40% of Females with Mantle Cell Lymphoma Are Managed with Initial Observation: Results from the MCL Biobank Observational Study
40% of Females with Mantle Cell Lymphoma Are Managed with Initial Observation: Results from the MCL Biobank Observational Study
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40%%20of%20女性%20with%20Mantle%20Cell%20淋巴瘤%20Are%20管理%20with%20初始%20观察：%20结果%20来自%20the%20MCL%20Biobank%20观察性%20研究
DOI：
10.1182/blood-2019-128340
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发表时间：
2019
期刊：
影响因子：
20.3
通讯作者：
S. Rule
中科院分区：
文献类型：
--
作者：
R. McCulloch;Alexandra G. Smith;Brian Wainman;W. Ingram;A. Lewis;M. Hawkins;N. Crosbie;A. Pettitt;S. Rule
背景资料：
虽然通常是一种侵袭性疾病，但一些套细胞淋巴瘤（MCL）患者会进行无痛治疗，可能无法从立即治疗中获益。几项评估MCL中观察和等待（W&W）策略的研究显示对患者生存没有损害，国际指南承认该策略适用于少数患者。致病机制的差异提供了对可变临床行为的深入了解，但很少有临床证据表明患者适合W&W。
MCL生物样本库观察性研究是一项前瞻性研究，旨在区分惰性和侵袭性MCL。在入组时收集组织样品和基线特征。该研究在英国招募了550多名患者，并继续开放招募。
方法：
该分析包括2015年1月至2018年3月期间入组的来自英国58家中心的315例患者。符合WHO诊断标准的所有新MCL诊断均合格。患者在诊断后90天内和接受治疗前入组。记录基线数据，包括研究者决定开始全身治疗或进入W&W。每6个月提供一次临床更新，并对患者进行至少12个月的随访。使用标准统计方法来检查哪些因素与初始疾病管理相关，哪些因素与长期使用W&W相关。测量从诊断日期至首次治疗日期的至治疗时间，未开始治疗的患者在末次随访日期删失。
结果如下：
所有患者的中位年龄为71岁（范围32-92岁），68.9%为男性，53.5%为MIPI高风险，中位随访时间为26个月。在基线时，67.3%的患者接受了前期全身治疗，4.1%接受了局部放疗，1.0%得到了缓解，27.6%在诊断后90天接受了W&W治疗。估计整个人群的2年OS为77.5%。
初始W&W治疗的患者往往比早期治疗的患者年龄大（中位数73岁对71岁），具有相似的体能评分（ECOG>1或1.16，p=0.68），WBC无显著差异（WBC>15或0.55，p=0.07）。尽管两组之间的高风险MIPI同样普遍（OR 1.3，p=0.31），但值得注意的是，观察组中没有75岁以下的患者具有高风险。CT上可测量的疾病的存在在两组之间进行区分（OR 0.23，p=<0.001），但是71%的W&W具有可测量的疾病，这表明大多数不是白血病亚型。W&W患者中细胞更新率较高、LDH升高和Ki 67 ≥ 30%的标志物明显较少见（OR 0.32，p=<0.001; OR 0.3，p=0.001）。40%的女性服用W&W，而男性为22%（OR 2.6，p=<0.001）。
在接受W&W随访的87例患者中，73.5%的患者在1年时仍在观察，50.6%的患者在2年时仍在观察，中位随访时间为2.4年。单变量分析显示，预测长期观察期的基线特征很少，部分与患者数量较少有关，但关键观察结果见图1。Ki 67 ≥30%的患者不太可能继续观察（HR 2.39，p=0.03），80岁以上的患者也是如此（HR 3.67，p=0.007），MIPI高风险患者与低风险患者相比（3.56，p=0.02）。
结论：
这项研究表明W&W在英国临床实践中的高患病率，它为临床医生提供了保证，其中一半保持观察超过2 yrs. LDH水平和Ki 67状态反映了疾病的生物学性质，因此，较低的水平预测更惰性的过程并不意外。然而，25%的患者在2年后观察到Ki 67 ≥30，仅这些指标不足以决定治疗。观察到老年患者的趋势可能反映了合并症患者的临床方法侵略性较低，而不是潜在的生物学。这解释了老年患者观察期缩短的趋势。W&W中女性患者的高患病率是一个引人注目的观察结果，暗示了需要进一步研究的性别之间的病理生理差异。
尽管该研究强调临床医生越来越容易在MCL中采用W&W，但它也表明需要更好的惰性疾病预测标志物。本研究旨在通过分析收集的组织样本来实现这一目标。
克劳斯比：詹森：酬金。规则：Sunesis：咨询，酬金; TG治疗：咨询、酬金;纳普：咨询服务;风筝：咨询服务;吉利德：咨询，酬金;药物周期：咨询，酬金; Celgene：咨询、酬金;阿斯利康：咨询、酬金;罗氏：咨询，酬金，研究资金;杨森：咨询，酬金，研究资金。
Background:
Although typically an aggressive disease some patients with Mantle Cell Lymphoma (MCL) follow an indolent course and may not benefit from immediate therapy. Several studies evaluating watch-and-wait (W&W) strategies in MCL show no detriment to patient survival and international guidelines acknowledge the strategy's suitability for a minority of patients. Differences in pathogenetic mechanisms have provided insight into variable clinical behaviour, but there is little clinical evidence to inform patient suitability for W&W.
