Nodal Peripheral T-cell Lymphomas Research Articles

Mutational profiling of Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorders do not resemble nodal peripheral T-cell lymphomas with follicular helper T-cell phenotype.

We performed targeted next-generation sequencing (NGS) of 62 selected genes, previously described as being mutated in T-cell lymphomas, in a total of 15 formalin-fixed paraffin-embedded (FFPE) pcSMTLPD patients.

Autologous hematopoietic cell transplantation consolidation for first response is associated with longer survival among patients with nodal peripheral T-cell lymphoma

Nodal peripheral T-cell lymphomas (PTCLs) are challenging subsets of non-Hodgkin lymphomas characterized by their heterogeneity and aggressive clinical behavior. Given the mixed outcomes reported in previous studies, the efficacy of autologous hematopoietic cell transplantation (auto-SCT) as a consolidation strategy following initial chemotherapy response remains uncertain. This study aims to evaluate the impact of upfront auto-SCT consolidation on overall survival (OS) and event-free survival (EFS) among patients with nodal PTCL who achieved a complete or partial response to initial chemotherapy. A retrospective cohort study was conducted at Moffitt Cancer Center, involving 123 patients with nodal PTCL treated between February 2005 and February 2021. Patients were stratified into two groups based on whether they received auto-SCT as part of their initial treatment strategy. Kaplan-Meier method and Cox proportional hazard models were used for statistical analysis to compare OS and EFS between groups. Patients undergoing auto-SCT after first response demonstrated significantly longer median OS (12.3 vs. 4.3 years; P = .035) and EFS (6.2 vs. 2.2 years; P = .003) compared to those who did not. Multivariate analyses indicated that auto-SCT at first response and younger age at diagnosis were favorable prognostic factors. The findings suggest that upfront auto-SCT consolidation can significantly improve long-term outcomes in patients with nodal PTCL, supporting the strategy of early auto-SCT consideration and referral following initial chemotherapy response. These results underscore the importance of integrating upfront auto-SCT into the treatment paradigm for nodal PTCL, emphasizing early referral to transplantation services to optimize patient outcomes.

Role of upfront autologous transplant for peripheral T-cell lymphoma patients achieving a complete remission with first-line therapy: a systematic review and meta-analysis.

There is currently no consensus on the role of upfront autologous transplantation (ASCT) for patients with peripheral T-cell lymphomas (PTCL), especially in patients achieving first complete remission (CR1) following chemotherapy, and data in the literature is conflicting. A systematic review and meta-analysis was performed to address this question. We searched key databases from January 2000 to February 2022. Six prospective and eleven retrospective studies were included among 2959 unique records. Median follow up in these studies ranged from 22 to 94 months. There was a trend towards benefit in PFS (HR = 0.80, 95% CI 0.62-1.05, p = 0.11) and OS (HR = 0.79, 95% CI 0.57-1.09, p = 0.15) in the ASCT compared to chemotherapy only group. Importantly, in transplant eligible patients in CR1, a significant benefit was demonstrated in both OS (HR = 0.59, 95% CI 0.36-0.95, p = 0.03) and PFS (HR = 0.61, 95% CI 0.47-0.81, p = 0.0004) in the ASCT group. Amongst the nodal PTCL subgroups, ASCT showed a significant PFS benefit for the AITL subgroup (HR = 0.43, 95% CI 0.20-0.94, p < 0.03) but not PTCL-NOS or ALK-ve ALCL subgroups. Our findings support upfront ASCT for transplant eligible PTCL patients achieving CR1 post chemotherapy. In particular, patients with AITL exhibited a significantly better PFS after upfront ASCT.

MicroRNA expression signature as a biomarker in the diagnosis of nodal T-cell lymphomas

