达沙替尼联合博纳吐单抗治疗成人费城染色体阳性急性淋巴细胞白血病。

Dasatinib-Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults.

机构信息

From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.

出版信息

N Engl J Med. 2020 Oct 22;383(17):1613-1623. doi: 10.1056/NEJMoa2016272.

DOI:10.1056/NEJMoa2016272

PMID:33085860

Abstract

BACKGROUND

Outcomes in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have improved with the use of tyrosine kinase inhibitors. Molecular remission is a primary goal of treatment.

METHODS

We conducted a phase 2 single-group trial of first-line therapy in adults with newly diagnosed Ph-positive ALL (with no upper age limit). Dasatinib plus glucocorticoids were administered, followed by two cycles of blinatumomab. The primary end point was a sustained molecular response in the bone marrow after this treatment.

RESULTS

Of the 63 patients (median age, 54 years; range, 24 to 82) who were enrolled, a complete remission was observed in 98%. At the end of dasatinib induction therapy (day 85), 29% of the patients had a molecular response, and this percentage increased to 60% after two cycles of blinatumomab; the percentage of patients with a molecular response increased further after additional blinatumomab cycles. At a median follow-up of 18 months, overall survival was 95% and disease-free survival was 88%; disease-free survival was lower among patients who had an deletion plus additional genetic aberrations ( or , , or both [i.e., ]). mutations were detected in 6 patients who had increased minimal residual disease during induction therapy, and all these mutations were cleared by blinatumomab. Six relapses occurred. Overall, 21 adverse events of grade 3 or higher were recorded. A total of 24 patients received a stem-cell allograft, and 1 death was related to transplantation (4%).

CONCLUSIONS

A chemotherapy-free induction and consolidation first-line treatment with dasatinib and blinatumomab that was based on a targeted and immunotherapeutic strategy was associated with high incidences of molecular response and survival and few toxic effects of grade 3 or higher in adults with Ph-positive ALL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others; GIMEMA LAL2116 D-ALBA EudraCT number, 2016-001083-11; ClinicalTrials.gov number, NCT02744768.).

摘要

背景

由于酪氨酸激酶抑制剂的应用，费城染色体（Ph）阳性急性淋巴细胞白血病（ALL）患者的预后得到改善。分子缓解是治疗的主要目标。

方法

我们开展了一项 2 期、单组临床试验，纳入了新诊断的 Ph 阳性 ALL 成人患者（无年龄上限），一线治疗采用达沙替尼联合糖皮质激素，随后给予两周期的blinatumomab。主要终点是该治疗后骨髓中持续的分子缓解。

结果

在入组的 63 例患者（中位年龄 54 岁；范围 24 至 82 岁）中，完全缓解率为 98%。达沙替尼诱导治疗结束时（第 85 天），29%的患者有分子缓解，在接受两周期的blinatumomab后，该比例增加至 60%；在接受更多blinatumomab 周期后，有分子缓解的患者比例进一步增加。中位随访 18 个月时，总生存率为 95%，无疾病生存率为 88%；有缺失及其他遗传异常（或、、或两者均有[即 ]）的患者无疾病生存率较低。在诱导治疗期间出现微小残留病灶增加的 6 例患者中检测到突变，所有这些突变均被blinatumomab清除。6 例患者复发。总的来说，有 21 例 3 级或以上的不良事件发生。共有 24 例患者接受了干细胞移植，1 例与移植相关的死亡（4%）。

结论

基于靶向和免疫治疗策略，采用无化疗诱导和巩固一线治疗，达沙替尼联合blinatumomab治疗 Ph 阳性 ALL 成人患者，分子缓解率和生存率高，3 级或以上毒性反应少。（由意大利癌症研究协会和其他机构资助；GIMEMA LAL2116 D-ALBA EudraCT 编号：2016-001083-11；ClinicalTrials.gov 编号：NCT02744768。）