Angioimmunoblastic T-cell Lymphoma Patients Research Articles

Diagnosis of bone marrow involvement in angioimmunoblastic T-cell lymphoma should be based on both [18F]FDG-PET/CT and bone marrow biopsy findings

Objective During the initial staging of certain lymphoma subtypes, 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG-PET/CT) has become an alternative to bone marrow biopsy (BMB) for detecting bone marrow (BM) involvement. However, whether [18F]FDG-PET/CT can accurately detect BM involvement in angioimmunoblastic T-cell lymphoma (AITL) remains unknown. Our study aimed to assess the diagnostic and prognostic capability of [18F]FDG-PET/CT for detecting BM involvement in AITL. Methods: This retrospective study included 84 individuals newly diagnosed with AITL who underwent baseline BMB and [18F]FDG-PET/CT. “BM involvement” was defined as one or both of the following: 1) angioimmunoblastic T-cells detected in the BM; or 2) initially heightened focal uptake having disappeared on follow-up [18F]FDG-PET/CT. The ability of [18F]FDG-PET/CT to detect BM cancerous lesions was respectively analyzed by BM involvement confirmed by BMB or the aforementioned definition as the reference standard. The patients’ clinical characteristics and survival and prognostic outcomes were respectively analyzed. Results Of the 84 participants, five (6.0%) displayed positive BMB and PET/BM results, 17 (20.2%) had BMB-positive but PET/BM-negative results, eight (9.5%) showed BMB-negative but PET/BM-positive outcomes, and 54 (64.3%) displayed negative BMB and PET/BM outcomes. Using pre-defined BM involvement as the reference standard, [18F]FDG-PET/CT exhibited a specificity of 100%, sensitivity of 40%, negative predictive value (NPV) of 75%, and positive predictive value (PPV) of 100%. In contrast, using BMB-detected BM involvement as reference, [18F]FDG-PET/CT exhibited a sensitivity, specificity, PPV, and NPV of 38.5%, 76.1%, 22.7%, and 87.1%, respectively. Among patients with PET/BM-positive and BMB-negative outcomes, 62.5% (5/8) underwent upstaging from III to IV. In 58.8% (10/17) of patients who were initially diagnosed with stage II/III disease based on the [18F]FDG-PET/CT results, repeat BMB resulted in upstaging to IV. PET/BM-negative patients had a higher 3-year progression-free survival rate (38.3% vs. 22.8%, p = 0.018) and 3-year overall survival rate (64.4% vs. 34.6%, p = 0.011) than PET/BM-positive patients. Conclusion In AITL patients, PET/BM-positive results may obviate the necessity for repeat BMB to ascertain confirm BM involvement. PET/BM-negative results do not definitively exclude BM involvement. The combined use of [18F]FDG-PET/CT and BMB can increase the diagnostic accuracy of BM involvement for AITL patients.

Comparison of chemotherapy and chidamide combined with chemotherapy in patients with untreated angioimmunoblastic T-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) is characterized by high recurrence rates and poor prognosis, and effective first-line treatment is lacking. Recently, histone deacetylase inhibitors (HDACi), such as chidamide, have been found to induce durable remissions in AITL patients. Patients with untreated AITL from March 2015 to March 2023 were retrospectively collected and divided into chemotherapy (ChT) group and chidamide combined with chemotherapy (C-ChT) group based on the first-line treatment received. The comparison of efficacy and safety between the two groups was conducted. 86 patients with newly diagnosed AITL were enrolled, in which 35 patients were in the ChT group and 51 in the C-ChT group. The objective response rate (ORR) of C-ChT group was significantly higher than that of ChT group (84.3% vs. 60%, P= 0.011), and had superior progression-free survival (PFS) (27 months vs. 12 months, P= 0.025). However, no significant difference in overall survival (OS) was observed between the two groups (P= 0.225). In addition, the responding patients who received autologous stem cell transplantation (ASCT) had superior PFS compared to those who did not (P= 0.015). Compared with ChT regimen, C-ChT regimen was well tolerated and had superior ORR and PFS in patients with untreated AITL. ASCT may contribute to longer PFS in remission patients.

Abstract SY16-01: What IDH mouse models have taught us about hematological diseases, from leukemia to T cell lymphoma

Abstract SY16-01: What IDH mouse models have taught us about hematological diseases, from leukemia to T cell lymphoma

The relationship and clinical significance of serum cytokine expression level and skin pruritus in patients with Hodgkin lymphoma and angioimmunoblastic T-cell lymphoma

