Background
Diffuse large B‐cell lymphoma (DLBCL) patients refractory to rituximab‐based immunochemotherapy have a dismal prognosis. However, the definition of refractory DLBCL remains inconsistent and no large cohort study data is available from Asian countries. To validate the definition and outcomes of refractory DLBCL in China, we conducted a multicenter, retrospective cohort study.
Methods
The REtrospective AnaLysis of Treatment REspoNse of refractory DLBCL (REAL‐TREND) study was performed using real‐world data from 8 centers in China. DLBCL patients with curative intent were included in the REAL‐TREND dataset. Overall survival (OS) was estimated using the Kaplan‐Meier method and compared by the log‐rank test. Due to heterogeneity in response rates among different centers, the response rates of refractory patients were pooled using random‐effect models. Multivariate survival analysis was performed using the Cox regression model.
Results
A total of 2778 DLBCL patients diagnosed between January, 2010 and December, 2015 were enrolled to this study. After validating previous definitions, the SCHOLAR‐1 study was most suitable to define refractory DLBCL. The estimated 5‐year cumulative incidence of refractory patients was 20% (95% confidence Interval [CI] = 18%‐22%). After the determination of refractory disease, overall response rate and complete remission rate were 30% (95% CI = 22%‐38%) and 9% (95% CI = 4%‐15%), respectively. Patients with either no response to immunochemotherapy or relapse within 12 months after stem‐cell transplantation had inferior survival with a median OS of 5.9 months (95% CI = 5.5‐7.1 months) and 2‐year OS rate of 16% (95% CI = 12%‐20%). International prognostic index score 4‐5 (hazard ratio [HR] = 2.22; 95% CI = 1.47‐3.35), central nervous system relapse (HR = 1.43; 95% CI = 1.04‐1.97), and best response status (HR = 2.68; 95% CI = 1.42‐5.03 for partial remission. HR = 5.97, 95% CI = 3.21‐11.11 for stable disease/progressive disease) were independent unfavorable prognostic factors.
Conclusions
This is the first large‐scale Asian cohort study focusing on outcomes of refractory DLBCL. The definition of the SCHOLAR‐1 study identifies patients with homogenously inferior survival, thus is appropriate to select refractory DLBCL. Due to poor clinical outcomes in the rituximab era, patients with refractory DLBCL may be potential candidates for novel treatment modalities.
The incidence of diffuse large B-cell lymphoma (DLBCL) increases by age and older DLBCL are commonly related to poor prognosis. However, the clinical and biological features of older DLBCL patients remain to be determined. A total of 2,445 patients with newly diagnosed DLBCL were enrolled for clinical data analysis according to age at diagnosis, with tumor samples of 1,150 patients assessed by DNA sequencing and 385 patients by RNA sequencing. Older DLBCL presented advanced disease stage, elevated serum lactate dehydrogenase, poor performance status, multiple extranodal involvement, high percentage of double expressor subtype, and adverse clinical outcome. According to molecular features, age was positively correlated with the oncogenic mutations of PIM1, MYD88, BTG2, CD79B, TET2, BTG1, CREBBP, TBL1XR1, and with the MYD88-like genetic subtype. These oncogenic mutations were involved in B-cell receptor/NF-κB signaling, B-cell differentiation, and histone acetylation based on biological functions. Older DLBCL also manifested reduction in CD4+ naïve T and CD8+ naïve T cells, and also increased recruitment of exhausted T cells and macrophages, leading to immunosuppressive tumor microenvironment. Our work thus contributes to the understanding of aging-related oncogenic mutations and tumor microenvironment alterations in lymphoma progression, and may provide new insights to mechanism-based targeted therapy in DLBCL.
Interferon regulatory factor 4 (IRF4) rearrangement is commonly detected in patients with a range of lymphoproliferative malignancies, including myelomas, large B cell lymphomas and low‐grade B cell neoplasms. However, IRF4 rearrangement is generally a relatively rare finding in these latter two cancer types. In the present article, we describe and summarize the clinicopathological and genetic features of 13 cases of B cell lymphoma with IRF4 rearrangement, including 12 cases of large B cell lymphoma and one case of low‐grade lymphoma exhibiting such rearrangement. These cases were detected in six females and seven males between 14 and 71 years of age. From a morphological perspective, large B cell lymphoma tumors included in this analysis exhibited large neoplastic cells in diffuse or follicular patterns, while the case of low‐grade lymphoma mainly composed of small lymphocytes. All analyzed cases exhibited a split in the IRF4 gene consistent with IRF4 translocation. Three of six analyzed large B cell lymphoma cases harbored IGLL5 mutations. Mutations in SAMHD1 were detected in the low‐grade lymphoma with IRF4 rearrangement case. In summary, our results offer further insight into the morphological and molecular heterogeneity of cases of B cell lymphoma exhibiting IRF4 rearrangements.
Long noncoding RNAs (lncRNAs) play an essential role in tumor progression. Few researches focused on the clinical and biological relevance of lncRNAs in peripheral T cell lymphoma (PTCL). In this research, a novel lncRNA (ENST00000503502) was identified overexpressed in the main subtypes of PTCL, and designated as T cell lymphoma-associated lncRNA1 (TCLlnc1). Serum TCLlnc1 was associated with extranodal involvement, high-risk International Prognostic Index, and poor prognosis of the patients. Both in vitro and in vivo, overexpression of TCLlnc1 promoted T-lymphoma cell proliferation and migration, both of which were counteracted by the knockdown of TCLlnc1 using small interfering RNAs. As the mechanism of action, TCLlnc1 directly interacted with transcription activator heterogeneous nuclear ribonucleoprotein D (HNRNPD) and Y-box binding protein-1 (YBX1) by acting as a modular scaffold. TCLlnc1/HNRNPD/YBX1 complex upregulated transcription of TGFB2 and TGFBR1 genes, activated the tumor growth factor-β signaling pathway, resulting in lymphoma progression, and might be a potential target in PTCL.
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