Predicting clinical outcome in individuals with small CLL B cell clones

 描述（由申请人提供）：我们的提案解决了以更准确和患者特异性的方式预测早期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，占所有血液肿瘤的约11%。CLL仍然是一种无法治愈的毁灭性恶性肿瘤。除了预期寿命大大短于一般人群中年龄匹配的个体外，CLL患者还必须应对感染，第二种癌症和自身免疫并发症的风险增加，这些并发症可能对他们的生活质量产生深远影响。然而，在CLL患者的临床过程中存在极端异质性，最好的说明是所有CLL患者中的70%最终需要治疗。后一种结果是复杂的，因为大多数新诊断的CLL患者向他们的医生呈现非常早期的疾病。虽然我们对CLL进展事件的理解有了显著的进步，但我们准确预测哪些早期患者将进展到需要治疗的能力仍然很粗糙。MBL-具有高计数MBL的个体具有循环克隆B细胞群，绝对B细胞计数<5x 109/L，并且没有淋巴增生性疾病的其他特征。患病率研究表明，40岁以上的一般人群中有3-5%患有MBL，这表明MBL可能是人类最常见的癌前病变之一，前驱状态比疾病本身常见200倍。现在已知几乎所有CLL病例都有预先存在的MBL，并且每年约1%的MBL个体进展为症状性CLL，这提供了MBL是癌前状态的证据。患有MBL或早期CLL的个体由于他们采取的未知过程而具有显著的焦虑。具有较高计数MBL和Rai 0 CLL的个体之间的区别已经使用5 x109/L的B细胞阈值任意定义（低于该阈值：MBL;高于该阈值：Rai 0 CLL）。鉴于此，我们倾向于将这些个体定义为具有小CLL样B细胞的患者。 克隆我们现在正准备通过这一提议，在我们的能力上取得重大突破，以更准确地确定哪些患有小CLL如B细胞克隆（早期CLL和MBL个体）的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进展风险的最准确方法。该预后指数使用相对简单，因为它结合了CLL过程的常规可用的临床、血清、遗传和分子标记物。我们在这项提案中的目标是使用关键的遗传和微环境特征进一步增强预后指标的c统计量，以便我们能够更准确地咨询和预测具有小CLL样B细胞克隆的个体的临床结果。在这项提案中，我们致力于开发一种可靠和准确的方法来确定哪些具有小循环B细胞克隆的个体具有临床意义的医学状况，并利用这些知识来开发一种增强的诊断方法，风险分层和临床管理。

 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.