Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Leuk Lymphoma. 2021 May;62(5):1167-1177. doi: 10.1080/10428194.2021.1910684. Epub 2021 Apr 11.
Targeting the JAK/STAT and BCL2 pathways in patients with relapsed/refractory T cell acute lymphoblastic leukemia (T-ALL) may provide an alternative approach to achieve clinical remissions. Ruxolitinib and venetoclax show a dose-dependent effect on T-ALL individually, but combination treatment reduces survival and proliferation of T-ALL . Using a xenograft model, the combination treatment fails to improve survival, with death from hind limb paralysis. Despite on-target inhibition by the drugs, histopathology demonstrates increased leukemic infiltration into the central nervous system (CNS) as compared to liver or bone marrow. Liquid chromatography-tandem mass spectroscopy shows that ruxolitinib and venetoclax insufficiently cross into the CNS. The addition of the CXCR4 inhibitor plerixafor with ruxolitinib and venetoclax reduces clinical scores and enhances survival. While combination therapy with ruxolitinib and venetoclax shows promise for treating T-ALL, additional inhibition of the CXCR4-CXCL12 axis may be needed to maximize the possibility of complete remission.
针对复发/难治性 T 细胞急性淋巴细胞白血病 (T-ALL) 患者的 JAK/STAT 和 BCL2 通路可能提供一种实现临床缓解的替代方法。鲁索利替尼和 Venetoclax 单独对 T-ALL 具有剂量依赖性作用，但联合治疗会降低 T-ALL 的存活率和增殖率。在异种移植模型中，联合治疗未能改善生存，导致后肢瘫痪死亡。尽管药物有靶向抑制作用，但组织病理学显示与肝或骨髓相比，白血病浸润中枢神经系统 (CNS) 增加。液相色谱-串联质谱显示，鲁索利替尼和 Venetoclax 不能充分进入 CNS。鲁索利替尼和 Venetoclax 联合 CXCR4 抑制剂plerixafor 可降低临床评分并提高生存率。虽然鲁索利替尼和 Venetoclax 的联合治疗对治疗 T-ALL 有一定的前景，但可能需要进一步抑制 CXCR4-CXCL12 轴以最大限度地提高完全缓解的可能性。
