Genomic and transcriptomic profiling of peripheral T cell lymphoma reveals distinct molecular and microenvironment subtypes.

Peripheral T cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin's lymphomas varying in clinical, phenotypic, and genetic features. The molecular pathogenesis and the role of the tumor microenvironment in PTCL are poorly understood, with limited biomarkers available for genetic subtyping and targeted therapies. Through an integrated genomic and transcriptomic study of 221 PTCL patients, we delineate the genetic landscape of PTCL, enabling molecular and microenvironment classification. According to the mutational status of RHOA, TET2, histone-modifying, and immune-related genes, PTCL is divided into 4 molecular subtypes with discrete patterns of gene expression, biological aberrations, and vulnerabilities to targeted agents. We also perform an unsupervised clustering on the microenvironment transcriptional signatures and categorize PTCL into 4 lymphoma microenvironment subtypes based on characteristic activation of oncogenic pathways and composition of immune communities. Our findings highlight the potential clinical rationale of future precision medicine strategies that target both molecular and microenvironment alterations in PTCL.

Up-front autologous stem cell transplant in peripheral T-cell lymphoma patients achieving complete response after first-line treatment: A multicentre real-world analysis.

We conducted a retrospective, multicentre study to compare consolidation therapy with or without first-line autologous stem cell transplant (ASCT) for peripheral T-cell lymphoma (PTCL) patients in a real-world setting. We enrolled 347 PTCL patients who achieved complete response after first-line treatment. Of these, 257 received consolidation chemotherapy (non-ASCT group) and 90 received ASCT (ASCT group). Clinical outcomes were comparable between ASCT and non-ASCT groups. After propensity score matching, the 2-year cumulative incidence of treatment-related mortality and relapse remained similar between groups (1.9% vs. 2.0%, p = 0.985; 24.7% vs. 47.1%, p = 0.021). However, significant differences emerged in progression-free survival and overall survival probabilities. Within the T-cell lymphoma subgroup, ASCT patients exhibited favourable outcomes compared to non-ASCT patients: 2-year progression-free survival (73.4% vs. 50.8%, p = 0.024) and overall survival (92.1% vs. 73.5%, p = 0.021). Notably, no significant differences were observed for patients with NK/T-cell lymphoma. These real-world data suggest that up-front ASCT is a safe and effective consolidation option for PTCL patients in remission, particularly those with T-cell lymphoma.

The genetic landscape of histologically transformed marginal zone lymphomas.

BACKGROUND: Marginal zone lymphomas (MZLs) comprise a diverse group of indolent lymphoproliferative disorders; however, some patients develop histologic transformation (HT) with rapid progression to aggressive lymphoma. METHODS: Forty-three MZLs with HT (HT-MZLs), 535 MZLs, and 174 de novo diffuse large B-cell lymphomas (DLBCLs) without rearrangements of MYC, BCL2, and BCL6 were collected. Among these, 22 HT-MZLs, 39 MZLs, and 174 DLBCLs were subjected to 148-gene targeted exome sequencing. The clinicopathologic features of patients who had HT-MZL and their genetic alterations were compared with those of patients who had MZLs and DLBCLs. RESULTS: All 43 HT-MZLs corresponded to DLBCLs. No HT-MZLs harbored BCL2 and MYC and/or BCL6 rearrangements. Bone marrow involvement and higher levels of lactate dehydrogenase were significantly more common in HT-MZLs than in MZLs. Furthermore, upregulated BCL6, MUM1, C-MYC, and Ki-67 expression was observed more frequently in HT-MZLs than in MZLs. TBL1XR1 was the most frequently altered gene (63.6%) in HT-MZLs, followed by CCND3 (31.8%), CARD11, ID3, and TP53 (22.7%). A trend toward worse progression-free survival in patients with TBL1XR1 mutations was observed. Compared with MZLs and non-germinal center B-cell (GCB) type DLBCLs, significantly higher frequencies of TBL1XR1 and ID3 mutations were identified in HT-MZLs. PIM1 mutations frequently occurred in DLBCLs and were significantly associated with TBL1XR1 mutations but were mutated less in HT-MZLs that had TBL1XR1 mutations. CONCLUSIONS: The current findings reveal the clinicopathologic and genetic features of HT-MZLs, suggesting that these tumors might constitute a group distinct from MZL and de novo non-GCB type DLBCL. TBL1XR1 mutations may be considered a predictor of HT in MZL.

CEOP/IVE/GDP alternating regimen compared with CEOP as the first-line therapy for newly diagnosed patients with peripheral T cell lymphoma: results from a phase 2, multicenter, randomized, controlled clinical trial.

