Angioimmunoblastic T-cell Lymphoma Research Articles

Clinical, Pathologic, and Molecular spectrum of Angioinmmunoblastic T-cell Lymphoma Cutaneous Lesions: Clinical, Pathologic, and Molecular Analysis.

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive malignancy that frequently presents with extranodal involvement. Cutaneous tropism is clinically and histopathologically variable, which may pose a diagnostic challenge. We conducted a retrospective analysis of 40 samples of 20 cases of cutaneous AITL, focusing on the clinicopathologic and molecular correlations between skin and lymph node (LN) samples. In all cases, cutaneous involvement was concurrent with or followed the diagnosis of nodal AITL, with no cases preceding systemic involvement. Clinically, cutaneous AITL presented in 2 main forms: an evanescent rash and persistent lesions, with histopathology revealing diverse infiltration patterns, including perivascular, nodular, granulomatous, panniculitic, vasculitis, and epidermotropic. Clinical presentation and histologic patterns tend to correlate. Histopathologically, plasma cells were present in 15/22 skin samples, 5 of them being kappa-light restricted but polytypic in corresponding LNs. Epstein-Barr virus+ B cells were present in 10 cutaneous lesions and were already present in corresponding LNs. Molecular studies found correlations in all but one case between LN and skin, particularly in the presence of RHOA and TET2 mutations, which were identified in 8 of 12 cases. Molecular analysis was also informative in 4 cases with low levels of infiltration. The study also highlighted unique cases with distinct clinical and histopathologic patterns coexisting in the same patient over time. One case exhibited simultaneous granulomatous and epidermotropic patterns in different skin lesions. Four cases of cutaneous B-cell lymphomas associated with AITL were identified. Our study underscores the importance of integrating clinical, histopathologic, and molecular data to accurately diagnose cutaneous AITL.

Single-cell transcriptomic and spatial analysis reveal the immunosuppressive microenvironment in relapsed/refractory angioimmunoblastic T-cell lymphoma

Angioimmunoblastic T-cell lymphoma (AITL) is a kind of aggressive T-cell lymphoma with significant enrichment of non-malignant tumor microenvironment (TME) cells. However, the complexity of TME in AITL progression is poorly understood. We performed single-cell RNA-Seq (scRNA-seq) and imaging mass cytometry (IMC) analysis to compare the cellular composition and spatial architecture between relapsed/refractory AITL (RR-AITL) and newly diagnosed AITL (ND-AITL). Our results showed that the malignant T follicular helper (Tfh) cells showed significantly increased proliferation driven by transcriptional activation of YY1 in RR-AITL, which is markedly associated with the poor prognosis of AITL patients. The CD8+ T cell proportion and cytotoxicity decreased in RR-AITL TME, resulting from elevated expression of the inhibitory checkpoints such as PD-1, TIGIT, and CTLA4. Notably, the transcriptional pattern of B cells in RR-AITL showed an intermediate state of malignant transformation to B-cell-lymphoma, and contributed to immune evasion by highly expressing CD47 and PD-L1. Besides, compared to ND-AITL samples, myeloid-cells-centered spatial communities were more prevalent but showed reduced phagocytic activity and impaired antigen processing and presentation in RR-AITL TME. Furthermore, specific inhibitory ligand-receptor interactions, such as CLEC2D-KLRB1, CTLA4-CD86, and MIF-CD74, were exclusively identified in the RR-AITL TME. Our study provides a high-resolution characterization of the immunosuppression ecosystem and reveals the potential therapeutic targets for RR-AITL patients.

Angioimmunoblastic T-cell lymphoma harboring a t(8;14)(q24;q11.2)/TCR::MYC translocation that presented with intestinal infiltration.

