DETECTION OF MINIMAL RESIDUAL LEUKEMIA IN CHILDREN

儿童微小残留白血病的检测

• 批准号: 3550123
• 负责人: DARIO CAMPANA
• 金额: $ 11.64万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-01 至 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3550123
• 关键词: CD antigens; acute lymphocytic leukemia; acute myelogenous leukemia; biomarker; bone marrow; child (0-11); cooperative study; gene expression; human subject; immunologic assay /test; karyotype; leukemia; longitudinal human study; neoplasm /cancer relapse /recurrence; pediatric neoplasm /cancer; phenotype; polymerase chain reaction; prognosis; protooncogene

Despite advancing cure rates in childhood acute lymphoblastic leukemia (ALL), 25-30% of patients eventually succumb to their disease. The outlook is far worse in acute myeloid leukemia (AML): only about 30% of children are cured in chemotherapy programs, and the option of bone marrow transplantation is either not available (because of the lack of suitable donors) or of limited value (because of high rates of marrow relapse, likely due to residual leukemia in the autografts). Early detection of low levels of residual leukemia would benefit both groups of patients. It would permit more timely investigation of retrieval therapy, possibly before the development of multi-drug resistance, as seen in patients with clinically overt relapse, and it would allow the source of relapse to be determined in patients undergoing autologous bone marrow transplantation, whether residual disease in the marrow implant or resistant leukemia remaining after ablative treatment. The hypothesis underlying this proposal is that many cases of acute leukemia possess distinctive combinations of immunologic markers that can be used to detect minimal residual disease (MRD) and thus identify patients requiring alternative treatment. The assay system to be used is capable of detecting 1 leukemic cells among 10,000 normal cells and therefore can quantify leukemia at the 10-4 level (standard morphologic tests for relapse require 1-5% identifiable blasts). In the first specific aim, marrow samples taken at five different intervals from patients with T- ALL, enrolled in a phase III clinical trial, will be assessed for the leukemia-specific TdT/CD3 phenotype. Similar studies will be performed on specimens from B-lineage ALL patients to detect CD19/CD13, CD19/CD33, CD19/CDw65 and CD34/CD21 phenotypes. Comparison of outcome data for children with and without MRD will demonstrate with 80% power the value of this approach for prospective identification of high-risk patients. The large patient accrual (> 200 subjects over 4 years) will also make it possible to directly compare the sensitivity and specificity of our immunologic assays with those of the polymerase chain reaction (PCR), as applied to clonal molecular abnormalities (specific aim 2). PCR analysis has been advocated as a clinically useful tool for MRD detection, but its efficacy relative to that of immunologic marker detection has not been assessed in a controlled, prospective trial. Finally, the usefulness of immunologic methods for MRD detection will be estimated in childhood AML, using marrow specimens from patients scheduled to undergo autologous transplantation (specific aim 3).

尽管儿童急性淋巴细胞白血病的治愈率不断提高， (ALL)25 - 30%的患者最终死于疾病。 的 在急性髓细胞白血病（AML）中，前景要差得多：只有约30%的 儿童在化疗项目中被治愈， 骨髓移植是不可用的（由于缺乏 合适的捐赠者）或价值有限（由于骨髓移植率高 复发，可能是由于自体移植物中残留的白血病）。 早期 检测到低水平的残留白血病将使两组受益 病人。 它将允许更及时地调查检索 治疗，可能在多药耐药性的发展之前， 在临床上明显复发的患者中观察到， 在接受自体骨治疗的患者中确定复发来源 骨髓移植，是否在骨髓植入物中残留病变 或消融治疗后残留的耐药白血病。 的假设 这一建议的基础是，许多急性白血病病例具有 免疫标记物的独特组合，可用于 检测微小残留病（MRD），从而识别患者 需要替代治疗。 待使用的测定系统能够 在10,000个正常细胞中检测到1个白血病细胞，因此可以 将白血病量化为10 - 4水平（标准形态学测试） 复发需要1 - 5%可识别的原始细胞）。 在第一个具体目标中， 在五个不同的时间间隔从T- 入组III期临床试验的ALL患者将接受 白血病特异性TdT/CD3表型。 将进行类似的研究 对来自B系ALL患者的标本进行检测，以检测CD 19/CD 13、CD 19/CD 33、 CD19/CDw65和CD34/CD21表型。 结果数据的比较 有和没有MRD的儿童将以80%的把握度证明 这种方法用于前瞻性识别高风险患者。 大量患者入组（4年内> 200例受试者）也将使 可以直接比较我们的灵敏度和特异性， 聚合酶链反应（PCR）的免疫测定，如 适用于克隆分子异常（具体目标2）。 pcr分析 已经被提倡为临床上有用的MRD检测工具，但其 相对于免疫标记检测的功效还没有被 在一项前瞻性对照试验中进行评估。 最后， 免疫学方法用于MRD检测将在儿童AML中进行评估， 使用来自计划接受自体移植的患者的骨髓样本， 移植（具体目标3）。