Pruritus of lymphoma is commonly associated with both Hodgkin lymphoma (HL) and angioimmunoblastic T cell lymphoma (AITL) and critically affects the life quality of patient. Recent evidence suggests that the pruritogenic cytokines seem to play a significant role in the genesis of chronic. This study aims to investigate the cytokines associated with itching in lymphoma patients and provide the basis for potential therapeutic targets. Serum samples were collected from 60 lymphoma patients, including 47 with Hodgkin lymphoma (HL) and 13 with angioimmunoblastic T-cell lymphoma (AITL), serving as the observation group (lymphoma group, LP group, n = 60). Additionally, serum samples from 8 healthy donors (HD group, n = 8) were collected for comparison. Within the lymphoma group, patients were stratified into those with pruritus (LWP group, n = 30) and those without pruritus (LWOP group, n = 30) based on the presence of skin pruritus symptoms. Elevated levels of multiple cytokines were significantly observed in the LP group in comparison to the HD group (p < 0.01). Patients in LWP group exhibited higher serum levels of IL-31 (p < 0.001), IL-1β (P = 0.039), and IL-1α (P = 0.037) compared to LWOP group. Notably, serum IL-31 levels were higher in advanced AITL patients (stage IV) than in early AITL patients (stage I-Ⅲ, P < 0.05). In subgroup analysis, patients with pruritus in the AITL group exhibited higher serum levels of MIG and CTACK compared to HL group, whereas PDGF-BB levels were significantly lower (p < 0.05). Elevated serum levels of IL-31, IL-1β, and IL-1α are linked to lymphoma-associated pruritus. Differences in serum cytokine profiles between HL and AITL subgroups are also highlighted. These findings offer valuable insights for clinical intervention in managing lymphoma-related pruritus.

Mutation characteristics of angioimmunoblastic T-cell lymphoma: an analysis of 75 cases

Objective: To investigate the characteristics of gene mutations in angioimmunoblastic T-cell lymphoma (AITL). Methods: Seventy-five AITL cases diagnosed at the Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China from June 2021 to June 2023 were included. Their formalin-fixed and paraffin-embedded or fresh tissues were subject to targeted next generation sequencing (NGS). The sequencing data was collected, and the distribution and type of gene mutations were analyzed. Results: 492 potential driver mutations were identified in 74 out of the 84 genes. Targeted sequencing data for the 75 AITL patients showed that the genes with mutation frequencies of ≥10% were TET2 (89.3%), RHOA (57.3%), IDH2 (37.3%), DNMT3A (36.0%), KMT2C (21.3%), PLCG1 (12.0%), and KDM6B (10.7%). There were significant co-occurrence relationships between TET2 and RHOA, TET2 and IDH2, and RHOA and IDH2 gene mutations (P<0.05), respectively, while TET2 and KDM6B gene mutations were mutually exclusive (P<0.05). Conclusions: The study reveals the mutational characteristics of AITL patients using NGS technology, which would provide insights for molecular diagnosis and targeted therapy of AITL.

Utility of 18F-FDG PET/CT for differential diagnosis between IgG4-related lymphadenopathy and angioimmunoblastic T-cell lymphoma

To explore the utility of the 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron-emission tomography (PET)/computed tomography (CT) in the differential diagnosis of IgG4-related lymphadenopathy (IgG4-RLAD) and angioimmunoblastic T-cell lymphoma (AITL). Retrospective analysis of 18F-FDG PET/CT imaging findings in clinically diagnosed IgG4-RLAD and AITL cases was undertaken to record the distribution, morphological characteristics, and imaging features of the affected lymph nodes, as well as FDG uptake of the spleen and bone marrow. Standardised uptake values normalised to lean body mass were evaluated for maximum (SULmax), average (SULavg), and peak values (SULpeak). Univariate and multivariate logistic regression was used to screen for statistically significant imaging findings to discriminate IgG4-RLAD from AITL. Twenty-two cases of IgG4-RLAD (17 men, five women, median age 49.5 years) and 22 cases of AITL (16 men, six women, median age 55 years) were finally included in the analysis. There were no AITL patients with involvement of a single lymph node region. AITL patients had more involvement of the different nodal regions except cervical and pelvic nodal regions. A practical assessment method based on a combination of SULpeak-LN/SULavg-liver, SULpeak-spleen, and the number of involved nodal regions, improved the performance for differential diagnosis between both groups with an overall classification accuracy of 90.9%. 18F-FDG PET/CT is a useful tool for distinguishing AITL from IgG4-RLAD, and it can also help determine the optimal biopsy site for suspected cases of IgG4-RLAD or AITL, reduce the need for re-biopsy procedures, and enable physicians to develop timely treatment strategies.