Although rearrangement of the MYC oncogene (MYC-R) is frequently observed in aggressive B-cell lymphomas, it is extremely rare in T-cell malignancies. A 64-year-old man who had been under observation for several years because of asymptomatic pulmonary extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALToma) was admitted to our hospital because of poor general condition and hypotension. Blood tests revealed thrombocytopenia and elevated serum lactate dehydrogenase levels, whereas computed tomography revealed systemic lymphadenopathy and splenomegaly. An inguinal lymph node biopsy precipitated a diagnosis of angioimmunoblastic T-cell lymphoma (AITL). Shortly after admission, the patient experienced spontaneous intestinal perforation and hemorrhage caused by multiple intestinal infiltrations of the AITL. Although chemotherapy was administered, the patient died several weeks after admission. A 46,XY,t(8;14)(q24;q11.2) karyotype was identified, and fluorescence in situ hybridization analyses showed split signals for the MYC and T-cell receptor (TCR) alpha genes, by which a TCR::MYC translocation was confirmed. Pathological autopsy analysis revealed systemic infiltration of the AITL and no MALToma lesions. Only a few cases of mature T-cell lymphoma harboring MYC-R have been reported in the literature thus far. To the best of our knowledge, this is the first reported case of AITL with TCR::MYC rearrangement. This condition could be associated with refractoriness to chemotherapy and aggressive clinical course with systemic infiltration that included the intestine.

A patient with concurrent EBV-negative diffuse large B-cell lymphoma and angioimmunoblastic T-cell lymphoma: a case report

IntroductionDiffuse large B-cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma that accounts for approximately a quarter of all lymphomas in the United States. It is rare to have co-occurring T cell lymphoma with DLBCL as they often develop following treatment of DLBCL rather than concomitantly.Case presentationWe report a 71-year-old male patient diagnosed with Epstein–Barr virus (EBV) -negative DLBCL with concurrent angioimmunoblastic T-cell lymphoma (AITL). A right inguinal lymph node biopsy demonstrated aggressive B-cell lymphoma consistent with DLBCL with the non-germinal center immunophenotype that was EBV-negative. Furthermore, abnormal T-cells with irregular nuclear contours were found in T cell receptor sequencing with monoclonal gamma and beta T cells. A bone marrow biopsy demonstrated occasional large atypical CD3+PD1+ T cells with corresponding identical T-cell receptor clones in the lymph node biopsy. Next-generation sequencing from the lymph node biopsy demonstrated dual inactivating TET2 mutations.ConclusionComposite DLBCL and AITL is a rare occurrence and the absence of EBV is even more so. Given the rare nature of having these two hematologic malignancies simultaneously, no standard of care exists. However, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is a regimen commonly used in both malignancies individually, and therefore this patient was treated using this approach achieving a partial remission after four cycles of therapy. Unfortunately, he developed refractory disease 1 month after completion of six cycles of R-CHOP.

The role of stem cell transplant (auto and allo) in PTCL and CTCL.

In contrast to B-cell lymphoma, the advent of modern targeting drugs and immunotherapeutics has not led to major breakthroughs in the treatment of peripheral T-cell lymphoma (PTCL) to date. Therefore, both autologous and allogeneic hematopoietic cell transplantation (HCT) continue to play a central role in the management of PTCL. Focusing on the most common entities (PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, and ALK-negative anaplastic large cell lymphoma), we summarize evidence, indications, and points to consider for transplant strategies in PTCL by treatment line. Although cutaneous T-cell lymphomas (CTCLs) are biologically and clinically distinct from the aforementioned PTCL, both disease groups appear to be susceptible to the graft-versus-lymphoma effects conferred by allogeneic HCT (alloHCT), setting the stage for alloHCT as a potentially curative treatment in otherwise incurable CTCL, such as mycosis fungoides/Sezary syndrome. Nevertheless, specific aspects regarding indication and prerequisites for alloHCT in CTCL need to be considered. Given the inherent toxicity of alloHCT and the significant risk of relapse after transplant, only intelligent strategies embedding alloHCT in current PTCL/CTCL treatment algorithms in terms of patient selection, timing, pretransplant preparation, and posttransplant maintenance provide optimal results. New targeted and cellular therapies, either complementary or competitive to HCT, are eagerly awaited in order to improve PTCL/CTCL outcomes.

A phase I study of romidepsin in combination with gemcitabine, oxaliplatin, and dexamethasone in patients with relapsed or refractory aggressive lymphomas enriched for T-cell lymphomas.

