意大利罗马萨皮恩扎大学Robin Foà团队研究了达沙替尼-博纳吐单抗治疗成人Ph阳性急性淋巴细胞白血病的效果。2020年10月22日，《新英格兰医学杂志》发表了该成果。

使用酪氨酸激酶抑制剂可改善费城染色体（Ph）阳性的急性淋巴细胞白血病（ALL）患者的预后。分子缓解是治疗的主要目标。

研究组招募了63名新诊断为Ph阳性ALL（无年龄上限）的成年人，进行了一项临床2期单组试验。所有患者均给予达沙替尼加糖皮质激素进行诱导治疗，之后再进行两个周期的博纳吐单抗治疗。主要终点是治疗后骨髓中持续的分子缓解。

63例患者的中位年龄为54岁，有98％观察到完全缓解。在达沙替尼诱导治疗结束时（第85天），有29％的患者出现了分子缓解，在接受两个周期的博纳吐单抗治疗后，这一百分比增加到60％；继续增加博纳吐单抗的治疗周期，获得分子缓解的患者百分比进一步增加。

中位随访18个月后，患者的总生存率为95％，无病生存率为88％。在患有IKZF1缺失伴其他基因突变（CDKN2A或CDKN2B，PAX5，或两者兼有）的患者中，无病生存率较低。

在诱导治疗期间微小残留病灶增加的6例患者中检测到ABL1突变，但博纳吐单抗清除了所有这些突变。有6例患者复发。共有21例患者发生3级及以上不良事件。共有24例患者接受了干细胞同种异体移植，其中1例死亡与移植有关（4％）。

研究结果表明，以靶向和免疫治疗策略为基础的达沙替尼和博纳吐单抗的无化疗诱导和巩固一线治疗，用于Ph阳性ALL的成年人，可显著提高分子缓解和生存率，且3级以上毒副作用较低。

附：英文原文

Title: Dasatinib–Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults

Author: Robin Foà, M.D.,, Renato Bassan, M.D.,, Antonella Vitale, M.D.,, Loredana Elia, M.D.,, Alfonso Piciocchi, M.S.,, Maria-Cristina Puzzolo, Ph.D.,, Martina Canichella, M.D.,, Piera Viero, M.D.,, Felicetto Ferrara, M.D.,, Monia Lunghi, M.D.,, Francesco Fabbiano, M.D.,, Massimiliano Bonifacio, M.D.,, Nicola Fracchiolla, M.D.,, Paolo Di Bartolomeo, M.D.,, Alessandra Mancino, M.S.,, Maria-Stefania De Propris, Ph.D.,, Marco Vignetti, M.D.,, Anna Guarini, Ph.D.,, Alessandro Rambaldi, M.D.,, and Sabina Chiaretti, M.D., Ph.D.

Issue&Volume: 2020-10-22

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 IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both [i.e., IKZF1plus]). ABL1 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.

DOI: 10.1056/NEJMoa2016272

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2016272