Mitoxantrone Hydrochloride Liposome, Gemcitabine, Vinorelbine with or without Rituximab (GVM±R) in Patients with Relapsed or Refractory Aggressive Non-Hodgkin's Lymphoma

Background: In patients with relapsed/refractory (r/r) aggressive non-Hodgkin lymphoma (aNHL), achieving a response to salvage therapy is a crucial predictor for long-term survival, as only chemosensitive patients have the opportunity to undergo autologous stem cell transplantation. Mitoxantrone hydrochloride liposome (PLM60) has shown good efficacy and safety in r/r peripheral T-cell lymphoma (PTCL) based on a prior study, with an objective response rate (ORR) of 40.7% and a complete response rate (CRR) of 20.4% (2020 ASH abstract 42). To determine the appropriate dosage of PLM60 in a multi-drug combination chemotherapy, we conducted a phase I clinical study aiming to explore the maximum tolerated dose (MTD) of PLM60 when combined with gemcitabine, vinorelbine, with or without rituximab (GVM±R). This trial was registered at www.clinicaltrials.gov as NCT05299164. Methods: The study was a prospective, single-center, single-arm, 3+3 dose-escalation study involving patients aged 18-70 years with r/r aNHL. PLM60 was administered on day 1 at four different dose levels (DL) (DL1: 16 mg/m 2, DL2: 18 mg/m 2, DL3: 20 mg/m 2, DL4: 22 mg/m 2), gemcitabine on day 1 and 8 at 800 mg/m 2, vinorelbine on day 1 and 8 at 20 mg/m 2, and rituximab on day 0 at 375 mg/m 2 (only administered in CD20+ lymphoma based on the investigator's judgment). The treatment was repeated every 21 days. Up to 6 cycles of therapy were planned. After the first cycle, dose-limiting toxicity (DLT) was assessed to determine the MTD of PLM60 in the GVM±R regimen. Results: As of July 15, 2023, the study had enrolled 12 eligible patients (DL1: n=6, DL2: n=6), with different aNHL subtypes, including 6 with diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), 3 with angioimmunoblastic T-cell lymphoma (AITL), 2 with PTCL, NOS, and 1 with sezary syndrome (SS). The median age of the patients was 49 years (range, 23 to 69), with 41.7% being male. All patients had advanced-stage disease, with 33.3% in stage III and 66.7% in stage IV. They had received a median of 2.5 lines of therapy (range, 2 to 7), and 91.7% (11/12) of patients had received anthracycline-containing chemotherapy in their prior treatment. All patients with DLBCL, NOS had received rituximab during their prior therapy. 66.7% (8/12) of the patients were refractory to their last line therapy, and 2 out of the 6 patients with DLBCL, NOS experienced relapse after anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy. During the study, two patients experienced DLTs of grade 4 neutropenia lasting for more than 7 days, with one occurring in the DL1 group and the other in the DL2 group. In response to these observations, an additional three patients were enrolled in each of the groups. The most common grade 3/4 TRAEs with an incidence ≥10% were leucopenia (91.7%), neutropenia (83.3%), thrombocytopenia (66.7%), anemia (41.7%), febrile neutropenia (25.0%), pneumonia (25.0%), and hypokalemia (25.0%). With a median follow-up of 2.5 months, 11 patients were evaluated for efficacy, showing an ORR of 72.7% (95% CI 39.0% to 94.0%) and a CRR of 45.5% (95% CI 16.8% to 76.6%). In the DL1 group (16 mg/m 2), the CRR was 50.0% (3/6), and the ORR was 66.7% (4/6), while the DL2 group (18 mg/m 2) had a CRR of 40.0% (2/5) and an ORR of 80.0% (4/5) (Table 1). Among the DLBCL patients, the CRR was 60.0% (3/5), and among AITL patients, the CRR was 66.7% (2/3). Patients with PTCL NOS and SS achieved partial responses (PR). Two DLBCL patients who had previously received multiple lines of therapy, including anti-CD19 CAR T-cell therapy, achieved CR after GVM±R treatment. Conclusions: The GVM±R regimen exhibited manageable safety and encouraging efficacy in patients with r/r aNHL, despite the fact that the majority of these patients had received anthracycline-containing chemotherapy in their previous treatment. The trial is still ongoing to determine the recommended phase 2 dose for the subsequent phase 2 clinical study.

Azacitidine for Injection Combined with Chidamide in Relapsed/Refractory Peripheral T-Cell Lymphoma: A Phase I Study

