MOLECULAR SUBTYPE-GUIDED R-MINE+X REGIMEN IN RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA: A SINGLE-ARM, OPEN-LABEL, MULTICENTER PHASE II STUDY

IF 3.9 4区医学 Q2 HEMATOLOGY

Hematological Oncology Pub Date : 2025-06-16 DOI:10.1002/hon.70094_317

J. Liang, H. Shen, H. Yin, J. Wu, Y. Li, L. Bi, W. Qin, L. Su, J. Liu, L. Wang, J. Li, W. Xu

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引用次数: 0

Abstract

W. Xu equally contributing author.

Background: The genetic heterogeneity of diffuse large B-cell lymphoma (DLBCL) significant influences prognosis and treatment response. Recent advances in molecular profiling have facilitated the identification of driver mutations (Zhang et al. 2023). Nevertheless, data on relapsed/refractory (R/R) DLBCL remain limited. Salvage chemotherapy R-MINE (rituximab, mitoxantrone, ifosfamide, etoposide) remains the therapeutic mainstay, yet suboptimal survival persists. To address this, we explored R-MINE by replacing conventional mitoxantrone with mitoxantrone hydrochloride liposome (Lipo-MIT) and incorporated molecular subtype-guided targeted agents (X) into the R-MINE+X regimen for R/R DLBCL.

Methods: This multicenter, single-arm, open-label, phase II study enrolled adult patients (pts) with R/R DLBCL. Following the first R-MINE cycle, pts received subtype-stratified targeted therapy (X) in combination with R-MINE. The R-MINE+X regimen (rituximab 375 mg/m², d0; Lipo-MIT 12‒20 mg/m², d1; ifosfamide 1.33 g/m², d1‒3; etoposide 65 mg/m², d1‒3) was administered for up to 3 cycles (each cycle lasting 21 days). Targeted combinations: MCD/BN2 (BTK inhibitors), EZB (chidamide), TP53 mutation (PD-1 monoclonal antibody), other subtypes (lenalidomide/investigator's choice). The primary endpoint was objective response rate (ORR). This study is registered (NCT05784987) at www.clinicaltrials.gov.

Results: From April 2022 to March 2025, sixty R/R DLBCL pts were enrolled (median age 62 [range 24–79]; 58.3% male). Among them, 45 (75.0%) pts had advanced-stage disease with stage III‒IV, and 28 (46.7%) pts had IPI scores of 3‒5. Forty (66.7%) pts were refractory to the last-line therapy, and 31 pts (51.7%) were primary refractory.

As of the date cutoff, a total of 49 pts had undergone at least once efficacy assessment, with the ORR of 75.5% (37/49) and complete response (CR) rate of 51.0% (25/49). With EZB group (n = 3), 2 pts achieved CR and 1 patient achieved partial response (PR). The MCD/BN2 group (n = 18) showed an ORR of 77.8% (14/18) and a CR rate of 55.6% (10/18). Among the TP53 mutation group (n = 2), 1 patient achieved PR. The ORR and CR rate of the other group (n = 24) were 75.0% (18/24) and 50.0% (12/24), respectively. Preliminary efficacy was demonstrated in advanced-stage disease, non-germinal center B cell like (non-GCB) and double expressor lymphoma (DEL) (Table 1). These results suggest particular therapeutic potential in populations with unfavorable prognostic features. With a median follow-up of only 3.1 months (95% CI: 2.2–4.0), the survival requires longer observation. The most common grade 3/4 treatment-related adverse events were neutropenia (35.0%), leucopenia (31.7%), anemia (25.0%), thrombocytopenia (15.0%), and hypokalemia (11.7%). No cardiac-related adverse events were reported.

Conclusions: The R-MINE+X regimen exhibited favorable tolerability and clinically meaningful efficacy in R/R DLBCL.

Research funding declaration: No funding disclosure

Encore Abstract: EHA 2025

Keywords: Aggressive B-cell non-Hodgkin lymphoma; Molecular Targeted Therapies; Ongoing Trials

No potential sources of conflict of interest.

