CONTRIBUTION OF RESIDUAL DISEASE & STEM CELL DAMAGE TO CANCER THERAPY OUTCOME

然而，如果在体内检测到癌细胞， 那么额外的治疗将是必要的治愈，这还没有 明确建立了最小数量的癌细胞， 现在可以用敏感的技术检测， 反应（PCR）扩增。 肿瘤特异性染色体PCR 基因重排或基因易位能够检测一个肿瘤 细胞在多达106个正常细胞，并提出了相当大的进步， 检测微小残留病（MRD）的先前技术。 中央 这一建议的论点是，根除残留的癌细胞， 需要治愈。 随着剂量的增加和成功 强化治疗策略，用于治疗血液系统 对于恶性肿瘤，必须解决两个关键问题。 首先， 第一，评估治疗的结果，第二，伴随的毒性 可容忍的，如果不可容忍，是否可以预防或逆转？ 以前的研究 已经证明根除PCR可检测的淋巴瘤细胞是 与高剂量治疗后的结局显著改善相关， 晚期淋巴瘤 然而，这一改善的结果是由于 正如我们和其他人所观察到的那样，消除淋巴瘤并非没有代价 ABMT后骨髓增生异常的发病率大大增加。 的能力 根据MRD的检测来预测结果将允许人们定制 治疗需要额外治疗的患者， 重要的是，为了避免在没有 可检测的MRD。 因此，本项目的主要目标是确定 消除微小残留病对治愈和 此外，为了确定达到这一目的疗法如何诱导干细胞， 将影响血液学治疗后结局的损伤 恶性肿瘤。 为此，我们提出了三个具体目标。 一是 开发和扩展基于PCR的检测方法，以检测、定量和确定 MRD在淋巴瘤和骨髓瘤患者中的临床意义 接受常规、高剂量消融和新型免疫治疗的白血病患者 第二，评估染色体核型的临床意义 接受常规治疗的患者中的异常和克隆性造血 和高剂量消融治疗。 基于干细胞损伤 我们计划第三，尝试分离干细胞， 患者在其疾病过程的早期， 发生了损害。 因为这可能意味着骨髓或 这些患者的外周血含有显著的肿瘤累及 我们的目标是尝试改进清除策略， 肿瘤负荷，并评估这些清除策略的疗效， PCR法 该项目的成功高度依赖于 新的肿瘤特异性易位的鉴定， 来自接受高剂量消融治疗的患者的肿瘤标本， 在新的治疗方法之前、期间和之后的骨髓样本。

Whereas it might seem obvious that if cancer cells are detected in the body then additional therapy will be necessary for cure, this has not been definitively established for the minimal numbers of cancer cells that can now be detected using sensitive techniques such as polymerase chain reaction (PCR) amplification. PCR of tumor specific chromosomal translocations or gene rearrangements is capable of detecting one tumor cell in up to 106 normal cells and presents a considerable advance over previous techniques to detect minimal residual disease (MRD). The central thesis of this proposal is that eradication of residual cancer cells is necessary for cure. With the increasing use and success of dose intensified treatment strategies for the treatment of the hematologic malignancies, two critical questions have to be addressed. First, how is the outcome of treatment assessed and second, are the attendant toxicities tolerable and if not, are they preventable or reversible? Previous studies have demonstrated that eradication of PCR detectable lymphoma cells is associated with greatly improved outcome after high dose therapy for advanced stage lymphoma. However, this improved outcome resulting from elimination of lymphoma is not without cost as we and others have observed a greatly increased incidence in myelodysplasia after ABMT. The ability to predict outcome based on the detection of MRD would allow one to tailor treatment ot patients who require additional therapy and, just as importantly, to avoid potentially toxic therapy in patients who have no detectable MRD. Therefore the primary goal of this project is to determine the contribution of the eradication of minimal residual disease to cure and in addition, to determine how therapy to achieve this aim induces stem cell damage that will affect outcome following treatment of hematologic malignancies. To this end we propose Three specific aims. First, to develop and extend PCR based assays to detect, quantitate and determine the clinical significance of MRD in patients with lymphoma and myeloma and leukemia who receive conventional, high dose ablative and novel immunologic strategies Second, to assess the clinical significance of karyotypic abnormalities and clonal hematopoiesis in patients receiving conventional and high dose ablative therapy. Based on the premise that stem cell damage is therapy induced we plan Thirdly, to attempt to isolate stem cells from patients early in the course of their disease before significant stem cell damage has occurred. Since this will likely mean that the bone marrow or peripheral blood from these patients contains significant tumor involvement we aim to attempt to improve purging strategies to deplete this increased tumor burden and to assess the efficacy of these purging strategies using PCR. The success of this project is highly interdependent upon the identification of novel tumor specific translocations, the availability of tumor specimens from patients undergoing high dose ablative therapy and bone marrow samples before during and after novel treatment approaches.