Outcomes and prognostic factors in angioimmunoblastic T-cell lymphoma: final report from the international T-cell Project.

Angioimmunoblastic T-cell lymphoma (AITL) is a unique subtype of peripheral T-cell lymphoma (PTCL) with distinct clinicopathologic features and poor prognosis. We performed a subset analysis of 282 patients with AITL enrolled between 2006 and 2018 in the international prospective T-cell Project (NCT01142674). The primary and secondary end points were 5-year overall survival (OS) and progression-free survival (PFS), respectively. We analyzed the prognostic impact of clinical covariates and progression of disease within 24 months (POD24) and developed a novel prognostic score. The median age was 64 years, and 90% of patients had advanced-stage disease. Eighty-one percent received anthracycline-based regimens, and 13% underwent consolidative autologous stem cell transplant (ASCT) in first complete remission (CR1). Five-year OS and PFS estimates were 44% and 32%, respectively, with improved outcomes for patients who underwent ASCT in CR1. In multivariate analysis, age ≥60 years, Eastern Cooperative Oncology Group performance status >2, elevated C-reactive protein, and elevated ß2 microglobulin were associated with inferior outcomes. A novel prognostic score (AITL score) combining these factors defined low-, intermediate-, and high-risk subgroups with 5-year OS estimates of 63%, 54%, and 21%, respectively, with greater discriminant power than established prognostic indices. Finally, POD24 was a powerful prognostic factor with 5-year OS of 63% for patients without POD24 compared with only 6% for patients with POD24 (P < .0001). These data will require validation in a prospective cohort of homogeneously treated patients. Optimal treatment of AITL continues to be an unmet need, and novel therapeutic approaches are required.

[RS3PE syndrome with angioimmunoblastic T-cell lymphoma early after the start of immunosuppressive therapy].

A 75-year-old man visited our Collagen Disease Department because of a fever, edema in the lower legs, and arthralgia. He presented with peripheral arthritis of the extremities and was negative for rheumatoid factor, leading to a diagnosis of RS3PE syndrome. A search for malignancy was performed, but no obvious malignant findings were found. After starting treatment with steroid, methotrexate, and tacrolimus, the patient's joint symptoms improved, but after five months, enlarged lymph nodes throughout the body were observed. A lymph node biopsy revealed a diagnosis of other iatrogenic immunodeficiency-associated lymphoproliferative disorders/angioimmunoblastic T-cell lymphoma (OI-LPD/AITL). After discontinuation of methotrexate and follow-up, no lymph node shrinkage was observed, and the patient had strong general malaise, so chemotherapy was started for AITL. After the start of chemotherapy, the patient's general symptoms improved quickly. RS3PE syndrome is a polyarticular, rheumatoid factor-negative, polyarticular synovitis with symmetric dorsolateral hand-palmar symmetric indentation edema that occurs mainly in elderly patients. It is also noted as a paraneoplastic syndrome, with 10%-40% of patients having malignant tumors. When our patient was diagnosed with RS3PE syndrome, a search for malignancy was performed, but there were no findings suggestive of malignant disease. However, after methotrexate and tacrolimus administration was started, the patient developed rapid lymph node enlargement, and the pathology showed AITL. The possibility of AITL as an underlying disease and RS3PE syndrome as a paraneoplastic syndrome, or conversely, OI-LPD/AITL associated with immunosuppressive therapy for RS3PE syndrome is considered. We herein report this case, as sufficient recognition is required for a proper diagnosis to be made and treatment of RS3PE syndrome to be performed.

Epigenetic focus on angioimmunoblastic T-cell lymphoma: pathogenesis and treatment.

PURPOSE OF REVIEW: Angioimmunoblastic T-cell lymphoma (AITL) is a frequent peripheral T-cell lymphoma affecting elderly patients with a poor outcome when treated with conventional chemotherapy. Molecular studies revealed a homogenous mutational landscape gathering anomalies in genes regulating the DNA methylation and hydroxymethylation and anomalies in T-cell signalling. RECENT FINDINGS: Recent studies indicate that AITL emerges from a TET2 and/or DNMT3A mutated clonal haematopoiesis. This clonal haematopoiesis bearing mutations altering DNA hydroxymethylation can explain the observed coexistence of AITL with myeloid neoplasms. In addition, AITL development requires AITL-specific mutations, such as the RHOAG17V mutations. Combination of TET2 and RHOAG17V alterations results in the development of AITL-like disease in mouse models. The impact of the presence of these mutations on patient outcome seems limited and new biological factor predicting treatment response and survival remains to be determined. At the therapeutic level, therapies targeting epigenetic changes, such as histone deacetylase inhibitors and the hypomethylating 5-azacytidine agent, could have efficacy in this disease and gave promising results. Recent progress in mouse model development should allow development of new treatments. SUMMARY: Epigenetic changes are frequent in AITL and could be a promising target.

