Examination of imatinib mesylate resistance in CML

描述（由申请方提供）：Dr. Oehler在5年内的目标是前瞻性评估慢性期（CP）CML患者对甲磺酸伊马替尼耐药的机制，并研究至少获得MCR的患者复发的生物学。根据IRIS研究结果，伊马替尼已成为一线治疗。然而，反应的持久性是未知的，同种异体移植仍然是唯一潜在的治愈方法。鉴于CML治疗策略的快速变化，明确需要在治疗早期（最好是治疗前）确定反应的预测因素。 具体目标1。评估伊马替尼的分子学反应和临床反应预测因子。通过RT-PCR评估的bcr-abl消失动力学可预测复发和对异基因移植和干扰素治疗的反应。Hasford评分已用于评估接受干扰素或化疗的患者的预后。将通过RTPCR评估分配至SWOG S 0325四个组的所有患者。 我们假设在开始治疗后3 - 6个月内bcr-abl降低的动力学与缓解持续时间相关，Hasford评分可预测伊马替尼的早期缓解。 具体目标2。通过基因组表达分析确定缓解和复发的遗传预测因子。微阵列技术已被用于开发基因组图谱，其可能比病理学或细胞遗传学更能预测预后。将通过微阵列分析在慢性期CML患者中鉴定治疗前基因组反应预测因子。这些预测因子将在SWOG S 0325上进行前瞻性验证。我们假设伊马替尼应答者与非应答者相比具有不同的表达谱，并且低、中和高风险Hasford评分将具有与结果相关的不同基因表达谱。 具体目标3。通过点突变分析和基因组表达分析确定复发的生物学。已经描述了对伊马替尼耐药的几种机制。将通过PCR-SSCP和灵敏的错配试验评估点突变的患病率，以确定治疗前和治疗早期的点突变频率。 我们假设突变频率很高，并且在治疗前可检测到。 将复发样品的基因表达模式与相应的诊断样品进行比较。 我们推测，以前未被发现的克隆的进化是复发的机制。

DESCRIPTION (provided by applicant): Dr. Oehler's objective over 5 years is to prospectively assess mechanisms of resistance to imatinib mesylate in chronic phase (CP) CML patients and investigate the biology of relapse in patients who have obtained at least a MCR. Imatinib has become first line therapy based on the IRIS study results. However, the durability of response is unknown, and allogeneic transplant remains the only potential cure. Given the rapid change in treatment strategy for CML there is a clear need to identify predictors of response early in therapy, ideally pre-treatment. Specific Aim 1. Assess molecular response and clinical predictors of response to imatinib. The kinetics of bcr-abl disappearance as assessed by RT-PCR predict relapse and response to allogeneic transplant and interferon therapy. The Hasford score has been utilized to assess prognosis in patients treated with interferon or chemotherapy. All patients assigned to the four arms of SWOG S0325 will be assessed by RTPCR. We hypothesize that the kinetics of bcr-abl decrease within three to six months of initiating treatment will correlate with duration of response, and that the Hasford score predicts early response to imatinib. Specific Aim 2. Determine the genetic predictors of response and relapse by genomic expression analysis. Microarray technology has been used to develop genomic profiles that may be more predictive of prognosis than pathology or cytogenetics. Pre-treatment genomic predictors of response will be identified in chronic phase CML patients by microarray analysis. These predictors will be validated prospectively on SWOG S0325. We hypothesize that imatinib responders will have different expression profiles than non-responders and that low, intermediate, and high risk Hasford scores will have distinct gene expression profiles that correlate with outcome. Specific Aim 3. Determine the biology of relapse by point mutation analysis and genomic expression analysis. Several mechanisms of resistance to imatinib have been described. The prevalence of point mutations will be assessed by PCR-SSCP and by a sensitive mismatch assay to determine the frequency of point mutations pre- and early in treatment. We hypothesize that mutations frequency is high and is detectable before treatment. The gene expression pattern of the relapsed sample will be compared with the corresponding diagnostic sample. We hypothesize that the evolution of a previously undetected clone is the mechanism of relapse.