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Optimization of high-dose methotrexate prophylaxis for central nervous system relapse in diffuse large B-cell lymphoma: a multicenter analysis

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Abstract

Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a rare but devastating event. Intravenous high-dose methotrexate (HD-MTX) is recommended as CNS prophylaxis, but the optimal timing and dose has not been elucidated. Here, we report a multicenter analysis of prophylactic HD-MTX administration for DLBCL. Two hundred eighty-four patients receiving HD-MTX either concurrent with each induction chemotherapy cycle (n = 221) or at the end of induction therapy (EOI, n = 63) were included. Patients with CNS-IPI scoring 4–6, and/or testicular involvement, and/or double/triple hit lymphoma, were stratified into the high-risk group and the others into the moderate-risk group. Concurrent HD-MTX was associated with increased risk of grade 3/4 treatment-related toxicity (OR,1.49; P = 0.006) and subsequent chemotherapy delays (OR, 1.87; P = 0.003) in multivariate analysis. With a median follow-up of 36.0 months, no significant difference in CNS relapse rate was identified between the concurrent and EOI groups (3.2% vs 4.8%, P = 0.34), even in the high-risk group. Analysis on systemic MTX dose suggested that high-dose MTX (≥ 2 g/m2) was associated with better CNS relapse control only in the high-risk group, but not in the moderate-risk group. This study may elucidate the superiority of EOI HD-MTX to some extent. High MTX dose (≥ 2 g/m2) may not be necessary for the moderate-risk patients.

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Availability of data and material

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

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Funding

This work was supported by grants from the National Natural Science Foundation of China (81973384); the Special Support Program of Sun Yat-sen University Cancer Center (PT19020401), the Science and Technology Planning Project of Guangzhou, China (202002030205), and the Clinical Oncology Foundation of Chinese Society of Clinical Oncology (Y-XD2019-124).

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Author notes

  1. Yu Fang, Ning Su, Shuyun Ma and Jun Cai contributed equally.

Authors and Affiliations

  1. Department of Medical Oncology, Sun Yat-Sen University Cancer Center, 651 Dong Feng RD East, Guangzhou, 510060, People’s Republic of China

    Yu Fang, Ning Su, Shuyun Ma, Jun Cai, Huiqiang Huang, Zhiming Li, He Huang, Yi Xia, Panpan Liu, Xiaopeng Tian, Jinni Wang, Yuchen Zhang & Qingqing Cai

  2. State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China

    Yu Fang, Ning Su, Shuyun Ma, Jun Cai, Huiqiang Huang, Zhiming Li, He Huang, Yi Xia, Panpan Liu, Xiaopeng Tian, Jinni Wang, Yuchen Zhang & Qingqing Cai

  3. Department of Oncology, Guangzhou Chest Hospital, Guangzhou, People’s Republic of China

    Ning Su

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

    Liye Zhong

  5. Lymphoma Division, Cancer Center of Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510120, People’s Republic of China

    Wenyu Li

  6. Department of Pathology, Zhujiang Hospital of Southern Medical University, Guangzhou, People’s Republic of China

    Linlang Guo

  7. Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China

    Zhihua Li

  8. Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China

    Yudan Wu

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  1. Yu Fang
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Contributions

Y.F. and Q.C. designed the study. Y.F. did the statistical analysis. Y.F., N.S., and S.M. wrote the manuscript. J.C., H.H., Z.L., H.H., Y.X., P.L., L.Z., W.L., L.G., Z.L., Y.W., X.T., J.W., and Y.Z. collected clinical data. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Qingqing Cai.

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The study was approved by the review board of each participating institution. All the procedures were performed in accordance with the 1964 Declaration of Helsinki principles and its later amendments or comparable ethical standards.

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Patients submitted their written informed consents in accordance with the Declaration of Helsinki.

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The authors declare no competing interests.

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Fig. S1 Non-linear relationship between methotraxate dose and survival outcomes in high- and moderate-risk groups

Association of methotraxate dose with progression-free survival (PFS) and overall survival (OS) in high- and moderate-risk group. (A) Unadjusted nonlinear relationship between methotraxate dose and survival outcomes. B, Nonlinear relationship between methotraxate dose and survival outcomes adjusted with age, gender, ECOG PS, LDH, stage and number of extranodal site. Hazard ratios (HR) are indicated by solid lines and 95% confidence intervals (CI) is by shaded areas.

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Fang, Y., Su, N., Ma, S. et al. Optimization of high-dose methotrexate prophylaxis for central nervous system relapse in diffuse large B-cell lymphoma: a multicenter analysis. Ann Hematol 101, 595–605 (2022). https://doi.org/10.1007/s00277-021-04739-x

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