Phase I Study of Temozolomide and Laromustine (VNP40101M) in Patients With Relapsed or Refractory Leukemia
Phase I Study of Temozolomide and Laromustine (VNP40101M) in Patients With Relapsed or Refractory Leukemia
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DOI：
10.3816/clml.2010.n.033
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发表时间：
2010-06-01
影响因子：
2.7
通讯作者：
Gerson, Stanton L.
中科院分区：
文献类型：
--
作者：
Rizzieri, David;LoRusso, Samantha;Gerson, Stanton L.
目的：虽然已知烷化剂对某些髓性白血病有效，但耐药性通常是通过O（6）-烷基鸟嘌呤-DNA烷基转移酶（AGT）介导的。替莫唑胺对AGT的抑制可能使白血病细胞对新型烷化剂拉罗莫司汀敏感。我们进行了一项I期转化研究，以评估血液恶性肿瘤患者接受拉莫司汀与替莫唑胺（TMZ）联合给药时的毒性并估计最大耐受剂量（MTD）。患者和方法：TMZ每日两次给药，共5剂，随后单次输注拉罗莫司汀。目标TMZ剂量是将可靠地导致> 90% AGT消耗的剂量。一旦确定目标TMZ剂量，则递增拉罗莫司汀剂量。共治疗了35例复发/难治性白血病患者。结果：TMZ 300 mg治疗5次，6例患者中有5例AGT水平下降> 90%。联合用药的MTD确定为TMZ 1500 mg和拉罗莫司汀300 mg/m2。来自组群1的7名患者中的3名实现AGT活性的> 90%消耗（范围，77%-100%消耗;中值，88%）。组群2中招募的6名患者中的5名实现AGT活性的> 90%消耗（范围，92%-100%消耗;中值，93.5%）。这确定了TMZ 300 mg剂量（总计1500 mg）将在后续队列中维持。大多数不良事件主要是血液学，也注意到感染和肺部并发症。3例（9%）既往患有难治性疾病的患者获得完全缓解，5例（14%）患者获得形态学无白血病但持续性细胞减少的骨髓状态。结论：拉罗莫司汀联合TMZ在可预测抑制AGT的剂量下可耐受和管理。在临床可耐受的剂量下观察到TMZ诱导的AGT可靠抑制。观察到该组合具有抗肿瘤作用的证据，表明应进行进一步的疗效研究。
Purpose: Although alkylators are known to be effective against some myeloid leukemias, resistance is often mediated via O(6)-alkylguanine-DNA alkyltransferase (AGT). Temozolomide's inhibition of AGT may sensitize leukemia cells to the novel alkylator laromustine. We conducted a phase I translational study to evaluate the toxicities and estimate the maximum tolerated dose (MTD) of laromustine when administered with temozolomide (TMZ) in patients with hematologic malignancies. Patients and Methods: TMZ was delivered twice daily for 5 doses followed by a single infusion of laromustine. The target TMZ dose was the dose that would reliably result in > 90% AGT depletion. Once the target TMZ dose was identified, the laromustine dose was escalated. A total of 35 patients with relapsed/refractory leukemia were treated. Results: Treatment with TMZ 300 mg for 5 doses resulted in > 90% depletion of AGT levels in 5 of 6 patients. The MTD of the combination was established at TMZ 1500 mg and laromustine 300 mg/m(2). Three of the 7 patients assayed from cohort 1 achieved > 90% depletion of AGT activity (range, 77%-100% depletion; median, 88%). Five of 6 patients enrolled in cohort 2 achieved > 90% depletion of AGT activity (range, 92%-100% depletion; median, 93.5%). This established that the 300-mg dose of TMZ (1500 mg total) would be maintained in subsequent cohorts. The majority of adverse events were primarily hematologic, with infectious and pulmonary complications also noted. Three (9%) of the patients with previous refractory disease achieved a complete remission, and 5 (14%) of the patients achieved a morphologic, leukemia-free, but persistent hypocellular bone marrow status. Conclusion: Laromustine in combination with TMZ is tolerable and manageable at doses that predictably suppress AGT. Reliable TMZ-induced inhibition of AGT was observed in doses that are clinically tolerable. Evidence of antitumor effect was observed with this combination, suggesting that further efficacy studies should be performed.