Department of Haematology, University Hospital F Mitterrand and Inserm UMR 1231, Dijon, France.
Department of Haematology, Institut P Calmette, Marseille, France.
Lancet Oncol. 2019 Feb;20(2):202-215. doi: 10.1016/S1470-2045(18)30784-8. Epub 2019 Jan 15.
Increased-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) improves progression-free survival in patients with advanced Hodgkin lymphoma compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), but is associated with increased risks of haematological toxicity, secondary myelodysplasia or leukaemia, and infertility. We investigated whether PET monitoring during treatment could allow dose de-escalation by switching regimen (BEACOPP to ABVD) in early responders without loss of disease control compared with standard treatment without PET monitoring.
AHL2011 is a randomised, non-inferiority, phase 3 study done in 90 centres across Belgium and France. Eligible patients were aged 16-60 years and had newly diagnosed Hodgkin lymphoma, excluding nodular lymphocyte predominant subtype, an Eastern Cooperative Oncology Group performance status score less than 3, a life expectancy of at least 3 months, an Ann Arbor disease stage III, IV, or IIB with mediastinum-to-thorax ratio of 0·33 or greater than or extranodal localisation, and had received no previous treatment for Hodgkin lymphoma. Randomisation was unmasked and done centrally by the permuted block method. Patients were randomly assigned to standard treatment (BEACOPP given every 21 days for six cycles) or PET-driven treatment. All patients received two cycles of upfront BEACOPP, after which PET assessment was done (PET2). In the standard treatment group, PET2 patients completed two additional cycles of BEACOPP induction therapy irrespective of PET2 findings. In the PET-driven treatment group, patients with positive PET2 scans received the further two cycles of BEACOPP and those with a negative PET2 scan switched to two cycles of ABVD for the remaining induction therapy. In both treatment groups, PET at the end of induction therapy was used to decide whether to continue with consolidation therapy in those with negative scans or start salvage therapy in patients with positive scans (either two cycles of ABVD in PET2-negative patients in the PET-driven arm or two cycles of BEACOPP). BEACOPP consisted of bleomycin 10 mg/m and vincristine 1·4 mg/m intravenously on day 8, etoposide 200 mg/m intravenously on days 1-3, doxorubicin 35 mg/m and cyclophosphamide 1250 mg/m intravenously on day 1, 100 mg/m oral procarbazine on days 1-7, and 40 mg/m oral prednisone on days 1-14. ABVD was given every 28 days (doxorubicin 25 mg/m, bleomycin 10 mg/m, vinblastine 6 mg/m, and dacarbazine 375 mg/m intravenously on days 1 and 15). The primary endpoint was investigator-assessed progression-free survival. Non-inferiority analyses were done by intention to treat and per protocol. The study had a non-inferiority margin of 10%, to show non-inferiority of PET-guided treatment versus standard care with 80% power and an alpha of 2·5% (one-sided). This study is registered with ClinicalTrials.gov, number NCT01358747.
From May 19, 2011, to April 29, 2014, 823 patients were enrolled-413 in the standard care group and 410 in the PET-driven group. 346 (84%) of 410 patients in the PET-driven treatment group were assigned to receive ABVD and 51 (12%) to continue receiving BEACOPP after PET2. With a median follow-up of 50·4 months (IQR 42·9-59·3), 5-year progression-free survival by intention to treat was 86·2%, 95% CI 81·6-89·8 in the standard treatment group versus 85·7%, 81·4-89·1 in the PET-driven treatment group (hazard ratio [HR] 1·084, 95% CI 0·737-1·596; p=0·65) and per protocol the values were 86·7%, 95% CI 81·9-90·3 and 85·4%, 80·7-89·0, respectively (HR 1·144, 0·758-1·726; p=0·74). The most common grade 3-4 adverse events were leucopenia (381 [92%] in the standard treatment group and 387 [95%] in the PET-driven treatment group), neutropenia (359 [87%] and 366 [90%]), anaemia (286 [69%] vs 114 [28%]), thrombocytopenia (271 [66%] and 163 [40%]), febrile neutropenia (145 [35%] and 93 [23%]), infections (88 [22%] and 47 [11%]), and gastrointestinal disorders (49 [11%] and 48 [11%]). Serious adverse events related to treatment were reported in 192 (47%) patients in the standard treatment group and 114 (28%) in the PET-driven treatment group, including infections (84 [20%] of 412 vs 50 [12%] of 407) and febrile neutropenia (21 [5%] vs 23 [6%]). Six (1%) patients in the standard care group died from treatment-related causes (two from septic shock, two from pneumopathy, one from heart failure, and one from acute myeloblastic leukaemia), as did two (<1%) in the PET-driven treatment group (one from septic shock and one from acute myeloblastic leukaemia).
PET after two cycles of induction BEACOPP chemotherapy safely guided treatment in patients with advanced Hodgkin lymphoma and allowed the use of ABVD in early responders without impairing disease control and reduced toxicities. PET staging allowed accurate monitoring of treatment in this trial and could be considered as a strategy for the routine management of patients with advanced Hodgkin lymphoma.
Programme Hospitalier de Recherche Clinique.