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分子亚型引导的r-mine + x方案治疗复发/难治性弥漫性大b细胞淋巴瘤：单臂、开放标签、多中心ii期研究

许伟是同等贡献作者。背景：弥漫性大b细胞淋巴瘤（DLBCL）的遗传异质性显著影响预后和治疗反应。分子谱分析的最新进展有助于识别驱动突变（Zhang et al. 2023）。然而，复发/难治（R/R） DLBCL的数据仍然有限。补救性化疗R-MINE（利妥昔单抗、米托蒽醌、异环磷酰胺、依托泊苷）仍然是主要的治疗方案，但生存率仍然不理想。为了解决这个问题，我们通过用盐酸米托蒽醌脂质体（lipop - mit）取代传统的米托蒽醌来探索R- mine，并将分子亚型引导的靶向药物(X)纳入R- mine +X方案中治疗R/R DLBCL。方法：这项多中心、单臂、开放标签、II期研究纳入了患有R/R DLBCL的成年患者（pts）。在第一个R-MINE周期后，患者接受亚型分层靶向治疗(X)联合R-MINE。R-MINE+X方案(利妥昔单抗375 mg/m2， d0；lipoo - mit 12 - 20mg /m2, d1；异环磷酰胺1.33 g/m2, d1-3；依托泊苷65 mg/m2， d1-3)给药3个周期（每个周期持续21天）。靶向组合：MCD/BN2 （BTK抑制剂），EZB（奇达胺），TP53突变（PD-1单克隆抗体），其他亚型（来那度胺/研究者选择）。主要终点为客观缓解率（ORR）。该研究在www.clinicaltrials.gov.Results注册（NCT05784987）：从2022年4月到2025年3月，60名R/R DLBCL患者入组(中位年龄62岁[范围24-79]；58.3%的男性)。其中45例（75.0%）为晚期疾病，III-IV期，28例（46.7%）患者IPI评分为3-5分。40例（66.7%）患者对最后一线治疗难治性，31例（51.7%）患者为原发性难治性。截止日期，共有49例患者接受了至少一次疗效评估，ORR为75.5%(37/49)，完全缓解（CR）率为51.0%（25/49）。EZB组（n = 3）， 2例达到CR， 1例达到部分缓解（PR）。MCD/BN2组（n = 18）的ORR为77.8% (14/18)，CR为55.6%（10/18）。TP53突变组（n = 2）中有1例患者达到PR，另一组（n = 24）的ORR和CR率分别为75.0%（18/24）和50.0%（12/24）。在晚期疾病、非生发中心B细胞样（non-GCB）和双表达性淋巴瘤（DEL）中显示了初步疗效（表1）。这些结果表明在具有不良预后特征的人群中具有特殊的治疗潜力。中位随访期仅为3.1个月（95% CI: 2.2-4.0），生存期需要更长时间的观察。最常见的3/4级治疗相关不良事件是中性粒细胞减少（35.0%）、白细胞减少（31.7%）、贫血（25.0%）、血小板减少（15.0%）和低钾血症（11.7%）。无心脏相关不良事件报道。结论：R- mine +X方案对R/R DLBCL具有良好的耐受性和临床意义。关键词：侵袭性b细胞非霍奇金淋巴瘤；分子靶向治疗；正在进行的试验没有潜在的利益冲突。

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来源期刊

Hematological Oncology 医学-血液学

CiteScore

4.20

自引率

6.10%

发文量

147

审稿时长

>12 weeks

期刊介绍： Hematological Oncology considers for publication articles dealing with experimental and clinical aspects of neoplastic diseases of the hemopoietic and lymphoid systems and relevant related matters. Translational studies applying basic science to clinical issues are particularly welcomed. Manuscripts dealing with the following areas are encouraged: -Clinical practice and management of hematological neoplasia, including: acute and chronic leukemias, malignant lymphomas, myeloproliferative disorders -Diagnostic investigations, including imaging and laboratory assays -Epidemiology, pathology and pathobiology of hematological neoplasia of hematological diseases -Therapeutic issues including Phase 1, 2 or 3 trials as well as allogeneic and autologous stem cell transplantation studies -Aspects of the cell biology, molecular biology, molecular genetics and cytogenetics of normal or diseased hematopoeisis and lymphopoiesis, including stem cells and cytokines and other regulatory systems. Concise, topical review material is welcomed, especially if it makes new concepts and ideas accessible to a wider community. Proposals for review material may be discussed with the Editor-in-Chief. Collections of case material and case reports will be considered only if they have broader scientific or clinical relevance.