Michallet Anne-Sophie, Dilhuydy Marie-Sarah, Subtil Fabien, Rouille Valerie, Mahe Beatrice, Laribi Kamel, Villemagne Bruno, Salles Gilles, Tournilhac Olivier, Delmer Alain, Portois Christelle, Pegourie Brigitte, Leblond Veronique, Tomowiak Cecile, de Guibert Sophie, Orsini Frederique, Banos Anne, Carassou Philippe, Cartron Guillaume, Fornecker Luc Mathieu, Ysebaert Loic, Dartigeas Caroline, Truchan Graczyk Malgorzata, Vilque Jean P, Aurran Thérèse, Cymbalista Florence, Lepretre Stéphane, Lévy Vincent, Nguyen-Khac Florence, Le Garff-Tavernier Magali, Aanei Carmen, Ticchioni Michel, Letestu Rémi, Feugier Pierre
Department of Hematology, Centre Léon Bérard, Lyon, France.
Department of Hematology, CHU Bordeaux, Bordeaux, France.
Lancet Haematol. 2019 Sep;6(9):e470-e479. doi: 10.1016/S2352-3026(19)30113-9. Epub 2019 Jul 16.
In patients with chronic lymphocytic leukaemia, achievement of a complete response with minimal residual disease of less than 0·01% (ie, <1 chronic lymphocytic leukaemia cell per 10 000 leukocytes) in bone marrow has been associated with improved progression-free survival. We aimed to explore the activity of induction therapy for 9 months with obinutuzumab and ibrutinib, followed up with a minimal residual disease-driven therapeutic strategy for 6 additional months, in previously untreated patients.
We did a single-arm, phase 2 trial in 27 university hospitals, general hospitals, and specialist cancer centres in France. Eligible patients were at least 18 years old and previously untreated, and had immunophenotypically confirmed B-cell chronic lymphocytic leukaemia; an Eastern Cooperative Oncology Group (ECOG) performance status score of less than 2; a Binet stage C according to IWCLL 2008 criteria or Binet stage A and B with active disease; no 17p deletion or absence of p53 mutation; and were considered medically fit. In the first part of the study (induction phase), all participants received eight intravenous infusions of obinutuzumab 1000 mg over six 4-weekly cycles and oral ibrutinib 420 mg once per day for 9 months. In part 2, after assessment on day 1 of month 9, patients with a complete response and bone marrow minimal residual disease of less than 0·01% received only oral ibrutinib 420 mg once per day for 6 additional months. Patients with a partial response, or with a complete response and bone marrow minimal residual disease of 0·01% or more, received 6 months of four 4-weekly cycles of intravenous fludarabine, cyclophosphamide, and obinutuzumab 1000 mg, alongside continuing ibrutinib 420 mg once per day. The primary endpoint was the proportion of patients achieving a complete response with bone marrow minimal residual disease less than 0·01% on day 1 of month 16 assessed by intention to treat (ITT). This trial is registered with ClinicalTrials.gov (number NCT02666898) and is still open for follow-up.
Between Oct 27, 2015, and May 16, 2017, 135 patients were enrolled. After induction treatment (day 1 of month 9), 130 patients were evaluable, of which ten (8%) achieved a complete response with bone marrow minimal residual disease of less than 0·01% and were assigned to ibrutinib, and 120 (92%) were assigned to ibrutinib plus fludarabine, cyclophosphamide, and obinutuzumab. After minimal residual disease-guided treatment (day 1 of month 16), 84 (62%, 90% CI 55-69) of 135 patients (ITT population) achieved a complete response with bone marrow minimal residual disease of less than 0·01%. The most common haematological adverse event was thrombocytopenia (in 45 [34%] of 133 patients at grade 1-2 in months 1-9 and in 43 [33%] of 130 patients at grade 1-2 in months 9-15). The most common non-haematological adverse events were infusion-related reactions (in 83 [62%] patients at grade 1-2 in months 1-9) and gastrointestinal disorders (in 62 [48%] patients at grades 1 and 2 in months 9-15). 49 serious adverse events occurred, most frequently infections (ten), cardiac events (eight), and haematological events (eight). No treatment-related deaths occurred.
