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.

Clinicopathologic characteristics, outcomes, and prognostic factors of angioimmunoblastic T-cell lymphoma in China.

BACKGROUND: This study aimed to better characterize the clinicopathologic characteristics, outcomes, and prognostic factors of AITL in China. METHODS: We retrospectively analyzed 312 patients with AITL enrolled between January 2011 and December 2020 from five institutions in China. RESULTS: The median age was 65 years, with 92.6% advanced stage, 59.7% elevated LDH, 46.1% anemia, and 44.0% hypergammaglobulinemia. The majority of patients (84.9%) received anthracycline-based regimens with or without etoposide, and only 6.1% underwent autologous stem cell transplantation following first remission. The 5-year OS and PFS estimates were 43.4% and 25.0% with no significant improvement of survival between patients treated during 2011-2015 and 2016-2020, respectively. Both the International Prognostic Index (IPI) and the prognostic index for PTCL, not otherwise specified (PIT), were predictive for OS. In multivariate analysis, age >70 years, elevated LDH, and albumin level <35 g/L were independent prognostic factors for OS. Combining these three factors, a novel prognostic model (the Chinese AITL score) was constructed, which stratified patients into low-, intermediate-, and high-risk groups, with 5-year OS rates of 69.0%, 41.5%, and 23.7%, respectively. This new model was successfully validated in an independent cohort. CONCLUSIONS: Patients with AITL were mainly treated with anthracycline-based regimens, and the outcomes were still unsatisfactory in China. Our novel prognostic model may improve our ability to identify patients at different risks for alternative therapies.

Relapsed Angioimmunoblastic T Cell Lymphoma with Fulminant Leukemic Involvement.

BACKGROUND Angioimmunoblastic T cell lymphoma (AITL) is an aggressive and rare entity that comprises about 1-2% of all non-Hodgkin lymphomas. This entity carries many challenges that start at the diagnosis, as most patients present with non-specific symptoms affecting different systems. As a result, the optimal approach, reaching the accurate diagnosis, and delivering needed treatment are delayed. Furthermore, it is not surprising that the initial set of biopsies are non-diagnostic given the heavy inflammatory background and scarcity of malignant cells in the early course of the disease. Other challenges include delivering the optimal curative therapy, as there is no such therapeutic option available yet. Although stem cell transplantation (SCT) can be considered a curative option, some patients have comorbidities and are not eligible for this option, and some other patients have relapse despite this aggressive approach, as was seen in our case. CASE REPORT We present an interesting case of AITL with florid leukemic infiltration at the time of relapse. We included a description of the patient's symptoms, diagnostic challenges, and clinical course, and provided therapy with demonstrative peripheral blood and flow cytometry images. Interestingly, there are very few reports in the literature that described leukemic infiltration of this entity. CONCLUSIONS Acknowledging the rarity of this aggressive lymphoma combined with all the challenges that face the involved health care workers, publishing this elaborative case report adds some insight and knowledge and helps improve our understanding of this entity.

T-Cell Lymphomas, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoproliferative disorders arising from mature T cells, accounting for about 10% of non-Hodgkin lymphomas. PTCL-not otherwise specified is the most common subtype, followed by angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma, anaplastic lymphoma kinase-negative, and enteropathy-associated T-cell lymphoma. This discussion section focuses on the diagnosis and treatment of PTCLs as outlined in the NCCN Guidelines for T-Cell Lymphomas.

Angioimmunoblastic T-cell lymphoma: treatment strategies and prognostic factors from a retrospective multicenter study in China.

Angioimmunoblastic T-cell lymphoma (AITL) is a unique sub-type of peripheral T-cell lymphoma (PTCL). We aimed to evaluate treatment programs and prognostic factors of 121 newly diagnosed patients with AITL in China from January 2001 to December 2018. The median age was 58 years with male predominance. Bone marrow involvement appeared in only 8.3% of patients, which was different from the previously published literature. The 5-year progression-free survival (PFS) and 5-year overall survival (OS) were 29.7% and 44.0%, respectively. Univariate and multivariate analyses showed that involvement of >5 nodal areas, age and Beta-2 microglubulin were highly predictive of OS but only the involvement of fewer than five nodal areas was significant for PFS. We identified a novel prognostic model including the three factors that may be applied in clinical practice and offer an alternative to IPI and PIT.

