Angioimmunoblastic T-cell Lymphoma Research Articles

TCL-323 Outcome of Relapsed and Refractory Peripheral T-Cell Lymphoma (PTCL) With Intention for Curative Therapy Incorporating High-Dose Chemotherapy and Hematopoietic Stem Cell Transplant (HDC/SCT).

Salvage therapy with high-dose chemotherapy and hematopoietic stem cell transplant (HDC/SCT) is recommended for patients with relapsed/refractory (R/R) PTCL. We evaluated the outcomes of R/R PTCL from the time of first relapse/progression in patients intended for SCT (ITT). The BC Cancer Lymphoid Cancer Database was reviewed, and patients ≥18 years with R/R PTCLs, such as systemic anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), and PTCL-not otherwise specified (PTCL-NOS), were included. Outcomes were assessed from the time of first relapse/progression and from the time of SCT. Of 114 included patients with ITT R/R PTCL, 60% had refractory disease and were more likely to have a high secondary IPI score, poor performance status, or advanced-stage disease. For second-line therapy, the majority received multi-agent chemotherapy (n = 83, 73%) with GDP, (gemcitabine, dexamethasone, and cisplatin) the most used regimen (n = 59, 52%), whereas 15 patients (13%) received novel agents (brentuximab vedotin [BV] = 12; romidepsin=2; pralatrexate=1). The overall response rate (ORR) to second-line therapy was 61% (24% complete response [CR]; 37% partial response [PR]). The ORR to GDP was 61% (17% CR; 44% PR), with higher responses observed in relapsed patients (81% vs. 41%, p=0.002). Seventy-three patients (63%) received HDC/SCT. Those who underwent allo-SCT were younger and more likely to have refractory disease (50% vs. 16%, p=0.001). Third-line therapy was required in 17/67 (25%), including novel agents in 9 cases. The median follow-up for living patients was 6.8 years. The 5-year progression-free survival (PFS) and overall survival (OS) from the time of first relapse/progression were 28% and 38%, respectively. The 5-year PFS from auto and allo-SCT were 34% and 52% (p = 0.3), and 5-year OS were 44% and 67% (p=0.5), respectively. Overall, outcomes for patients with ITT R/R PTCL remain suboptimal, with long-term survival in only one-third of patients; however, over half remained alive at 5 years if they were able to receive an SCT. A third line of therapy may serve as a successful bridge to SCT, and novel agents should be considered. Despite a higher proportion of refractory patients, results are encouraging with allo-SCT.

50 (PB040) - A phase 1/2, open-label, multicenter study to investigate the safety, pharmacokinetics, and efficacy of fadraciclib (CYC065), an oral CDK2/9 inhibitor, in subjects with advanced solid tumors and lymphoma

