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CHRONIC MYELOGENOUS LEUKEMIA

Validation of the imatinib-therapy failure model

Leukemia volume 37, pages 1166–1169 (2023)Cite this article

Subjects

Data from 519 consecutive subjects ≥18 years with newly-diagnosed chronic phase CML with a e14a2 and/or e13a2 BCR::ABL transcript receiving initial imatinib-therapy at Peking University People’s Hospital January, 2006 to May, 2022 and not included in the prior training dataset were evaluated for validation dataset-1. Data from 2870 subjects from 76 other Chinese centres diagnosed at the same period with the same inclusion and exclusion criteria were evaluated as validation dataset-2. Therapy-failure was defined as not meeting TKI-therapy milestones in the 2020 ELN recommendation, loss of responses including CHR, CCyR or MMR, progression to accelerated or blast phases or death [2, 5]. Failure-free survival (FFS) was calculated from the start of imatinib-therapy to a failure event or censored at the time of TKI-stopping or switching to another TKI, a transplant, death or the last follow-up. We analyzed only the first episode in subjects with >1 therapy-failure. The last follow-up was September 30th, 2022.

In the validation dataset-2, 2,870 subjects with chronic phase CML receiving initial imatinib-therapy at 76 other Chinese centres were interrogated. Subject co-variates are displayed in Supplementary Table 1. Compared with validation dataset-1, subjects in validation dataset-2 had the lower proportion of Sokal high-risk population (p = 0.007) and co-morbidity(ies) (p < 0.001). Follow-up interval in the dataset-2 was significantly briefer compared with dataset-1 (p < 0.001). In validation dataset-2, 647 subjects (23%) failed initial imatinib-therapy at a median of 11 months (IQR, 6–18 months). Reasons of therapy failure included not meeting therapy goals at 3 (n = 142), 6 (n = 185) or 12 (n = 107) months, loss of prior response (n = 101), a TKI-resistant mutation (n = 22) or high-risk ACAs in Ph-chromosome positive cells (n = 12) and/or progression to accelerated (n = 46) or blast phase (n = 32). No subject died before failing imatinib. 770 (27%), 679 (24%), 846 (29%), 449 (16%) and 126 (4%) subjects were classified as very-low-, low-, intermediate-, high- and very-high-risk cohorts. 6-year cumulative incidences of therapy-failure were 10% (9, 11%), 17% (15, 19%), 38% (34, 42%), 45% (39, 51%), 62% (51, 73%; p for trend <0.001, Fig. 2C). In multi-variable analyses IMTF risk cohort was significantly-associated with imatinib-therapy failure. Male sex was also associated with imatinib therapy-failure (p < 0.001, Supplementary Table 3). 6-year probabilities of FFS were 90% (89, 91), 82% (79, 85%), 58% (53, 64%), 53% (43, 63%), 30% (14, 46%; p for trend <0.001, Fig. 2D). HRs for therapy-failure with the very-low-risk cohort as reference were 2.1 (1.6, 2.9; p = 0.002), 5.0 (3.8, 6.6; p < 0.001), 7.6 (5.3, 11.1; p < 0.001) and 14.8 (9.0, 24.4; p < 0.001; p for trend < 0.001). Male sex was also associated with poor FFS (p < 0.001, Supplementary Table 3). C-statistics at 1-, 3- and 5-year were 0.76 (0.73, 0.78), 0.75 (0.72, 0.77) and 0.75 (0.73, 0.78).

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Fig. 1
Fig. 2

Data availability

The data that support the findings of this study are available from the corresponding author upon request.

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Acknowledgements

We would like to thank the following medical staffs who provided patients data: Xiaohui Suo, Weihua Zhang and Yuanjun Zheng, Lijie Yang, Zhiqiang Sun, Rongxia Wei, Jijun Wang and Lan Ma, Qingshu Zeng, Zhen Xiao, Junxia Meng and Xiaonan Zhang, Hebing Zhou, Congmeng Lin, Pengliang Xin, Yanping Ma and Xiaoyan Ge, Yujuan Yang, Yujing and Lijun Wang, Huanling Zhu, Ling Pan and Yunfan Yang, Xingxia Zhang, Hongguo Zhao and Hairong Fei, Yonghuai Feng, Linhua Yang, Xiaoyi Lv, Hai Yi and Yilan Liu, Yun Zeng, Hua Fan, Liling Zheng, Jianmin Luo, Jianhui Qiao, Luoming Hua, Shasha Zhao, Yin Sai, Ronghua Hu, Lianyu Shen, Li Ding, Fang Ye, Shunjie Wu, Min Ouyang and Meixiang Zhao, Qin Li, Liru Wang, Wangxiang Huang, Wenqian Li, Jianli Wang, Yun Li and Jing Liu. QJ acknowledges support from the National Natural Science Foundation of China (No. 81970140). RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme.

Funding

Funded, in part, by the National Nature Science Foundation of China (No. 81970140) and CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2019-I2M-5-034).