BackgroundThe diagnosis of T-cell lymphomas is typically established through a multiparameter approach that combines clinical, morphologic, immunophenotypic, and genetic features, utilizing a variety of histopathologic and molecular techniques. However, accurate diagnosis of such lymphomas and distinguishing them from reactive lymph nodes remains challenging due to their low prevalence and heterogeneous features, hence limiting the confidence of pathologists. We investigated the use of microRNA (miRNA) expression signatures as an adjunctive tool in the diagnosis and classification of T-cell lymphomas that involve lymph nodes. This study seeks to distinguish reactive lymph nodes (RLN) from two types of frequently occurring nodal T-cell lymphomas: nodal T-follicular helper (TFH) cell lymphomas (nTFHL) and peripheral T-cell lymphomas, not otherwise specified (nPTCL).MethodsFrom the formalin-fixed paraffin-embedded (FFPE) samples from a cohort of 88 subjects, 246 miRNAs were quantified and analyzed by differential expression. Two-class logistic regression and random forest plot models were built to distinguish RLN from the nodal T-cell lymphomas. Gene set enrichment analysis was performed on the target genes of the miRNA to identify pathways and transcription factors that may be regulated by the differentially expressed miRNAs in each subtype.ResultsUsing logistic regression analysis, we identified miRNA signatures that can distinguish RLN from nodal T-cell lymphomas (AUC of 0.92 ± 0.05), from nTFHL (AUC of 0.94 ± 0.05) and from nPTCL (AUC of 0.94 ± 0.08). Random forest plot modelling was also capable of distinguishing between RLN and nodal T-cell lymphomas, but performed worse than logistic regression. However, the miRNA signatures are not able to discriminate between nTFHL and nPTCL, owing to large similarity in miRNA expression patterns. Bioinformatic analysis of the gene targets of unique miRNA expression revealed the enrichment of both known and potentially understudied signalling pathways and genes in such lymphomas.ConclusionThis study suggests that miRNA biomarkers may serve as a promising, cost-effective tool to aid the diagnosis of nodal T-cell lymphomas, which can be challenging. Bioinformatic analysis of differentially expressed miRNAs revealed both relevant or understudied signalling pathways that may contribute to the progression and development of each T-cell lymphoma entity. This may help us gain further insight into the biology of T-cell lymphomagenesis.

Clinicopathological implications of immunohistochemical expression of TBX21, CXCR3, GATA3, CCR4, and TCF1 in nodal follicular helper T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified.

The classification of nodal peripheral T-cell lymphoma (PTCL) has evolved according to histology, cell-of-origin, and genetic alterations. However, the comprehensive expression pattern of follicular helper T-cell (Tfh) markers, T-cell factor-1 (TCF1), and Th1- and Th2-like molecules in nodal PTCL is unclear. Eighty-two cases of nodal PTCL were classified into 53 angioimmunoblastic T-cell lymphomas (AITLs)/nodal T-follicular helper cell lymphoma (nTFHL)-AI, 18 PTCLs-Tfh/nTFHL-not otherwise specified (NOS), and 11 PTCLs-NOS according to the revised 4th/5th World Health Organization classifications. Immunohistochemistry for TCF1, TBX21, CXCR3, GATA3, and CCR4 was performed. TCF1 was highly expressed in up to 68% of patients with nTFHL but also in 44% of patients with PTCL-NOS (p > .05). CXCR3 expression was higher in AITLs than in non-AITLs (p = .035), whereas GATA3 expression was higher in non-AITL than in AITL (p = .007) and in PTCL-Tfh compared to AITL (p = .010). Of the cases, 70% of AITL, 44% of PTCLTfh/ nTFHL-NOS, and 36% of PTCL-NOS were subclassified as the TBX21 subtype; and 15% of AITL, 38% of PTCL-Tfh/nTFHL-NOS, and 36% of PTCL-NOS were subclassified as the GATA3 subtype. The others were an unclassified subtype. CCR4 expression was associated with poor progression-free survival (PFS) in patients with PTCL-Tfh (p < .001) and nTFHL (p = .023). The GATA3 subtype showed poor overall survival in PTCL-NOS compared to TBX21 (p = .046) and tended to be associated with poor PFS in patients with non-AITL (p = .054). The TBX21 subtype was more prevalent than the GATA3 subtype in AITL. The GATA3 subtype was associated with poor prognosis in patients with non-AITL and PTCL-NOS.

Comparison of Follicular Helper T-Cell Markers with the Expression of the Follicular Homing Marker CXCR5 in Peripheral T-Cell Lymphomas-A Reappraisal of Follicular Helper T-Cell Lymphomas.

Peripheral T-cell lymphomas (PTCLs) expressing multiple follicular T helper (TFH) cell-related antigens are now classified as TFH lymphomas (TFHL), including angioimmunoblastic, follicular, and not otherwise specified (NOS) types. CXCR5 is the TFH cell-defining chemokine receptor that, together with its ligand CXCL13, plays a critical role in the development of follicles and the positioning of TFH and B cells within follicles. A comprehensive immunomorphologic study was performed to investigate the expression pattern of CXCR5 in a large cohort of nodal PTCLs, particularly those with a TFH cell phenotype, and to compare its expression with six other TFH cell-related antigens. We found that CXCR5 is widely expressed in neoplastic TFH cells, except in TFHL-NOS, and represents a specific marker of this lymphoma entity. Our results suggest that CXCR5 directs the distribution of neoplastic T cells in the affected lymph nodes and may influence the formation of the pathognomic pathological FDC network.

