Therapeutic Effect of CAOLD Chemotherapy Regimen on Patients With Relapsed/Refractory Angioimmunoblastic T-Cell Lymphoma: A Case Study

Angioimmunoblastic T-cell lymphoma (AITL) is a kind of peripheral T-cell lymphomas (PTCLs) with a highly invasive feature. At present, patients are often treated with CHOP or CHOP-like regimens which is of poor prognosis whilst having high recurrence rate. Once the patient fails to achieve remission or relapse after the first-line treatment, many salvage chemotherapy regimens are always ineffective, and the long-term survival will be difficult to achieve for them. In this circumstance, more effective therapy methods are needed. In this study, two patients with relapsed/refractory AITL were treated with the CAOLD regimen [cyclophosphamide 400 mg/m2 qd d1, cytarabine 30 mg/m2 qd d1–d4, vindesine 2 mg/m2 qd d1, pegaspargase (PEG-ASP) 2,500 IU/m2 qd d2, dexamethasone 7.5 mg/m2 qd d1–d5], and long-term remission was achieved after chemotherapy. One is still alive after achieving complete remission (CR) after two cycles of chemotherapy, who has been followed up for 82 months. Besides, another patient achieved partial remission (PR) after the first course of chemotherapy. Then, CR was obtained after four courses of consolidation chemotherapy. The patient has been followed up for 63 months and is still alive. Both of them achieved long-time survival. These two successful cases demonstrated that the CAOLD regimen can be a better choice for relapsed/refractory AITL and offers hope of breakthrough in this medical field.

Whole-genome Sequencing of Angioimmunoblastic T-Cell Lymphoma Combined With Plasma Cell Leukemia: A Case Report and Review of the Literature

Purpose Angioimmunoblastic T-cell lymphoma (AITL) is a distinct subtype of peripheral T-cell lymphomas, sometimes involves proliferation of plasma cells. Currently, only 7 cases of AITL with monoclonal plasmacytosis have been reported. However, the molecular mechanisms underlying the interaction between monoclonal plasma cells and T cells have not been identified. We describe a rare case of AITL with plasma cell leukemia (PCL) in this report. Methods The patient was a 67-year-old female diagnosed with AITL and PCL. CD138 positive plasma cells and CD138-negative mixed bone marrow populations of this patient were collected for whole-genome sequencing (WGS). A review of the literature on AITL cases with monoclonal plasma cells is presented.Results WGS showed that the two cell populatoins shared 282 non-synonymous single nucleotide variants (SNVs) and excess of G to A and C to T transitions. We identified 14 potential driver genes in this patient. Functional enriched analysis of mutant genes confirmed several significantly enriched pathways, including VEGF signaling. The patient was treated with one cycle of PD (combined Bortezomib and Dexamethasone) and Chidamide. However, the patient developed severe pneumonia and pancytopenia, refused to receive further treatment, and died one week after discharge. Conclusion Being aware of the coexistence of PCL and AITL is important for accurate diagnosis and appropriate treatment. In addition, our results suggested the involvement of a group of genes and pathways in AITL with coexisting PCL, providing valuable information for further exploration of the underlying molecular mechanisms.

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.

Erythema Multiforme Major in Angioimmunoblastic T-cell Lymphoma

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Rapid Progression of Angioimmunoblastic T Cell Lymphoma Following BNT162b2 mRNA Vaccine Booster Shot: A Case Report

Since nucleoside-modified mRNA vaccines strongly activate T follicular helper cells, it is important to explore the possible impact of approved SARS-CoV-2 mRNA vaccines on neoplasms affecting this cell type. Herein, we report and discuss unexpected rapid progression of lymphomatous lesions after administration of a BNT162b2 mRNA vaccine booster in a man recently diagnosed with AITL.

Germinal Center B Cells Derived from TET2-Mutated Clonal Hematopoiesis Provide a Microenviromental Niche for Tumor Cells in Angioimmunoblastic T-Cell Lymphoma

