Predicting clinical outcome in individuals with small CLL B cell clones

 描述(由申请人提供)：我们的建议解决了以更准确和患者特有的方式预测早期CLL和MBL临床病程的重要问题。慢性淋巴细胞白血病(CLL)是最常见的淋巴系统恶性肿瘤之一，约占所有血液系统肿瘤的11%。慢性淋巴细胞性白血病仍然是一种无法治愈的毁灭性的恶性肿瘤。除了预期寿命比普通人群中年龄匹配的人短得多外，慢性淋巴细胞性白血病患者还必须应对感染、第二次癌症和自身免疫并发症的风险增加，这些并发症可能会对他们的生活质量产生深远的影响。然而，CLL患者的临床过程具有极端的异质性，70%的CLL患者最终将需要治疗，这一事实最好地说明了这一点。后一种结果是复杂的，因为大多数新诊断的CLL患者表现为非常早期的疾病。虽然我们对慢性淋巴细胞性白血病进展事件的了解已经有了显著的进步，但我们准确预测哪个早期患者将进展到需要治疗的能力仍然很粗糙。MBL-MBL数高的个体有循环中的克隆性B细胞群，B细胞绝对数为5x109/L，没有淋巴增生性疾病的其他特征。流行率研究表明，40岁以上的普通人群中有3%-5%患有MBL，这表明MBL可能是人类最常见的癌前状态之一，先兆状态是疾病本身的200倍。现已知，几乎所有的CLL病例都已存在MBL，每年约有1%的MBL患者进展为有症状的CLL，这为MBL是一种癌前状态提供了证据。患有MBL或早期CLL的个体由于他们采取的未知过程而有显著的焦虑。使用5x109/L的B细胞阈值(低于这个阈值：MBL；高于这个阈值：RAI 0CLL)，任意定义了具有更高计数的MBL和RAI 0CLL的个体之间的区别。鉴于此，我们倾向于将这些患者定义为小CLL患者，如B细胞 克隆人。我们现在准备通过这项提议在我们的能力上取得戏剧性的突破，以便更准确地确定哪些患有类似B细胞克隆的小CLL患者(早期CLL和MBL患者)将进展并需要治疗。这是因为我们最近发现了一种新的预后模型，其c统计量为0.75，这是目前预测CLL进展风险的最准确手段。这一预后指标使用相对简单，因为它结合了CLL过程中常规可用的临床、血清、遗传和分子标志物。在这项建议中，我们的目标是利用关键的遗传和微环境特征进一步增强预后指数的c-统计量，以便我们能够更准确地咨询和预测像B细胞克隆这样的小CLL患者的临床结果。在这项建议中，我们致力于开发一种可靠和准确的方法来确定哪些循环中的小B细胞克隆患者具有临床意义的疾病，并利用这些知识来开发一种增强的诊断、风险分层和临床管理方法。

 DESCRIPTION (provided by applicant): Our proposal addresses the important issue of predicting in a more accurate and patient specific manner the clinical course for early stage CLL and MBL. CLL-Chronic lymphocytic leukemia (CLL) is one of the most common lymphoid malignancies, accounting for ~11% of all hematologic neoplasms. CLL remains an incurable and devastating malignancy. In addition to having a life expectancy that is substantially shorter than that of age-matched individuals in the general population, individuals living with CLL must also deal with an increased risk of infections, second cancers, and autoimmune complications that can have profound consequences for their quality of life. However there is extreme heterogeneity in the clinical course of CLL patients best illustrated by the fact that 70% of all CLL patients will ultimately require therapy. This latter outcome is complicated since most newly diagnosed CLL patients present to their physician with very early stage disease. While there have been remarkable advances in our understanding of progression events in CLL, our ability to accurately predict which early stage patient will progress to need for therapy is still crude. MBL-Individuals with high count MBL have a circulating clonal B-cell population, an absolute B-cell count <5x109/L and no other features of a lymphoproliferative disorder. Prevalence studies suggest that 3-5% of the general population over the age of 40 have MBL indicating that MBL may be one of the most common premalignant conditions in humans and that the precursor state is 200 times more common than the disease itself. It is now known that nearly all cases of CLL had pre-existent MBL and that ~1%/year of individuals with MBL progress to symptomatic CLL, providing evidence that MBL is a premalignant state. Individuals with either MBL or early stage CLL have significant anxiety because of the unknown course they make take. The distinction between individuals with higher count MBL and Rai 0 CLL has been arbitrarily defined using a B-cell threshold of 5 x109/L (below this threshold: MBL; above this threshold: Rai 0 CLL). Given this we prefer to define these individuals as patients with small CLL like B-cell clones. We are now poised via this proposal to make dramatic breakthroughs in our ability to more accurately determine which patients with small CLL like B-cell clones (early stage CLL and MBL individuals) will progress and require therapy. This is because of our recent discovery of a novel prognostic model that has a c-statistic of .75 which is currently the most accurate means of predicting risk for progression in CLL. This prognostic index is relatively simple to use as it incorporates routinely available clinical, serum, genetic and molecular markers of the CLL process. It is our quest in this proposal to further enhance the c-statistic of the prognostic inde using key genetic and microenvironmental features so that we can be even more accurate in our ability to counsel and predict the clinical outcome of individuals with small CLL like B-cell clones. In this proposal we work to develop a reliable and accurate way to determine which individuals with small circulating B-cell clones have a clinically significant medical condition an to use this knowledge to develop an enhanced approach to diagnosis, risk stratification, and clinical management.