Histone deacetylase inhibitors (HDACi) and combination chemotherapy are independently used to treat relapsed/refractory (R/R) lymphoma. In vitro studies suggest that the addition of HDACi to platinum-based chemotherapy is synergistic. We conducted a phase I study of romidepsin, gemcitabine, oxaliplatin and dexamethasone (Romi-GemOxD) in R/R aggressive lymphomas with an expansion cohort in T-cell lymphomas. Twenty-four patients were enrolled with median age 70; 6 patients had diffuse large B-cell lymphoma (DLBCL) and 18 patients had peripheral T-cell lymphomas (PTCL-NOS: 10, angioimmunoblastic T-cell lymphoma [AITL]: 7, ALK-negative anaplastic large cell lymphoma: 1). Patients had received a median of 2 prior lines of therapy and 10 patients were refractory to last line of therapy. Using a standard 3+3 dose escalation design, the maximum tolerated dose of romidepsin was determined to be 10 mg/m2 in combination with GemOxD. There were no unexpected toxicities. The most common grade ≥3 treatment-emergent adverse events were thrombocytopenia (79%) and lymphopenia (46%). The overall response rate for Romi-GemOxD was 52% (12/23) with complete response (CR) rate of 43% (10/23). All six patients with AITL evaluable for efficacy achieved CR. Durable responses were seen in patients with AITL, PTCL-NOS and DLBCL. Without additional therapy, four patients remained in remission for more than two years, with three patients progressing at 46.5, 30.8, and 32.6 months and one remission ongoing at 83 months. Four patients proceeded to consolidative stem cell transplant following induction. Romi-GemOxD represents a well-tolerated, time-limited, effective option for patients, particularly for those with AITL in which durable responses were seen. NCT02181218Micro Abstract: In a phase I study of romidepsin in combination with gemcitabine, oxaliplatin and dexamethasone in patients with relapsed/refractory aggressive lymphomas, the maximum tolerated dose of romidepsin was 10 mg/m2. The complete response rate in patients with angioimmunoblastic T-cell lymphoma was 100% (6/6) with median duration of response of 28.9 months. This salvage option warrants further consideration, especially in T-cell lymphomas.

Erythema multiforme-like eruption in a case of angioimmunoblastic T-cell lymphoma: A case report and review of literature

Erythema multiforme-like eruption in a case of angioimmunoblastic T-cell lymphoma: A case report and review of literature

Systematic literature review of published cases of reactive plasmacytosis in peripheral blood and bone marrow

AimsThis study aims to summarise published cases of reactive plasmacytosis to provide a resource to aid haematopathologists and clinicians in the diagnostic workup of reactive plasmacytosis.MethodsWe searched published articles on...

Challenging Management of Relapsed/Refractory Angioimmunoblastic T-Cell Lymphoma: Insights from Two Complex Cases with Long-Term Response to Belinostat

Challenging Management of Relapsed/Refractory Angioimmunoblastic T-Cell Lymphoma: Insights from Two Complex Cases with Long-Term Response to Belinostat

Mitoxantrone Hydrochloride Liposome (Lipo-MIT) Combined with Azacitidine and Chidamide Can be an Effective Chemotherapy Regimen for Patients with Angioimmunoblastic T-Cell Lymphoma (AITL)

Mitoxantrone Hydrochloride Liposome (Lipo-MIT) Combined with Azacitidine and Chidamide Can be an Effective Chemotherapy Regimen for Patients with Angioimmunoblastic T-Cell Lymphoma (AITL)

Novel Cell Lines Identify Cell-Intrinsic and Targetable Features of Angioimmunoblastic T-Cell Lymphoma

Novel Cell Lines Identify Cell-Intrinsic and Targetable Features of Angioimmunoblastic T-Cell Lymphoma

Global outcomes and prognosis for relapsed/refractory mature T-cell and NK-cell lymphomas: results from the PETAL consortium