Background Angioimmunoblastic T-cell lymphoma (AITL) is proposed to be initiated by age-related clonal hematopoiesis (ACH) with TET2mutations, whereas the G17V RHOA mutation in TET2-mutated immature cells facilitates development of T follicular helper (T FH)-like tumor cells. Notably, we and others have reported that immune cells derived from ACH with TET2 mutations infiltrate AITL tissues. However, how ACH-derived immune cells function as a microenvironmental niche in AITL remains largely unknown. Objective To elucidate the role of TET2-mutated immune cells in AITL tumorigenesis. Methods The G17V RHOA transgenic mice were crossed with mice lacking Tet2 in all blood cells (Mx-Crex Tet2f/f, A) and in T cells (Cd4-Crex Tet2f/f, B), respectively. Single-cell RNA sequencing (Sc-seq) was performed on >60,000 cells from AITL in mice (AITLm, n=2) and human (AITLh, n=5), and their controls to reveal the immune profiles. We used Seurat and Monocle3 pipelines for analysis of Sc-seq. Whole genome bisulfite sequencing (WGBS) was used to analyze the methylome of germinal center B (GCB) cells in AITLm and control. Results AITLm occurred only in A, but not in B. Then, we intraperitoneally transplanted Cd4 + tumor-containing cells together with various lineages of immune cells sorted from AITLm into nude mice. AITLm developed only when B-lineage cells were cotransplanted with Cd4 + tumor-containing cells. Unsupervised clustering of the Sc-seq data identified 6 T-, 6 B- and 3 myeloid clusters in AITLm. B-cell clusters were annotated into naïve B-, memory B-, GCB-, and plasma clusters along the B-cell differentiation through Geneset variable analysis (GSVA) and trajectory analysis. We found that the aberrant GCB clusters, simultaneously exhibiting DZ-like proliferation markers (Aicda and Mki67) and LZ-like activation markers (Cd40, Cd83) were markedly expanded in AITLm. Geneset Enrichment Analysis (GSEA) revealed that MYC targets and other signaling pathways involved in cell proliferation were highly enriched in the GCB clusters in AITLm. WGBS showed that the number of hypermethylated regions (HyperDMRs) was markedly higher than that of hypomethylated regions (HypoDMRs) at all the regions; promoters, exons, introns, untranslated and intergenic regions. Among HyperDMRs, Atp13a2, Pdzd2, Rapgef4, Irf4 and Egr3 expressions were downregulated in the GCB clusters of Sc-seq in AITLm. Remarkably, the number of BCR clones in GCB of AITLm were significantly less than those in controls. In addition, in AITLm mice, the number of somatic mutations in GCB cells was significantly higher than that in T FH-like tumor cells. Remarkably, we detected unique core histone mutations in the GCB cells of AITLm, including the recurrent p.Ser87Asn Histone3 mutations. Next, In silico network analysis using Sc-seq data between GCB and T FH-like clusters identified that 11 interactions, including Cd40-Cd40lg were significantly enhanced in AITLm compared to controls. Flowcytomeric analysis revealed that cell-surface expression of Cd40 were significantly higher in the GCB cells of AITLm than those of control. Pathologically, the follicular structure was disrupted in AITLm. Consequently, Cd40lg +Cd4 +tumor cells and Cd40 +Cd19 + cells were both diffusely distributed and sometimes localized adjacent to each other. Finally, administration of an anti-Cd40lg antibody prolonged the survival of nude mice transplanted with AITLm. In AITLh with TET2 mutations, unsupervised clustering of Sc-seq identified T-, B-, and myeloid-cell clusters and a cluster characterized by proliferative markers. In B-lineage cells, 9 clusters were re-clustered and annotated to naïve or memory B-, GCB- and plasmablast clusters under the same manner of mouse data. Gene ontology analysis from differential expression genes in each cluster showed that the GCB- and CD40-related genesets were enriched not only in the GCB cluster but also in the naive to memory B clusters. Furthermore, the AITL-B-specific geneset, which referred from genes (CD40, CD83, AICDA, MKI67) highly expressed in the GCB cluster in AITLm was enriched not only in the GCB cluster, but also in the naive to memory B clusters in AITLh. Conclusion This study suggests a new concept that ACH-derived GCB cells with TET2 mutations can undergo independent clonal evolution and function as microenvironmental cells to support tumorigenesis in AITL via the CD40-CD40LG axis. Disclosures Usuki: Astellas Pharma Inc.: Research Funding, Speakers Bureau; AbbVie GK: Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Research Funding; SymBio Pharmaceuticals Ltd.: Research Funding, Speakers Bureau; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; Sumitomo-Dainippon Pharma Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding, Speakers Bureau; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Research Funding; Celgene K.K.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Nippon-Boehringer-Ingelheim Co., Ltd.: Research Funding; Mundipharma K.K.: Research Funding; Amgen-Astellas Biopharma K.K.: Research Funding; Nippon-Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Kyowa-Kirin Co., Ltd.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; MSD K.K.: Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Research Funding, Speakers Bureau; Yakult Honsha Co., Ltd.: Research Funding, Speakers Bureau; Bristol-Myers-Squibb K.K.: Research Funding, Speakers Bureau; Apellis Pharmaceuticals, Inc.: Research Funding; Incyte Biosciences Japan G.K.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Speakers Bureau; Amgen K.K.: Research Funding.