Prognostic value of peripheral blood and bone marrow infiltration assessed by flow cytometry in dogs with de novo nodal peripheral T-cell lymphoma receiving alkylating-rich chemotherapy

Peripheral T-cell lymphoma (PTCL) is highly aggressive in dogs and demonstrates a poor response to traditional chemotherapy. The aim of this retrospective study was to assess the prognostic significance of peripheral blood (PB) and bone marrow (BM) infiltration evaluated by flow cytometry (FC) in dogs with treatment-naïve and histologically confirmed PTCL. To be included, dogs had to undergo complete staging, including FC on lymph nodes, PB and BM samples. Additionally, dogs had to receive an alkylating-rich protocol and have a complete follow-up. Treatment response was evaluated based on RECIST criteria at each chemotherapy session, and the end-staging was conducted at the completion of treatment. Endpoints were time to progression (TTP) and lymphoma-specific survival (LSS). The relationship between TTP/LSS and the percentage of PB and BM infiltration, categorized as > 1%, > 3%, > 5%, > 10%, > 15% and > 20% was investigated.Fifty dogs were included: based on imaging and FC, 78.0% had stage 5 disease, 14.0% had stage 4, 6.0% had stage 3 and 2.0% had stage 1. By multivariable analysis, the CD4-negative phenotype was the only factor associated with a shorter TTP (P = 0.049), while BM infiltration was significantly associated with LSS (P = 0.037). Dogs with BM infiltration > 5% had shorter median LSS (114 days; 95%CI: 0–240) compared to dogs with BM infiltration ≤ 5% (178 days; 95%CI: 145–211). Lack of complete response (P = 0.039) and administration of corticosteroids before chemotherapy (P = 0.026) also significantly worsened LSS. BM flow cytometric evaluation could be considered an essential part of staging work-up for dogs with PTCL and has prognostic relevance.

Efficacy and Safety of Valemetostat Monotherapy in Patients with Relapsed or Refractory Peripheral T-Cell Lymphomas: Primary Results of the Phase 2 VALENTINE-PTCL01 Study

Introduction: Peripheral T-cell lymphoma (PTCL) is an aggressive non-Hodgkin lymphoma (NHL), with limited available treatment options for patients (pts) with relapsed or refractory (R/R) disease. Valemetostat tosylate (valemetostat) is a novel and potent dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1, which is approved in Japan for the treatment of R/R adult T-cell leukemia/lymphoma (ATLL). Here, we report primary results for pts with R/R PTCL treated with valemetostat in the open-label, single-arm, global, phase 2 VALENTINE-PTCL01 study (DS3201-A-U202; NCT04703192). Methods: Pts were ≥ 18 years of age, had a confirmed diagnosis of PTCL, had R/R disease after ≥ 1 prior line of systemic therapy, and pts with anaplastic large cell lymphoma (ALCL) had received prior brentuximab vedotin treatment. Pts received oral valemetostat 200 mg/day in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR), assessed by blinded independent central review of PTCL following computed tomography (CT)-based response assessment according to Lugano 2014 criteria. Secondary efficacy endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Positron emission tomography (PET)-CT-based response assessment by Lugano 2014 criteria was an exploratory endpoint. Efficacy analyses included all pts who received ≥ 1 dose of valemetostat and had an eligible PTCL subtype confirmed by central hematopathology review; safety analyses included all pts who received ≥ 1 dose of valemetostat. Results: A total of 133 pts with R/R PTCL were enrolled and received ≥ 1 dose of valemetostat. Pts had a median age of 69 years (range 22-85) and 91 pts (68.4%) were male. Pts had received a median of 2 prior lines of therapy (range 1-12) and 35 pts (26.3%) received prior hematopoietic cell transplant (HCT; autologous, n = 32; allogeneic, n = 5). PTCL subtype eligibility was confirmed in 119 pts: 42 pts (31.6%) had angioimmunoblastic T-cell lymphoma (AITL), 41 (30.8%) had PTCL, not otherwise specified (PTCL, NOS), 9 (6.8%) had ALCL (7 [5.3%] ALK-negative and 2 [1.5%] ALK-positive), 8 (6.0%) had nodal PTCL with T follicular helper cell phenotype, and 19 (14.3%) had other PTCL subtypes. As of data cutoff (May 5, 2023), 32 pts (24.1%) were still receiving treatment; reasons for treatment discontinuation included progressive or relapsed disease in 46 pts (34.6%), clinical progression in 19 pts (14.3%), adverse event in 13 pts (9.8%), and 12 pts (9.0%) discontinued study drug to proceed with allogeneic HCT. Median treatment duration was 18 weeks (range 0.3-93.4) and median duration of follow-up was 10.5 months (range 0.2-21.5). Among 119 efficacy-evaluable pts, the CT-based ORR was 43.7% (n = 52) (95% confidence interval [CI], 34.6-53.1), including 17 pts (14.3%) achieving CR and 35 pts (29.4%) achieving PR as best overall response. Median DOR was 11.9 months (95% CI, 7.8-not evaluable [NE]) and median time to response was 8.1 weeks (range 5-37). ORR by PTCL subtype ranged from 31.7% for PTCL, NOS to 54.8% for AITL (Table 1). Using PET-CT-based response assessment, ORR was 52.1% (n = 62) (95% CI, 42.8-61.3), including 32 pts (26.9%) with a complete metabolic response. Median CT-based PFS was 5.5 months (95% CI, 3.5-8.3) and median OS was 17.0 months (95% CI, 13.5-NE). Of 133 pts in the safety analysis set, 128 pts (96.2%) experienced ≥ 1 treatment-emergent adverse event (TEAE) of any grade, 77 pts (57.9%) experienced grade ≥ 3 TEAEs, and 53 pts (39.8%) experienced serious adverse events. The most common all grade and grade ≥ 3 TEAE was thrombocytopenia (Table 2). Overall, 13 pts (9.8%) experienced a TEAE that led to treatment discontinuation, 21 pts (15.8%) had a TEAE that led to dose reduction, and 66 pts (49.6%) had a TEAE that led to dose interruption. Conclusions: Valemetostat demonstrated a high ORR of 43.7% with durable responses (median DOR of 11.9 months) in pts with R/R PTCL, and responses were observed across all PTCL subtypes. A valemetostat dose of 200 mg/day was tolerable; safety analysis showed that the most common TEAEs were cytopenias. These primary results from the VALENTINE-PTCL01 study suggest that valemetostat provides a clinically meaningful benefit for pts with R/R PTCL.