与多柔比星、博来霉素、长春碱和达卡巴嗪（ABVD）相比，增加剂量的博来霉素、依托泊苷、多柔比星、环磷酰胺、长春新碱、丙卡巴肼和泼尼松（BEACOPP）可提高晚期霍奇金淋巴瘤患者的无进展生存期，但与血液学毒性、继发性骨髓增生异常或白血病以及不孕风险增加相关。我们研究了在没有疾病控制损失的情况下，治疗中 PET 监测是否可以通过切换方案（BEACOPP 转为 ABVD）在早期反应者中进行剂量下调，而无需进行无 PET 监测的标准治疗。
AHL2011 是一项在比利时和法国的 90 个中心进行的随机、非劣效性、3 期研究。符合条件的患者年龄为 16-60 岁，患有新诊断的霍奇金淋巴瘤，不包括结节性淋巴细胞为主型，东部肿瘤协作组体能状态评分为 3 分以下，预期寿命至少 3 个月，疾病分期为 III、IV 或 IIB，伴有纵隔与胸廓比为 0.33 或更大或有结外局部病变，且此前未接受过霍奇金淋巴瘤治疗。随机分组采用中心区组随机化方法，且为非盲法。患者被随机分配到标准治疗组（每 21 天接受 6 个周期的 BEACOPP）或 PET 驱动治疗组。所有患者均接受 2 个周期的 upfront BEACOPP，之后进行 PET 评估（PET2）。在标准治疗组中，PET2 患者无论 PET2 结果如何，均完成另外两个周期的 BEACOPP 诱导治疗。在 PET 驱动治疗组中，PET2 扫描阳性的患者接受进一步两个周期的 BEACOPP，而 PET2 扫描阴性的患者则切换为两个周期的 ABVD 用于其余的诱导治疗。在两组中，阴性扫描的患者继续巩固治疗，阳性扫描的患者开始挽救治疗（PET2 阴性患者接受两个周期的 ABVD，PET2 阳性患者接受两个周期的 BEACOPP），均使用诱导治疗结束时的 PET 决定。BEACOPP 由第 8 天静脉注射的博来霉素 10mg/m2和长春新碱 1.4mg/m2、第 1-3 天静脉注射依托泊苷 200mg/m2、第 1 天静脉注射阿霉素 35mg/m2 和环磷酰胺 1250mg/m2、第 1-7 天口服 100mg/m2 的丙卡巴肼和第 1-14 天口服 40mg/m2 的泼尼松组成。ABVD 每 28 天给药一次（第 1 和 15 天静脉注射阿霉素 25mg/m2、博来霉素 10mg/m2、长春新碱 6mg/m2 和达卡巴嗪 375mg/m2）。主要终点是研究者评估的无进展生存期。非劣效性分析采用意向治疗和方案分析。该研究的非劣效性边界为 10%，在 80%的效能和 2.5%的单侧α（2.5%）下，显示 PET 指导治疗与标准护理相比非劣效。这项研究在 ClinicalTrials.gov 注册，编号为 NCT01358747。
2011 年 5 月 19 日至 2014 年 4 月 29 日，共纳入 823 名患者-标准护理组 413 名，PET 驱动治疗组 410 名。在 PET 驱动治疗组的 410 名患者中，有 346 名（84%）被分配接受 ABVD，51 名（12%）继续接受 BEACOPP 治疗。中位随访 50.4 个月（四分位距 42.9-59.3），意向治疗的 5 年无进展生存期为 86.2%，95%CI 81.6-89.8，在标准治疗组与 PET 驱动治疗组分别为 85.7%，95%CI 81.4-89.1（风险比[HR]1.084，95%CI 0.737-1.596；p=0.65），方案分析时分别为 86.7%，95%CI 81.9-90.3 和 85.4%，90.0-89.0（HR 1.144，0.758-1.726；p=0.74）。最常见的 3-4 级不良事件是白细胞减少症（标准治疗组 381 例[92%]，PET 驱动治疗组 387 例[95%]）、中性粒细胞减少症（标准治疗组 359 例[87%]，PET 驱动治疗组 366 例[90%]）、贫血症（标准治疗组 286 例[69%]，PET 驱动治疗组 114 例[28%]）、血小板减少症（标准治疗组 271 例[66%]，PET 驱动治疗组 163 例[40%]）、发热性中性粒细胞减少症（标准治疗组 145 例[35%]，PET 驱动治疗组 93 例[23%]）、感染（标准治疗组 88 例[22%]，PET 驱动治疗组 47 例[11%]）和胃肠道疾病（标准治疗组 49 例[11%]，PET 驱动治疗组 48 例[11%]）。标准治疗组有 192 例（47%）患者和 PET 驱动治疗组有 114 例（28%）患者报告了与治疗相关的严重不良事件，包括感染（标准治疗组 84 例[20%]，PET 驱动治疗组 50 例[12%]）和发热性中性粒细胞减少症（标准治疗组 21 例[5%]，PET 驱动治疗组 23 例[6%]）。标准治疗组有 6 例（1%）患者死于治疗相关原因（2 例死于感染性休克，2 例死于肺炎，1 例死于心力衰竭，1 例死于急性髓系白血病），PET 驱动治疗组有 2 例（<1%）患者死于感染性休克和急性髓系白血病。
在晚期霍奇金淋巴瘤患者中，PET 在两个周期的诱导 BEACOPP 化疗后安全地指导治疗，并允许在早期反应者中使用 ABVD，而不会损害疾病控制和降低毒性。PET 分期使该试验中的治疗得到了准确监测，并可被视为治疗晚期霍奇金淋巴瘤的一种策略。
医院临床研究计划。
