ASCO 2012：苯达莫司汀-利妥昔治疗惰性淋巴瘤更佳

2012-06-04 00:00:00 来源：医脉通阅读：30次

德国根据StiL NHL1研究的最新结果表明，对于惰性及慢性期的淋巴瘤来说，简单的两药联合可以取代更积极的化疗。研究领导者德国Giessen 大学医院的Mathias Rummel博士表示，这个结果足够支撑临床实践的改变，鉴于苯达莫司汀-利妥昔单抗方案可使无进展生存期增加1倍且相关毒性发生率显著降低，应考虑将该方案作为这类患者的首选一线治疗。研究结果在本届的ASCO年会上进行了报告。

R-chop是老年惰性淋巴瘤、套细胞淋巴瘤、巨球蛋白血症及边缘区淋巴瘤患者的标准治疗方案，但对惰性淋巴瘤患者进行如此积极的化疗是否必要一直在争论中。

StiL NHL1是在德国开展的一项大规模随机试验，共纳入514例在社区或医院接受治疗的滤泡性、巨球蛋白血症、边缘区、小淋巴细胞性或套细胞淋巴瘤患者，比较了2种方案的无进展生存期。受试者随机分组，最多接受6个周期的苯达莫司汀(90 mg/m2，第1和第2天)+利妥昔单抗(375 mg/m2，第1天)，或CHOP(环磷酰胺750 mg/m2，第1天；阿霉素50 mg/m2，第1天；长春新碱1.4 mg/m2，第1天；强的松100 mg，第1~5天)+利妥昔单抗(375 mg/m2，第1天)。两组分别纳入261例和253例患者。

此项研究表明，使用苯达莫司汀和利妥昔单抗联合治疗惰性淋巴瘤更有效且毒性更小。

苯达莫司50年前又东德开发，在1989年西德的医生开始使用，Ⅱ期试验中其90%的有效率令人惊讶。在2009年，Ⅲ期试验结果显示两药联合相比于R-CHOP结果更好。虽然两药联合有一定的吸收，但并不普遍。

苯达莫司联合利妥昔组的主要终点无进展生存时间是R-CHOP组的两倍（69.5VS 31.2个月）。统计学差异明显。风险比为0.58。两组的总缓解率接近（92.7％VS 91.3％），但苯达莫司联合利妥昔单抗组的完全缓解率更高（39.8％VS 30.0％）。两组总生存人数差异不明显（43人 VS 45人死亡数），但试验中有交叉情况，37%的R-CHOP组有疾病进展的患者又接受了苯达莫司联合利妥昔的治疗。苯达莫司汀-利妥昔单抗的生存优势存在于几乎所有的组织学亚组，仅有边缘区淋巴瘤例外。

毒性方面，苯达莫司汀-利妥昔单抗组的3/4级血液毒性显著少于CHOP-利妥昔单抗组(P＜0.0001)。发生白细胞减少的治疗周期所占比例，苯达莫司汀-利妥昔单抗组为12%，CHOP-利妥昔单抗组则高达38%。发生中性粒细胞减少的治疗周期所占比例，两组分别为11%和46%。苯达莫司汀-利妥昔单抗组需要使用粒细胞集落刺激因子(G-CSF)的治疗周期所占比例也显著低于CHOP-利妥昔单抗组(4% vs. 20%)。两组的贫血和血小板减少发生率相似，均较低(仅在不到2%的治疗周期中发生)。值得一提的是，苯达莫司联合利妥昔组无一患者脱发，而R-CHOP组几乎所有的患者都发生了脱发。此外，苯达莫司联合利妥昔单抗组出现知觉异常及口腔炎的比例也低于R-CHOP组（18% VS 73%，16% VS 47%）。

不过，苯达莫司汀-利妥昔单抗组中红斑(42/261 vs. 23/253)和过敏反应(40例 vs. 15例)更多见。二者均不是剂量依赖性毒性。感染并发症较常见，两组分别有96例和127例患者受累。

研究者称下一步将开展名为维持的新试验，将在591例患者中评价利妥昔单抗维持治疗的效果。受试者将接受2年利妥昔单抗维持治疗，继而随机分组接受观察或再接受2年利妥昔单抗维持治疗。

目前，苯达莫司应用于治疗对利妥昔单抗耐受的患者，但很多医生将其用于一线及二线治疗，且在患者没有出现利妥昔单抗耐受前就使用了。Rummel博士表示，此结果或有助于临床实践的改变，希望苯达莫司联合利妥昔单抗方案能成为惰性淋巴瘤的首选治疗方法。

研究摘要
Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): Updated results from the StiL NHL1 study.

Background: This multicenter, randomized, phase III study compared B-R and CHOP-R as first-line treatment in indolent lymphoma and MCL and was presented at ASH 2009 including a comprehensive safety analysis. Here we present an updated analysis with a cut-off date for 31 Oct 2011.

Methods: 549 patients (pts) with indolent or MCL were randomized to receive B-R or CHOP-R for a max of 6 cycles. The primary endpoint was PFS.

Results: 514 pts randomized pts were evaluable (261 B-R; 253 CHOP-R). Patient characteristics were well balanced between arms; median age was 64 years. At a median follow-up of 45 months, PFS was significantly prolonged with B-R compared with CHOP-R (HR 0.58, 95% CI 0.44–0.74; P<0.001). Median PFS was 69.5 versus 31.2 months, respectively. The PFS benefit with B-R was maintained in all histological subtypes except marginal zone lymphoma. The PFS benefit with B-R was independent of age; HR 0.52 (P=0.002) in pts ≤60 years (n=199), and HR 0.62 (P=0.002) in pts >60 years (n=315). In pts with normal LDH (62%), PFS was significantly prolonged with B-R compared with CHOP-R (P<0.001), while in the elevated LDH group (38%) PFS was numerically, but not significantly increased with B-R compared with CHOP-R (P=0.118). In patients with follicular lymphoma, FLIPI subgroups defined by 0–2 factors (favorable) and 3–5 factors (unfavorable) had a longer PFS with B-R than with CHOP-R (P=0.043 and P=0.068 for the favorable and unfavorable FLIPI subgroups, respectively). Seventy four salvage treatments had been initiated in the B-R group; compared with 116 in the CHOP-R group, of those in the CHOP-R group 52 pts received B-R as salvage regimen. Overall survival did not differ between the treatment arms, with 43 and 45 deaths in the B-R and CHOP-R arms, respectively. Twenty secondary malignancies were observed in the B-R group compared with 23 in the CHOP-R group, with 1 hematological malignancy in each group (1 MDS in B-R, 1 AML in CHOP-R).

Conclusions: In patients with previously untreated indolent lymphoma, and elderly patients with MCL, B-R demonstrates a PFS benefit and improved tolerability compared with CHOP-R.

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