Refining Diagnostic Subtypes of Peripheral T-Cell Lymphoma Using a Multiparameter Approach

Peripheral T-cell lymphoma (PTCL) encompasses a diverse group of post-thymic lymphomas, with ~40% of cases not further classifiable and designated as PTCL-not otherwise specified (PTCL-NOS). Two molecular prognostic subtypes of PTCL-NOS, PTCL-TBX21 and PTCL-GATA3, were identified through gene expression profiling (GEP). A subset of PTCL-NOS with T-follicular helper (TFH) differentiation was subsequently categorized as nodal PTCL with TFH phenotype (PTCL-TFH), also known in current classifications as nodal PTCL-TFH, NOS, or TFH lymphoma, NOS. However, the boundary between PTCL-NOS and PTCL-TFH remains poorly defined. To refine these subtypes, 101 PTCL-NOS with centralized pathology review and extensive immunophenotyping by immunohistochemistry (IHC) using 22 antibodies, digital GEP (nCounter, NanoString Inc) (n= 70), and RNA sequencing (n= 73) were included in this study. IHC was used to identify PTCL-TFH cases (those with strong expression of more than two TFH markers); the remaining patients were classified as PTCL-GATA3 and PTCL-TBX21 using pre-defined GEP signatures. Cases were reclassified into PTCL-NOS (n= 63) and PTCL-TFH (n= 38), with PTCL-NOS subclassified into PTCL-GATA3 (n= 22; 34%) and PTCL-TBX21 (n= 41; 66%) and showing significant differences in OS (p&amp;lt;0.001). PTCL-GATA3 was characterized by medium to large transformed cells (average= 90%, 70-100%) and had minimal tumor microenvironment (TME) (TME-poor: 100%). In contrast, PTCL-TBX21 was more heterogeneous, associated with pleomorphic cells in a polymorphous background (TME-rich: 78%), including Lennert lymphoma-like cases (22%). mRNA and CIBERSORT analysis substantiated the findings and identified a subset enriched in cytotoxic features in the PTCL-TBX21 subtype. IHC indicated that PTCL-GATA3 cases were CD4+/CD8- (83%) or CD4-/CD8- (17%) and lacked expression of CD8 or cytotoxic markers compared to PTCL-TBX21 (p&amp;lt;0.01). PTCL-GATA3 showed significantly higher expression of LEF1 (average= 80%), Ki67 (80%), and MYC (25%) than PTCL-TBX21 (25%, 30%, &amp;lt;5%, respectively, p&amp;lt;0.01). mRNA and protein expression of these biomarkers showed a significant positive correlation (r=0.5, p&amp;lt;0.001), and expectedly higher mRNA expression of LEF1 and MYC was observed in the PTCL-GATA3 versus PTCL-TBX21 (p&amp;lt;0.05). Strong expression of CD30 (&amp;gt;50% of cells) was only seen in PTCL-GATA3 cases. EBER positivity, found only in rare background cells, was not significantly different (18% of PTCL-GATA3 vs. 12% of PTCL-TBX21). Within PTCL-TBX21, we identified cytotoxic and non-cytotoxic subsets with divergent morphological, phenotypic, and clinical findings. The cytotoxic PTCL-TBX21 exhibited an activated cytotoxic phenotype (23/25, 96%), denoted by TIA1 and granzyme-B and/or perforin expression. Extranodal involvement and single-cell apoptosis were observed in 17% and 45% of the cytotoxic cases, respectively, but absent in non-cytotoxic PTCL-TBX21 cases. A trend towards higher Ki67 expression (average= 40% vs. 20%, p= 0.08) was seen in the cytotoxic subgroup. In contrast, the non-cytotoxic PTCL-TBX21 was associated with a CD4+/CD8- phenotype and higher ICOS expression (average= 30%) and CCR4 (60%) compared to the cytotoxic PTCL-TBX21 (p= 0.001). PTCL-TFH cases showed a CD4+/CD8- phenotype (90%) and rarely a CD4-/CD8- phenotype (10%). While a subset of PTCL-TFH cases had AITL-like features such as numerous clear cells and/or prominent vasculature (31% of cases), which were not seen in the other subgroups, the remaining cases exhibited morphology that was indistinguishable from other PTLC-NOS cases including sheets of transformed cells or pleomorphic cells in a polymorphous background. Morphologically, PTCL-TFH cases, like PTCL-TBX21 were associated with a rich TME (TME-rich: 75%). CIBERSORT analysis showed enrichment of plasma cells (p&amp;lt;0.01) in PTCL-TFH, compared to PTCL-TBX21, and validated by morphology (30% of cases vs. 5%). Expression of one TFH marker was frequent in some PTCL-NOS cases (PTCL-GATA3= 41% of cases, PTCL-TBX21-non cytotoxic= 47%, PTCL-TBX21-cytotoxic= 5%). Conclusion: Our comprehensive evaluation underscores the importance of integrating morphology, immunophenotyping, and GEP in achieving an accurate diagnosis, potentially leading to more tailored treatment strategies for PTCL. Correlation with pending whole-exome sequencing studies will be provided at the time of presentation.