The MCL Biobank Observational Study is a prospective study designed to distinguish indolent from aggressive forms of MCL. Tissue samples and baseline characteristics are collected at enrolment. The study has recruited over 550 patients across the UK and remains open to recruitment.
Method:
This analysis includes 315 patients from 58 centers in the United Kingdom enrolled between January 2015 and March 2018. All new MCL diagnoses compatible with WHO diagnostic criteria were eligible. Patients were enrolled within 90 days of diagnosis and prior to receiving therapy. Baseline data was recorded including investigator decision to start systemic therapy or enter W&W. Clinical updates were provided at 6 month intervals and patients were followed-up for a minimum of 12 months. Standard statistical methods were used to examine which factors were associated with initial disease management and those remaining on W&W long-term. Time to treatment was measured from date of diagnosis until date of first treatment, patients who had not commenced treatment were censored at the last date of follow-up.
Results:
Median age of all patients was 71 (range 32-92), 68.9% were male, 53.5% were MIPI high risk and median follow up 26 months. At baseline 67.3% of patients received upfront systemic therapy, 4.1% received localized radiotherapy, 1.0% were palliated and 27.6% were on W&W 90 days beyond diagnosis. Estimated 2-year OS of the whole population was 77.5%.
Patients on initial W&W tended to be older than those treated early (median 73 yrs vs. 71 yrs), had similar performance score (ECOG>1 OR 1.16, p=0.68) and no significant difference in WBC (WBC>15 OR 0.55, p=0.07). Although high risk MIPI was equally prevalent between the groups (OR 1.3, p=0.31) it was notable that no patient under 75 years was high risk in the observation group. Presence of measurable disease on CT discriminated between the two groups (OR 0.23, p=<0.001), but 71% of W&W had measurable disease indicating most were not the leukemic subtype. Markers of higher cell turnover, raised LDH and Ki67≥30%, were significantly less common in W&W patients (OR 0.32, p=<0.001; OR 0.3, p=0.001). 40% of women were put on W&W compared to 22% of men (OR 2.6, p=<0.001).
Of 87 patients followed on W&W 73.5% remained on observation at 1 year and 50.6% at 2 years, with median follow up 2.4 years. Univariate analysis revealed few baseline characteristics to be predictive for prolonged period of observation, in part relating to the low patient numbers, but key observations are displayed in figure 1. Patients with Ki67≥30% were less likely to remain on observation (HR 2.39, p=0.03), as were patients over 80 years old (HR 3.67, p=0.007), and those MIPI high risk compared to low risk (3.56, p=0.02).
Conclusion:
This study demonstrates the high prevalence of W&W in UK clinical practice and it provides reassurance to clinicians that half remain on observation beyond 2 yrs. LDH level and Ki67 status reflect the biological nature of disease and it is therefore not unexpected that lower levels predict for a more indolent course. However, with Ki67≥30 in 25% of patients observed beyond 2 years these measures alone are not sufficient to decide treatment. The tendency for older patients to be observed likely reflects a less aggressive clinical approach in patients with co-morbidities, and not the underlying biology. This explains the tendency for shortened observation period in older patients. The high prevalence of female patients in W&W is a striking observation that alludes to pathophysiological differences between the sexes that warrants further investigation.
Although the study highlights clinicians are increasingly at ease adopting W&W in MCL, it also demonstrates the need for better predictive markers of indolent disease. This study aims to achieve this with analysis of the collected tissue samples.
Crosbie: Janssen: Honoraria. Rule:Sunesis: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Napp: Consultancy; Kite: Consultancy; Gilead: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.