Background: Peripheral T-cell lymphoma (PTCL) is a group of highly heterogeneous malignant tumors with poor prognosis, especially in patients with relapesd/refractory. The efficacy of traditional salvage chemotherapy in the treatment of Relapsed/Refractory (R/R) PTCL was poor, and the median OS and PFS after the first recurrence or progression were only 5.5 months and 3.1 months, respectively. There is an urgent need for more effective treatment regimens to improve the poor prognosis of these patients. Epigenetics, as a new discipline involved in gene expression regulation, provides a new approach for the occurrence, development mechanism research and clinical diagnosis and treatment of PTCL.This phase I study is a prospective, single center clinical study and designed to evaluate the safety, tolerability and efficacy of Azacitidine for injection combined with Chidamide in Relapsed/Refractory peripheral T-cell lymphoma. Methods: Eligible pts (18-75 years of age, ECOG PS 0-2) had histologically confirmed peripheral T-cell lymphoma that was either relapsed or refractory to at least 1 line of therapy. Considering that both Dose Group 2 (Azacitidine 75mg/m 2, Chidamide 20mg) and Group 3 (Azacitidine 50mg/m 2, Chidamide 30mg) adjust the dosage of a single drug based on Dose Group 1 (Azacitidine 50mg/m 2 ih d1-7, Chidamide 20mg po biw; 4 weeks/cycle), this study derived a “3+3” two-dimensional dose increasing design based on the classic “3+3” design, which allows two Dose Groups (Dose Group 2 and Group 3) to start ramp up trials simultaneously according to random principles. Enrollment in dose group 4(Azacitidine 75mg/m 2, Chidamide 30mg) can begin when either group 2 or 3 completes and no DLT occurs. The primary objectives of this study were to evaluate the safety and preliminary anti-tumor activity of Azacitidine for injection combined with Chidamide according to the Lugano 2014 criteria. Adverse events (AEs) were reported according to CTCAE v5.0. Results: Nineteen R/R PTCL pts (median age: 61 years, range: 52-71 years; male: 11 (57.9%) pts; ECOG PS=0: 10 (52.6%) pts) who was either relapsed or refractory to at least 1 line of therapy (median therapy lines:2) were enrolled. Among them, 11 pts were angioimmunoblastic T-cell lymphoma (AITL) and 8 pts were PTCL, NOS. 16 pts could evaluate the efficacy and safety. For 16 treated patients, treatment-related adverse events (TRAEs) of any grade occurred in 15 (93.7%) pts, ≥3 TRAEs occurred in 7 (43.8%) pts. The most frequent TRAEs (≥ 20%) were Pain at the injection site (n=12, 75.0%), Neutropenia (n=9, 56.3%), Erythema at the injection site (n=8, 50.0%), Nausea (n=7, 43.8%), Thrombocytopenia (n=6, 37.5%), Feeble (n=6, 37.5%), Anemia (n=5, 31.3%), Diarrhea (n=5, 31.3%), Neutropenia with fever (n=4, 25.0%). The most frequent grade ≥ 3 TRAEs (≥5%) was Neutropenia (n=3, 18.8%). 3 pts experienced TRAE leading to drug dosage adjustment. The recommended phase II dose (RP2D) was Azacitidine 75mg/m2, Chidamide 20mg (Dose Group 2). As of data cut-off date, 3 pts remained on Azacitidine for injection combined with Chidamide therapy. The objective response rate (ORR) and disease control rate (DCR) were 56.25% (9/16; 95% CI: 31.9-80.5) and 75% (12/16; 95% CI: 53.8-96.2), respectively. For AITL pts, the ORR was and DCR were 60% (6/10; 95% CI: 36.0-84.0) and 80% (8/10; 95% CI: 60.4-99.6), and 4 pts achieved CR. For all PTCL pts enrolled, Median PFS 6.45 months (95% CI: 3.97-12.7); Median OS 17.5 months (95% CI: 2.11-32.9). Conclusion: Azacitidine for injection combined with Chidamide showed a promising anti-tumor effectivity with a manageable safety profile in Relapsed/Refractory peripheral T-cell lymphoma patients, especially for AITL patients.

Angioimmunoblastic T-cell lymphoma: Novel recurrent mutations and prognostic biomarkers by cell-free DNA profiling.

Molecular and clinical stratification of patients with angioimmunoblastic T-cell lymphoma (AITL) is unsatisfactory, which hinders the development of personalized therapies. This study aimed to identify molecular biomarkers for AITL based on peripheral cell-free DNA (cfDNA) that could be used to predict prognosis and guide treatment non-invasively. A customized panel containing 46 genes was used to study pretreatment cfDNA and paired tumour tissues in 64 Chinese AITL patients from three clinical centres, and gene mutations in cfDNA and tumour tissue were assessed for concordance (34 paired samples). Then, the association of gene mutations and prognosis was analysed, and a functional enrichment analysis was performed. The sequencing results showed good consistency between cfDNA samples and paired tissue samples. KDM5A, STAT1, FANCM, ERBB4, PIK3R5 and NSD1 were identified as novel recurrent mutations. Mutations in FANCM or combinations of RHOA, KDM5A and FAT1 were associated with poor prognosis. Additionally, functional analysis revealed that RHOAG17 might serve as a predictive biomarker of PD-1 blockade respondence. Our findings confirmed the role of cfDNA as a liquid biopsy in AITL, and revealed novel molecular determinants that can stratify patients and guide treatment options.

