Accurate Prediction of Acute Myeloid Leukemia Relapse

描述（由申请人提供）：40%的急性髓性白血病（AML）儿童在达到缓解后会出现明显的疾病复发，其最终预后通常很差。不幸的是，这种疾病的复发率不能准确预测与目前的实验室技术。随着多维流式细胞术的出现，当常规光学显微镜无法检测到罕见的白血病细胞时，可以识别它们。使用异常的细胞表面抗原表达模式观察AML区分这些细胞从正常骨髓，我们已经确定了患者窝藏可检测的残留白血病细胞在完全缓解。在一项针对252名儿童AML患者的前瞻性合作试验中，携带可检测到的白血病缓解期儿童复发的可能性是未检测到白血病的儿童的4倍，死亡的可能性是未检测到白血病的儿童的3倍。事实上，诱导治疗后白血病的流式细胞术证据是与不良结局相关的最有力的独立预后因素。有和无隐匿性白血病患者的3年总生存率分别为41%和69%（P=0.006）。这些发现为高危患者加强缓解后治疗奠定了基础。在疾病负担最小的时间预测复发将具有显著的临床价值，因为它将允许用更积极的治疗形式（即，同种异体骨髓移植）以实现提高的总体治愈率。此外，随着流式细胞术检测的改进，有可能安全地降低给予低风险患者的化疗剂量和强度，作为限制与积极治疗相关的短期和长期健康后果的手段。 我们的前瞻性研究表明，多维流式细胞术检测白血病细胞是高度特异性的，事实上，几乎每一个残留白血病的患者检测的白血病检测没有接受后续的同种异体移植随后复发。然而，通过该测定未检测到白血病的缓解患者中的显著部分也经历疾病复发。出于这个原因，我们现在试图评估几种提高检测灵敏度的方法。具体而言，我们计划：（1）研究每个测定管中增加的细胞数量，（2）评价各种新的髓样和淋巴样抗体组合，这些抗体组合应该允许在正常细胞和它们的恶性对应物之间进行更大的区分，以及（3）增加每个管中抗体组合的数量。通过这些增强和修改，我们相信我们将能够准确预测超过80%的AML缓解儿童的复发。

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.