评估单用根除幽门螺杆菌的抗生素治疗I-II1期弥漫大B细胞淋巴瘤的疗效：多中心II期临床试验(HGL-1 Trial)最终结果报道

2011 ash    摘要号：958

中国肿瘤化疗  发布日期：2012-2-16

背景：胃粘膜相关边缘区b细胞淋巴瘤（malt）的发病机制与感染幽门螺杆菌(hp)有关。根除hp的抗生素治疗能获得60-80%的完全缓解率，是该病的标准治疗。35%的胃弥漫大b细胞淋巴瘤(dlbcl)也可检测到hp，而同时伴有malt区域病变者的hp检出率较单纯的dlbcl者高（65% vs. 15%）。然而，根除hp抗生素治疗在胃dlbcl中的作用仍然有待研究，目前只有少量单中心的回顾性研究结果。因此，我们在西方国家中进行了首项评估单用根除hp的抗生素治疗i-ii1期胃dlbcl的疗效的ii期多中心临床试验，并在此报道最终结果。武汉协和医院肿瘤中心刘红利

目的：评估单用根除hp的抗生素治疗i-ii1期胃dlbcl的可行性、活性和疗效。

方法：入组标准包括：病理确诊dlbcl，伴或不伴有malt区域病变；多次胃镜活检或呼气实验证实hp感染；musshoff分期为i-ii1期；胃周淋巴结直径<1.5 厘米；乳酸脱氢酶正常；大于18岁；ecog体力状态小于3分，无hiv感染，无既往肿瘤史；无出血病灶(血红蛋白>9 g/dl)；入组患者接受连续7天的抗hp口服治疗（克拉霉素500 mg bid，替硝唑500 mg bid，奥美拉唑20 mg bid）。服药30天和60天后，通过超声胃镜镜检，活检和呼气实验评估hp根除情况和肿瘤的客观缓解情况。hp未根除的患者将根据当地的指南接受二线的hp抗生素治疗。hp已根除的患者中，肿瘤完全缓解（cr）者进入随访；部分缓解（pr）者接受单药利妥昔单抗补充治疗；疾病稳定（sd）或疾病进展（pd）的患者接受传统化疗(r-chop ± 放疗)

结果：从2003 年到 2010年共入组16例患者（中位年龄70岁，范围：38-87岁；11例为男性患者）。11例患者为单纯dlbcl，5例患者同时伴有malt区域病变。10例患者分期为ii1期，5例为ie期。5例患者有贫血；2例患者伴有hcv感染。所有患者均无全身症状。
所有患者对根除hp的抗生素治疗耐受性良好。15例患者于30天后证实了hp已经根除，1例患者通过二线抗生素治疗根除hp。8例（50%）患者的肿瘤完全缓解，3例患者部分缓解，(客观有效率orr=69%; 95%可信区间：47%-91%)。pr的患者中，2例经单药利妥昔单抗治疗后达到cr。总的cr率达到63% (95% 可信区间：39%-87%)。客观疗效与分期和是否伴随malt区域病变无关。
中位随访53月，10例cr患者中有9例仍为无病状态，1例在10个月时复发，中位无病生存时间（dfs）大于68月。7例治疗失败的患者包括：5例经hp抗生素治疗后sd或pd的患者，1例未接受利妥昔单抗补充治疗的pr患者，还有1例复发患者。所有治疗失败患者均接受了传统化疗并获得完全缓解，而且在13-128个月后均未复发（中位随访时间大于41月）。无患者因肿瘤死亡；2例患者分别死于心衰和胆囊癌；剩余14例患者均存活（13例无病生存），5年生存率达94%。

结论：i-ii1期胃弥漫大b细胞淋巴瘤患者接受单用根除幽门螺杆菌的抗生素治疗的安全性良好，无需化疗半数患者即可获得长期缓解，值得注意的是，其中大于三分之二的患者年龄大于65岁。并且，抗生素治疗无效的患者经传统挽救治疗可获得缓解。将会对入组的hp感染相关的胃dlbcl病例进行病理学和分子水平的进一步研究，以识别出适合抗生素治疗的最佳人群。

