Wei Xu

Improving the prognosis of patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) remains an unmet need. This multicenter, phase II

Orelabrutinib is a potent, irreversible, and highly-selective BTK inhibitor that has been approved for the treatment of relapsed/refractory chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). This randomized, phase 3 study (ClinicalTrials.gov identifier: NCT04578613) compared orelabrutinib with chemoimmunotherapy in patients with treatment-naïve CLL/SLL. From February 20, 2021, to July 8, 2024, 192 eligible patients were randomly assigned (1:1) to receive either orelabrutinib (91 patients) or chlorambucil plus rituximab (101 patients), comprising the intention-to-treat population. At a median follow-up of 21.4 months (data cutoff, May 17, 2024), the primary endpoint of progression-free survival (PFS) per independent review committee (IRC) was not reached (NR; 95% CI, not estimable [NE]-NE) with orelabrutinib versus 19.4 months (95% CI, 16.6-NE) with chlorambucil plus rituximab (hazard ratio [HR], 0.32; 95% CI, 0.18-0.58; p < 0.0001; crossing the efficacy boundary). The IRC-assessed overall response rate (90.1% vs 79.2%; p = 0.041) and duration of response (HR, 0.30; 95% CI, 0.15-0.60; p = 0.0003) also favored orelabrutinib over chlorambucil plus rituximab. In the safety population, treatment-related adverse events occurred in 82 of 91 patients (90.1%) receiving orelabrutinib and 89 of 98 patients (90.8%) receiving chlorambucil plus rituximab, with 32 (35.2%) and 59 (60.2%) at grade 3 or worse, respectively. Orelabrutinib maintained or improved patient-reported outcomes compared with chemoimmunotherapy. In summary, orelabrutinib significantly improved PFS and response versus chemoimmunotherapy in patients with treatment-naïve CLL/SLL, with a manageable safety profile, supporting it as an effective alternative first-line option.

Circulating tumor DNA (ctDNA) profiling offers a noninvasive approach to monitor minimal residual disease (MRD) and clonal evolution in diffuse large B-cel

This clinical trial (NCT05347641) evaluated efficacy and safety of penpulimab combined with rituximab, high-dose methotrexate, and cytarabine (Pen-RMA) in patients with newly diagnosed (ND) primary central nervous system lymphoma (PCNSL). Patients received an induction treatment of six cycles of Pen-RMA every 3 weeks. Patients younger than 60 years who achieved at least partial remission (PR) underwent autologous stem cell transplantation (ASCT), followed by 8 cycles of penpulimab as maintenance therapy. For patients over 60 years or not eligible for ASCT who achieved complete remission (CR) after induction therapy received 8 cycles of penpulimab as maintenance treatment, and those who achieved PR were treated with whole brain radiotherapy (WBRT) combined with 8 cycles of penpulimab. Patients who achieved stable disease (SD) or progressive disease (PD) were withdrawn from this study. The primary endpoint was 2-year progression-free survival (PFS). Between April 2022 and December 2023, twenty-six ND-PCNSL patients were enrolled, and 23 patients were included in the intention-to-treat analysis. The median age was 65 (38‒74) yr. The overall response rate (ORR) and CR rate after the induction therapy were 95.7% and 91.3%, respectively. At a median follow-up of 29.4 months, the median PFS and overall survival (OS) were not reached. 2-year PFS and OS were 70.7% and 75.0%, respectively. The most frequent treatment-related adverse events were leukopenia, anemia, neutropenia, and thrombocytopenia. Grade 3 or worse treatment-related adverse events occurred in 7 (30.4%) of 23 patients. Cerebrospinal fluid (CSF) circulating-tumor DNA (ctDNA) monitoring was performed in 13 patients with imaging CR and 1 with PR after induction treatment. Among them, 8 had CSF ctDNA clearance while 6 were positive. Overall, Pen-RMA regimen demonstrated encouraging antitumor activity with a manageable toxicity in PCNSL.

This phase II clinical trial evaluated the R2-GemOx-PD1i regimen, a combination of penpulimab (a modified PD1 inhibitor) with lenalidomide and rituximab, g

Circulating tumor DNA (ctDNA) has been recognized as a promising tumor-specific biomarker, but its molecular features in peripheral T cell lymphoma (PTCL) have not been well explored. We investigated the translational significance of liquid biopsy in a uniformly treated PTCL cohort (N=64). Our study found that pretreatment ctDNA burden was strongly associated with clinical risk factors and identified as a superior predictor of progression-free survival and overall survival. Although 46.9% of patients achieved complete response at the end of therapy (EOT), only 25.9% achieved negative minimal residual disease (MRDend-) and demonstrated superior prognosis. These findings suggests that MRD status at EOT may be a critical factor in disease progression and recurrence for PTCL patients. Additionally, the most frequently altered genes were identified as TET2 (6.7%), DNMT3A (48.5%), RHOA (27.3%), and TP53 (15.2%), which were not cleared by first-line CHOP-like regimens. Most importantly, clonal evolution was displayed during induction therapy and follow-up across all histological subtypes of PTCL patients. These findings support that EOT MRD status could serve as an important prognostic marker for PTCL patients and clear the direction of exploration and selection the new drugs particularly targeted to TET2/DNMT3A/RHOA mutation integrating with conventional treatments for PTCL patients.

Prognostic Role of SOCS1 Mutations in Diffuse Large B-Cell Lymphoma

BTG1 Mutation Correlates with Inferior Prognosis in Diffuse Large B-Cell Lymphoma

Anaplastic large cell lymphoma (ALCL) is a heterogeneous subtype of T‐cell lymphoma usually driven by genetic alterations affecting the anaplastic lymphoma kinase (ALK) gene. Despite the relatively favorable prognosis of ALK‐positive (ALK⁺) ALCL, approximately 30–40% of patients experience relapses or disease progression. This work identifies protein tyrosine phosphatase PTPN2 as a critical gene essential for the growth and survival of ALK⁺ ALCL by CRISPR/Cas9 editing. PTPN2 depletion can significantly suppress tumor cell proliferation, induce apoptosis, and provoke cell cycle arrest. Mechanistically, PTPN2 negatively regulates transferrin receptor (TFRC) expression to promote mitochondrial renewal via PTEN induced kinase 1 (PINK1)‐PRKN (parkin RBR E3 ubiquitin protein ligase)‐mediated mitophagy. The process functions independently of ferroptosis. Interestingly, TFRC is directly regulated by the transcription factor hypoxia‐inducible factor 1 alpha (HIF1A) in its promoter. Notably, an orally bioavailable potent PTPN2/N1 active‐site inhibitor ABBV‐CLS‐484 (AC484) demonstrates significant therapeutic potential against ALK⁺ ALCL by disturbing mitochondrial renewal and blocking TFRC‐mediated PINK1‐PRKN‐dependent mitophagy to exert anti‐tumor activities, providing critical insights into the selection of targeted treatment strategies for ALK⁺ ALCL patients and a strong rationale for advancing AC484 into clinical trials.