The derived neutrophil-to-lymphocyte ratio is an independent prognostic factor in patients with angioimmunoblastic T-cell lymphoma.

To determine whether inflammatory markers, derived neutrophil-to-lymphocyte ratio (dNLR), haemoglobin/platelet ratio (HPR) or platelet/lymphocyte ratio (PLR) are predictive for prognosis in angioimmunoblastic T-cell lymphoma (AITL), we derived dNLR, HPR and PLR values for 110 AITL patients and appropriate cut-off point values to define overall survival (OS) and progression-free survival (PFS). dNLR ≥ 2·2, HPR ≥ 0·4 or PLR < 100 were significant factors for shorter OS and PFS. On univariate analysis, these three parameters were significantly associated with worse OS and PFS. On multivariate analysis, only dNLR remained a significant, independent prognostic factor for both OS and PFS.

Angioimmunoblastic T-cell lymphoma: the many-faced lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) is an uncommon subtype of mature peripheral T-cell lymphoma (PTCL). The history of AITL is much longer and deeper than the literature would suggest given the many names that have preceded it. Advanced-stage disease is common with uncharacteristic laboratory and autoimmune findings that often slow or mask the diagnosis. Significant strides in the immunohistochemical and molecular signature of AITL have brought increased ability to diagnose this uncommon type of PTCL. The 2016 World Health Organization classification of lymphoid neoplasms recently acknowledged the complexity of this diagnosis with the addition of other AITL-like subsets. AITL now resides under the umbrella of nodal T-cell lymphomas with follicular T helper phenotype. Induction strategies continue to focus on increasing complete remission rates that allow more transplant-eligible patients to proceed toward consolidative high-dose therapy and autologous stem cell rescue with improving long-term survival. There are several clinical trials in which recently approved drugs with known activity in AITL are paired with induction regimens with the hope of demonstrating long-term progression-free survival over cyclophosphamide, doxorubicin, vincristine, and prednisone. The treatment of relapsed or refractory AITL remains an unmet need. The spectrum of AITL from diagnosis to treatment is reviewed subsequently in a fashion that may one day lead to personalized treatment approaches in a many-faced disease.

Angioimmunoblastic T-Cell Lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) is one of the most common types of T-cell lymphoma, representing about 15-20% of cases of peripheral T-cell lymphoma (PTCL). It is characterized by a unique clinical presentation and distinct pathologic and molecular features. Classes of drugs particularly active in AITL are emerging; however, treatment of relapsed and refractory disease remains a challenge. This chapter reviews the epidemiology, clinical presentation, pathogenesis, diagnosis, and treatment of AITL.

Epstein-Barr Virus-Induced Cutaneous Diffuse Large B-Cell Lymphoma in a Patient With Angioimmunoblastic T-Cell Lymphoma.

Cutaneous manifestations of Epstein-Barr virus (EBV)-driven B-cell lymphoid proliferations occur rarely as a result of severe immunodeficiency. To date, only a few cases of extranodal EBV-associated B-cell lymphomas arising in patients with angioimmunoblastic T-cell lymphoma (AITL) have been reported, and less common is a cutaneous presentation. AITL is a rare aggressive tumor that carries a poor prognosis and prompt diagnosis, and recognition of EBV-associated diffuse B-cell lymphoma is essential in these patients to instigate the correct treatment.

Cardiac Tamponade as Initial Presentation of Angioimmunoblastic T-Cell Lymphoma.

A 21-year-old man presented initially with impending cardiac tamponade secondary to an angioimmunoblastic T-cell lymphoma (AITL). Following unsuccessful pericardiocentesis and subxiphoid pericardiostomy, the patient's deteriorating hemodynamics prompted an urgent sternotomy. Histopathological diagnosis confirmed AITL. While chemotherapy remains the most effective treatment of AITL, life-threatening complications of the tumor necessitates surgical intervention.

Angioimmunoblastic T cell lymphoma: an unusual presentation of posttransplant lymphoproliferative disorder in a pediatric patient.

Posttransplant lymphoproliferative disorders (PTLD) are a potentially life-threatening complication of immunosuppression in transplant recipients. The majority of cases are Epstein-Barr virus-associated lesions of B cell origin. T cell PTLD is rare, particularly in pediatric patients. We present an unusual case of monomorphic T cell PTLD with features of angioimmunoblastic T cell lymphoma in an 8-year-old heart transplant patient, presenting with cranial nerve palsy.

