Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
Clin Lymphoma Myeloma Leuk. 2023 Apr;23(4):219-231. doi: 10.1016/j.clml.2022.12.014. Epub 2023 Jan 6.
Development of myelofibrosis (MF) therapeutics has reached fruition as the transformative impact of JAK2 inhibitors in the MPN landscape is complemented/expanded by a profusion of novel monotherapies and rational combinations in the frontline and second line settings. Agents in advanced clinical development span various mechanisms of action (eg, epigenetic or apoptotic regulation), may address urgent unmet clinical needs (cytopenias), increase the depth/duration of spleen and symptom responses elicited by ruxolitinib, improve other aspects of the disease besides splenomegaly/constitutional symptoms (eg, resistance to ruxolitinib, bone marrow fibrosis or disease course), provide personalized strategies, and extend overall survival (OS). Ruxolitinib had a dramatic impact on the quality of life and OS of MF patients. Recently, pacritinib received regulatory approval for severely thrombocytopenic MF patients. Momelotinib is advantageously poised among JAK inhibitors given its differentiated mode of action (suppression of hepcidin expression). Momelotinib demonstrated significant improvements in anemia measures, spleen responses, and MF-associated symptoms in MF patients with anemia; and will likely receive regulatory approval in 2023. An array of other novel agents combined with ruxolitinib, such as pelabresib, navitoclax, parsaclisib, or as monotherapies (navtemadlin) are evaluated in pivotal phase 3 trials. Imetelstat (telomerase inhibitor) is currently evaluated in the second line setting; OS was set as the primary endpoint, marking an unprecedented goal in MF trials, wherein SVR35 and TSS50 at 24 weeks have been typical endpoints heretofore. Transfusion independence may be considered another clinically meaningful endpoint in MF trials given its correlation with OS. Overall, therapeutics are at the cusp of an exponential expansion and advancements that will likely lead to the golden era in treatment of MF.
骨髓纤维化（MF）治疗药物的开发已经取得了成果，JAK2 抑制剂在 MPN 领域的变革性影响，通过众多新型单药疗法和一线及二线治疗中的合理联合得到了补充/扩展。处于临床开发后期的药物涵盖了各种作用机制（例如，表观遗传或细胞凋亡调节），可能解决迫切的未满足的临床需求（细胞减少症），增加鲁索利替尼引起的脾脏和症状反应的深度/持续时间，改善除脾肿大/全身症状以外的疾病的其他方面（例如，对鲁索利替尼的耐药性、骨髓纤维化或疾病进程），提供个性化策略，并延长总生存期（OS）。鲁索利替尼对 MF 患者的生活质量和 OS 产生了巨大影响。最近，pacritinib 因严重血小板减少症的 MF 患者获得了监管批准。鉴于 momelotinib 作用机制的差异（抑制铁调素表达），在 JAK 抑制剂中具有优势地位。Momelotinib 在伴有贫血的 MF 患者中显著改善了贫血指标、脾脏反应和 MF 相关症状；并可能在 2023 年获得监管批准。其他一系列新型药物与鲁索利替尼联合使用，例如 pelabresib、navitoclax、parsaclisib 或作为单药（navtemadlin），正在进行关键的 3 期试验评估。Imetelstat（端粒酶抑制剂）目前正在二线治疗中进行评估；OS 被设定为主要终点，这是 MF 试验中前所未有的目标，迄今为止，SVR35 和 24 周时的 TSS50 一直是典型的终点。鉴于输血独立性与 OS 相关，它可能被认为是 MF 试验中的另一个具有临床意义的终点。总体而言，治疗方法正处于指数扩张和进步的边缘，这可能导致 MF 治疗的黄金时代的到来。