Background: Fadraciclib is a highly selective, orally- and intravenously-available, 2nd generation amino-purine inhibitor of CDK2 and CDK9. Translational biology supports the development of fadraciclib as a therapeutic agent for cancers dependent on MCL1 and MYC through the inhibition of CDK9, and for cancers associated with CCNE1 amplification, a known resistance factor for trastuzumab and CDK4/6 inhibitors, through the inhibition of CDK2. By inhibiting CDK2 and 9, fadraciclib causes apoptotic death of cancer cells at sub-micromolar concentrations. In an earlier Phase 1 study of IV fadraciclib, confirmed CR has been achieved in a subject with MCL1-amplified endometrial cancer. Oral fadraciclib is highly bioavailable allowing flexibility of dosing and schedule. Methods: Fadraciclib is being evaluated in a global, open-label, non-randomized, dose-escalation (phase 1) study in subjects with advanced solid tumors or lymphoma, and proof of concept (phase 2) in subjects with targeted indications, designated CYC065-101, (NCT04983810). Phase 1 explores both schedule and dose of oral fadraciclib monotherapy in 28-day cycles to identify MTD and/or RP2D. Once RP2D is established, phase 2 will enroll 12 to 40 subjects in seven specific tumor-type groups and a basket cohort, utilizing a Simon two-stage optimal design to evaluate clinical activity. Phase 2 groups include endometrial or ovarian cancer, biliary tract cancer, hepatocellular carcinoma, breast cancer, B-cell lymphoma, T-cell lymphoma, metastatic colorectal cancer and a basket cohort for tumors with MCL1, MYC or CCNE amplification/overexpression. Results: CYC065-101 study started enrolling subjects in July 2021 and is ongoing at City of Hope National Cancer Center, MD Anderson Cancer Center, Seoul National University Hospital, and Vall d’Hebron Institute of Oncology. As of June 2022, 17 subjects have received fadraciclib at dose levels 1 to 5. Fadraciclib was well tolerated at all dose levels with no DLT and no SUSAR observed. Preliminary efficacy data are available for 16 patients. One patient with CTCL showed PR per mSWAT response criteria. At dose level 5, a patient with endometrial cancer showed 15% reduction of target lesions after first cycle of treatment, and a patient with Angioimmunoblastic T-Cell Lymphoma (AITL) showed extensive reduction in multiple lesions after first cycle of treatment. PK, PD, and PGx including NGS and RNA-Seq are being evaluated in phase 1 subjects. Preliminary PK analysis suggests dose dependent exposure. Studies on MYC, MCL1, and PPP1R10 mRNA in peripheral blood samples after fadraciclib treatment will be shown. Conclusion: Based on data from the CYC065-101 study, fadraciclib appears to be well tolerated from dose levels 1 to 5. No drug related SAEs, SUSAR or DLTs were reported. The trial is ongoing with a primary endpoint of defining MTD and RP2D. Conflict of interest: Advisory Board: D. Oh: AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA M. Villanona-Calero: Eli Lilly Corporate-sponsored Research: S. Piha-Paul: AbbVie, ABM Therapeutics, Acepodia, Alkermes Aminex Therapeutics Amphivena Therapeutics, BioMarin Pharmaceutical, Boehringer Ingelheim Bristol Myers Squib Cerulean Pharma, Chugai Pharmaceutical, Curis, Cyclacel Pharmaceuticals Daiichi Sankyo Eli Lilly ENB Therapeutics Five Prime Therapeutics F-Star Beta Limited F-Star Therapeutics Gene Quantum Genmab A/S Gilead Sciences, GlaxoSmithKline Helix BioPharma, HiberCell, Immunomedics, Incyte, Jacobio Pharmaceuticals, Lytix Biopharma AS Medimmune, Medivation, Merck Sharp and Dohme, Novartis Pharmaceuticals Pieris Pharmaceuticals, Pfizer Phanes Therapeutics Principia Biopharma, Puma Biotechnology, Purinomia Biotech, Rapt Therapeutics, Seattle Genetics Silverback Therapeutics Synlogic Therapeutics Taiho Oncology Tesaro, TransThera Bio ZielBio, NCI/NIH, P30CA016672 – Core Grant (CCSG Shared Resources) Consulting: CRC Oncology D. Oh: Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok E. Garralda: Research: Novartis/Roche/Thermo Fisher/AstraZeneca/Taiho/ BeiGene Consultant/Advisor: Roche/Genentech - F.Hoffmann/La Roche/ Ellipses Pharma/Neomed Therapeutics1 Inc/Boehringer Ingelheim/Janssen Global Services/SeaGen/Alkermes/Thermo Fisher/Bristol-Mayers Squibb/ MabDiscovery/Anaveon/F-Star Therapeutics/Hengrui Speakers Bureau: Merck Sharp & Dohme/Roche/Thermo Fisher/Lilly/Novartis Clinical Trials PI or Co-PI (Institution): Affimed Gmbh - Amgen SA – Anaveon AG – AstraZeneca AB – Biontech Gmbh – Catalym Gmbh - Cytomx - F.Hoffmann La Roche Ltd – F-Star Beta Limited - Genentech Inc - Genmab B.V. – Hutchison Medipharma Limited – Icon - Imcheck Therapeutics – Immunocore Ltd – Janssen-Cilag SA – Medimmune Llc – Merck Kgga – Novartis Farmacéutica, S.A – Peptomyc – Ribon Therapeutics – Roche Farma SA – Seattle Genetics Inc – Symphogen A/S – Taiho Pharma Usa Inc M. Vieito: Travel grants: Roche, EMD/Serono Consulting: Roche, Debiopharm M. Villanona-Calero: Speakers Bureau: Amgen Other Substantive Relationships: J. Huang: Employee of Cyclacel, the trial sponsor M. Kirschbaum: Employee of Cyclacel, the trial sponsor M. Villanona-Calero: Stocks: Moderna

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

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. Here, to the best of our knowledge, spatial transcriptomics was applied for the first time to study AITL. 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. 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.