AbstractVariances in global access to drugs and treatment practices make it challenging to understand the benefit of contemporary therapies in patients with relapsed and refractory (R/R) mature T-cell and natural killer–cell lymphomas (MTCL and MNKCL). We conducted an international retrospective cohort study of 925 patients with R/R MTCL and MNKCL. In peripheral T-cell lymphoma–not otherwise specified and anaplastic lymphoma kinase–negative anaplastic large cell lymphoma (ALK– ALCL), patients with relapsed lymphoma demonstrated a superior median overall survival (OS) relative to refractory from the time of second-line treatment. We identified several independent predictors of OS for R/R lymphoma including age >60 years, primary refractory disease, histological subtype other than angioimmunoblastic T-cell lymphoma (AITL), extranodal sites >1, Ki67 ≥40%, and absolute lymphocyte count less than the lower limit of normal. A multivariable model incorporating these formed the basis for a prognostic index for R/R TCL, in which patients are stratified into low-risk (0-1 risk factor), intermediate-risk (2-3 risk factors), or high-risk (≥4 risk factors) groups, which were associated with 3-year OS of 57.14%, 23.3%, and 7%, respectively. Patients received either a "novel" single agent (SA; 35%) or cytotoxic chemotherapy (CC; 60%) for their second-line treatment. Higher progression-free survival was observed with SA over CC for the entire cohort with a higher 3-year OS in AITL and ALK– ALCL. Among the SA, small-molecule inhibitors demonstrated OS advantage relative to CC in AITL. Our results highlight continued efficacy of novel drugs globally and the potential of a new prediction model in informing heterogeneous prognosis within the R/R population of MTCL and MNKCL.

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

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of neoplasms, with many cases remaining unclassifiable and categorized as PTCL-not otherwise specified (PTCL-NOS). Gene expression profiling (GEP) has delineated 2 prognostic subtypes within PTCL-NOS, PTCL-TBX21 and PTCL-GATA3, characterized by distinctive transcriptomes and a different prognosis. To further evaluate the pathologic features of these subgroups, 101 PTCL cases that did not meet specific criteria for well-defined T-cell lymphoma entities underwent detailed pathologic, immunophenotypic (including T follicular helper [TFH] biomarkers), and GEP analyses, separating them into PTCL-NOS (n = 63) and PTCL-TFH (also known as nodal PTCL-TFH, NOS, and TFH lymphoma, NOS) (n = 38). PTCL-NOS cases were further categorized into PTCL-GATA3 (n = 22; 34%) and PTCL-TBX21 (n = 41; 66%), and a significant association (P < .02) with overall survival was reaffirmed. Histopathologic assessment showed PTCL-GATA3 cases were characterized by monotonous medium-sized or large transformed cells with a minimal tumor microenvironment (TME) compared with PTCL-TBX21 cases, which consisted of pleomorphic cells in a polymorphous TME (P < .05). GEP analysis validated these TME distinctions. Immunophenotypic analysis showed that PTCL-GATA3 cases were predominantly CD4+CD8- and associated with significantly higher LEF1, MYC, and CD30 expression (P < .05). PTCL-TBX21 displayed a more diverse biomarker profile with the following 2 subgroups: one expressing cytotoxic antigens and enriched in CD8+CD4− or CD8−CD4− phenotype, and another lacking cytotoxic markers but showing a CD4+CD8− phenotype with increased ICOS expression, but devoid of other TFH markers. The PTCL-TFH cases correlated with an angioimmunoblastic T-cell lymphoma gene signature, had more Epstein-Barr encoding region-positive cells than the PTCL-GATA3 and PTCL-TBX21 cases, and a subset had some morphologic features of angioimmunoblastic T-cell lymphoma (P < .01). This study highlights the unique morphologic and phenotypic variations within the newly identified PTCL subtypes and should enable a more precise diagnosis and tailored therapeutic strategies in the future.

Dual epigenetic therapy plus chemotherapy in peripheral T cell lymphoma with T follicular helper phenotype

The nonrandomized phase II study by Ding etal. explored the combination of azacitidine and chidamide with or without GemOx chemotherapy in relapsed/refractory peripheral Tcell lymphoma and demonstrated that the dual epigenetic therapy is safe and efficacious, particularly in the angioimmunoblastic Tcell lymphoma subset.1 Further investigation into adding chemotherapy is warranted, building on the promising results seen in this trial.

