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Successful treatment of two relapsed/refractory t(8;21) acute myeloid leukemia patients by CD19-directed chimeric antigen receptor T cells

Bone Marrow Transplantation volume 54, pages 1138–1140 (2019)Cite this article

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Although progresses in acute myeloid leukemia (AML) treatments, a significant number of patients are still refractory to their treatment or experience relapse especially post transplantation. Therefore, it is crucial to develop novel therapeutic strategies to deal with this problem [1]. With clinical success of chimeric antigen receptor T cells (CAR-T) targeting CD19 (CAR-T-19) therapies against B-lineage malignancies [2], many studies have attempted to translate the success of CAR-T therapy to AML. However, there are still numerous clinical challenges for CAR-T therapy in AML and lacking of specific antigen target is a major obstacle to CAR-T therapy for AML [2]. Considering CAR-T-19 is a highly therapeutic and safe approach in B-cell lineage malignancies, we explored the therapeutic effect and clinical safety of application of CAR-T-19 in two R/R t(8;21) AML patients with CD19 expression.

Case 1 is a 15-year-old male admitted to hospital because of fever and pancytopenia. Bone marrow (BM) smear showed 67% blasts. Flow cytometry (FCM) analysis identified AML. His karyotype was 46, XY, t(8;21),(q22;q22). AML1-ETO rearrangement and c-kit germline mutation were detected. He was then treated with standard “3+7”regimen with idarubicin and cytarabine (IA) as induction and achieved hematological complete remission (hCR) followed by two cycles of consolidations (IA and high dose cytarabine chemotherapy). The patient achieved molecular CR (mCR) with AML1-ETO copies undetectable. Then the patient underwent matched sibling donor allogeneic hematological stem cell transplantation (allo-HSCT). Minimal residual disease (MRD), donor chimerism, and AML1-ETO copies were monitored monthly. However, AML1-ETO copies were undetectable for several months and then increased dynamically in both BM and peripheral blood (PB) 5 months post allo-HSCT suggesting the patient got molecular relapse. Moreover, blasts, which now expressed CD19 (40.1%) were noted (Fig. S1). The patient then received lymphodepletion chemotherapy with Decitabine 20 mg/m2 /d × 5d, Fludarabine 30 mg/m2 /d × 3d, and Cyclophosphamide 300 mg/m2 /d × 3d (DAC+FC) followed by allogeneic CAR-T-19 cells from his sibling donor infusion (Fig.S3A). Case 2 is a 18-year-old male admitted to hospital because of fever and hemorrhinia. BM morphology and immunophenotyping identified AML. His karyotype was 46, XY, t(8;21),(q22;q22), inv(9)[cp2]/46,XY[1]. AML1-ETO rearrangement and c-kit, ASXL2 as well as TET-2 mutation were detected. The patient was also treated with standard “3+7”IA regimen as induction and achieved hCR followed by the same regimen for a consolidation therapy. Then the patient quit therapy due to financial problem. Unfortunately, 10 months after last chemotherapy, he got hematological relapse and was treated with IA as reinduction and achieved hCR followed by multiple consolidation chemotherapies. However, the patient got relapsed again with up to 22% blasts in BM and AML1-ETO was up to 174,107 copies (AML-ETO transcripts were normalized to 104 ABL copies). FCM analysis revealed 22.6% CD19+ among the blasts (Fig. S2). To reducing tumor burden, the patient was exposed to a chemotherapy with ECAG (etopside 50 mg/d × 4d, cytarabine 10 mg/m2 q12h × 7d, aclarubicin 10 mg/d × 4d, and granulocyte colony-stimulating factor) combined with DAC+FC regimen before autologous CAR-T-19 therapy (Fig. S3A). Two days after chemotherapy, CAR-T-19 cells provided by unicar-therapy bio-medicine technology co.(Shanghai, China) at a total dose of 5–10 × 106 cells per kilogram (kg)  were infused to both cases by dose escalation within 2–3 days. The research protocol was approved by the institutional review boards of the first affiliated hospital of Soochow University and both patients gave written informed consent.

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Acknowledgements

The authors thank all members of the study team, the patient, and their family. This work was supported by the research grants from the National Key R&D Program of China (2016YFC0902800), National natural science Foundation of China (81873443, 81270645, 81400155, 81500146), Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), Frontier Clinical Technical Project of the Science and Technology Department of Jiangsu Province (BE2017655), Jiangsu Provincial Medical Talent (ZDRCA2016045), Jiangsu Natural Science Foundation of China (BK20140374) and Top-notch young health talents(to CQ), 5th Suzhou health professionals program.

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  1. These authors contributed equally: Changju Qu, Zheng Li, Liqing Kang

  2. These authors jointly supervised this work: Xiaowen Tang, Depei Wu

Authors and Affiliations

  1. Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, 215000, Suzhou, China

    Changju Qu, Zheng Li, Haiping Dai, Jia Yin, Guanghua Chen, Mingqing Zhu, Li Yao, Ting Xu, Xiaopeng Tian, Yang Xu, Jia Chen, Xiaming Zhu, Depei Wu & Xiaowen Tang

  2. Institute of Blood and Marrow Transplantation, 215000, Suzhou, China

    Changju Qu, Zheng Li, Haiping Dai, Jia Yin, Guanghua Chen, Mingqing Zhu, Li Yao, Ting Xu, Xiaopeng Tian, Yang Xu, Jia Chen, Xiaming Zhu, Depei Wu & Xiaowen Tang

  3. Collaborative Innovation Center of Hematology, Soochow University, 215123, Suzhou, China

    Changju Qu, Zheng Li, Haiping Dai, Jia Yin, Guanghua Chen, Mingqing Zhu, Li Yao, Ting Xu, Xiaopeng Tian, Yang Xu, Jia Chen, Xiaming Zhu, Depei Wu & Xiaowen Tang

  4. College of Chemistry and Molecular Engineering, East China Normal University, 200062, Suzhou, China

    Liqing Kang & Lei Yu

  5. Shanghai Unicar-Therapy Bio-medicine Technology Co., Ltd, 201203, Suzhou, China

    Liqing Kang & Lei Yu

  6. Department of Hematology, The First People’s Hospital of Lianyungang, 222061, Suzhou, China

    Ying Wang

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Qu, C., Li, Z., Kang, L. et al. Successful treatment of two relapsed/refractory t(8;21) acute myeloid leukemia patients by CD19-directed chimeric antigen receptor T cells. Bone Marrow Transplant 54, 1138–1140 (2019). https://doi.org/10.1038/s41409-018-0423-y

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