Obinutuzumab and ibrutinib induction therapy followed by a minimal residual disease driven strategy is safe and active in patients with previously untreated chronic lymphocytic leukaemia. With longer follow-up, including assessing the evolution of minimal residual disease, if response is maintained, this strategy could be an option in the first-line setting in patients with chronic lymphocytic leukaemia, although randomised evidence is needed.
Roche, Janssen.
在慢性淋巴细胞白血病患者中，骨髓中获得完全缓解且微小残留病小于0.01%（即每10000个白细胞中慢性淋巴细胞白血病细胞少于1个）与无进展生存期改善相关。我们旨在探讨在既往未接受治疗的患者中，使用奥妥珠单抗和伊布替尼进行9个月诱导治疗，随后采用微小残留病驱动的治疗策略再持续6个月的疗效。
我们在法国的27家大学医院、综合医院和专科癌症中心进行了一项单臂2期试验。符合条件的患者年龄至少18岁且既往未接受治疗，免疫表型确诊为B细胞慢性淋巴细胞白血病；东部肿瘤协作组（ECOG）体能状态评分小于2；根据IWCLL 2008标准为Binet C期，或Binet A期和B期且疾病活跃；无17p缺失或p53突变缺失；且被认为身体状况适合。在研究的第一部分（诱导期），所有参与者在六个每4周一次的周期内接受八次静脉输注1000mg奥妥珠单抗，并口服伊布替尼420mg，每日一次，持续9个月。在第2部分，在第9个月第1天进行评估后，完全缓解且骨髓微小残留病小于0.01%的患者仅口服伊布替尼420mg，每日一次，再持续6个月。部分缓解或完全缓解但骨髓微小残留病为0.01%或更高的患者接受6个月的四个每4周一次的周期的静脉注射氟达拉滨、环磷酰胺和1000mg奥妥珠单抗，同时继续口服伊布替尼420mg，每日一次。主要终点是在意向性治疗（ITT）分析中，第16个月第1天骨髓微小残留病小于0.01%且达到完全缓解的患者比例。该试验已在ClinicalTrials.gov注册（编号NCT02666898），目前仍在开放随访中。
2015年10月27日至2017年5月16日期间，共纳入135例患者。诱导治疗后（第9个月第1天），130例患者可评估，其中10例（8%）达到完全缓解且骨髓微小残留病小于0.01%，被分配接受伊布替尼治疗，120例（92%）被分配接受伊布替尼加氟达拉滨、环磷酰胺和奥妥珠单抗治疗。在微小残留病指导治疗后（第16个月第1天），135例患者（ITT人群）中有84例（62%，90%CI 55 - 69）达到完全缓解且骨髓微小残留病小于0.01%。最常见的血液学不良事件是血小板减少（133例患者中有45例[34%]在第1 - 9个月为1 - 2级，130例患者中有43例[33%]在第9 - 15个月为1 - 2级）。最常见的非血液学不良事件是输液相关反应（83例患者中有62例[62%]在第1 - 9个月为1 - 2级）和胃肠道疾病（62例患者中有48例[48%]在第9 - 15个月为1、2级）。发生了49例严重不良事件，最常见的是感染（10例）、心脏事件（8例）和血液学事件（8例）。未发生与治疗相关的死亡。
奥妥珠单抗和伊布替尼诱导治疗后采用微小残留病驱动的策略在既往未接受治疗的慢性淋巴细胞白血病患者中是安全且有效的。随着更长时间的随访，包括评估微小残留病的演变情况，如果缓解得以维持，该策略可能成为慢性淋巴细胞白血病患者一线治疗的一个选择，尽管还需要随机对照证据。
罗氏公司、杨森公司。
