Accurate Prediction of Acute Myeloid Leukemia Relapse

描述(申请人提供)：在获得缓解的急性髓系白血病(AML)儿童中，有40%的人后来经历了坦率的复发，他们的最终预后通常很差。不幸的是，目前的实验室技术无法准确预测这种疾病的复发。随着多维流式细胞术的出现，罕见的白血病细胞可以在常规光学显微镜下无法检测到的情况下被识别出来。使用在AML中观察到的异常细胞表面抗原表达模式来区分这些细胞与正常骨髓，我们已经确定了在完全缓解期间存在可检测到的残留白血病细胞的患者。在一项对252名儿童AML患者进行的前瞻性合作试验中，患有可检测到的白血病缓解期的儿童复发的可能性是未检测到白血病的儿童的四倍，死亡的可能性是未检测到白血病的儿童的三倍。事实上，诱导治疗后白血病的流式细胞术证据成为与不良预后相关的最强大的独立预后因素。隐匿性白血病患者和非隐匿性白血病患者的3年生存率分别为41%和69%(P=0.006)。这些发现为加强高危患者的缓解后治疗奠定了基础。在疾病负担最小的时候预测复发将具有重要的临床价值，因为它将允许早期干预，采用更积极的治疗形式(即异基因骨髓移植)，以实现更高的总体治愈率。此外，随着流式细胞术分析方法的改进，降低低风险患者的化疗剂量和强度成为可能，作为限制积极治疗带来的短期和长期健康后果的一种手段。 我们的前瞻性研究表明，多维流式细胞术对白血病细胞具有高度的特异性，事实上，几乎所有通过MDF分析可检测到的残留白血病患者在随后没有接受同种异体移植的情况下都会复发。然而，在这项检测中没有检测到白血病的缓解期患者中，有相当一部分也经历了疾病复发。出于这个原因，我们现在寻求评估几种提高检测灵敏度的方法。具体地说，我们计划：(1)研究每个试管增加的细胞数量，(2)评估各种新的髓系和淋巴系抗体组合，这些组合应该能够更好地区分正常细胞和它们的恶性细胞，以及(3)增加每个试管的抗体组合数量。有了这些增强和修改，我们相信我们将能够准确地预测超过80%的AML儿童病情缓解。

Description (provided by applicant): Forty percent of children with acute myeloid leukemia (AML) who achieve remission subsequently experience frank relapse of their disease and their ultimate prognosis is typically poor. Unfortunately, such disease recurrences cannot be accurately predicted with current laboratory techniques. With the advent of multidimensional flow cytometry, rare leukemic cells can be identified when they are undetectable by conventional light microscopy. Using aberrant cell surface antigen expression patterns observed in AML to distinguish these cells from normal bone marrow, we have identified patients harboring detectable residual leukemic cells during complete remission. In a prospective, cooperative trial of 252 pediatric AML patients, children harboring detectable leukemia in remission were four times more likely to experience relapse and three times more likely to die than those without detectable leukemia. In fact, flow cytometric evidence of leukemia after induction therapy emerged as the most powerful independent prognostic factor associated with poor outcome. Overall survival at 3 years was 41% vs. 69% for patients with and without occult leukemia, respectively (P=0.006). These findings establish rationale for intensifying post-remission therapy in high-risk patients. Prediction of relapse at a time of minimal disease burden would be of significant clinical value, as it would allow early intervention with a more aggressive form of therapy (i.e., allogeneic marrow transplant) to achieve an improved overall cure rate. Moreover, as the flow cytometric assay improves, it may become possible to safely decrease the dose and intensity of chemotherapy given to low-risk patients as a means of limiting the short- and long-term health consequences associated with aggressive treatment. Our prospective studies have demonstrated that the multidimensional flow cytometric assay is highly specific for leukemic cells, in fact, almost every patient with residual leukemia detectable by the MDF assay who did not receive a subsequent allogeneic transplant subsequently relapsed. However, a significant portion of remission patients in whom no leukemia was detected by this assay also experienced disease recurrence. For this reason, we now seek to evaluate several means of increasing the sensitivity of the assay. Specifically we plan to: (1) study an increased number of cells per assay tube, (2) evaluate various novel myeloid and lymphoid antibody combinations that should allow greater distinction between normal cells and their malignant counterparts, and (3) increase the number of antibody combinations per tube. With these enhancements and modifications, we believe we will be able to accurately predict relapse in more than 80% of children with AML who achieve remission.