Recent Advances in Diagnosis and Therapy of Angioimmunoblastic T Cell Lymphoma.

Angioimmunoblastic T cell lymphoma (AITL) is a common subtype of mature peripheral T cell lymphoma (PTCL). As per the 2016 World Health Organization classification, AITL is now considered as a subtype of nodal T cell lymphoma with follicular helper T cells. The diagnosis is challenging and requires a constellation of clinical, laboratory and histopathological findings. Significant progress in the molecular pathophysiology of AITL has been achieved in the past two decades. Characteristic genomic features have been recognized that could provide a potential platform for better diagnosis and future prognostic models. Frontline therapy for AITL was mainly depending on chemotherapy and the management of relapsed or refractory AITL is still unsatisfactory with a very poor prognosis. Upfront transplantation offers better survival. Novel agents have been introduced recently with promising outcomes. Several clinical trials of combinations using novel agents are underway. Herein, we briefly review recent advances in AITL diagnosis and the evolving treatment landscape.

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.

Effects of stem cell transplantation in patients with peripheral T-cell lymphoma not otherwise specified and angioimmunoblastic T-cell lymphoma.

The effects of stem cell transplantation (SCT) in patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) remain controversial. We analyzed the feasibility of SCT and risk factors associated with outcomes of PTCL-NOS and AITL patients to identify the potential clinical efficacy of SCT. We retrospectively analyzed the data of PTCL-NOS (n = 83) and AITL (n = 112) patients who received autologous (n = 10 and 16, respectively) or allogeneic (n = 12 and 4, respectively) SCT, or no SCT (n = 61 and 92, respectively) between 2008 and 2018. All PTCL-NOS and AITL diagnoses were reconfirmed by an experienced hematopathologist. Median age at PTCL-NOS and AITL diagnoses in the SCT group was younger than that in the no SCT group. Significant risk factors for lower overall survival were intermediate-high and high-risk international prognostic indexes in PTCL-NOS patients (P = 0.0052), and a > 2 modified prognostic index for T-cell lymphoma (P = 0.0079) and no SCT (P = 0.028) in AITL patients. Autologous or allogeneic SCT compared with no SCT in AITL patients resulted in 3-year overall survival of 68.6% and 100% vs. 57.2% (P = 0.018). Strategies should be developed to improve selection of PTCL-NOS and AITL patients suitable for SCT and/or additional novel therapies.

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.

[Diagnosis and treatment of angioimmunoblastic T-cell lymphoma and related cancers].

Gene and protein expression profiling has clarified that tumor cells in angioimmunoblastic T-cell lymphoma (AITL) have T follicular helper (TFH) cell characteristics. In AITL, typical genomic abnormalities have been reported that combine G17V RHOA mutations, gene mutations involved in epigenetic pathways, and those involved in T-cell receptor signal pathways. Besides AITL, some lymphomas display a TFH phenotype, prompting the proposal of a new disease classification encompassing those. Interestingly, lymphomas with TFH phenotype characteristics also share most genomic abnormalities with AITL. Furthermore, because AITL genomic abnormalities are highly disease specific, they can be used for diagnosis. Although AITL is a refractory disease, several new drugs have been approved for relapsed and refractory cases. Precision medicine targeting genomic aberrations characteristic of AITL is being investigated.

Clinical spectrum, evolution, and management of autoimmune cytopenias associated with angioimmunoblastic T-cell lymphoma.