Past, present and future therapeutic approaches in nodal peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCL) encompass over 30 different entities and although they share post-thymic T- or NK-cell derivation, the disease biology and genomic landscape are very diverse across subtypes. In Western populations, nodal PTCL are the most frequently encountered entities in clinical practice and although important achievements have been made in deciphering the underlying biology and in therapeutic advances, there are still large gaps in disease understanding and clinical scenarios in which controversy over best practice continues. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)- based chemotherapy continues to be the 'standard' treatment, with the addition of brentuximab vedotin (BV) in the combination CHP (cyclosphosphamide, doxorubicin, prednisone)-BV representing a new treatment paradigm in CD30+ PTCL although its benefit is less certain in the non-anaplastic large cell lymphoma subtypes. Given the high risk of relapse, consolidative autologous stem cell transplant is considered in nodal PTCL, outside of ALK-positive anaplastic large cell lymphoma; however, in the absence of a randomized controlled trials, practices vary. Beyond CHP-BV, most study activity has focused on adding a novel agent to CHOP (i.e., CHOP + drug X). However, with high complete remission rates observed with some novel therapy combinations, these regimens are being tested in the front-line setting, with a particular rationale in follicular helper T-cell lymphomas which have a clear sensitivity to epigenetic modifying therapies. This is well exemplified in the relapsed/refractory setting in which rational combination therapies are being developed for specific subtypes or guided by underlying biology. Taken together, we have finally moved into an era of a more personalized approach to the management of nodal PTCL.

Prognostic Value of FDG PET/CT in Patients with Nodal Peripheral T-Cell Lymphoma.

This study evaluated the prognostic significance of FDG PET/CT in patients with nodal peripheral T-cell lymphoma (PTCL). We retrospectively reviewed patients with histologically confirmed nodal PTCL who underwent FDG PET/CT at baseline, after three cycles of first-line chemotherapy (interim), and at the end of therapy. Response was assessed visually using the Deauville 5-point scale (D5PS); scores of 1, 2, and 3 were considered PET-negative, and scores of 4 and 5 were considered PET-positive. The associations between FDG PET/CT findings and survival were assessed using Cox regression analysis. A total of 79 patients (44 males and 35 females; median age 56 years) were included in this study. In response assessment, 17 (22%) had an interim PET-positive result and 10 (13%) had an end-of-therapy PET-positive result. During a median follow-up of 50 months, 37 patients (47%) presented with disease progression and 30 patients (38%) died. The estimated 5-year progression-free survival (PFS) and overall survival (OS) were 57% and 64%, respectively. An interim PET-positive result was the only significant indicator of PFS. Higher International Prognostic Index and end-of-therapy PET-positive result were significant independent prognostic factors of OS. Interim and end-of-therapy FDG PET/CT responses based on D5PS are meaningful in predicting the outcomes of patients with nodal PTCL.