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

This study aimed to better characterize the clinicopathologic characteristics, outcomes, and prognostic factors of AITL in China. We retrospectively analyzed 312 patients with AITL enrolled between January 2011 and December 2020 from five institutions in China. 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. 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.

Different Uptake of 68Ga-FAPI and 18F-FDG in Lymphadenopathy Caused by Angioimmunoblastic T-Cell Lymphoma in a Patient with Colon Cancer.

An 82-year-old man with a history of colon cancer was found with multiple lymphadenopathies and a pulmonary mass. Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) detected generalized hypermetabolic lymph nodes and an FDG-avid pulmonary mass. PET/CT with 68Ga-labeled fibroblast activation protein inhibitor (FAPI) revealed intense uptake in the lung mass, consistent with metastatic disease from colon cancer. However, the lymphadenopathies were not avid for 68Ga-FAPI, suggesting a different etiology. The biopsy of a cervical node confirmed angioimmunoblastic T-cell lymphoma. The case showcased the potential of 68Ga-FAPI in differentiation of solid tumor and hematological disease due to different histopathologic nature of stromal fibrosis.

Research progress of tumor infiltrating lymphocytes in angioimmunoblastic T-cell lymphoma

血管免疫母细胞性T细胞淋巴瘤（AITL）是较常见的外周T细胞淋巴瘤，不同患者临床过程、预后及对治疗的反应差异较大。AITL肿瘤微环境（TME）的细胞数量和成分可变，除肿瘤细胞外，还包括非肿瘤细胞和基质，如肿瘤浸润淋巴细胞（tumor infiltrating lymphocytes，TILs）、巨噬细胞、肥大细胞等，以及丰富的细胞因子成分，其中，TILs是TME的关键成员，可能对AITL的发生发展具有重要意义。本文将从AITL中TILs的主要构成与预后、不同TILs与治疗的关系及其研究方法等进行综述，总结AITL中TILs的特征并探讨其潜在的临床意义，以期寻找免疫治疗的新靶点，开辟AITL免疫药物治疗研发的新领域。.

Clinicopathological features of angioimmunoblastic T-cell lymphoma pattern Ⅰ

Objective: To investigate the clinicopathological features of angioimmunoblastic T-cell lymphoma pattern Ⅰ (AITL Pattern Ⅰ). Methods: The clinicopathological data of 11 AITL Pattern Ⅰ cases that were diagnosed at the Beijing Friendship Hospital Affiliated to Capital Medical University (10 cases) and Beijing Lu Daopei Hospital (1 cases) from January 2019 to October 2021 were retrospectively collected. Immunophenotype, Epstein-Barr virus infection status and T cell receptor (TCR) clonality of the tumor cells were tested, and clinicopathological features of cases were analyzed. Results: Among the 11 AITL Pattern Ⅰ cases, the male to female ratio was 1.2∶1.0. The median age was 59 years (range 47-78 years). Seven cases had B symptoms, while eleven cases presented with systemic lymphadenopathy. According to Ann Arbor system staging, two cases were classified as stage Ⅰ-Ⅱ, and 9 cases as stage Ⅲ-Ⅳ. Hepatosplenomegaly was present in two cases (2/11), three cases (3/11) had skin rash and pruritus, and two cases (2/11) had pleural effusion. Previously, 6 cases (6/11) were diagnosed as reactive hyperplasia, 1 case (1/11) as EBV-associated lymphoproliferative disorder, and 4 cases (4/11) as hyperplasia of lymphoid tissue, which was unable to exclude lymphoma. Histologically, all the 11 cases showed hyperplastic follicles in the paracortical regions with well-formed germinal centers. The hyperplastic follicles showed ill-defined borders and attenuated mantle zones in 7 cases. Mantle zones completely disappeared in 4 cases. The follicles were surrounded by a thin layer of atypical lymphocytes with bright or faintly stained cytoplasm. In 2 cases, the clear cells were located between the germinal centers and the thin residual mantle cell layers, showing a circular growth pattern. The cells were medium in size, with irregular karyotype, coarse chromatin and indistinct nucleoli. Immunohistochemically, CD21 staining showed that the meshworks of follicular dendritic cells(FDC)were mainly confined to the follicles. There was a subtle expansion of the meshworks of FDC in 4 cases with ill-defined borders. The atypical cells surrounding the follicles expressed CD3 (11/11), CD4 (11/11), PD-1 (11/11), CXCL13 (6/11), ICOS (10/11) and CD10 (7/11). PD-1 staining showed a strong perifollicular pattern, and a small number of positive cells were scattered around the high endothelial veins in the interfollicular region. CXCL13, ICOS and CD10 showed similar distribution patterns. EBV-encoded small RNA probe (EBER) in situ hybridization showed that EBER positive B lymphocytes were scattered in the interfollicular region (5-20/HPF) in all cases. T cell receptor gene rearrangement was monoclonal in all cases. Conclusions: Diagnosing AITL Pattern Ⅰ may be challenging and requires comprehensive analysis of clinical manifestations, histological morphology, immunophenotype and gene rearrangement results.

