初诊经典型霍奇金淋巴瘤患者的治疗前血清细胞因子水平可预测早期复发和较差预后

中国肿瘤化疗  发布日期：2012-2-2武汉协和医院肿瘤中心刘红利

背景: 尽管标准的临床预后因素,如国际预后指数(IPS),可预测经典型霍奇金淋巴瘤(cHL)患者的预后,利用生物学技术还可能进一步提高预测的准确性。因此,我们对可反映肿瘤的生物学活性及宿主反应的治疗前血清细胞因子水平进行检测，探究其是否可为cHL患者的预后提供更多的信息.

方法: 入组病例为参加了爱荷华大学与梅奥医学院的SPORE 分子流行病学(MER)前瞻性研究的初诊cHL患者。采用ELISA芯片(Invitrogen, Camarillo, CA)检测患者的治疗前血清细胞因子水平。通过Luminex-100 系统 (Version 1.7 ，Luminex, Austin, TX) 分析30种细胞因子，其中包括了Th1和Th2相关因子的促炎因子。采用MasterPlex QT 1.0 系统 (MiraiBio, Alameda, CA)进行数据分析。同时也对参加了一项探究淋巴瘤病因的病例对照研究中的50例非淋巴瘤患者的血清进行了以上分析。每种细胞因子水平的正常上限值根据正常对照人群值的95%水平来界定。临床数据根据标准规范摘录。对所有患者的无事件（肿瘤进展、再治疗或任何原因导致的死亡）生存和总生存（即EFS和OS）进行系统随访。采用COX比例风险模型评估细胞因子与预后的关系。

结果：入组共140例于2002.9至2008.2确诊的可获得治疗前血清的经典型霍奇金淋巴瘤患者。患者的中位年龄为40岁（年龄范围为18-89），53%为男性。77例（55%）患者为局限期，63例（45%）患者为晚期。121例(86%)患者接受ABVD方案化疗，其余患者则接受Stanford ?(9%), BEACOPP 方案(4%) ， MOPP 方案 (2%)化疗。中位随访47个月（范围0-87），25例(18%)患者复发，16例（11%）患者死亡。与正常对照相比，cHL患者的12种血清细胞因子（EGF，FGFb，GCSF，HGF，IL-6，IL-8，IL-12, IL-2R, IP-10, MIG, TNFa 和 VEGF) 水平显著增高。与临床因素进行相关分析，结果IL-2R, IP-10, MIG, IL-6 和 HGF水平与血沉增高，B症状，分期晚以及脾侵犯有关；IL-8水平增高与巨块病变的发生有关。HGF, IL-6, IL-8, IL-2R, IP-10 和MIG水平增高均与较差的EFS有关，但是仅有IL-2R (p=0.002)和IL-6 (p<0.001)为EFS和OS的独立预后因素。另外，在根据IL-6 和IL-2R水平建立的2-细胞因子模型里，两种细胞因子均增高的患者比细胞因子正常，或者仅一种细胞因子增高的患者更易出现早期复发和死亡（1年EFS为40% vs 97%和93%，p<0.0001; 2年OS为 49% vs 98% 和 95%, p<0.0001)。当仅分析预后好的IPS低危(IPS 0-3)患者时候，此2-细胞因子模型仍可预测患者的早期复发（1年EFS为54% vs 95%和97%，p<0.0001)。

结论：cHL患者治疗前血清细胞因子的升高与复发机率增加及生存期缩短有关。治疗前血清细胞因子，尤其是IL-6和IL-2R的血清水平，可识别出早期复发病例。对这类患者采用新的治疗手段可能有获益。

429 Pretreatment Serum Cytokines Predict Early Disease Relapse and A Poor Prognosis In Newly Diagnosed Classical Hodgkin Lymphoma (cHL) Patients

Program: Oral and Poster Abstracts
Type: Oral
Session: 621. Hodgkin Lymphoma - Biology, excluding Therapy

BACKGROUND: While standard clinical prognostic factors such as those included in the International Prognostic Score (IPS) predict outcome in cHL patients, predicting the outcome of patients might be further refined using biological factors. We therefore tested whether pretreatment serum cytokines, that measure the biological activity of the tumor as well as the host response, could provide additional prognostic information in cHL patients.

METHODS: Newly diagnosed cHL patients were prospectively enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER).  Serum cytokines were measured from pretreatment blood draws using a multiplex ELISA (Invitrogen, Camarillo, CA). Thirty cytokines, including pro-inflammatory, Th1 and Th2 associated cytokines, were analyzed using the Luminex-100 system Version 1.7 (Luminex, Austin, TX). Data analysis was performed using the MasterPlex QT 1.0 system (MiraiBio, Alameda, CA). The assay was also performed on research serum draws from 50 non-lymphoma epidemiology controls enrolled on a corresponding lymphoma etiology case-control study.  The upper limit of normal for each cytokine was defined as the 95th percentile from the control distribution.  Clinical data were abstracted using a standard protocol and all patients were followed systematically for event-free (progression, retreatment, or death due to any cause) and overall survival (EFS and OS, respectively).  Cox proportional hazards models were used to evaluate the association between cytokines and outcome.  

RESULTS:   140 HL patients with cHL diagnosed between September 2002 and February 2008 with available pretreatment serum were included.  The median age was 40 years (range 18-89) and 53% were male.  Seventy-seven patients (55%) had limited stage disease and 63 (45%) had advanced disease. One hundred and twenty one patients (86%) were treated with ABVD chemotherapy, while the remainder received the Stanford V regimen (9%), BEACOPP (4%) or MOPP chemotherapy (2%). At a median follow-up of 47 months (range 0-87), 25 patients (18%) had an event and 16 patients had died (11%). The serum levels of 12 cytokines (EGF, FGFb, GCSF, HGF, IL-6, IL-8, IL-12, IL-2R, IP-10, MIG, TNFa and VEGF) were significantly higher in cHL patients than controls. When correlated with clinical factors, IL-2R, IP-10, MIG, IL-6 and HGF were associated with an increased sedimentation rate, B-symptoms, advanced stage and splenic involvement. Elevated IL-8 levels were associated with bulky disease. Elevated levels of HGF, IL-6, IL-8, IL-2R, IP-10 and MIG were all associated with a poorer EFS, however only IL-2R (p=0.002) and IL-6 (p<0.001) were independently prognostic for both EFS and OS. Furthermore, using IL-6 and IL-2R in a 2-cytokine model (see Figure), patients with elevation of both cytokines had a dramatically greater likelihood of early relapse and death than those with normal levels or elevations of only one of the cytokines (1-year EFS 40% compared to 97% and 93% respectively, p<0.0001; 2-year OS 49% compared to 98% and 95%, p<0.0001). While elevated IL-6 and IL-2R levels correlated with the IPS (p=0.002), this 2-cytokine model remained independently predictive of prognosis. In fact, when only good risk patients (IPS 0-3) were considered, the 2-cytokine model remained predictive of patients at risk for early relapse (1-year EFS 54% versus 95% and 97%, p<0.0001).

CONCLUSION: Elevated pretreatment serum cytokines are associated with an increased likelihood of disease relapse and an inferior survival in patients with cHL. The pretreatment cytokine profile, particularly serum levels of IL-6 and IL-2R, may identify cHL patients at high risk for early disease relapse who may benefit from novel therapeutic approaches.