[Angioimmunoblastic T-cell lymphoma].

Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of nodal peripheral T-cell lymphoma associated with aggressive clinical course that affects mostly the elderly. Clinical features at diagnosis are characterized by polyclonal hypergammaglobulinemia, B-symptoms, and advanced stage. It usually responds to anthracycline-based chemotherapy but eventually relapses with a median progression free survival of less than 2 years. High dose chemotherapy followed by autologous stem cell transplantation is an option for improving prognosis both in first-line and in relapsed or refractory settings. Several prospective clinical trials are evaluating the role of high dose chemotherapy as a consolidation in first-line treatment for T-cell lymphoma including AITL.

Therapy refractory angioimmunoblastic T-cell lymphoma in complete remission with lenalidomide.

The prognosis of therapy refractory angioimmunoblastic lymphoma (AITL) is very poor. In this report we describe a patient with AITL refractory to 2 lines of chemotherapy. He was treated with lenalidomide 15 mg continuously and prednisone. After 2 yr follow-up, the patient has no detectable disease. Lenalidomide was well tolerated without side-effects. Lenalidomide even in lower dosed combined with steroids can induce complete responses in patients with refractory AITL.

Advances in the pathogenesis and therapeutic strategies of angioimmunoblastic T-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of peripheral T-cell lymphomas with its cell origin determined to be follicular helper T-cells. AITL is characterized by a prominent tumor microenvironment involving dysregulation of immune cells, signaling pathways, and extracellular matrix. Significant progress has been made in the molecular pathophysiology of AITL, including genetic mutations, immune metabolism, hematopoietic-derived microenvironment, and non-hematopoietic microenvironment cells. Early diagnosis, detection of severe complications, and timely effective treatment are crucial for managing AITL. Treatment typically involves various combination chemotherapies, but the prognosis is often poor, and relapsed and refractory AITL remains challenging, necessitating improved treatment strategies. Therefore, this article provides an overview of the pathogenesis and latest advances in the treatment of AITL, with a focus on potential therapeutic targets, novel treatment strategies, and emerging immunotherapeutic approaches.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: This study demonstrates that spleen involvement might be used as a prognostic indicator for AITL patients.

Spontaneous remission of angioimmunoblastic T-cell lymphoma in a child with ataxia-telangiectasia: a case report.

BACKGROUND: Angioimmunoblastic T-cell lymphoma is an uncommon subtype of peripheral T-cell lymphoma in children with fewer than 20 cases reported in literature. CASE PRESENTATION: A 3-year-old Omani boy was diagnosed with ataxia-talengectasia presenting with fever and generalized lymphadenopathy. His biopsy revealed atypical lymphocytic infiltrate consistent with the diagnosis of angioimmunoblastic T-cell lymphoma. Within 3 weeks from the initial presentation and without any neoadjuvant therapy, he showed complete recovery of symptoms with absence of fever and regression of all previously affected lymph nodes. He has remained in remission ever since. CONCLUSION: This is the first report of spontaneous improvement of angioimmunoblastic T-cell lymphoma in a patient with ataxia-telangiectasia who was 3 years old at presentation. Owing to the paucity of similar cases, this report adds valuable diagnostic, therapeutic, and monitoring data.

Targeting intratumoral B cells with rituximab in addition to CHOP in angioimmunoblastic T-cell lymphoma. A clinicobiological study of the GELA.

BACKGROUND: In angioimmunoblastic T-cell lymphoma, symptoms linked to B-lymphocyte activation are common, and variable numbers of CD20(+) large B-blasts, often infected by Epstein-Barr virus, are found in tumor tissues. We postulated that the disruption of putative B-T interactions and/or depletion of the Epstein-Barr virus reservoir by an anti-CD20 monoclonal antibody (rituximab) could improve the clinical outcome produced by conventional chemotherapy. DESIGN AND METHODS: Twenty-five newly diagnosed patients were treated, in a phase II study, with eight cycles of rituximab + chemotherapy (R-CHOP21). Tumor infiltration, B-blasts and Epstein-Barr virus status in tumor tissue and peripheral blood were fully characterized at diagnosis and were correlated with clinical outcome. RESULTS: A complete response rate of 44% (95% CI, 24% to 65%) was observed. With a median follow-up of 24 months, the 2-year progression-free survival rate was 42% (95% CI, 22% to 61%) and overall survival rate was 62% (95% CI, 40% to 78%). The presence of Epstein-Barr virus DNA in peripheral blood mononuclear cells (14/21 patients) correlated with Epstein-Barr virus score in lymph nodes (P<0.004) and the detection of circulating tumor cells (P=0.0019). Despite peripheral Epstein-Barr virus clearance after treatment, the viral load at diagnosis (>100 copy/µg DNA) was associated with shorter progression-free survival (P=0.06). CONCLUSIONS: We report here the results of the first clinical trial targeting both the neoplastic T cells and the microenvironment-associated CD20(+) B lymphocytes in angioimmunoblastic T-cell lymphoma, showing no clear benefit of adding rituximab to conventional chemotherapy. A strong relationship, not previously described, between circulating Epstein-Barr virus and circulating tumor cells is highlighted.

