The Durable Clearance of the T315I BCR-ABL Mutated Clone in Chronic Phase Chronic Myelogenous Leukemia Patients on Omacetaxine Allows Tyrosine Kinase Inhibitor Rechallenge
The Durable Clearance of the T315I BCR-ABL Mutated Clone in Chronic Phase Chronic Myelogenous Leukemia Patients on Omacetaxine Allows Tyrosine Kinase Inhibitor Rechallenge
复制标题
DOI：
10.3816/clml.2010.n.073
复制
发表时间：
2010-10-01
影响因子：
2.7
通讯作者：
Hayette, Sandrine
中科院分区：
文献类型：
--
作者：
Nicolini, Franck E.;Chomel, Jean-Claude;Hayette, Sandrine
目的：在接受酪氨酸激酶抑制剂 (TKI) 治疗的慢性粒细胞白血病 (CML) 病程中，BCR-ABL(T315I) 突变的发生通常会导致生存率较差，并且在没有任何同种异体供体的情况下，治疗选择仍然很少。患者和方法：我们研究了皮下注射奥马西他星（OMA，或高三尖杉酯碱）周期对 8 名 TKI 耐药慢性期 CML 患者中未突变和 T315I 突变的 BCR-ABL 转录物的影响，并解决了 OMA 给药是否可以使患者对 TKI 重新敏感的问题。使用新的定量敏感技术（敏感度阈值，0.05%）定期监测患者的总疾病负担和 BCR-ABL(T315I) 转录本，最多进行 27 个 OMA 周期。结果：总体而言，患者表现出血液学、细胞遗传学或分子学方面的改善。在平均 10.5 个周期（范围，3-27 个周期）的 OMA 后，50% 的患者观察到 T315I 突变转录本最初快速下降并持续消失。由于未突变的白血病负担减少幅度不大，2 名患者在 OMA 上持续 BCR-ABLT315I 转录物阴性 9 个月后接受尼洛替尼治疗，而在尼洛替尼挑战中位随访 12 个月后，突变转录物仍然检测不到。结论：我们认为 OMA（即非靶向治疗）可能提供更好的疾病控制，允许可能由 TKI 释放后克隆取消选择引起的突变克隆消失，和/或 OMA 通过未知机制对 T315I 突变细胞具有优先活性。这些观察结果表明，OMA 可以让患有耐药性慢性期 CML 的患者安全地再次接受 TKI 治疗。
Purpose: The onset of a BCR-ABL(T315I) mutation during the course of chronic myelogenous leukemia (CML) on tyrosine kinase inhibitors (TKIs) usually results in poor survival, and therapeutic options remain few in the absence of any allogeneic donor. Patients and Methods: We have investigated the affect of subcutaneous omacetaxine (OMA, or homoharringtonine) cycles on unmutated and T315I-mutated BCR-ABL transcripts in a series of 8 TKI-resistant chronic-phase CML patients and we have addressed the question of whether the administration of OMA could resensitize patients to TKIs. Patients were regularly monitored for total disease burden and for BCR-ABL(T315I) transcripts using a new quantitative sensitive technique (sensitivity threshold, 0.05%), for up to 27 cycles of OMA. Results: Overall, patients demonstrated hematologic, cytogenetic, or molecular improvement. An initial rapid decline and a sustained disappearance of T315I-mutated transcripts were observed in 50% of patients, after a median of 10.5 cycles (range, 3-27 cycles) of OMA. As the unmutated leukemic burden reduction was modest, 2 patients were submitted to nilotinib after 9 months of sustained BCR-ABLT315I transcripts negativity on OMA and mutated transcripts remained undetectable after a median follow-up of 12 months on nilotinib challenge. Conclusion: We suggest that OMA (ie, a non-targeted therapy) might provide a better disease control allowing the disappearance of the mutated clone probably elicited by the clone deselection after TKI release, and/or a preferential activity of OMA on the T315I-mutated cells through unknown mechanisms. These observations suggest that OMA could allow a safe TKI rechallenge in patients with resistant chronic-phase CML.