Immune infiltration and drug specificity analysis of different subtypes based on functional status in angioimmunoblastic T-cell lymphoma

Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma (PTCL) strongly correlated with worse clinical outcomes. However, the role of characteristic pathway-related genes in patients with AITL (e.g., subtype typing and pathogenesis) remains unknown. In this study, we intended to understand the potential role and prognostic value of characteristic pathways in AITL and identified a model for subtype identification based on pathway-related functional status. Transcriptomic (RNA-seq) data were obtained from the Gene Expression Omnibus database for three sets of tumor tissues from AITL patients. AITL was divided into three clusters based on the pathway profile of patients and the best clustering k = 3, and differentially expressed genes (DEGs) in the three clusters were analyzed. The top 45 important variables associated with characteristic pathways, such as Huntington's disease, VEGF signaling pathway, nucleotide excision repair, ubiquitin-mediated proteolysis, purine metabolism, olfactory transduction, etc., were used to construct a subtype identification model. The model was experimentally validated and proved to possess good predictive efficacy. In addition, pathway-related subtype typing was significantly associated with different immune cell infiltration in AITL. Further analysis revealed that the drug IC50 values predicted also differed markedly among the different subtypes, thus further identifying some subtype-specific drugs. Our study indicates a potential role of characteristic pathways in AITL staging for the first time, provides novel insights for future research targeting AITL, and points to potential therapeutic options for patients with different subtypes of AITL.

Angioimmunoblastic T cell lymphoma prognostic index in Asian population identifies low risk patients with unique gene expression profiles

Introduction: Angioimmunoblastic T cell Lymphoma (AITL) is a subtype of peripheral T cell lymphoma and prognosis is generally felt to be poor. Molecular characteristics differentiating good or poor risk AITL has not been identified. In our Asian multicentre study, we investigate the clinical prognostic factors affecting the outcomes of our AITL patients. We also interrogate the gene expression profiles in our patients to identify if there may be different immune and cell signalling signatures in different risk groups. Methods: Patients who were diagnosed with AITL and seen at National Cancer Centre Singapore, Singapore General Hospital and National University Cancer Institute, Singapore between June 1999 and December 2019 were retrospectively analysed. Relevant demographical and clinical characteristics were collected. Outcomes of interest were that of 5-year overall survival (OS) and 5-year progression free survival (PFS). Kaplan-Meier curves were plotted to estimate survival for each individual clinical parameter. Parameters found to be significant on univariate analysis were subsequently used in the generation of multivariate cox regression models. NanoString PanCancer IO360 panel (NanoString Technologies, Seattle, WA, USA) was used to interrogate gene expression on AITL FFPE tissue, following manufacturer’s protocol using the nCounter platform. Results: A total of 174 patients were identified. Median duration of follow up was 20.4 months. Median PFS and OS was 1.8 years and 5.6 years respectively. In multivariate analyses, Age >60, bone marrow Involvement, Total white cell count and serum Lactate dehydrogenase were associated with poorer PFS and OS. A prognostic index (AITL-PI) differentiated patients into low (0–1 factors, n = 64), moderate (2 factors, n = 59) and high-risk (3–4 factors, n = 49) subgroups with 5-year OS of 84.0%, 44.0% and 28.0% respectively (p < 0.0001). Gene expression studies performed in 23 patients found disparate immune cell type profiles and oncogenic signalling pathway signatures in the low risk as compared to the intermediate and high-risk groups. In the low risk group, neutrophilic, T-regulatory and Th-1 cell profiles were predominant whereas cytotoxic cell profile was predominant in the intermediate and high-risk groups. The low risk group was more active in the myeloid compartment, WNT, cytokine and chemokine, TGF-β and hedgehog signalling pathways whereas cytotoxicity, interferon and lymphoid compartment signalling signatures returned higher in the intermediate and high-risk groups. The research was funded by: NCCS Cancer Fund (Research) (NCCSCF-R-YR2021-JUN-SSD1), Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore Ministry of Health’s National Medical Research Council Research Transition Awards (TA21jun-0005 and TA20nov-0020), Large Collaborative Grant (OFLCG18May-0028), and Collaborative centre grant (TETRAD II). Keywords: Aggressive T-cell non-Hodgkin lymphoma, Diagnostic and Prognostic Biomarkers No conflicts of interests pertinent to the abstract.

A randomized phase II trial of CHOP versus ICED and autologous stem cell transplantation in newly diagnosed T‐cell lymphoma