PD-1 combined with TRBC1 and pan-T cell antibodies for robustly monitoring angioimmunoblastic T-cell lymphoma.

BackgroundThe diagnosis of AITL is challenging. It may be delayed or even missed due to critical clinical conditions and its histologic and immunophenotypic overlap with other neoplastic and reactive lymphoid proliferations.ObjectiveThe key objective is to obtain an efficient diagnosis, sensitive disease monitoring and treatment efficacy assessment of AITL using multiparameter flow cytometry (MFC).MethodsIn total, 167 de novo AITL patients were immunophenotypically profiled using sensitive MFC. We precisely identified the aberrant T-cell populations of AITL and performed an in-depth description of their phenotypic characteristics in comparison with their residual normal CD4+ T cells. A comparison of Programmed death receptor-1 (PD-1) expression was performed among AITL and other T-cell lymphomas.ResultsMFC detected a neoplastic T-cell population in 94.1% (80/85) of tissue, 71.5% (108/151) of bone marrow (BM), 100% (8/8) of peripheral blood (PB) and 78.6% (11/14) of body fluid samples. The most frequent immunophenotypic aberrations included the absence and diminished expression of CD3 (71.25% in tissues, 71.3% in BM, 75% in PB, 81.8% in hydrothorax and ascites specimens), followed by the loss or partial loss of CD7 (71.25% in LN, 67.6% in BM, 50% in PB, 81.8% in hydrothorax and ascites specimens). The immunophenotyping of neoplastic T-cell populations showed a high degree of similarity among different sites of the same patient and they might change over time but were relatively stable. Bright PD-1 expression showed high sensitivity and specificity in differentiating AITL from other T-cell lymphomas. In 14 AITL patients, neoplastic T-cell populations were initially missed by T-cell screening tube but were successfully discovered by bright PD-1 expression.ConclusionT-cell screening tube can reliably screen neoplastic T-cell populations in AITL patients with typical immunophenotyping, such as loss of surface CD3 and loss of CD7 with a relatively high ratio. Bright PD-1 expression is essential for identifying aberrant T cells in almost all AITLs. The clonality assessment antibody TRBC1 is efficient for robustly and cheaply assessing T-cell clonality. Using PD-1 and TRBC1 combined with pan-T cell antibodies can make a precise diagnosis of AITL and also sensitively monitor minimal residual disease regardless of the antigenic drift of the neoplastic T cells.

A Case of Angioimmunoblastic T-cell Lymphoma (AITL)

A 84-year-old female noticed erythema over her whole body for several months and was referred to our department for evaluation of her skin eruption. A physical examination revealed millet-sized erythematous papules and macules all over her body, a high body temperature, and a decreased level of consciousness. A laboratory examination showed an elevated white blood cell count (8200/μl), atypical lymphocytes (3%) and sIL-2R (4030U / ml). Computed Tomography showed systemic lymphadenopathy. A lymph node biopsy taken from the left inguinal lymph node revealed destruction of the lymph nodes, enlargement of the high endothelial venules, and atypical lymphocyte infiltration. Based on the clinical findings and laboratory examination, we diagnosed angioimmunoblastic Tcell lymphoma (AITL). AITL is a relatively rare peripheral T-cell lymphoma with severe systemic symptoms such as fever and lymph node swelling. While approximately half of all cases experience skin symptoms, which are one of the initial symptoms, it is difficult to determine the diagnosis due to the various clinical features or many non-specific rashes. We should keep in mind a differential diagnosis of lymphoma in cases of the presence of persistent eruption, systemic symptoms, and the existence of atypical lymphocytes in peripheral blood.

