Genetic subtype-guided immunochemotherapy in relapsed and refractory diffuse large B cell lymphoma: a phase 2 investigator-initiated nonrandomized clinical trial (GUIDANCE-06)
Abstract Improving the outcome of relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) remained an unmet need. The aim of this single-center, phase 2 trial was to evaluate the efficacy and safety of genetic subtype-guided immunochemotherapy (R-ICE-X) in patients with R/R DLBCL: R-ICE-zan...
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Nature Publishing Group
2025-07-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02316-6 |
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| author | Yi-Ge Shen Qing Shi Wei Tang Peng-Peng Xu Yi-Wen Cao Meng-Meng Ji Zhong Zheng Shu Cheng Li Wang Wei-Li Zhao |
| author_facet | Yi-Ge Shen Qing Shi Wei Tang Peng-Peng Xu Yi-Wen Cao Meng-Meng Ji Zhong Zheng Shu Cheng Li Wang Wei-Li Zhao |
| author_sort | Yi-Ge Shen |
| collection | DOAJ |
| description | Abstract Improving the outcome of relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) remained an unmet need. The aim of this single-center, phase 2 trial was to evaluate the efficacy and safety of genetic subtype-guided immunochemotherapy (R-ICE-X) in patients with R/R DLBCL: R-ICE-zanubrutinib for MCD-like and BN2-like, R-ICE-lenalidomide for N1-like and NOS, R-ICE-decitabine for TP53 Mut, R-ICE-chidamide for EZB-like, and R-ICE-tofacitinib for ST2-like subtype. Enrolled patients were treated with assigned regimens for three cycles, and then responders were treated with autologous hematopoietic stem cell transplantation (ASCT) or 3 cycles of R-ICE-X consolidation and lenalidomide maintenance. The primary endpoint was the complete response (CR) rate. The secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety assessment. Between April 26, 2022, and July 31, 2024, 76 patients were enrolled, with 74 adhering to and 2 deviating from the protocol. Among all, the CR rate was 56.6% (95% CI, 45.2–68.0%), and the ORR was 76.3% (95% CI, 66.5–86.1%) at the end of induction. With a median follow-up of 19.5 months, the 2-year PFS rate was 69.3% (95% CI, 56.6–79.0%), and the 2-year OS rate was 88.3% (95% CI, 77.6–94.0%). The primary grade 3-4 adverse events were neutropenia (30%) and thrombocytopenia (25%). The presence of bulky disease and CD70 mutation was linked to poor prognosis. Further gene set enrichment analysis revealed that up-regulated PI3K-AKT-mTOR signaling pathway and reduced immune cell infiltration were significantly associated with disease progression. Patients with mesenchymal or inflammatory lymphoma microenvironment subtypes benefited from R-ICE-X treatment. Our findings highlight the efficacy and safety of R-ICE-X, a mechanism-based tailored therapy, which dually targets genetic and microenvironmental alterations in R/R DLBCL. |
| format | Article |
| id | doaj-art-7ca9dd6b80c14780bd706aca1a45f8f2 |
| institution | Kabale University |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
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| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-7ca9dd6b80c14780bd706aca1a45f8f22025-08-20T03:43:37ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-07-0110111110.1038/s41392-025-02316-6Genetic subtype-guided immunochemotherapy in relapsed and refractory diffuse large B cell lymphoma: a phase 2 investigator-initiated nonrandomized clinical trial (GUIDANCE-06)Yi-Ge Shen0Qing Shi1Wei Tang2Peng-Peng Xu3Yi-Wen Cao4Meng-Meng Ji5Zhong Zheng6Shu Cheng7Li Wang8Wei-Li Zhao9Shanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineAbstract Improving the outcome of relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) remained an unmet need. The aim of this single-center, phase 2 trial was to evaluate the efficacy and safety of genetic subtype-guided immunochemotherapy (R-ICE-X) in patients with R/R DLBCL: R-ICE-zanubrutinib for MCD-like and BN2-like, R-ICE-lenalidomide for N1-like and NOS, R-ICE-decitabine for TP53 Mut, R-ICE-chidamide for EZB-like, and R-ICE-tofacitinib for ST2-like subtype. Enrolled patients were treated with assigned regimens for three cycles, and then responders were treated with autologous hematopoietic stem cell transplantation (ASCT) or 3 cycles of R-ICE-X consolidation and lenalidomide maintenance. The primary endpoint was the complete response (CR) rate. The secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety assessment. Between April 26, 2022, and July 31, 2024, 76 patients were enrolled, with 74 adhering to and 2 deviating from the protocol. Among all, the CR rate was 56.6% (95% CI, 45.2–68.0%), and the ORR was 76.3% (95% CI, 66.5–86.1%) at the end of induction. With a median follow-up of 19.5 months, the 2-year PFS rate was 69.3% (95% CI, 56.6–79.0%), and the 2-year OS rate was 88.3% (95% CI, 77.6–94.0%). The primary grade 3-4 adverse events were neutropenia (30%) and thrombocytopenia (25%). The presence of bulky disease and CD70 mutation was linked to poor prognosis. Further gene set enrichment analysis revealed that up-regulated PI3K-AKT-mTOR signaling pathway and reduced immune cell infiltration were significantly associated with disease progression. Patients with mesenchymal or inflammatory lymphoma microenvironment subtypes benefited from R-ICE-X treatment. Our findings highlight the efficacy and safety of R-ICE-X, a mechanism-based tailored therapy, which dually targets genetic and microenvironmental alterations in R/R DLBCL.https://doi.org/10.1038/s41392-025-02316-6 |
| spellingShingle | Yi-Ge Shen Qing Shi Wei Tang Peng-Peng Xu Yi-Wen Cao Meng-Meng Ji Zhong Zheng Shu Cheng Li Wang Wei-Li Zhao Genetic subtype-guided immunochemotherapy in relapsed and refractory diffuse large B cell lymphoma: a phase 2 investigator-initiated nonrandomized clinical trial (GUIDANCE-06) Signal Transduction and Targeted Therapy |
| title | Genetic subtype-guided immunochemotherapy in relapsed and refractory diffuse large B cell lymphoma: a phase 2 investigator-initiated nonrandomized clinical trial (GUIDANCE-06) |
| title_full | Genetic subtype-guided immunochemotherapy in relapsed and refractory diffuse large B cell lymphoma: a phase 2 investigator-initiated nonrandomized clinical trial (GUIDANCE-06) |
| title_fullStr | Genetic subtype-guided immunochemotherapy in relapsed and refractory diffuse large B cell lymphoma: a phase 2 investigator-initiated nonrandomized clinical trial (GUIDANCE-06) |
| title_full_unstemmed | Genetic subtype-guided immunochemotherapy in relapsed and refractory diffuse large B cell lymphoma: a phase 2 investigator-initiated nonrandomized clinical trial (GUIDANCE-06) |
| title_short | Genetic subtype-guided immunochemotherapy in relapsed and refractory diffuse large B cell lymphoma: a phase 2 investigator-initiated nonrandomized clinical trial (GUIDANCE-06) |
| title_sort | genetic subtype guided immunochemotherapy in relapsed and refractory diffuse large b cell lymphoma a phase 2 investigator initiated nonrandomized clinical trial guidance 06 |
| url | https://doi.org/10.1038/s41392-025-02316-6 |
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