Purpose: Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin lymphomas, and their prognoses are still poor because of frequent relapses and the absence of optimal standard therapy. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has been the backbone of frontline chemotherapy for PTCL for many years. However, it is not clear whether anthracycline-based chemotherapies such as CHOP could be standard induction therapy for PTCL. Thus, we conducted a randomized phase II study to compare the efficacy of CHOP with fractionated ifosfamide, carboplatin, etoposide, and dexamethasone (ICED). Patients and Methods: This study was a phase II, multicenter, open-label randomized trial at 21 hospitals that belonged to the Consortium for Improving Survival of Lymphoma (CISL) in Korea (CISL-1504/ROSE study). Eligible participants were patients aged 20–65 years with previously untreated histologically confirmed PTCLs based on the World Health Organization classification 2008 including PTCL-not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK-negative anaplastic large-cell lymphoma (ALCL), enteropathy-associated T-cell lymphoma (EATL), and hepatosplenic T-cell lymphoma (HSTL). Patients with ALK-positive ALCL, extranodal NK/T-cell lymphoma, and mycosis fungoides/sezary syndrome were not included in the study. Patients were randomized at a 1:1 ratio to receive either CHOP or ICED every 3 weeks for 6 cycles. Upfront autologous stem cell transplantation (ASCT) was done for patients achieving complete or partial response and the primary end point was progression-free survival (PFS). Results: Between September 2015 and March 2021, 145 patients were screened, and 138 patients were enrolled. The characteristics were not different between CHOP (n = 69) and ICED (n = 66), and PTCL-NOS (n = 60) and AITL (n = 53) were dominant. The objective response rate was not different between CHOP (41/69, 59.4%) and ICED (37/66, 56.1%), and the 3-year PFS was not different between CHOP (36.7%) and ICED (33.1%, P = 0.709). Around 80% of patients who completed either CHOP or ICED followed by upfront ASCT showed 3-year overall survival (Figure 1). There was no statistically significant difference in PFS between the CHOP and ICED arms for any subgroup analyzed except AITL. CHOP was favored over ICED in AITL patients, whereas ICED was favored over CHOP in EATL/HSTL patients. ICED was associated with more anemia, neutropenia, and thrombocytopenia of all grades and grade 3 or worse, and the frequency of febrile neutropenia was higher in the ICED arm. Keywords: aggressive T-cell non-Hodgkin lymphoma, chemotherapy, stem cell transplant No conflicts of interests pertinent to the abstract.

Peripheral T-cell lymphoma-not otherwise specified, angioimmunoblastic T-cell lymphoma and anaplastic large cell lymphoma: Are the outcomes any different in Hispanics?

e18773 Background: Peripheral T cell lymphoma – not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL) are unusual non-Hodgkin lymphomas with miscellaneous clinical characteristics which share the same treatment regimen (Blood PMID28115372 Cancer Treat ResPMID30596215 Blood PMID28115369). Gene expression profiling has facilitated their diagnosis; but much remains to be learned about risk factors, biological and clinical implications (Oncologist PMID16880242). This is the first national population-based analysis evaluating ethnic differences for Hispanics (HI) diagnosed with PTCL-NOS, AITL and ALCLin the US. Methods: Data were analyzed on PTCL-NOS, AITL and ALCL patients in the US reported to the Surveillance, Epidemiology, and End Results (SEER) database between 2000-2018. Demographic, clinical and survival patterns were analyzed. Kaplan-Meier and Cox regression analyses were used when appropriate. Multivariate analysis and propensity score matching were performed with adjustment for age, stage and B-symptoms. Results: 12,749 patients were diagnosed with PTCL-NOS, AITL and ALCL (1,666 cases were HI = 798 PTCL-NOS, 316 AITL and 552 ALCL). Male predominated for HI and Non-HI (NH) in the 3 malignancies. HI were diagnosed at a younger median age than NH, PTCL-NOS 60 years(y) vs 65y, AITL 65y vs 69y, and ALCL 45y vs 55y, respectively [p &lt;0.001]. White race predominated for both. When diagnosed with PTCL-NOS or AITL, HI were more likely diagnosed from 2015-2018 but those with ALCL were identified from 2000-2004. For the 3 malignancies limited information regarding B symptoms was available. Most of the cases of HI and NH were diagnosed at advanced stages in all subtypes. Overall, for both the tendency was towards not receiving radiation. HI vs NH diagnosed with PTLC-NOS had median survival of 1.2 vs 1.3y; AITL was 2.2 vs 1.7y and ALCL 6.0 vs 9.3y. Survival probability for 2, 5 and 10y were comparable among HI and NH for all malignancies and no difference in OS was noted. On multivariate analysis, patients who were older than 80y and between 60-80 y, had worse OS compared to those &lt;60y. For all subtypes, those who were diagnosed at stage III/IV had worse OS than those at early stage I/II. Conclusions: Similar OS for HI and NH diagnosed with PTCL-NOS, AITL and ALCL. Nonetheless, diagnosis at younger age and early stage play a significant role to better survival. Although HI were more subjected to early age at diagnosis and less likely to be at a stage I/II, no impact in survival was evidenced, which suggests that unique responses may counteract within this race. It is captivating that no gradual increase in diagnosis was noted despite the continuous development of genetic testing and improved diagnostic tools, which highlights that socioeconomical variables may have been influencing its access.

Involvement of spleen is associated with shorter survival in patients with angioimmunoblastic T cell lymphoma.

