Moffitt Cancer Center, Tampa, FL, USA.
Service de Gériatrie, Centre Hospitaliser Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France.
Curr Oncol Rep. 2022 Dec;24(12):1695-1703. doi: 10.1007/s11912-022-01324-x. Epub 2022 Aug 20.
To explore the effectiveness of trilaciclib and ALRN-6924 in the prevention of cancer chemotherapy-induced toxicity in older patients. New chemoprotective agents are necessary because age is the main risk factor for chemotherapy complications that account largely for the poorer outcome of cancer in the elderly. Trilaciclib and ALRN-6924 cause a reversible block of the proliferation of normal cells through cell cycle arrest (CCA). With this mechanism, they may prevent the toxicity of cycle-active cancer treatment including neutropenia, anemia, thrombocytopenia, lymphopenia, mucositis, and alopecia.
Myelopoietic growth factors may prevent neutropenia in the aged, but they may cause severe bone pain, may aggravate thrombocytopenia and anemia, and may cause myelodysplasia and acute leukemia as a late complication. The prevention of thrombocytopenia, anemia, mucositis, and alopecia is unsatisfactory at present. These complications may jeopardize the treatment outcome as they require a reduction of treatment dose/intensity and because many patients find the resulting symptoms intolerable. In three studies of patients with extensive disease small cell lung cancer (ES-SCLC), trilaciclib reduced the severity and duration of neutropenia and thrombocytopenia as well as the need for blood transfusions. In addition, it produced a significant expansion of T-cell clones. Trilaciclib received FDA approval for the prevention of chemotherapy-induced myelosuppression in patients with ES-SCLC. ALRN-6924 is currently studied in phase II study of ES-SCLC. In a phase IB of 38 patients, ALRN-6924 prevented myelosuppression to an extent comparable with trilaciclib. Both drugs proved as effective in patients 65 and older as they were in the younger ones. In an "ex vivo" study, ALRN-6924 protected the epithelial stem cells of hair follicles from taxanes and promised to prevent alopecia. The possibility that CCA of tumor cells may reduce the effectiveness of cycle-active chemotherapy is a major concern. For this reason, the use of trilaciclib, an inhibitor of CDK 4/6, should be limited to tumors with inactivated RB1, and the use of ALRN-6924, an inhibitor of P53, should be limited to tumors with inactivated P53. Chemotherapy-related toxicities limit dose intensity and contribute to significant morbidity and mortality in elderly cancer patients. Trilaciclib and ALRN-6924 are of particular interest to geriatric oncologists because of their novel mechanism of action. Ameliorating chemotherapy-induced toxicities holds the promise of transforming the practice of geriatric oncology by enabling chemotherapeutic regimens that are currently not feasible for this patient population. Specifically, these agents may prevent chemotherapy-induced neutropenia and thrombocytopenia, perhaps the most life-threatening complications of cytotoxic chemotherapy, thereby obviating the need for the use of rescue strategies such as hematopoietic growth factors. In addition, these agents offer the potential for broad tissue protection from other chemotherapy-related toxicities, including mucositis, diarrhea, and alopecia, which historically have been poorly managed. Importantly, by preventing a spectrum of chemotherapy-related toxicities, these agents may permit the administration of chemotherapy at full-dose intensity, prevent functional decline, and grant maintenance of resilience to older cancer patients. As a result, the successful prevention of chemotherapy-induced side effects may not only mitigate the costs of care but also improve patient outcomes and quality of life. Finally, chemoprotective strategies offer the opportunity to apply geriatric principles to clinical trials of cancer treatment. In particular, they may allow the testing of prolongation of "active life expectancy" as a major goal of clinical trials in elderly patients. They may also enable novel and more practical forms of clinical trials. By assessing the risk of chemotherapy-related toxicity with the Chemotherapy Risk Assessment Scale for High Age Patients (CRASH) or the Cancer and Aging Research Group (CARG) instruments, these agents may permit researchers to utilize patients as their own controls and endorse the approval of supportive care drugs based upon the risk profile of individual patients.
探讨 Trilaciclib 和 ALRN-6924 在预防老年患者癌症化疗毒性方面的有效性。由于年龄是导致化疗并发症的主要风险因素，而这些并发症在很大程度上导致了老年人癌症的预后较差，因此需要新的化学保护剂。Trilaciclib 和 ALRN-6924 通过细胞周期阻滞（CCA）引起正常细胞增殖的可逆阻断。通过这种机制，它们可以预防包括中性粒细胞减少症、贫血、血小板减少症、淋巴细胞减少症、黏膜炎和脱发在内的细胞周期活性癌症治疗的毒性。
骨髓生长因子可能预防老年人的中性粒细胞减少症，但它们可能引起严重的骨痛，可能加重血小板减少症和贫血，并可能导致骨髓增生异常和急性白血病作为晚期并发症。目前，血小板减少症、贫血、黏膜炎和脱发的预防效果并不理想。这些并发症可能危及治疗结果，因为它们需要减少治疗剂量/强度，而且许多患者发现由此产生的症状无法忍受。在三项广泛期小细胞肺癌（ES-SCLC）患者的研究中，Trilaciclib 降低了中性粒细胞减少症和血小板减少症的严重程度和持续时间，以及输血的需求。此外，它还产生了 T 细胞克隆的显著扩张。Trilaciclib 获得了 FDA 批准，用于预防 ES-SCLC 患者的化疗引起的骨髓抑制。ALRN-6924 目前正在 ES-SCLC 的 II 期研究中进行研究。在 38 例患者的 I 期研究中，ALRN-6924 预防骨髓抑制的效果与 Trilaciclib 相当。这两种药物在 65 岁及以上的患者和年轻患者中都同样有效。在一项“离体”研究中，ALRN-6924 保护毛囊上皮干细胞免受紫杉烷类药物的侵害，并有望预防脱发。肿瘤细胞的 CCA 可能降低细胞周期活性化疗的有效性，这是一个主要关注点。因此，CDK 4/6 抑制剂 Trilaciclib 的使用应限于 RB1 失活的肿瘤，而 P53 抑制剂 ALRN-6924 的使用应限于 P53 失活的肿瘤。化疗相关毒性限制了剂量强度，并导致老年癌症患者的发病率和死亡率显著增加。Trilaciclib 和 ALRN-6924 引起老年肿瘤学家的特别关注，因为它们具有新颖的作用机制。通过改善化疗引起的毒性，可以通过实施目前对这一患者群体不可行的化疗方案，从而改变老年肿瘤学的实践。具体来说，这些药物可以预防化疗引起的中性粒细胞减少症和血小板减少症，这可能是细胞毒性化疗最致命的并发症，从而避免使用造血生长因子等救援策略。此外，这些药物还有可能广泛保护其他与化疗相关的毒性，包括黏膜炎、腹泻和脱发，这些毒性在历史上一直难以控制。重要的是，通过预防一系列与化疗相关的毒性，这些药物可以允许以全剂量强度给予化疗，防止功能下降，并使老年癌症患者保持恢复能力。因此，成功预防化疗引起的副作用不仅可以减轻护理成本，还可以改善患者的结局和生活质量。最后，化学保护策略为将老年原则应用于癌症治疗的临床试验提供了机会。特别是，它们可以允许将延长“积极预期寿命”作为老年患者临床试验的主要目标。它们还可以启用新的和更实用的临床试验形式。通过使用 Chemotherapy Risk Assessment Scale for High Age Patients (CRASH) 或 Cancer and Aging Research Group (CARG) 工具评估化疗相关毒性的风险，这些药物可以使研究人员利用患者作为自己的对照，并根据个体患者的风险状况批准支持性护理药物。