Clonal GCB Cells Support Angioimmunoblastic T-cell Lymphoma Tumorigenesis.

Germinal center B (GCB) cells provide a niche to support the development of angioimmunoblastic T-cell lymphoma.

Inflammatory diseases in hematology: a review.

Hematopoietic cells are instrumental in generating and propagating protective inflammatory responses to infection or injury. However, excessive inflammation contributes to many diseases of the blood, bone marrow, and lymphatic system. We review three clinical categories of hematological inflammatory diseases in which recent clinical and translational advances have been made. The first category is monogenic inflammatory diseases. Genotype-driven research has revealed that previously mysterious diseases with protean manifestations are characterized by mutations that may be germline (e.g., deficiency of ADA2 or GATA2 deficiency) or somatic [e.g., vacuoles, enzyme E1, X-linked, autoinflammatory, somatic (VEXAS) syndrome]. The second category is the cytokine storm syndromes, including hemophagocytic lymphohistiocytosis, and Castleman disease. Cytokine storm syndromes are characterized by excessive production of inflammatory cytokines including interleukin-6 and interferon-γ, causing end-organ damage and high mortality. Finally, we review disorders associated with monoclonal and polyclonal hypergammaglobulinemia. The serum protein electrophoresis (SPEP) is typically ordered to screen for common diseases such as myeloma and humoral immunodeficiency. However, monoclonal and polyclonal hypergammaglobulinemia on SPEP can also provide important information in rare inflammatory diseases. For example, the autoinflammatory disease Schnitzler syndrome is notoriously difficult to diagnose. Although this orphan disease has eluded precise genetic or histological characterization, the presence of a monoclonal paraprotein, typically IgM, is an obligate diagnostic criterion. Likewise, polyclonal hypergammaglobulinemia may be an important early, noninvasive diagnostic clue for patients presenting with rare neoplastic diseases such as Rosai-Dorfman disease and angioimmunoblastic T-cell lymphoma. Applying these three categories to patients with unexplained inflammatory syndromes can facilitate the diagnosis of rare and underrecognized diseases.

Clinicopathological characteristics of angioimmunoblastic T-cell lymphoma involving gastrointestinal tract

目的： 探讨血管免疫母细胞性T细胞淋巴瘤（AITL）累及胃肠道的临床病理学特点、诊断及预后。 方法： 收集郑州大学第一附属医院2021年9月诊断的1例肠道活检的AITL，复习临床特点，行HE染色、免疫组织化学、EB病毒编码的RNA（EBER）原位杂交、T细胞受体（TCR）基因重排（BIOMED2法）及二代测序检测1 166个基因，并复习总结文献中报道的AITL累及胃肠道的特征。 结果： 患者女，53岁，肠镜示回盲部至直肠多发结节状、息肉样隆起；HE示典型AITL的形态，肿瘤主要浸润黏膜固有层，局部侵及黏膜下层，未见固有腺体侵犯及黏膜表面溃疡；免疫组织化学：肿瘤细胞表达T系标志物（CD3、CD4、CD5）及滤泡辅助T细胞标志物（PD-1及CXCL13），CD21示滤泡树突状细胞网增生紊乱，Ki-67阳性指数约40%；EBER原位杂交见散在细胞阳性；二代测序检测发现3组融合基因：EIF4E3-FOXP1、RP11-434C1.1-ETV6、RP11-380O24.1-SRGAP3。随访2个月，患者化疗1个疗程后因肠出血死亡。 结论： 胃肠道部位AITL罕见，常为淋巴结AITL累及所致，患者预后差，形态学及免疫表型与淋巴结AITL相似，结合患者临床表现、组织学特点及基因检测可避免漏诊及误诊。.

The clinicopathological characteristics of C-MYC protein in angioimmunoblastic T-cell lymphoma.