The prognosis of patients with angioimmunoblastic T cell lymphoma (AITL) remains dismal, with their 5-year overall survival (OS) and progression-free survival (PFS) rates of 32-41% and 18-38%, respectively. Spleen involvement occurs in a proportion of patients with AITL. But still, it is unclear whether spleen involvement impacts the prognosis of AITL patients. In this study, we aim to establish new prognostic indicators for the identification of high-risk patients to draft optimal treatment regimens. We collected and counted the clinical data of 54 patients with AITL treated with CHOP-based first-line chemotherapy regimen between 2010 and 2021 at Hubei Cancer Hospital and Hunan Cancer Hospital. In addition, all patients received PET-CT scan prior to receiving treatment. We performed univariate and multivariate analyses to assess the predictive role of tumor characteristics, laboratory, and radiographic data for the prognosis of AITL. We observed that PFS and OS are worse in patients with high ECOG scores, spleen involvement, and low serum albumin levels in patients with AITL. In univariate analysis, stage (HR 3.515 [1.142-10.822], p = 0.028) and spleen involvement (HR 8.378 [1.085-64.696, p = 0.042) were correlated with PFS in patients with AITL. Besides, stage (HR 3.439 [1.108-10.674], p = 0.033) and spleen involvement (HR 11.002 [1.420-85.254], p = 0.022) were significantly correlated with OS. Consistently, spleen involvement was correlated with OS (HR 16.571 [1.350-203.446], p = 0.028) and PFS (HR 10.905 [1.037-114.690], p = 0.047) in AITL patients in a multivariate analysis. This study demonstrates that spleen involvement might be used as a prognostic indicator for AITL patients.

Angioimmunoblastic T-cell lymphoma and correlated neoplasms with T-cell follicular helper phenotype: from molecular mechanisms to therapeutic advances.

Angioimmunoblastic T-cell lymphoma (AITL) is the second most frequent subtype of mature T-cell lymphoma (MTCL) in the Western world. It derives from the monoclonal proliferation of T-follicular helper (TFH) cells and is characterized by an exacerbated inflammatory response and immune dysregulation, with predisposition to autoimmunity phenomena and recurrent infections. Its genesis is based on a multistep integrative model, where age-related and initiator mutations involve epigenetic regulatory genes, such as TET-2 and DNMT3A. Subsequently, driver-mutations, such as RhoA G17V and IDH-2 R172K/S promote the expansion of clonal TFH-cells ("second-hit"), that finally begin to secrete cytokines and chemokines, such as IL-6, IL-21, CXCL-13 and VEGF, modulating a network of complex relationships between TFH-cells and a defective tumor microenvironment (TME), characterized by expansion of follicular dendritic cells (FDC), vessels and EBV-positive immunoblasts. This unique pathogenesis leads to peculiar clinical manifestations, generating the so-called "immunodysplastic syndrome", typical of AITL. Its differential diagnosis is broad, involving viral infections, collagenosis and adverse drug reactions, which led many authors to use the term "many-faced lymphoma" when referring to AITL. Although great advances in its biological knowledge have been obtained in the last two decades, its treatment is still an unmet medical need, with highly reserved clinical outcomes. Outside the setting of clinical trials, AITL patients are still treated with multidrug therapy based on anthracyclines (CHOP-like), followed by up-front consolidation with autologous stem cell transplantation (ASCT). In this setting, the estimated 5-year overall survival (OS) is around 30-40%. New drugs, such as hypomethylating agents (HMAs) and histone deacetylase inhibitors (HDAi), have been used for relapsed/refractory (R/R) disease with promising results. Such agents have their use based on a biological rationale, have significant potential to improve the outcomes of patients with AITL and may represent a paradigm shift in the therapeutic approach to this lymphoma in the near future.

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.

IDH2 and TET2 mutations synergize to modulate T Follicular Helper cell functional interaction with the AITL microenvironment.

Angioimmunoblastic Tcell lymphoma (AITL) is a peripheral Tcell lymphoma that originates from T follicular helper (Tfh) cells and exhibits a prominent tumor microenvironment (TME). IDH2 and TET2 mutations co-occur frequently in AITL, but their contribution to tumorigenesis is poorly understood. We developed an AITL mouse model that is driven by Idh2 and Tet2 mutations. Malignant Tfh cells display aberrant transcriptomic and epigenetic programs that impair TCR signaling. Neoplastic Tfh cells bearing combined Idh2 and Tet2 mutations show altered cross-talk with germinal center B cells that promotes B cell clonal expansion while decreasing Fas-FasL interaction and reducing B cell apoptosis. The plasma cell count and angiogenesis are also increased in the Idh2-mutated tumors, implying a major relationship between Idh2 mutation and the characteristic AITL TME. Our mouse model recapitulates several features of human IDH2-mutated AITL and provides a rationale for exploring therapeutic targeting of Tfh-TME cross-talk for AITL patients.

Genetic abnormalities assist in pathological diagnosis and EBV-positive cell density impact survival in Chinese angioimmunoblastic T-cell lymphoma patients.