Author information

Author notes

  1. These authors contributed equally: Xiaoshuai Zhang, Robert Peter Gale, Bingcheng Liu, Jian Huang, Yanli Zhang, Xin Du.

Authors and Affiliations

  1. Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China

    Xiaoshuai Zhang, Xiaojun Huang & Qian Jiang

  2. Centre for Hematology Research, Department of Immunology and Inflammation, Imperial College London, London, UK

    Robert Peter Gale

  3. National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China

    Bingcheng Liu

  4. Department of Hematology, he First Affiliated Hospital of Zhejiang University, College of Medicine, Zhejiang University, Department of Hematology, The Fourth Affiliated Hospital of Zhejiang University, College of Medicine, Zhejiang University, Zhejiang Provincial Clinical Research Center for Haematological Disorders, Zhejiang, China

    Jian Huang

  5. Henan Cancer Hospital, The Affiliate Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Yanli Zhang

  6. Division of Hematology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Guangdong, China

    Xin Du

  7. Department of Hematology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China

    Jianyu Weng

  8. Union hospital, Tongji Medical college, Huazhong University of Science and Technology, Wuhan, China

    Weiming Li

  9. Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Na Xu & Xiaoli Liu

  10. Department of Hematology, Qilu Hospital of Shandong University, Jinan, China

    Chunyan Chen

  11. Department of hematology, First Hospital of Jilin University, Jilin, China

    Hai Lin

  12. Xi’an international medical center hospital, Shanxi, China

    Guohui Li

  13. Department of Hematology, Xijing Hospital, Airforce Military Medical University, Shanxi, China

    Rong Liang

  14. Shengjing Hospital of China Medical University, Shenyang, China

    Zhuogang Liu & Wei Yang

  15. Sichuan Academy of Medical Sciences Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China

    Xiaodong Wang

  16. Department of Hematology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China

    Yanqing Zhang

  17. The affiliated hospital of Inner Mongolia Medical University, Inner Mongolia, China

    Yanqiu Han

  18. Department of Hematology, Cancer Center, The First Hospital of Jilin University, Changchun, China

    Chunshui Liu

  19. Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fujian, China

    Jianda Hu

  20. Department of Hematology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China

    Lie Lin

  21. Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China

    Zhenfang Liu

  22. Department of Hematology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Li Meng

  23. Department of Hematology, Shenzhen Baoan Hospital, Shenzhen University Second Affiliated Hospital, Shenzhen, China

    Chuanqing Tu & Caifeng Zheng

  24. Department of Hematology, the Second Hospital Affiliated to Kunming Medical University, Kunming, Yunnan, China

    Zeping Zhou

  25. Department of Hematology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, Henan, China

    Yanliang Bai

  26. National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation of Soochow University, Suzhou, China

    Huiying Qiu & Suning Chen

  27. Center of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, China

    Fei Li

  28. Department of Hematology, The Second Affiliated Hospital of Fujian Medical University, Fujian, China

    Jianxin Guo

  29. Department of Hematology, Huazhong University of Science and Technology Union Shenzhen Hospital (Nanshan Hospital), Shenzhen, China

    Zelin Liu

  30. Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Hui Sun

  31. Department of Leukemia, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Li Zhou

  32. Department of Hematology, Beijing Hospital, National Center of Gerontology, Beijing, China

    Ru Feng

  33. Department of hematology, The first affiliated hospital of Dalian Medical University, Dalian, China

    Xiuli Sun

  34. Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China

    Xiaojun Huang & Qian Jiang

  35. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 1, China

    Xiaojun Huang

  36. Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, Beijing, China

    Xiaojun Huang

Authors
  1. Xiaoshuai Zhang
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Contributions

QJ designed the study. QJ, XSZ, and RPG analyzed the data. QJ, XJH, XSZ and RPG prepared the typescript. QJ, XJH, BCL, JH, YLZ, XD, JYW, WML, XLL, NX, CYC, HL, GHL, RL, ZGL, XDW, YQZ, YQH, CSL, JDH, LL, ZYZ, WY, ZFL, LM, CQT, ZPZ, YLB, HYQ, SNC, FL, JXG, ZLL, HS, LZ, RF and XLS provided the most part of patients data in this study. All authors approved the final typescript, take responsibility for the content and agree to submit for publication.

Corresponding authors

Correspondence to Xiaojun Huang or Qian Jiang.

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Competing interests

RPG is a consultant to NexImmune Inc. and Ananexa Pharma Ascentage Pharm Group, Antengene Biotech LLC, Medical Director, FFF Enterprises Inc.; partner, AZAC Inc.; Board of Directors, Russian Foundation for Cancer Research Support; and Scientific Advisory Board: StemRad Ltd.

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Approved by the Ethics Committee of People’s Hospital Beijing compliant with principles of the Helsinki Declaration.

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Zhang, X., Gale, R.P., Liu, B. et al. Validation of the imatinib-therapy failure model. Leukemia 37, 1166–1169 (2023). https://doi.org/10.1038/s41375-023-01875-3

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