A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial
A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial
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DOI：
10.1016/s0140-6736(07)61126-x
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发表时间：
2007-07-21
期刊：
影响因子：
168.9
通讯作者：
Valsecchi, Maria Grazia
中科院分区：
文献类型：
--
作者：
Pieters, Rob;Schrappe, Martin;Valsecchi, Maria Grazia
背景 1 岁以下婴儿患急性淋巴细胞白血病的情况很少见，患有该病的婴儿的预后比年龄较大的儿童更差。我们发起了一项国际研究，旨在调查一种新的混合治疗方案的效果，该方案包含旨在治疗急性淋巴细胞白血病和急性髓性白血病的元素，并确定婴儿结局的任何预后因素。我们还进行了一项随机试验，以确定后期强化疗程的价值。方法 1999 年至 2005 年间，22 个国家的 17 个研究组招募了 0-12 个月大的患者。根据外周血对 7 天泼尼松前期的反应对符合条件的患者进行风险分层，然后给予基于急性淋巴细胞白血病标准方案的混合方案，其中包括一些专为治疗急性髓细胞性白血病而设计的元素白血病。在维持阶段之前，完全缓解的患者子集被随机分配接受标准治疗或采用高剂量阿糖胞苷和甲氨蝶呤的更强化化疗疗程。主要结局是初始患者队列的无事件生存期（EFS）和随机分配到治疗组的患者的无病生存期（DFS）。数据是在意向治疗的基础上进行分析的。该试验在 ClinicalTrials.gov 上注册，编号为 NCT 00015873，并在对照试验.com 上注册，编号为 ISRCTN24251487。 结果 在 482 名接受混合治疗的入组患者中，260 名患者 (58%) 在中位随访 38 个月（范围 1-78）个月时完全缓解，4 年时的 EFS 为 47.0%（SE 2.6， 95% CI 41.9-52.1）。在 5 周诱导治疗后完全缓解的 445 名患者中，191 名患者被随机分组：95 名患者接受后期强化疗程，96 名患者接受对照组。中位随访时间为 42 个月（范围 1-73），治疗组中有 60 名患者和对照组有 57 名患者没有疾病。两组之间 4 年 DFS 没有差异（治疗组为 60.9% [SE 5.2]，对照组为 57.0% [5.5]；p=0.81）。在强化阶段，71 名随机分配到治疗组且可获得毒性数据的患者中，35 名（49%）名患者出现感染，21 名（30%）名患者出现粘膜炎，22 名（31%）名患者出现肝脏毒性作用，2 名（3%）名患者出现神经毒性。 （混合谱系白血病）MLL 基因中的所有类型的重排、非常高的白细胞计数、年龄小于 6 个月以及对泼尼松前期反应不佳均与较差的结局独立相关。 解释 采用我们的混合方案治疗的患者，尤其是对泼尼松反应不佳的患者，其 EFS 高于大多数报道的婴儿 ALL 治疗结局。延迟强化化疗对患者没有好处。
Background Acute lymphoblastic leukaemia in infants younger than 1 year is rare, and infants with the disease have worse outcomes than do older children. We initiated an international study to investigate the effects of a new hybrid treatment protocol with elements designed to treat both acute lymphoblastic: leukaemia and acute myeloid leukaemia, and to identify any prognostic factors for outcome in infants. We also did a randomised trial to establish the value of a late intensification course.Methods Patients aged 0-12 months were enrolled by 17 study groups in 22 countries between 1999 and 2005. Eligible patients were stratified for risk according to their peripheral blood response to a 7-day prednisone prophase, and then given a hybrid regimen based on the standard protocol for acute lymphoblastic leukaemia, with some elements designed for treatment of acute myeloid leukaemia. Before the maintenance phase, a subset of patients in complete remission were randomly assigned to receive either standard treatment or a more intensive chemotherapy course with high-dose cytarabine and methotrexate. The primary outcomes were event-free survival (EFS) for the initial cohort of patients and disease-free survival (DFS) for the patients randomly assigned to a treatment group. Data were analysed on an intention-to-treat basis. This trial was registered with ClinicalTrials.gov, number NCT 00015873, and at controlled-trials.com, number ISRCTN24251487.Findings In the 482 enrolled patients who underwent hybrid treatment, 260 (58%) were in complete remission at a median follow-up of 38 (range 1-78) months, and EFS at 4 years was 47.0% (SE 2.6, 95% CI 41.9-52.1). Of 445 patients in complete remission after 5 weeks of induction treatment, 191 were randomised: 95 patients to receive a late intensification course, and 96 to a control group. At a median follow-up of 42 (range 1-73) months, 60 patients in the treatment group and 57 controls were disease-free. DFS at 4 years did not differ between the two groups (60.9% [SE 5.2] for treatment group vs 57.0% [5.5] for controls; p=0.81). During the intensification phase, of 71 patients randomly assigned to the treatment group, and for whom toxicity data were available, 35 (49%) had infections, 21 (30%) patients had mucositis, 22 (31%) patients had toxic effects on the liver, and 2 (3%) had neurotoxicity. All types of rearrangements in the (mixed lineage leukaemia) MLL gene, very high white blood cell count, age of younger than 6 months, and a poor response to the prednisone prophase were independently associated with inferior outcomes.Interpretation Patients treated with our hybrid protocol, and especially those who responded poorly to prednisone, had higher EFS than most reported outcomes for treatment of infant ALL. Delayed intensification of chemotherapy did not benefit patients.