TP53 mutations identify high-risk events for peripheral T-cell lymphoma treated with CHOP-based chemotherapy.

Nodal peripheral T-cell lymphomas (PTCL), the most common PTCLs, are generally treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based curative-intent chemotherapy. Recent molecular data have assisted in prognosticating these PTCLs, but most reports lack detailed baseline clinical characteristics and treatment courses. We retrospectively evaluated cases of PTCL treated with CHOP-based chemotherapy that had tumors sequenced by the Memorial Sloan Kettering Integrated Mutational Profiling of Actionable Cancer Targets next-generation sequencing panel to identify variables correlating with inferior survival. We identified 132 patients who met these criteria. Clinical factors correlating with an increased risk of progression (by multivariate analysis) included advanced-stage disease and bone marrow involvement. The only somatic genetic aberrancies correlating with inferior progression-free survival (PFS) were TP53 mutations and TP53/17p deletions. PFS remained inferior when stratifying by TP53 mutation status, with a median PFS of 4.5months for PTCL with a TP53 mutation (n= 21) vs 10.5months for PTCL without a TP53 mutation (n= 111). No TP53 aberrancy correlated with inferior overall survival (OS). Although rare (n= 9), CDKN2A-deleted PTCL correlated with inferior OS, witha median of 17.6months vs 56.7months for patients without CDKN2A deletions. This retrospective study suggests that patients with PTCL with TP53 mutations experience inferior PFS when treated with curative-intent chemotherapy, warranting prospective confirmation.

The SALENTO prognostic model for limited-stage peripheral T-cell lymphoma from the International T-Cell Project Network.

The natural history of limited-stage peripheral T-cell lymphomas (PTCLs) remains poorly defined. We investigated outcomes and prognostic variables in patients registered in the T-Cell Project (TCP) (#NCT01142674) to develop a model to predict overall survival (OS) for the common nodal PTCL subtypes (PTCL-NOS, AITL, ALCL). The model was validated in an independent data set from Australian and Brazilian registries. 211 patients registered in the TCP between 2006-2018 were studied. The median age was 59 years (range 18-88) and median follow-up was 49 months. One hundred twenty-seven patients (78%) received anthracycline-based regimens, 5 patients (3%) radiotherapy alone (RT), 24 patients (15%) chemotherapy+RT. 5-year OS and PFS were 47% and 37%, respectively. Age >60 years, elevated LDH and low serum albumin were independent prognostic factors. The model identified 3 groups with low- (26%, score 0), intermediate- (41%, score 1), and high-risk (33%, score 2-3) with 5-year OS of 78% (95% confidence interval [95% CI], 29-127), 46% (95% CI, 24-68), and 25% (95% CI, 20-30), respectively (P < 0.001) and 5-year PFS of 66% (95% CI, 33-99), 37% (95% CI, 9-65), and 17% (95% CI, 9-25), respectively (P < 0.001). The model demonstrated greater discriminatory power than established prognostic indices and an analogous distribution and outcomes in the 3 groups in the validation cohort of 103 patients. The SALENTO Model (Limited Stage Peripheral T-Cell Lymphoma Prognostic Model) is an objective, simple and robust prognostic tool. The high-risk group has poor outcomes, comparable to advanced stage disease, and should be considered for innovative first-line approaches.

SOHO State of the Art Updates and Next Questions | New Pathways and New Targets in PTCL: Staying on Target.

While the peripheral T-cell lymphomas (PTCL) remain a therapeutic challenge, and increasingly account for a disproportionate number of lymphoma-related deaths, improved understanding of disease pathogenesis and classification, and the development of novel therapeutic agents over the past decade, all provide reasons for a more optimistic outlook in the next. Despite their genetic and molecular heterogeneity, many PTCL are dependent upon signaling input provided by antigen, costimulatory, and cytokine receptors. While gain-of-function alterations effecting these pathways are recurrently observed in many PTCL, more often than not, signaling remains ligand-and tumor microenvironment (TME)-dependent. Consequently, the TME and its constituents are increasingly recognized as "on target". Utilizing a "3 signal" model, we will review new-and old-therapeutic targets that are relevant for the more common nodal PTCL subtypes.

Hematological Oncology journal women in lymphoma special issue: Latest updates in nodal peripheral T-cell lymphoma.

In the last decade, there has been increased understanding of the pathologic features and biology of peripheral T cell lymphomas (PTCLs) through development of multi omics and molecular profiling techniques. In addition, international collaborations through multi center trials as well as prospective registry studies have improved our knowledge of host and tumor genomic factors and treatment factors affecting disease outcomes. In our review today, we aim to highlight the current epidemiology, latest advances in classification, disease biology and the evolving treatment landscape for nodal PTCLs.