OBJECTIVE: Angioimmunoblastic T-cell lymphoma (AITL) is frequently associated with autoimmune cytopenia (AIC). Whether such patients have a particular phenotype and require particular management is unclear. METHOD: Angioimmunoblastic T-cell lymphoma patients from the multicentric database of the Lymphoma Study Association presenting with AIC during disease course were included and matched to AITL patients without AIC (1/5 ratio). RESULTS: At diagnosis, AIC patients (n = 28) had more spleen and bone marrow involvement (54% vs 19% and 71% vs 34%, P < 0.001), Epstein-Barr virus replication (89% vs 39%, P < 0.001), gamma globulin titers (median 23 vs 15 g/L, P = 0.002), and proliferating B cells and plasmablasts in biopsies, as compared to control patients (n = 136). The 28 AIC patients had 41 episodes of AIC, diagnosed concomitantly with AITL in 23 (82%) cases. After a median follow-up of 24 months (range 3-155), 10 patients relapsed, all associated with AITL relapse. CONCLUSION: Our results provide new insight into AIC associated with AITL by highlighting the significant interplay between AITL and B-cell activation leading to subsequent autoimmunity.

The role of autologous stem cell transplantation in patients with nodal peripheral T-cell lymphomas in first complete remission: Report from COMPLETE, a prospective, multicenter cohort study.

BACKGROUND: The role of autologous stem cell transplantation (ASCT) in the first complete remission (CR1) of peripheral T-cell lymphomas (PTCLs) is not well defined. This study analyzed the impact of ASCT on the clinical outcomes of patients with newly diagnosed PTCL in CR1. METHODS: Patients with newly diagnosed, histologically confirmed, aggressive PTCL were prospectively enrolled into the Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE) study, and those in CR1 were included in this analysis. RESULTS: Two hundred thirteen patients with PTCL achieved CR1, and 119 patients with nodal PTCL, defined as anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified, were identified. Eighty-three patients did not undergo ASCT, whereas 36 underwent consolidative ASCT in CR1. At the median follow-up of 2.8 years, the median overall survival was not reached for the entire cohort of patients who underwent ASCT, whereas it was 57.6 months for those not receiving ASCT (P = .06). ASCT was associated with superior survival for patients with advanced-stage disease or intermediate-to-high International Prognostic Index scores. ASCT significantly improved overall and progression-free survival for patients with AITL but not for patients with other PTCL subtypes. In a multivariable analysis, ASCT was independently associated with improved survival (hazard ratio, 0.37; 95% confidence interval, 0.15-0.89). CONCLUSIONS: This is the first large prospective cohort study directly comparing the survival outcomes of patients with nodal PTCL in CR1 with or without consolidative ASCT. ASCT may provide a benefit in specific clinical scenarios, but the broader applicability of this strategy should be determined in prospective, randomized trials. These results provide a platform for designing future studies of previously untreated PTCL.

Risk factors and timing of autologous stem cell transplantation for patients with peripheral T-cell lymphoma.

High-dose chemotherapy with autologous stem cell transplantation (HDC-ASCT) is an option for patients with peripheral T-cell lymphoma (PTCL); however, neither prospective nor retrospective studies support proceeding with ASCT upfront, and the timing of HDC-ASCT remains controversial. We retrospectively analyzed the risk factors for outcomes of 570 patients with PTCL, including PTCL not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL), who received ASCT for frontline consolidation (n = 98 and 75, respectively) or alternative therapies after either relapse (n = 112 and 75) or primary induction failure (PIF; n = 127 and 83) between 2000 and 2015. Significant risk factors for overall survival (OS) after upfront ASCT were a ≥ 2 prognostic index for T-cell lymphoma (P < 0.001) and partial response (PR) at ASCT (P = 0.041) in PTCL-NOS patients, and > 60 years of age (P = 0.0028) and PR at ASCT (P = 0.0013) in AITL patients. Performance status of ≥ 2 at ASCT (P < 0.001), receiving ≥ 3 regimens before ASCT (P = 0.018), and PR at ASCT (P = 0.018) in PTCL-NOS patients and > 60 years of age at ASCT (P = 0.0077) in AITL patients were risk factors for OS after ASCT with a chemosensitive PIF status. Strategies that carefully select PTCL patients may allow identification of individuals suitable for ASCT.

Angioimmunoblastic T-cell lymphoma: a prognostic model from a retrospective study.