To investigate the relationship between expression of C-MYC protein and clinicopathologic characteristics in angioimmunoblastic T-cell lymphoma (AITL), then discuss the prognosis. Patient samples were collected and made into tissue microarray for the same experimental condition. Pathomorphological features and immunohistochemistry of specific markers were used to determine the diagnosis of AITL. Epstein-Barr virus (EBV) infection was detected by EBV-encoded small RNA by in situ molecular hybridizations. B cells atypical hyperplasia was explored by the immunohistochemistry and gene rearrangement, C-MYC protein was expressed by the immunohistochemical staining and C-MYC gene abnormalities were detected by fluorescence in situ hybridization (FISH). 44 AITL patients were divided into two groups and the relation among C-MYC protein, EBV infection and B cells hyperplasia was observed. We followed up the overall survival rate (OS) and progression-free survival (PFS), and analyzed C-MYC protein, and the relationship between the prognosis of survival. Among 44 AITL patients, 29 cases (65.9%) were C-MYC protein-positive, and 32 (32/44, 72.3%) were EBV-positive. The expression rate of C-MYC protein in the high-risk group ranked by international prognostic index (IPI) and stage III-IV were higher than that in the low-risk group and stage I-II (P<0.05). The expression rate of C-MYC protein was higher in B cells excessive proliferation group, including simple hyperplasia, atypical hyperplasia, monoclonal B cells hyperplasia, and the diffuse large B lymphoma than in the low-proliferation group (P<0.05). The expression rate of C-MYC protein in EBV-positive patients was indifferent compared with the negative group (P>0.05). C-MYC gene rearrangement was not found in any samples, while the multi-copies of the C-MYC gene were found in only one case. As followed, 5-year OS was significantly low, and there was no significant difference in OS between the C-MYC protein-positive and negative groups. PFS in the positive group was significantly lower than that of the negative group. The difference in response to treatment between the two groups was statistically significant (P<0.05). We discussed the clinicopathologic characteristics and significance in AITLs, which predominantly express MYC-protein in <50% of cells, lacking C-MYC gene rearrangement. C-MYC protein-positive or negative expression was closely related to B cells excessive proliferation. C-MYC protein may be used as an indicator to judge the malignancy and to predict the prognosis of AITL.

Diagnostic utility of the aberrant immunohistochemical expression of CD3 molecules for peripheral T-cell lymphomas

The histological diagnosis of peripheral T-cell lymphomas (PTCLs) is often challenging. Flow cytometry (FCM) sometimes shows the loss of pan-T-cell markers for PTCLs, suggesting the neoplastic nature of these cells. Immunohistochemically, the total loss of pan-T-cell markers has been demonstrated in PTCLs. Furthermore, except for the total loss, the aberrant immunohistochemical expressions of pan-T-cell markers have also been empirically observed in PTCLs, but the details remain unexamined. Therefore, the present study semi-quantitatively evaluated the aberrant expression of cytoplasmic CD3ε (cCD3ε), the most common immunohistochemical pan-T-cell marker, in 91 PTCL cases. The expressions of the other CD3 molecules, CD3δ, CD3γ, and CD3ζ were also examined. Frequencies of the total immunohistochemical loss of CD3 molecules and loss of surface CD3ε (sCD3ε) in FCM were analyzed for comparison. The results showed atypical, aberrant expression patterns for immunohistochemical CD3 molecules: perinuclear, cytoplasmic, membranous, and partial negative. The frequency of each molecule was as follows: cCD3ε 40.7 %, CD3δ 26.4 %, CD3γ 53.8 %, and CD3ζ 54.9 %, especially the latter two showed high frequency in peripheral T-cell lymphoma, not otherwise specified, angioimmunoblastic T-cell lymphoma, and adult T-cell lymphoma/leukemia. Immunohistochemical total loss was less than aberrant expression in all CD3 molecules, with the frequency of cCD3ε being the lowest (6.6 %). The loss of sCD3ε in FCM was observed in 43.3 % of cases, with a similar frequency to the aberrant expression of cCD3ε. In conclusion, the aberrant immunohistochemical expression of cCD3ε was a useful finding as is sCD3ε loss in FCM, but CD3γ and CD3ζ were more useful, facilitating the diagnosis of PTCLs.

Epidemiological Characteristics of Peripheral T-Cell Lymphoma: A Population-Based Study.

ObjectsThe aim of this study is to explore the epidemiological characteristics of peripheral T-cell lymphoma in Beijing.Methods All data were extracted from the Beijing Cancer Registry database from January 1, 2007, to December 31, 2018. Segi’s World Standard Population was used to estimate the age-standardized rate (ASR). