Zhang Mingming, Fu Shan, Feng Jingjing, Hong Ruimin, Wei Guoqing, Zhao Houli, Zhao Mengyu, Xu Huijun, Cui Jiazhen, Huang Simao, Wu Xiaoyu, Liu Lianxuan, Sun Jie, Wu Wenjun, Zhu Yuanyuan, He Jingsong, Zhao Yi, Cai Zhen, Zheng Weiyan, Ye Xiujin, Shi Jimin, Luo Yi, Wang Dongrui, Chang Alex H, Hu Yongxian, Huang He
Bone Marrow Transplantation Center, the First Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China.
Institute of Hematology, Zhejiang University, Hangzhou, China.
JAMA Oncol. 2025 Apr 17. doi: 10.1001/jamaoncol.2025.0674.
A combination of tyrosine kinase inhibitors and chimeric antigen receptor (CAR) T cells has made a breakthrough in refractory or relapsed Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). However, it remains unclear if this treatment in newly diagnosed Ph-positive ALL is associated with high rates of complete molecular remission (CMR) and leukemia-free survival.
To evaluate the efficacy and safety of dasatinib in combination with CAR T cells as frontline therapy in adults with newly diagnosed Ph-positive ALL.
DESIGN, SETTING, AND PARTICIPANTS: This trial was conducted at a single center, the First Affiliated Hospital of Zhejiang University School of Medicine. Patients were enrolled in this phase 2, single-arm nonrandomized clinical trial between March 5, 2021, and April 13, 2024. The data cutoff date was February 10, 2025. The data analysis was conducted on February 11, 2025. The median duration of follow-up was 23.9 (range, 7.3-47.7) months. A total of 29 adults with newly diagnosed Ph-positive ALL and adequate organ function were screened for eligibility, and 1 patient who received a diagnosis of blast-phase chronic myeloid leukemia was excluded.
Dasatinib was administered with a 2-week vindesine and dexamethasone regimen as induction, followed by sequential CD19 and CD22 CAR T-cell therapies and single-agent dasatinib maintenance.
The primary end point was CMR rate after CD19 CAR T-cell therapy. CMR was defined as undetectable BCR/ABL1 transcripts as measured by quantitative reverse transcription polymerase chain reaction with a sensitivity of 10-4 in the bone marrow.
Twenty-eight patients (median [range] age, 48.5 [18.0-69.0] years; 10 female individuals [36%]) were enrolled, and 1 patient withdrew after induction. The CMR rate was 25% (7 of 28) after induction and increased to 85% (23 of 27) after CD19 CAR T-cell therapy. Twenty-five patients (89.3%) received sequential CD22 CAR T-cell therapy, and the CMR rate was 76% (19 of 25). Of the 52 CAR T-cell therapies, only 21 cases of grade 1 cytokine release syndrome occurred. After a median follow-up of 23.9 (range, 7.3-47.7) months, the 2-year overall survival and leukemia-free survival were 92%.
The results of this nonrandomized clinical trial suggest that the combination of dasatinib and CAR T-cell therapy showed encouraging efficacy in newly diagnosed Ph-positive ALL with acceptable toxic effects. Further studies with larger cohorts and longer follow-up durations are needed.
ClinicalTrials.gov Identifier: NCT04788472.
酪氨酸激酶抑制剂与嵌合抗原受体（CAR）T细胞的联合应用在难治性或复发性费城染色体（Ph）阳性急性淋巴细胞白血病（ALL）治疗中取得了突破。然而，新诊断的Ph阳性ALL患者接受这种治疗是否与高完全分子缓解（CMR）率和无白血病生存率相关仍不清楚。
评估达沙替尼联合CAR T细胞作为新诊断的Ph阳性ALL成人患者一线治疗的疗效和安全性。
设计、地点和参与者：本试验在浙江大学医学院附属第一医院这一单一中心进行。患者于2021年3月5日至2024年4月13日参加了这项2期单臂非随机临床试验。数据截止日期为2025年2月10日。数据分析于2025年2月11日进行。中位随访时间为23.9（范围7.3 - 47.7）个月。共筛选了29例新诊断的Ph阳性ALL且器官功能良好的成人患者，1例诊断为急变期慢性髓性白血病的患者被排除。
达沙替尼与为期2周的长春地辛和地塞米松方案联合用于诱导治疗，随后依次进行CD19和CD22 CAR T细胞治疗以及单药达沙替尼维持治疗。
主要终点是CD19 CAR T细胞治疗后的CMR率。CMR定义为通过定量逆转录聚合酶链反应检测骨髓中BCR/ABL1转录本不可检测，灵敏度为10 - 4。
28例患者（中位[范围]年龄48.5[18.0 - 69.0]岁；10名女性[36%]）入组，1例患者在诱导治疗后退出。诱导治疗后的CMR率为25%（28例中的7例），CD19 CAR T细胞治疗后升至85%（27例中的23例）。25例患者（89.3%）接受了序贯CD22 CAR T细胞治疗，CMR率为76%（25例中的19例）。在52次CAR T细胞治疗中，仅发生21例1级细胞因子释放综合征。中位随访23.9（范围7.3 - 47.7）个月后，2年总生存率和无白血病生存率均为92%。
这项非随机临床试验结果表明，达沙替尼与CAR T细胞治疗联合应用在新诊断的Ph阳性ALL中显示出令人鼓舞的疗效，且毒性可接受。需要进一步开展更大样本量队列和更长随访时间的研究。
ClinicalTrials.gov标识符：NCT04788472。
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