To explore the application of genetic abnormalities in the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) and the reliable pathological prognostic factors. This study included 53 AITL cases, which were reviewed for morphological patterns, immunophenotypes, presence of Hodgkin and Reed-Sternberg (HRS)-like cells, and co-occurrence of B cell proliferation. The Epstein-Barr virus (EBV)-positive cells in tissues were counted, and cases were classified into "EBV encoded RNA (EBER) high-density" group if >50/HPF. Targeted exome sequencing was performed. Mutation data can assist AITL diagnosis: 1) with considerable HRS-like cells (20 cases): RHOA mutated in 14 cases (IDH2 co-mutated in 3 cases, 4 cases with rare RHOA mutation), TET2 was mutated in 5 cases (1 case co-mutated with DNMT3A), and DNMT3A mutated in 1 case; 2) accompanied with B cell lymphoma (7 cases): RHOA mutated in 4 cases (1 case had IDH2 mutation), TET2 mutated in 2 cases and DNMT3A mutated in 1 case; 3) mimic peripheral T cell lymphoma, not otherwise specified (5 cases): RHOA mutated in 2 cases (IDH2 co-mutated in 1 case), TET2 mutated in 3 cases, and DNMT3A mutated in 1 case; 4) pattern 1 (1 case), RHOA and TET2 co-mutated. Besides RHOAG17V (30/35), rare variant included RHOAK18N, RHOAR68H, RHOAC83Y, RHOAD120G and RHOAG17del, IDH2R172 co-mutated with IDH2M397V in one case. There were recurrent mutations of FAT3, PCLO and PIEZO1 and genes of epigenetic remodeling, T-cell activation, APC and PI3K/AKT pathway. EBER high-density independently indicated adverse overall survival and progression-free survival (P=0.046 and P=0.008, Kaplan-Meier/log-rank). Over half AITL cases might be confused in diagnosis for certain conditions without mutation data. Targeted exome sequencing with a comprehensive panel is crucial to detect both hot-spot and rare mutation variants for RHOA and IDH2 and other recurrent mutated genes in addition to TET2 and DNMT3A. EBER high-density independently indicated adverse survival.

Incidence, Survival Outcome, and Prognostic Nomogram of Patients with Angioimmunoblastic T-cell Lymphoma: a Population-based Analysis

Due to the rarity of angioimmunoblastic T-cell lymphoma (AITL), very limited data concerning its incidence patterns and prognostic factors are available. This study aimed to explore the incidence, characteristics, survival outcomes, and prognostic factors of AITL. Age-adjusted incidence and temporal trends were calculated based on 1247 AITL patients from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)-13 database. A total of 1525 AITL patients from the SEER-18 database and 43 patients from our single center were included for survival analysis and nomogram construction. The age-adjusted incidence for overall cohort was 0.123 [95% confidence interval (CI), 0.117-0.131) per 100 000 during 1992-2017. The overall incidence increased steeply at the rate of 15.3% (95%CI 11.0%-19.8%, P<0.001) per year during 1992-2004, but remained stable during 2004-2017 (P=0.200). Similar incidence trends were observed in age, sex, and stage subgroups. The final nomograms consisted of four variables: age at diagnosis, sex, Ann Arbor stage, and primary site. The concordance index (C-index) of the nomogram for 5-year overall survival prediction was 0.717, 0.690 and 0.820 in the training cohort, validation cohort-1 and cohort-2, respectively. Regarding the disease-specific survival (DSS), the nomogram also demonstrated a good discrimination level, with the C-index for predicting the probability of DSS at 5 years of 0.716, 0.682 and 0.813 for the three cohorts, respectively. The calibration displayed good concordance between the nomogram-predicted and actual observed outcomes. The age-adjusted incidence for AITL was low during 1992-2017. The incidence continuously increased during 1992-2004, but remained stable during 2004-2017. The nomograms as proposed may provide a favorable and accurate prognostic survival prediction in AITL.

The added prognostic values of baseline PET dissemination parameter in patients with angioimmunoblastic T-cell lymphoma.

To explore the prognostic values of baseline 2-deoxy-2-[18F] fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) dissemination parameter in angioimmunoblastic T-cell lymphoma (AITL) and its added values to total metabolic tumour volume (TMTV). Eighty-one AITL patients with at least two FDG-avid lesions in baseline PET/CT were retrospectively included. PET parameters including TMTV and the distance between the two lesions that are the furthest apart (Dmax) were obtained. Univariate Cox analysis showed that both Dmax and TMTV were risk factors for progression-free survival (PFS) and overall survival (OS). Multivariate Cox analysis models of different combinations showed that high Dmax (>65.7cm) could independently predict both PFS and OS, while high TMTV (>456.6cm3) was only significant for OS. A concise PET model based on TMTV and Dmax can effectively risk-stratify patients. PFS and OS rates were significantly lower in patients with high Dmax and high TMTV than in patients with low Dmax and low TMTV (3-year PFS rate: 15.0%vs. 48.7%, p=0.001; 3-year OS rate: 27.6%vs. 79.0%, p<0.001). Dmax can directly reflect the disease dissemination characteristic and has a significant prognostic value for FDG-avid AITL patients. It has the potential to be introduced into new risk stratification models for tailored treatment.