BACKGROUND: Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)/CHOP-like chemotherapy is widely used in peripheral T cell lymphoma (PTCL). Here we conducted a phase 2, multicenter, randomized, controlled trial, comparing the efficacy and safety of CEOP/IVE/GDP alternating regimen with CEOP in newly diagnosed PTCL. METHODS: PTCL patients, except for anaplastic large cell lymphoma-anaplastic lymphoma kinase positive, were 1:1 randomly assigned to receive CEOP/IVE/GDP (CEOP, cyclophosphamide 750 mg/m2, epirubicin 70 mg/m2, vincristine 1.4 mg/m2 [maximum 2 mg] on day 1, and prednisone 60 mg/m2 [maximum 100 mg] on days 1-5 every 21 days, at the first and fourth cycle; IVE, ifosfamide 2000 mg/m2 on days 1-3, epirubicin 70 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1-3 every 21 days, at the second and fifth cycle; and GDP, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 25 mg/m2 on days 1-3, and dexamethasone 40 mg on days 1-4 every 21 days, at the third and sixth cycle) and CEOP (every 21 days for 6 cycles). Analysis of efficacy and safety was of the intent-to-treatment population. The primary endpoint was a complete response rate at the end of treatment. Meanwhile, whole exome sequencing and targeted sequencing were performed in 62 patients with available tumor samples to explore prognostic biomarkers in this cohort as an exploratory post hoc analysis. RESULTS: Among 106 patients, 53 each were enrolled to CEOP/IVE/GDP and CEOP. With 51 evaluable patients each in two groups, a complete response rate of the CEOP/IVE/GDP group was similar to that of the CEOP group (37.3% vs. 31.4%, p = 0.532). There was no difference in median progression-free survival (PFS; 15.4 months vs. 9.2 months, p = 0.122) or overall survival (OS; 24.3 months vs. 21.9 months, p = 0.178). Grade 3-4 hematological and non-hematological adverse events were comparable. Histone modification genes were most frequently mutated (25/62, 40.3%), namely KMT2D, KMT2A, SETD2, EP300, and CREBBP. Multivariate analysis indicated that CREBBP and IDH2 mutations were independent factors predicting poor PFS and OS (all p < 0.001), while KMT2D predicting poor PFS (p = 0.002). CONCLUSIONS: CEOP/IVE/GDP alternating regimen showed no remission or survival advantage to standard chemotherapy. Future clinical trials should aim to develop alternative regimen targeting disease biology as demonstrated by recurrent mutations in epigenetic factors. TRIAL REGISTRATION: The study was registered on ClinicalTrial.gov (NCT02533700) on August 27, 2015.

Iron deficiency anaemia can be improved after eradication of Helicobacter pylori.

BACKGROUND: Recent guidelines on iron deficiency anaemia (IDA) have confirmed the aetiological role of Helicobacter pylori (H pylori), but the relationship still remains controversial. METHODS: Starting in May 2009, searches of the following databases were undertaken: Medline (1966 to April 2009), Embase (1980 to April 2009), the Cochrane library (1800 to June 2008), Cochrane Central Register of Controlled Trials, Premedline, Healthstar, CBMdisc and the Chinese National Knowledge Infrastructure Database (January 1970 to April 2009). Changes in haemoglobin (Hb) concentrations and serum ferritin (SF) concentrations were recorded for intervention and control groups. The meta-analysis used random effect models and subgroup analyses were performed to explain heterogeneity. RESULTS: Eight studies met the inclusion criteria. All studies were performed in Asia, an area with a high incidence of IDA and H pylori. The pooled analysis of eight studies showed that H pylori eradication therapy can improve IDA, since changes in Hb and SF concentrations in the intervention groups were higher than in controls. The weighted mean difference (WMD) of Hb was 12.88 g/l (95% CI 6.03 to 19.74 g/l, p<0.00001); the WMD of SF was 10.05 mug/l (95% CI 5.48 to 14.63 mug/l, p<0.00001). CONCLUSIONS: H pylori eradication therapy combined with iron administration is more effective than iron administration alone for the treatment of IDA. Eradication therapy has different effects on adults and children. Bismuth based triple therapy has a better response in terms of increased Hb and SF concentrations than proton pump inhibitor (PPI) based triple therapy.

Does Helicobacter pylori infection play a role in iron deficiency anemia? A meta-analysis.

AIM: To perform a meta-analysis of observational studies and randomized controlled trials (RCTs) on the association between Helicobacter pylori (H. pylori) and iron deficiency anemia (IDA). METHODS: A defined search strategy was used to search Medline, Embase, the Cochrane Library, Clinical Trials, Cochrane Central Register of Controlled Trials, Premedline and Healthstar. Odds ratio (OR) was used to evaluate observational epidemiology studies, and weighted mean difference (WMD) was used to demonstrate the difference between control and intervention groups. RESULTS: Fifteen observational studies and 5 RCTs were identified and used for calculation. The pooled OR for observational studies was 2.22 (95% CI: 1.52-3.24, P < 0.0001). The WMD for hemoglobin (HB) was 4.06 g/L (95% CI: -2.57-10.69, P = 0.01), and the WMD for serum ferritin (SF) was 9.47 mug/L (95% CI: -0.50-19.43, P < 0.0001). Results were heterogeneous for all comparisons. CONCLUSION: This meta-analysis on observational studies suggests an association between H. pylori and IDA. In RCTs, eradication of H. pylori can improve HB and SF levels but not significantly.