继发性浆细胞白血病（sPCL）是一种罕见的、进展迅速的浆细胞恶性肿瘤，多发生于晚期难治性多发性骨髓瘤，因此治疗选择有限。我们对13例sPCL进行了分析，评估了它们对靶向BCL2（venetoclax）或BCLXL（A1155463）的BH3模拟物的敏感性，并显示3例sPCL对venetoclax的治疗效果明显，3例sPCL对A1155463的治疗效果明显。因此，对对BCLXL抑制敏感的2例sPCL进行BH3分析，确认了它们具有高BCLXL启动的特征。虽然使用BH3模拟物靶向BCLXL可以诱导血小板的靶向药物毒性，但最近发展的DT2216是一种临床阶段的BCLXL蛋白酶解靶向嵌合物PROTAC化合物，提供了一种靶向BCLXL的替代策略。事实上，DT2216通过VHL E3连接酶特异性降解BCLXL，而不引起血小板减少。我们研究表明，在人类骨髓瘤细胞系和sPCL中，对DT2216的敏感性与对A1155463的敏感性强相关。有趣的是，我们展示了在经过48小时处理后，DT2216的低剂量（nM范围）足以特异性降解全部细胞系中的BCLXL，与VHL表达一致，而不考虑DT2216的敏感性。在骨髓瘤细胞中，DT2216引发细胞凋亡和BAX和BAK的激活。总之，我们的研究证明了sPCL对BCLXL成瘾的患者，即使是一个小但极具挑战性的人群，也有可能从DT2216获得治疗益处。对这一sPCL患者亚组进行DT2216的临床试验是有必要的。版权所有© 2023 Champion, Soler, Maïga, Bellanger, Pellat-Deceunynck, Talbot, Touzeau, Amiot and Gomez-Bougie.

Secondary plasma cell leukemia (sPCL) is a rare form of aggressive plasma cell malignancy arising mostly at end-stage refractory multiple myeloma and consequently presenting limited therapeutic options. We analyzed 13 sPCL for their sensitivity to BH3 mimetics targeting either BCL2 (venetoclax) or BCLXL (A1155463) and showed that 3 sPCL were efficiently killed by venetoclax and 3 sPCL by A1155463. Accordingly, BH3 profiling of 2 sPCL sensitive to BCLXL inhibition confirmed their high BCLXL primed profile. While targeting BCLXL using BH3 mimetics induces platelets on-target drug toxicity, the recent development of DT2216, a clinical-stage BCLXL proteolysis targeting chimera PROTAC compound, provides an alternative strategy to target BCLXL. Indeed, DT2216 specifically degrades BCLXL via VHL E3 ligase, without inducing thrombocytopenia. We demonstrated in human myeloma cell lines and sPCL that sensitivity to DT2216 strongly correlated with the sensitivity to A1155463. Interestingly, we showed that low doses of DT2216 (nM range) were sufficient to specifically degrade BCLXL after 48 hours of treatment, consistent with VHL expression, in all cell lines but irrespectively to DT2216 sensitivity. In myeloma cells, DT2216 induced apoptotic cell death and triggered BAX and BAK activation. In conclusion, our study demonstrated that patients with sPCL addicted to BCLXL, a small but a very challenging group, could potentially receive therapeutic benefit from DT2216. Clinical trials of DT2216 in this subset of sPCL patients are warranted.Copyright © 2023 Champion, Soler, Maïga, Bellanger, Pellat-Deceunynck, Talbot, Touzeau, Amiot and Gomez-Bougie.