Blinatumomab 联合化疗治疗婴儿急性淋巴细胞白血病。

Blinatumomab Added to Chemotherapy in Infant Lymphoblastic Leukemia.

机构信息

From the Princess Máxima Center for Pediatric Oncology (I.M.S., P.E.S.-H., R.P.), and the Dutch Childhood Oncology Group (I.M.S., R.P.) - both in Utrecht, the Netherlands; Tettamanti Center (P.L.) and Biostatistics and Clinical Epidemiology (M.G.V.), Fondazione IRCCS San Gerardo dei Tintori, Monza, the School of Medicine and Surgery, University of Milano-Bicocca, Milan (M.G.V.), and the Department of Pediatric Hematology-Oncology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Gesù, Catholic University of the Sacred Heart, Rome (F.L.) - all in Italy; Australian and New Zealand Children's Hematology and Oncology Group, Perth Children's Hospital (R.S.K.), Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia (R.S.K.), and Curtin Medical School, Curtin University (R.S.K.) - all in Perth, WA, Australia; St. Anna Children's Hospital, Department of Pediatric Hematology and Oncology, Medical University of Vienna, and St. Anna Children's Cancer Research Institute - both in Vienna (A.A.); the German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia, Hamburg (G.E.) the Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg (G.E.), and the ALL-Berlin-Frankfurt-Münster (BFM) Group, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel (M.S.) - all in Germany; the Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University Hospital, Copenhagen (K.N.); Czech Working Group for Pediatric Hematology (J.S.) and CLIP (Childhood Leukemia Investigation Prague), Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol (J.S.) - all in Prague, Czech Republic; Hôpital Universitaire des Enfants Reine Fabiola, Brussels (A.F.); and the Department of Pediatric Hematology, University Robert Debre Hospital, Assistance Publique-Hôpitaux de Paris, Paris (B.B.).

出版信息

N Engl J Med. 2023 Apr 27;388(17):1572-1581. doi: 10.1056/NEJMoa2214171.

DOI:10.1056/NEJMoa2214171

PMID:37099340

Abstract

BACKGROUND

-rearranged acute lymphoblastic leukemia (ALL) in infants is an aggressive disease with 3-year event-free survival below 40%. Most relapses occur during treatment, with two thirds occurring within 1 year and 90% within 2 years after diagnosis. Outcomes have not improved in recent decades despite intensification of chemotherapy.

METHODS

We studied the safety and efficacy of blinatumomab, a bispecific T-cell engager molecule targeting CD19, in infants with -rearranged ALL. Thirty patients younger than 1 year of age with newly diagnosed -rearranged ALL were given the chemotherapy used in the Interfant-06 trial with the addition of one postinduction course of blinatumomab (15 μg per square meter of body-surface area per day; 28-day continuous infusion). The primary end point was clinically relevant toxic effects, defined as any toxic effect that was possibly or definitely attributable to blinatumomab and resulted in permanent discontinuation of blinatumomab or death. Minimal residual disease (MRD) was measured by polymerase chain reaction. Data on adverse events were collected. Outcome data were compared with historical control data from the Interfant-06 trial.

RESULTS

The median follow-up was 26.3 months (range, 3.9 to 48.2). All 30 patients received the full course of blinatumomab. No toxic effects meeting the definition of the primary end point occurred. Ten serious adverse events were reported (fever [4 events], infection [4], hypertension [1], and vomiting [1]). The toxic-effects profile was consistent with that reported in older patients. A total of 28 patients (93%) either were MRD-negative (16 patients) or had low levels of MRD (<5×10 [i.e., <5 leukemic cells per 10,000 normal cells], 12 patients) after the blinatumomab infusion. All the patients who continued chemotherapy became MRD-negative during further treatment. Two-year disease-free survival was 81.6% in our study (95% confidence interval [CI], 60.8 to 92.0), as compared with 49.4% (95% CI, 42.5 to 56.0) in the Interfant-06 trial; the corresponding values for overall survival were 93.3% (95% CI, 75.9 to 98.3) and 65.8% (95% CI, 58.9 to 71.8).

CONCLUSIONS

Blinatumomab added to Interfant-06 chemotherapy appeared to be safe and had a high level of efficacy in infants with newly diagnosed -rearranged ALL as compared with historical controls from the Interfant-06 trial. (Funded by the Princess Máxima Center Foundation and others; EudraCT number, 2016-004674-17.).

摘要

背景

重排急性淋巴细胞白血病（ALL）在婴儿中是一种侵袭性疾病，3 年无事件生存率低于 40%。大多数复发发生在治疗期间，三分之二发生在诊断后 1 年内，90%发生在诊断后 2 年内。尽管化疗强化，最近几十年来治疗结果并没有改善。

方法

我们研究了blinatumomab（一种针对 CD19 的双特异性 T 细胞衔接分子）在婴儿 - 重排 ALL 中的安全性和疗效。30 名年龄小于 1 岁的新诊断为 - 重排 ALL 的患者接受了 Interfant-06 试验中使用的化疗，并在诱导后加用blinatumomab（15μg/平方米体表面积/天；28 天连续输注）。主要终点是临床相关的毒性作用，定义为可能或确定归因于blinatumomab的任何毒性作用，并导致blinatumomab永久停药或死亡。微小残留病（MRD）通过聚合酶链反应测量。收集不良事件数据。将结果数据与 Interfant-06 试验中的历史对照数据进行比较。

结果

中位随访时间为 26.3 个月（范围为 3.9 至 48.2）。所有 30 名患者均接受了完整的 blinatumomab 疗程。没有发生符合主要终点定义的毒性作用。报告了 10 例严重不良事件（发热[4 例]、感染[4 例]、高血压[1 例]和呕吐[1 例]）。毒性作用谱与老年患者报告的一致。在 blinatumomab 输注后，共有 28 名患者（93%）或 MRD 阴性（16 名患者）或 MRD 水平低（<5×10[即每 10,000 个正常细胞中 <5 个白血病细胞]，12 名患者）。所有继续化疗的患者在进一步治疗中均转为 MRD 阴性。本研究 2 年无病生存率为 81.6%（95%置信区间[CI]，60.8 至 92.0），而 Interfant-06 试验中为 49.4%（95%CI，42.5 至 56.0）；总生存率相应为 93.3%（95%CI，75.9 至 98.3）和 65.8%（95%CI，58.9 至 71.8）。