Angioimmunoblastic T-cell lymphoma (AITL) is a distinct subtype of peripheral T-cell lymphoma with unique clinical and pathological features. This study aim to design a prognostic model specifically for AITL, providing risk stratification in affected patients. A total of 115 newly diagnosed AITL patients were retrospectively analyzed. The estimated five-year overall survival (OS) rate for all patients was 45.4%. Multivariate analysis found prognostic factors for survival were bone marrow involvement, number of extranodal sites >1, and performance status >1. We categorized three risk groups: group 1, no adverse factor; group 2, one factor; and group 3, two or three factors. Five-year OS was 86.9% for Group 1, 46.3% for Group 2, and 16.2% for Group 3 (p < .0001). The novel prognostic model balanced the distribution of patients into different risk groups with better predictive discrimination as compared to the International Prognostic Index and Prognostic Index for PTCL, unless otherwise specified.

Clinicopathological Study of 30 Cases of Peripheral T-cell Lymphoma with Hodgkin and Reed-Sternberg-like B-cells from Japan.

The presence of Hodgkin and Reed-Sternberg (HRS)-like B-cells in peripheral T-cell lymphoma (PTCL) is rare and its clinicopathological features still remain unclear. Here, we describe 30 cases of PTCL with HRS-like B-cells from Japan. Twenty-three cases (77%) presented evidence of follicular T-helper phenotype (TFH) derivation: 12 were angioimmunoblastic T-cell lymphoma and 11 PTCL with TFH phenotype (PTCL-TFH). The remaining seven cases were diagnosed as PTCL, not otherwise specified (PTCL-NOS). Epstein-Barr virus (EBV) reactivation was detected in 25 cases (83%), but HRS-like B-cells were EBER in only 20 cases (67%). The median age at diagnosis was 77 years (range, 39-91 y), including 24 patients (80%) were older than 60 years of age. Most of the patients presented at an advanced clinical stage and were associated with higher risk according to the International Prognostic Index. The 3-year overall and progression-free survival rates were 44% and 27%, respectively. No significant clinicopathological differences were detected between PTCL-TFH, PTCL-NOS and the angioimmunoblastic cases. Cases with EBER HRS-like B-cells were associated with inferior overall and progression-free survival compared to those with EBER HRS-like B-cells, but the difference was not significant. In conclusion, HRS-like B-cells were found in a subset of T-cell lymphomas, especially in association with the TFH phenotype and EBV reactivation. These cells have a tendency to affect elderly patients and to be associated with advanced clinical stages and dismal prognosis. The EBV status of HRS-like B-cells does not seem to affect the clinicopathological features of this group of PTCLs.

How I manage peripheral T-cell lymphoma, not otherwise specified and angioimmunoblastic T-cell lymphoma: current practice and a glimpse into the future.

Peripheral T-cell lymphoma (PTCL), not otherwise specified (NOS) and angioimmunoblastic T-cell lymphoma (AITL) are the most frequent of more than 20 mature PTCL entities featuring a broad spectrum of morphological, immunophenotypic, molecular and clinical characteristics. Unfortunately, recent progress in understanding the (epi)genetic background of PTCL has not been met with similar advances in treatment. Thus, CHO(E)P [cyclophosphamide, doxorubicin, vincristine, and prednisone (plus etoposide)] remains standard first-line therapy. Patients without comorbidities achieving complete or partial remission proceed to autologous stem cell transplantation. With this approach about 50% of patients survive long-term. Patients relapsing after or progressing during first-line therapy have a dismal prognosis. They receive salvage gemcitabine-therapy followed by allogeneic transplantation whenever possible. After allografting, approximately half of the patients survive long-term; any other treatment is palliative. New drugs investigated in phase II studies achieved response rates between 10% and 30%; long-term remissions are the exception to the rule. While most new drugs are not licensed and not readily available, a plethora of other innovative drugs targeting (epi-)genetic abnormalities are in early development. These, together with combinations of new and old drugs, will hopefully increase response to first-line therapy, bridge more patients to transplantation, and finally improve prognosis for all patients with PTCL.