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Prognostic significance of clinical risk models and genomic alterations in Waldenström macroglobulinemia before or after the BTK inhibitor era

Leukemia (2026)Cite this article

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Abstract

Waldenström macroglobulinemia (WM) is a rare indolent B-cell lymphoma with marked clinical and molecular heterogeneity. Clinical risk models, including IPSSWM, rIPSSWM, and MSSWM, were developed prior to the widespread use of Bruton tyrosine kinase inhibitors (BTKi), and their performance in the BTKi era remains uncertain. In addition, the prognostic impact of various genomic alterations is controversial. We retrospectively analyzed 453 symptomatic WM patients, including 203 who received non-BTKi therapy and 250 who received BTKi-based therapy. All three models significantly stratified prognosis in the non-BTKi cohort, with rIPSSWM showing the highest predictive accuracy, but none effectively predicted survival in BTKi-treated patients. Notably, among patients receiving first-line BTKi-based therapy, high-risk patients by any model achieved survival outcomes comparable to those of lower-risk patients, suggesting that upfront BTKi can overcome the adverse impact of high-risk clinical features. At the molecular level, MYD88 mutation was significantly associated with favorable outcomes exclusively in patients treated with first-line BTKi-based therapy, while CXCR4 and TP53 mutations predicted significantly inferior prognosis in both BTKi-based and non-BTKi cohorts. Our findings indicate that although clinical risk models remain relevant for patients receiving non-BTKi therapy, molecular features, especially MYD88, CXCR4, and TP53 mutations, provide superior prognostic insights for patients with BTKi-based regimens.

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Fig. 1: Overall survival of three risk models in patients receiving non-BTKi and BTKi-based therapy.
Fig. 2: Survival outcomes of the three risk models in the first-line BTKi therapy cohort.
Fig. 3: Survival outcomes of different first-line therapy regimens.
Fig. 4: Survival outcomes of MYD88 and CXCR4 mutation status in different first-line therapy regimens.
Fig. 5: Genomic landscape and prognostic impact of the top mutations in WM.
Fig. 6: Survival outcomes of patients with TP53MUT and TP53WT in different first-line therapy cohorts.

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Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by grants from the National Nature Science Foundation of China (82200215, 82570248, 82370197, 82170194), the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2025-I2M-C&T-B-074), Beijing Xisike Clinical Oncology Research Foundation (Y-2024AZ(BTK)ZD--0074) and the Shenzhen Science and Technology Innovation Commission (JCYJ20240813140803005).

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  1. These authors contributed equally: Yuting Yan, Weihao Chen.

Authors and Affiliations

  1. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology& Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China

    Yuting Yan, Weihao Chen, Ying Yu, Yuxi Li, Wenjie Xiong, Xinyi Zhang, Tingyu Wang, Wei Liu, Weiwei Sui, Zhen Yu, Mu Hao, Gang An, Dehui Zou, Lugui Qiu & Shuhua Yi

  2. Tianjin Institutes of Health Science, Tianjin, China

    Yuting Yan, Weihao Chen, Ying Yu, Yuxi Li, Wenjie Xiong, Xinyi Zhang, Tingyu Wang, Wei Liu, Weiwei Sui, Zhen Yu, Mu Hao, Gang An, Dehui Zou, Lugui Qiu & Shuhua Yi

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Consortia

for the Chinese Workshop of Indolent Lymphomas

  • Yuting Yan
  • , Weihao Chen
  • , Ying Yu
  • , Yuxi Li
  • , Wenjie Xiong
  • , Xinyi Zhang
  • , Tingyu Wang
  • , Wei Liu
  • , Weiwei Sui
  • , Zhen Yu
  • , Mu Hao
  • , Gang An
  • , Dehui Zou
  • , Lugui Qiu
  •  & Shuhua Yi

Contributions

SHY conceptualized the study design. YTY and WHC collected patients’ data and wrote the manuscript. YTY and WHC conducted data analysis and statistics. YY, YXL, WJX, XYZ, TYW, WL, WWS, ZY, MH, GA, and DHZ acquired the data and managed the patients. LGQ and SHY revised the manuscript critically and approved the final version.

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Correspondence to Shuhua Yi.

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Yan, Y., Chen, W., Yu, Y. et al. Prognostic significance of clinical risk models and genomic alterations in Waldenström macroglobulinemia before or after the BTK inhibitor era. Leukemia (2026). https://doi.org/10.1038/s41375-026-02919-0

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