THE GENETIC SUBTYPES AND THE TUMOR MICROENVIRONMENT SIGNATURES ARE ASSOCIATED WITH DISTINCT OUTCOMES IN PERIPHERAL T‐CELL LYMPHOMA

Background: Emerging evidence suggests the prognostic impact of the tumor microenvironment (TME) in peripheral T-cell lymphomas (PTCLs). To better understand PTCL pathobiology, we performed an integrative multi-omics study to explore the genetic subtypes and the TME signatures of PTCLs, especially nodal T-follicular helper T-cell lymphomas (nTFHLs) and PTCL, not otherwise specified (PTCL-NOS). Method: We performed whole-exome sequencing of 92 nTFHLs and 37 PTCL-NOSs, a total of 129 cases. Ninety-two nTFHLs included 85 angioimmunoblastic T-cell lymphomas (AITLs), four nPTCL with TFH phenotypes, two follicular T-cell lymphomas, and one unclassifiable nTFHL. Genetic drivers were integrated using non-negative matrix factorization consensus clustering (NMF). We estimated the proportion of immune cell fractions from bulk RNA sequencing data (n = 57) using CIBERSORTx and classified the TME signatures using hierarchical clustering. Results: NMF clustering analysis revealed three genetic subtypes within our cohort, except for 10 cases lacking recurrent genetic abnormalities (denoted as cluster 0). C2 was characterized by TP53 mutation, CDKN2A loss, PTEN loss, and chromosomal instability, corresponding to the previously described GATA3-PTCL subtype. C1 and C3 shared TFH-related genomic alterations, but C3 had significantly higher frequencies of chromosome (Chr) 5 gain, Chr 21 gain, RHOA, IDH2, and CD28 mutations. A higher frequency of rash and higher C-reactive protein levels than the other AITLs characterized C3-AITL. Pairwise association analysis of genomic alterations revealed that multiple TET2 mutations, rather than a single TET2 mutation, significantly co-occurred with IDH2 and RHOA mutations. A Bradley-Terry model estimated that the first TET2 and DNMT3A mutations occurred earlier, and the second or later TET2, RHOA, and IDH2 mutations occurred later. Compared to C1, significantly inferior survival was observed in C2 (hazard ratio (HR), 2.52; 95% CI, 1.37–4.63) and C3(HR, 2.14; 95% CI, 1.17–3.89; Figure A). The TME signatures were divided into TME1 (B-cells and follicular helper T-cells), TME2 (activated memory CD4 T-cells, M2 macrophages, and CD8 T-cells), and TME3 (naïve CD4 T-cells and activated mast cells). mTORC1 signaling was enriched in the TME2 signature compared to TME1 and TME3 signatures. The TME2 signature was significantly associated with shorter survival than the TME3 signature (HR: 3.4, 95% CI 1.6–7.5; Figure B). C2 had significantly more TME2 signature than C1 (64.3% vs. 7.7%), while C1 had significantly more TME3 signature than C2 (80.8% vs. 28.6%, p = 0.006; Figure C). Keywords: genomics, epigenomics, and other -omics, microenvironment Encore Abstract—previously submitted to EHA 2023 The research was funded by: Japan Society for the Promotion of Science KAKENHI grants (grant numbers: 19K23879, 22K19451, and 21H02945) and Japan Agency for Medical Research and Development (AMED) grants (20ck0106544 and 21ck0106644)

Frontline Management of Nodal Peripheral T-Cell Lymphomas.

Peripheral T-cell lymphomas (PTCLs) represent only 10%-15% of all non-Hodgkin lymphoma but encompass a diverse group of diseases with over 30 different subtypes. As a result of both disease heterogeneity and rarity, therapeutic progress of PTCLs has lagged behind B-cell lymphomas with very few randomized controlled studies to guide management. The most common subtypes are the so-called nodal PTCLs: PTCL-not otherwise specified (NOS), anaplastic large cell lymphoma (ALCL), and nodal T follicular helper cell lymphoma (TFHL) lymphoma, the latter of which includes angioimmunoblastic T-cell lymphoma. Anthracycline-based primary chemotherapy is still the mainstay of treatment for these common PTCL subtypes, but in recent years, we have moved into an era where more personalized therapy can be applied in some settings. Cyclophosphamide, doxorubicin, prednisone, and brentuximab vedotin CHP-BV is the first therapy in PTCL to show an overall survival benefit and represents a new standard for ALCL; however, there is less therapeutic certainty in other CD30-positive PTCLs. Recurrent mutations of epigenetic modifier genes typify TFHLs lymphomas, and collective studies demonstrate a heightened sensitivity to epigenetic therapies, leading to trials integrating these agents in the frontline setting. Molecular studies of PTCL-NOS have defined at least two subtypes, GATA3 and TBX21, the former having a poorer prognosis, but how this guides therapeutics remains unknown. Outside of ALCL, there is a growing debate as to whether trials should focus on adding a novel agent to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or whether combination novel therapies should be explored in the frontline therapy setting. Finally, the role of consolidative autologous stem-cell transplant in first remission remains an area of active debate.