Secondary Epstein-Barr virus associated lymphoproliferative disorder developing in a patient with angioimmunoblastic T cell lymphoma on vorinostat.

Ebstein-Barr Virus (EBV)-related lymphoproliferative disorders primarily occur in the setting of immunosuppression, most commonly after solid organ transplantation. The frequency depends on the degree of immunosuppression and the specific organ transplanted, but can be as high as 3­9% in heart or lung transplant patients. Less frequent outside of the transplant setting, EBV-related lymphoproliferative disorders classified as other iatrogenic immunodeficiency associated lymphoproliferative disorders in the WHO Classification, which are different than iatrogenically related lymphomas supervening on hematological malignancies, have been associated with other immunosuppressive therapies such as 6-Mercaptopurine, azathioprine, or alemtuzumab. These disorders have also been reported to develop spontaneously in patients with T cell lymphomas (angioimmunoblastic and peripheral T cell NOS). Here we report the case of a patient with an angioimmunoblastic T cell lymphoma on therapy with vorinostat who developed an EBV related B-cell lymphoproliferative disorder involving bilateral adrenal glands. Angioimmunoblastic T cell lymphoma is associated with severe immunodeficiency and risk for opportunistic infections. This immune dysregulation has been implicated in its association with EBV related lymphoproliferative disorders. In this patient, vorinostat therapy also appears to be linked to the development of an EBV-related lymphoproliferative disorder.

Spatial Transcriptomics Analysis Reveals that CCL17 and CCL22 are Robust Indicators of a Suppressive Immune Environment in Angioimmunoblastic T Cell Lymphoma (AITL).

BACKGROUND: T cell lymphoma is a complex and highly aggressive clinicopathological entity with a poor outcome. The angioimmunoblastic T-cell lymphoma (AITL) tumor immune microenvironment is poorly investigated. METHODS: Here, to the best of our knowledge, spatial transcriptomics was applied for the first time to study AITL. RESULTS: Using this method, we observed that AITL was surrounded by cells bearing immune-suppressive markers. CCL17 and CCL22, the dominant ligands for CCR4, were up-regulated, while the expression of natural killer (NK) cell and CD8+ cytotoxic T lymphocyte (CTL) markers decreased. Colocalization of Treg cells with the CD4+ TFH-GC region was also deduced from the bioinformatic analysis. The results obtained with spatial transcriptomics confirm that AITL has a suppressive immune environment. Chemotherapy based on the CHOP regimen (cyclophosphamide, doxorubicin, vincristine plus prednisone) induced complete remission (CR) in this AITL patient. However, the duration of remission (DoR) remains a concern. CONCLUSIONS: This study demonstrates that AITL has an immune suppressive environment and suggests that anti-CCR4 therapy could be a promising treatment for this lethal disease.

[Angioimmunoblastic T-cell lymphoma with marked polyclonal plasmacytosis in peripheral blood and bone marrow mimicking plasma cell leukemia].

A 70-year-old man was admitted to our hospital with fever, generalized lymphadenopathy and hypoxia in October 2009. Blood examination demonstrated leukocytosis, anemia, thrombocytopenia and hyper γ-globulinemia. Peripheral blood and bone marrow smear showed marked plasma cell proliferation mimicking plasma cell leukemia. However, flow cytometric analysis showed that plasma cells were of polyclonal origin and M-protein was not detected by immunofixation of serum protein. Elevations of soluble interleukin 2 receptor and serum IL-6 were observed. A heavy Epstein-Barr viral load was detected in serum by real-time PCR. Biopsy was obtained from the right inguinal lymph node. The pathological diagnosis was angioimmunoblastic T-cell lymphoma (AITL) and rearrangement of the T-cell receptor Cß1 gene was detected. The patient was treated with CHOP therapy, and all clinical manifestations, including fever, lymphadenopathy, anemia, thrombocytopenia, hyper γ-globulinemia, plasmacytosis and hypoxia, were improved. Only a few reported cases have demonstrated AITL with marked polyclonal plasmacytosis. Although pathological mechanisms of plasmacytosis in AITL patients have not been fully elucidated, it is suggested that IL-6 and IL-10 were involved in its pathogenesis in the present case.