Phosphatidylinositol 3-kinase (PI3K) inhibitors are effective in chronic lymphocytic leukemia (CLL). However, the severe toxicity profile associated with the first-generation inhibitors idelalisib and duvelisib, combined with the availability of other more tolerable agents, have limited their use. CLL is still considered incurable, and relapse after treatment, development of resistance, and treatment intolerance are common. It is therefore of interest to optimize the administration of currently approved PI3K inhibitors and to develop next-generation agents to improve tolerability, so that this class of agents will be considered an effective and safe treatment option when needed. These efforts are reflected in the large number of emerging clinical trials with PI3K inhibitors in CLL. Current strategies to overcome treatment limitations include intermittent dosing, which is established for copanlisib and zandelisib and under investigation for duvelisib and parsaclisib. A second strategy is to combine the PI3K inhibitor with another novel agent, either as a continuous regimen or a fixed-duration regimen, to deepen responses. In addition to these approaches, it is of interest to identify higher-resolution actionable biomarkers that can predict treatment responses and toxicity, and inform personalized treatment decisions. Here, we discuss the current status of PI3K inhibitors in CLL, factors limiting the use of currently approved PI3K inhibitors in CLL, current strategies to overcome these limitations, and where to go next.

中文翻译：

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PI3K 抑制剂治疗慢性淋巴细胞白血病：我们下一步该何去何从？

磷脂酰肌醇 3-激酶 (PI3K) 抑制剂对慢性淋巴细胞白血病 (CLL) 有效。然而，与第一代抑制剂 idelalisib 和 duvelisib 相关的严重毒性，加上其他更耐受的药物的可用性，限制了它们的使用。CLL 仍然被认为是无法治愈的，治疗后复发、产生耐药性和治疗不耐受很常见。因此，优化目前批准的 PI3K 抑制剂的给药方式并开发下一代药物以提高耐受性是有意义的，以便此类药物在需要时被认为是有效且安全的治疗选择。这些努力反映在大量新兴的 PI3K 抑制剂治疗 CLL 的临床试验中。目前克服治疗局限性的策略包括间歇给药，该策略针对 copanlisib 和 zandelisib 建立，针对 duvelisib 和 parsaclisib 正在研究中。第二种策略是将 PI3K 抑制剂与另一种新型药物联合使用，作为连续方案或固定持续时间方案，以加深反应。除了这些方法之外，识别更高分辨率的可操作生物标志物也很有意义，这些生物标志物可以预测治疗反应和毒性，并为个性化治疗决策提供信息。在这里，我们讨论 PI3K 抑制剂在 CLL 中的现状、限制目前批准的 PI3K 抑制剂在 CLL 中使用的因素、克服这些限制的当前策略以及下一步的发展方向。