Challenges in nodal peripheral T-cell lymphomas: from biological advances to clinical applicability.

T cell lymphomas are a heterogenous group with varying biological and clinical features that tend to have poor outcomes with a few exceptions. They account for 10-15% of all non-Hodgkin lymphomas (NHL), and 20% of aggressive NHL. There has been little change in the overall prognosis of T cell lymphomas over the last 2 decades. Most subtypes carry an inferior prognosis when compared to the B cell lymphomas, with a 5-year OS of 30%. Gene expression profiling and other molecular techniques has enabled a deeper understanding of these differences in the various subtypes as reflected in the latest 5th WHO and ICC classification of T cell lymphomas. It is becoming increasingly clear that therapeutic approaches that target specific cellular pathways are needed to improve the clinical outcomes of T cell lymphomas. This review will focus on nodal T cell lymphomas and describe novel treatments and their applicability to the various subtypes.

Follicular Helper T-Cell-derived Nodal Lymphomas: Study of Histomorphologic, Immunophenotypic, Clinical, and RHOA G17V Mutational Profile.

The study was designed to review the demographic, clinical, and pathologic characteristics of follicular helper T cells (TFH)-derived nodal PTCL in India including angioimmunoblastic T-cell lymphoma (AITL), peripheral T-cell lymphoma (PTCL) with follicular helper T cell phenotype (P-TFH), and follicular T-cell lymphoma with additional immunohistochemistry (IHC) and RHOAG17V mutational analysis, as well as their impact on survival. This retrospective study included 88 cases of PTCL that were reclassified using IHC for TFH markers (PD1, ICOS, BCL6, and CD10) and dendritic-meshwork markers (CD21, CD23). Cases of TFH cell origin were evaluated for RHOAG17V mutation using Sanger sequencing and amplification-refractory mutation system-polymerase chain reaction (PCR) (validated using cloning and quantitative PCR) with detailed clinicopathologic correlation. Extensive re-evaluation with added IHC panel resulted in a total of 19 cases being reclassified, and the final subtypes were AITL (37 cases, 42%), PTCL-not otherwise specified (44, 50%), P-TFH (6, 7%), and follicular T-cell lymphoma (1, 1%). The presence of at least 2 TFH markers (>20% immunopositivity) determined the TFH origin. AITL patients tended to be male and showed increased presence of B-symptoms and hepatosplenomegaly. Histomorphology revealed that 92% of AITL cases had pattern 3 involvement. Sanger sequencing with conventional PCR did not yield any mutation, while RHOAG17V was detected by amplification-refractory mutation system-PCR in AITL (51%, P =0.027) and P-TFH (17%), which was validated with cloning followed by sequencing. Cases of RHOAG17V-mutant AITL had a worse Eastern Cooperative Oncology Group performance status initially but fared better in terms of overall outcome ( P =0.029). Although not specific for AITL, RHOAG17V mutation shows an association with diagnosis and requires sensitive methods for detection due to low-tumor burden. The mutant status of AITL could have prognostic implications and translational relevance.

Tyrosine kinases in nodal peripheral T-cell lymphomas.

Nodal peripheral T-cell lymphomas (PTCL) are uncommon and heterogeneous tumors characterized by a dismal prognosis. Targeted therapy has been proposed. However, reliable targets are mostly represented by a few surface antigens (e.g., CD52 and CD30), chemokine receptors (e.g., CCR4), and epigenetic gene expression regulation. In the last two decades, however, several studies have supported the idea that tyrosine kinase (TK) deregulation might be relevant for both the pathogenesis and treatment of PTCL. Indeed, they can be expressed or activated as a consequence of their involvement in genetic lesions, such as translocations, or by ligand overexpression. The most striking example is ALK in anaplastic large-cell lymphomas (ALCL). ALK activity is necessary to support cell proliferation and survival, and its inhibition leads to cell death. Notably, STAT3 was found to be the main downstream ALK effector. Other TKs are consistently expressed and active in PTCLs, such as PDGFRA, and members of the T-cell receptor signaling family, such as SYK. Notably, as in the case of ALK, STAT proteins have emerged as key downstream factors for most of the involved TK.