In certain clinical situations, such as severe thrombocytopenia, administration of most JAK inhibitors are contraindicated. Thus, there is an unmet medical need for the development of novel agents for patients with MF. SMAC mimetics [or inhibitor of apoptosis (IAP) antagonists] induce apoptosis in cancer cells. Because these agents are hypothesized to have increased activity in a tumor necrosis factor-α cytokine-rich microenvironment, as is the case with MF, we conducted a single-center, investigator-initiated phase 2 clinical trial, with a monovalent SMAC mimetic LCL161 (oral, starting dose, 1500 mg per week) in patients with intermediate to high-risk MF. In an older group, 66% with ≥2 prior therapies and a median baseline platelet count of 52 × 103/μL and 28% with ASXL1 mutations, we observed a 30% objective response by Revised International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) 2013 criteria. Notably, 6 responding patients achieved clinical improvement of anemia: 4, hemoglobin response; 2, transfusion independence. Median OS was 34 months (range, 2.2-60.1+). Reductions of cIAPs were observed in all responders. The most common toxicity was nausea/vomiting (N/V) in 64% (mostly grade 1/2); fatigue in 46%; and dizziness/vertigo in 30%. There were 4 grade 3/4 adverse events (2, syncope; 1, N/V; 1, skin eruption/pruritis). There were 2 deaths during the study period, both unrelated to the study drug. SMAC mimetics may represent an option for older patients with thrombocytopenia or for those in whom prior JAK inhibitors has failed. This trial was registered at www.clinicaltrials.gov as #NCT02098161.
接受JAK抑制剂治疗后，高危和难治性骨髓纤维化（MF）患者的预后仍然很差，除JAK抑制剂类药物外，尚无其他获批的药物疗法。在某些临床情况下，如严重血小板减少症，大多数JAK抑制剂的使用是禁忌的。因此，开发针对MF患者的新型药物存在未满足的医疗需求。SMAC模拟物[或凋亡抑制蛋白（IAP）拮抗剂]可诱导癌细胞凋亡。由于假设这些药物在富含肿瘤坏死因子-α细胞因子的微环境中活性增加，骨髓纤维化就是这种情况，我们开展了一项由研究者发起的单中心2期临床试验，对中高危MF患者使用单价SMAC模拟物LCL161（口服，起始剂量为每周1500毫克）。在一个老年组中，66%的患者接受过≥2种先前治疗，基线血小板计数中位数为52×10³/μL，28%的患者存在ASXL1突变，根据2013年修订的国际工作组-骨髓增殖性肿瘤研究与治疗（IWG-MRT）标准，我们观察到客观缓解率为30%。值得注意的是，6例缓解患者实现贫血临床改善：4例血红蛋白反应；2例不再需要输血。总生存期（OS）中位数为34个月（范围为2.2 - 60.1+）。所有缓解者均观察到细胞凋亡抑制蛋白（cIAPs）减少。最常见的毒性反应为恶心/呕吐（N/V），发生率为64%（大多为1/2级）；疲劳发生率为46%；头晕/眩晕发生率为30%。有4例3/4级不良事件（2例晕厥；1例N/V；1例皮疹/瘙痒）。研究期间有2例死亡，均与研究药物无关。SMAC模拟物可能是老年血小板减少患者或先前JAK抑制剂治疗失败患者的一种选择。该试验已在www.clinicaltrials.gov上注册，编号为#NCT02098161。
