TRIALS OF CLADRIBINE PLUS OTHER AGENTS FOR PEDIATRIC AML

儿童急性髓性白血病（AML）的最佳治疗方法尚未确定。包括骨髓移植在内的当代治疗方案的结果表明，儿童和青少年急性髓性白血病的长期预后虽然有所改善，但仍然很差。在申请人所在机构进行的研究表明，2-氯脱氧腺苷（cladribine, 2-CDA）作为单一药物可有效诱导儿科AML患者的血液学缓解。虽然对这些研究的分析仍在进行中，但总体临床结果显示，约25%的先前未接受治疗的患者在单独使用2-CDA治疗一个疗程后血液学完全缓解，约50%的患者在两个疗程后完全缓解。然而，为了实现2-CDA治疗AML的真正潜力，必须发现2-CDA与另一种或多种药物的联合使用，其中该组合具有最大的抗白血病作用，同时将毒性保持在可接受的水平。在拟议的研究中，将研究2-CDA与另一种治疗剂的两种组合。一项是2-CDA联合阿糖胞苷（araC）治疗先前未治疗患者的研究，另一项是2-CDA联合拓扑替康的I期研究。前一项研究的主要目的是：1)评价2-CDA与araC联合使用的活性和毒性；2)测定2- cda对阿糖胞苷三磷酸水平的影响。本研究的初步临床结果令人鼓舞。关于第二种组合，在成人中单独使用拓扑替康的研究表明，这可能是一种适合与2-CDA配对的药物，并且使用培养的人骨髓细胞的临床前结果表明，在适当的计划下，2-CDA和拓扑替康的细胞毒性作用是累加性的。2-CDA和拓扑替康的初始临床研究将是一项针对目前没有其他治疗方法的复发性儿科AML患者的I期研究，目标将是：1)确定2-CDA和拓扑替康联合用药的最大耐受剂量；2)确定血液和非血液毒性的极限。当达到这些目标，特别是观察到临床反应时，将设计II期试验。

DESCRIPTION: (Applicant's Abstract) The optimal treatment of acute myeloid leukemia (AML) in children is not yet defined. Results of contemporary treatment regimens, including those that employ bone marrow transplantation, have shown that the long-term prognosis of children and adolescents with AML, while improving, remains poor. In studies conducted at the applicant's institution it has been shown that 2-chlorodeoxyadenosine (cladribine, 2-CDA) is effective as a single agent for inducing hematologic remissions in pediatric patients with AML. Although analysis of these studies is still in progress, the overall clinical result is that about 25% of previously untreated patients show complete hematologic remission after one course of treatment with 2-CDA alone, and about 50% after two courses. For the real potential of 2-CDA for the treatment of AML to be realized, however, it is essential that a combination of 2-CDA with another drug or drugs be discovered in which the combination has the maximum additive antileukemic effect while toxicity is held to an acceptable level. In the proposed research two combinations of 2-CDA with another therapeutic agent will be investigated. One is a study of the combination of 2-CDA with cytarabine (araC) in the therapy of previously untreated patients, and the other a Phase I study of the combination of 2-CDA with topotecan. The primary objectives of the former study are: 1) to evaluate the activity and toxicity of the combination of 2-CDA plus araC; and 2) to determine the influence of 2-CDA on cytarabine triphosphate levels. Preliminary clinical results of this study are encouraging. In regard to the second combination, studies in adults with topotecan alone suggest that this might be a suitable drug to pair with 2-CDA, and preclinical results using human myeloid cells in culture indicate additive cytotoxic effects of 2-CDA and topotecan when scheduling is appropriate. The initial clinical study with 2-CDA and topotecan will be a phase I investigation in relapsed pediatric AML patients for whom no other therapy is currently available, and the objectives will be: 1) to determine the maximum tolerated doses of 2-CDA and topotecan in combination; and 2) to determine the limiting hematologic and non-hematologic toxicity. When these objectives have been met, and particularly if clinical responses are observed, a phase II trial will be designed.