958 final results of a multicenter phase ii trial assessing the activity and efficacy of helicobacter pylori-eradicating antibiotic therapy as exclusive treatment for patients with stage i-ii1 diffuse large b-cell lymphoma of the stomach (the hgl-1 trial)

background:  helicobacter pylori (hp) infection is associated with the pathogenesis of marginal zone b-cell lymphoma of mucosa-associated lymphoid tissue (malt)-type of the stomach, and hp-eradicating antibiotic therapy is the standard treatment for this lymphoma, with complete remission rates of 60-80%.hp is also detected in 35% of diffuse large b-cell lymphomas (dlbcl) of the stomach, being more common in cases with concomitant malt areas with respect to de novo cases (65% vs. 15%). however, the role of hp-eradicating antibiotic therapy in gastric dlbcl remains to be elucidated, since only rare and small, monoinstitutional retrospective studies are available. herein, we report the final results of a multicentre phase ii trial, the first one in western countries, addressing the role of hp-eradicating therapy as exclusive treatment in patients with gastric dlbcl.

aims: to assess feasibility, activity and efficacy of hp-eradicating therapy as exclusive treatment for limited-stage dlbcl of the stomach.

methods: inclusion criteria were histopathologic diagnosis of dlbcl, with or without concomitant malt-type areas; hp-infection assessed by multiple gastric biopsies and/or breath test; stage i-ii1 of disease according to musshoff staging system; perigastric lymph nodes diameter <1.5 cm; normal lactate dehydrogenase (ldh) serum level; age ≥18 years old; ecog-performance status <3; absence of hiv-infection or history of previous cancer; absence of bleeding lesions (hemoglobin >9 g/dl). registered patients received clarithromycin 500 mg bid, tinidazole 500 mg bid and omeprazole 20 mg bid, orally, for 7 consecutive days. objective response and bacterial eradication were assessed at 30 and 60 days from antibiotics by gastric endoscopy-ultrasonography, biopsies and breath test. patients who did not achieve hp eradication received a second-line antibiotic therapy according to local guidelines. eradicated patients who achieved complete lymphoma remission (cr) were referred to follow-up; patients with partial response (pr) received rituximab as complementary therapy; patients with stable (sd) or progressive (pd) disease received conventional treatment (r-chop ± radiotherapy).

results: from 2003 to 2010, 16 patients (median age 70; range 38-87; 11 males) were enrolled. eleven patients had de novo dlbcl, while 5 patients presented concomitant malt areas. ten patients had stage ii1 disease, 5 had stage ie. five patients presented anemia; two patients had concomitant hcv infection. none presented systemic symptoms.
eradicating therapy was completed in all patients with excellent tolerability. eradication was documented at one month in 15 patients and after second-line antibiotic-therapy in the remainder patient. lymphoma regression was complete in 8 (50%) patients and partial in 3 (orr= 69%; 95% ci= 47%-91%). two of the three prs achieved cr after rituximab, with a crr after experimental therapy of 63% (95% ci= 39%-87%). objective response was not associated with stage or concomitant malt areas.  
at a median follow-up of 53 months, 9 of the 10 patients who achieved cr after experimental therapy remain relapse-free, the remainder experienced relapse at 10 months, with a median dfs of 68+ months. treatment failure was observed in 7 patients: 5 patients with sd/pd after antibiotics, one patient in pr who did not receive rituximab and the single patient with relapsing disease; they were referred to conventional chemoradiation treatment, achieving cr in all cases, and none of them experienced relapse after 13-128 months (median 41+).
no patient died of lymphoma; two patients died of cardiac failure and gallbladder cancer, respectively; the remaining 14 patients are alive (13 disease-free), with a 5-yr os of 94%.

conclusions: patients with stage i-ii1 hp-associated dlbcl of the stomach can be safely managed with antibiotics alone. half of treated patients will achieve long-term remission without chemotherapy, a critical issue considering that two-thirds of patients are >65 years old. importantly, unresponsive patients can be safely salvaged with conventional treatment. registered cases of hp-associated dlbcl of the stomach will be characterized under pathologic and molecular perspectives to identify parameters useful to distinguish the best candidates for eradicating therapy.