Real-world study and prognostic analysis of angioimmunoblastic T-cell lymphoma.

To analyze the clinical prognostic factors and treatments for angioimmunoblastic T-cell lymphoma (AITL) and develop a novel prognostic model specifically for AITL. We retrospectively analyzed 231 patients with AITL from the First Affiliated Hospital of Zhengzhou University. Patients were enrolled between January 2014 and July 2023. The primary end points were overall survival (OS) and progression-free survival (PFS). The patients' median age was 63 years, with 88.3% at an advanced stage (III/IV). The majority of patients (47.6%) received anthracycline-containing regimens, and there was no significant difference in survival compared with those treated with epigenetic-targeting and gemcitabine- containing regimens. The median PFS and OS were 6 and 17 months, respectively. In multivariate analysis, age >60 years, Eastern Cooperative Oncology Group performance status ≥2, elevated LDH, and splenomegaly were associated with inferior OS. Based on these four factors, a novel prognostic model (AITL model) was constructed that stratified patients into low-, intermediate-, and high-risk groups, with 2-year OS estimates of 63.6%, 42.1%, and 18.6%, respectively. Currently, there is no consensus on the optimal initial therapy for AITL, and the efficacy of anthracycline-containing regimens remains suboptimal. The novel model developed herein demonstrates predictive significance for both OS and PFS, and exhibits better stratification and discrimination capabilities.

Effect of Endothelial Activation and Stress Index(EASIX) on Prognosis of Peripheral T-Cell Lymphoma Patient

To investigate the effect of endothelial activation and stress index (EASIX) on the prognosis of patients with angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), and to compare the clinical characteristics of patients in the low EASIX and high EASIX groups. The clinical data of 59 newly diagnosed AITL and PTCL-NOS patients admitted to the Affiliated Hospital of Xuzhou Medical University from January 2010 to September 2021 were retrospectively analyzed. The optimal cut-off value of EASIX was determined by receiver operating characteristic (ROC) curve; The chi-square test was used to analyze the correlation between EASIX and clinical features of patients with AITL and PTCL-NOS; The Kaplan-Meier survival curve was used to analyze the overall survival (OS) and progression-free survival (PFS) of the patients; Univariate and multivariate analyses were performed by using Cox proportional hazards model. The optimal cut-off value of EASIX was 0.95, based on which the patients were divided into a low EASIX (<0.95) group and a high EASIX (≥0.95) group. Compared with the low EASIX group, the high EASIX group had a higher proportion of patients with advanced Ann Arbor stage, higher risk according to IPI, elevated LDH, hypoproteinemia, anemia, B symptoms,extranodal involvement, and bone marrow involvement. Survival analysis showed that the OS and PFS of patients in the high EASIX group were significantly shorter than those in the lower EASIX group(P <0.001). The multivariate analysis showed that EASIX was an independent risk factor for OS ［HR=7.217 (95%CI : 1.959-26.587), P =0.003］ and PFS ［HR=2.718(95%CI : 1.032-7.161), P =0.043］ of PTCL patients. High EASIX in newly diagnosed patients with AITL and PTCL-NOS suggests a poor prognosis, and high EASIX is a risk factor affecting prognosis of the patients.

A Novel Case of Reactive Perforating Collagenosis (RPC) with Cutaneous Infiltration of EBV+ Angioimmunoblastic T-cell Lymphoma (AITL).

Reactive perforating collagenosis (RPC) is a cutaneous disorder that has rarely been associated with haematological malignancies. We present the case of a 47-year-old man with a 6-month history of Epstein–Barr virus-positive angioimmunoblastic T-cell lymphoma (AITL) who was undergoing chemotherapy and had an extremely pruritic, papular eruption that had worsened over the past 7 months. Skin biopsy findings revealed RPC. He was treated with triamcinolone cream and hydroxyzine alongside his chemotherapy; this resolved his symptoms. This patient’s case offers a unique clinicopathological presentation of RPC in the setting of AITL in the skin and demonstrates the importance of a dermatologist's management of cutaneous disorders in patients with cancer to improve their quality of life.

