Background

The ALLR3 trial investigated outcomes of children with B-cell precursor acute lymphoblastic leukaemia who had late bone marrow relapses. We analysed long-term follow-up outcomes of these patients.

Methods

ALLR3 was an open-label randomised clinical trial that recruited children aged 1–18 years with B-cell precursor acute lymphoblastic leukaemia who had late bone marrow relapses. Eligible patients were recruited from centres in Australia, Ireland, the Netherlands, New Zealand, and the UK. Patients were randomly assigned from Jan 31, 2003, to Dec 31, 2007, and the trial closed to recruitment on Oct 31, 2013. Randomly assigned patients were allocated to receive either idarubicin or mitoxantrone in induction by stratified concealed randomisation; after randomisation stopped in Dec 31, 2007, all patients were allocated to receive mitoxantrone. After three blocks of therapy, patients with high minimal residual disease (≥10⁻⁴ cells) at the end of induction were allocated to undergo allogeneic stem-cell transplantation and those with low minimal residual disease (<10⁻⁴ cells) at the end of induction were allocated to receive chemotherapy. Minimal residual disease level was measured by real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements. The primary endpoint of the original ALLR3 clinical trial was progression-free survival of randomly assigned patients. The primary endpoint of this long-term follow-up analysis was progression-free survival of patients with late bone marrow relapses stratified by minimal residual disease level. Outcomes were correlated with age, site, time to recurrence, and genetic subtypes, and analysed by both intention to treat and actual treatment received. This trial is registered on the ISRCTN registry, number ISRCTN45724312, and on ClinicalTrials.gov, number NCT00967057.

Findings

Between Feb 2, 2003, and Oct 28, 2013, 228 patients with B-cell precursor acute lymphoblastic leukaemia and late bone marrow relapses were treated. After a median follow-up of 84 months (IQR 48–109), progression-free survival of all randomly assigned patients was 60% (95% CI 54–70). 220 patients achieved second complete remission, and minimal residual disease was evaluable in 192 (87%). 110 patients with late bone marrow relapses and high minimal residual disease at the end of induction were allocated to undergo stem-cell transplantation, and 82 patients with low minimal residual disease at the end of induction were allocated to receive chemotherapy. In the patients allocated to undergo stem-cell transplantation, four relapses and three deaths were reported before the procedure, and 11 patients were not transplanted. Of the 92 patients transplanted, 58 (63%) remained in second complete remission, 13 (14%) died of complications, and 21 (23%) relapsed after stem-cell transplantation. In patients allocated to receive chemotherapy, one early treatment-related death was reported and 11 patients were transplanted. Of the 70 patients who continued on chemotherapy, 49 (70%) remained in second complete remission, two (3%) died of complications, and 19 (27%) relapsed. Progression-free survival at 5 years was 56% (95% CI 46–65) in those with high minimal residual disease and 72% (60–81) in patients with low minimal residual disease (p=0·0078). Treatment-related serious adverse events were not analysed in the long-term follow-up.

Interpretation

Patients with B-cell precursor acute lymphoblastic leukaemia with late bone marrow relapses and low minimal residual disease at end of induction had favourable outcomes with chemotherapy without undergoing stem-cell transplantation. Patients with high minimal residual disease benefited from stem-cell transplantation, and targeted therapies might offer further improvements in outcomes for these patients.

Funding

Bloodwise (Formerly Leukaemia and Lymphoma Research) UK, Cancer Research UK, Sporting Chance Cancer Foundation, National Health and Medical Research Council Australia, KindreneKankervrij Netherlands, European Union Seventh Framework Programme, India Alliance Wellcome DBT Margdarshi Fellowship.

中文翻译：

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儿童 B 细胞前体急性淋巴细胞白血病晚期骨髓复发患者的结果：ALLR3 开放标签随机试验的长期随访

背景

ALLR3 试验调查了晚期骨髓复发的 B 细胞前体急性淋巴细胞白血病儿童的结局。我们分析了这些患者的长期随访结果。

方法

ALLR3 是一项开放标签随机临床试验，招募了 1-18 岁患有 B 细胞前体急性淋巴细胞白血病且晚期骨髓复发的儿童。符合条件的患者是从澳大利亚、爱尔兰、荷兰、新西兰和英国的中心招募的。患者从2003年1月31日至2007年12月31日被随机分配，试验于2013年10月31日结束招募。通过分层隐藏随机分组，随机分配的患者被分配接受伊达比星或米托蒽醌诱导治疗；2007 年 12 月 31 日随机分组停止后，所有患者均被分配接受米托蒽醌治疗。经过三组治疗后，诱导结束时微小残留病高（≥10 ^-4细胞）的患者被分配接受同种异体干细胞移植，诱导结束时微小残留病低（<10 ^-4细胞）的患者被分配接受同种异体干细胞移植。诱导期被分配接受化疗。通过免疫球蛋白和 T 细胞受体基因重排的实时定量 PCR 分析来测量微小残留疾病水平。最初 ALLR3 临床试验的主要终点是随机分配患者的无进展生存期。这项长期随访分析的主要终点是按微小残留病水平分层的晚期骨髓复发患者的无进展生存期。结果与年龄、部位、复发时间和遗传亚型相关，并通过治疗意向和实际接受的治疗进行分析。该试验已在 ISRCTN 登记处注册（编号 ISRCTN45724312），并在 ClinicalTrials.gov 上注册（编号 NCT00967057）。

发现

2003年2月2日至2013年10月28日期间，共治疗了228名B细胞前体急性淋巴细胞白血病和晚期骨髓复发患者。中位随访 84 个月 (IQR 48-109) 后，所有随机分配的患者的无进展生存率为 60% (95% CI 54-70)。220 名患者实现第二次完全缓解，192 名患者（87%）的微小残留病可评估。110例晚期骨髓复发且诱导结束时微小残留病高的患者被分配进行干细胞移植，82例诱导结束时微小残留病低的患者被分配接受化疗。在分配接受干细胞移植的患者中，有 4 名患者在手术前出现复发，3 名患者死亡，还有 11 名患者没有接受移植。在92名接受移植的患者中，58名（63%）仍处于第二次完全缓解，13名（14%）死于并发症，21名（23%）在干细胞移植后复发。在分配接受化疗的患者中，有 1 名患者因早期治疗相关死亡，11 名患者接受了移植。在继续接受化疗的 70 名患者中，49 名 (70%) 仍处于第二次完全缓解，两名 (3%) 死于并发症，19 名 (27%) 复发。高微小残留病患者的 5 年无进展生存率为 56% (95% CI 46–65)，低微小残留病患者的 5 年无进展生存率为 72% (60–81) (p=0·0078)。长期随访中未分析与治疗相关的严重不良事件。

解释

患有晚期骨髓复发且诱导结束时微小残留病较低的 B 细胞前体急性淋巴细胞白血病患者在不接受干细胞移植的情况下通过化疗获得了良好的结果。微小残留病高的患者受益于干细胞移植，靶向治疗可能会进一步改善这些患者的预后。

资金

Bloodwise（前身为白血病和淋巴瘤研究）英国、英国癌症研究中心、Sporting Chance 癌症基金会、澳大利亚国家健康和医学研究理事会、荷兰 KindreneKankervrij、欧盟第七框架计划、印度联盟 Wellcome DBT Margdarshi 奖学金。