In vivo CAR T cell therapy against angioimmunoblastic T cell lymphoma

BackgroundFor angioimmunoblastic T cell lymphoma (AITL), a rare cancer, no specific treatments are available and survival outcome is poor. We previously developed a murine model for AITL that mimics closely human disease and allows to evaluate new treatments. As in human AITL, the murine CD4+ follicular helper T (Tfh) cells are drivers of the malignancy. Therefore, chimeric antigen receptor (CAR) T cell therapy might represent a new therapeutic option.MethodsTo prevent fratricide among CAR T cells when delivering an CD4-specific CAR, we used a lentiviral vector (LV) encoding an anti-CD4 CAR, allowing exclusive entry into CD8 T cells.ResultsThese anti-CD4CAR CD8-targeted LVs achieved in murine AITL biopsies high CAR-expression levels in CD8 T cells. Malignant CD4 Tfh cells were eliminated from the mAITL lymphoma, while the CAR + CD8 T cells expanded upon encounter with the CD4 receptor and were shaped into functional cytotoxic cells. Finally, in vivo injection of the CAR + CD8-LVs into our preclinical AITL mouse model carrying lymphomas, significantly prolonged mice survival. Moreover, the in vivo generated functional CAR + CD8 T cells efficiently reduced neoplastic T cell numbers in the mAITL tumors.ConclusionThis is the first description of in vivo generated CAR T cells for therapy of a T cell lymphoma. The strategy described offers a new therapeutic concept for patients suffering from CD4-driven T cell lymphomas.

Predicting the efficiency of chidamide in patients with angioimmunoblastic T-cell lymphoma using machine learning algorithm.

Chidamide is subtype-selective histone deacetylase (HDAC) inhibitor that showed promising result in clinical trials to improve prognosis of angioimmunoblastic T-cell lymphoma (AITL) patients. However, in real world settings, contradictory reports existed as to whether chidamide improve overall survival (OS). Therefore, we aimed to develop an interpretable machine learning (Machine learning)-based model to predict the 2-year overall survival of AITL patients based on chidamide usage and baseline features. A total of 183 patients with AITL were randomly divided into training set and testing set. We used 5ML algorithms to build predictive models. Recursive feature elimination (RFE) method was used to filter for the most important features. The ML models were interpreted and the relevance of the selected features was determined using the Shapley additive explanations (SHAP) method and the local interpretable model-agnostic explanationalgorithm. A total of 183 patients with newly diagnosed AITL from 2012 to 2022 from 3 centers in China were enrolled in our study. Seventy-one patients were dead within 2years after diagnosis. Five ML algorithms were built based on chidamide usage and 16 baseline features to predict 2-year OS. Catboost model presented to be the best predictive model. After RFE screening, 12 variables demonstrated the best performance (AUC = 0.8651). Using chidamide ranked third among all the variables that correlated with 2-year OS. This study demonstrated that the Catboost model with 12 variables could effectively predict the 2-year OS of AITL patients. Combining chidamide in the treatment therapy was positively correlated with longer OS of AITL patients.

Wild-type Blocking PCR Combined with Sanger Sequencing for Detection of Low-frequency Somatic Mutation.

When monitoring minimal residual disease (MRD) after tumor treatment, there are higher requirements of the lower limit of detection than when detecting for drug resistance mutations and circulating tumor cell mutations during therapy. Traditional Sanger sequencing has 5%-20% wild-type mutation detection, so its limit of detection cannot meet the corresponding requirements. The wild-type blocking technologies that have been reported to overcome this include blocker displacement amplification (BDA), non-extendable locked nucleic acid (LNA), hot-spot-specific probes (HSSP), etc. These technologies use specific oligonucleotide sequences to block wild-type or recognize wild-type and then combine this with other methods to prevent wild-type amplification and amplify mutant amplification, leading to characteristics like high sensitivity, flexibility, and convenience. This protocol uses BDA, a wild-type blocking PCR combined with Sanger sequencing, to optimize the detection of RHOA G17V low-frequency somatic mutations, and the detection sensitivity can reach 0.5%, which can provide a basis for MRD monitoring of angioimmunoblastic T-cell lymphoma.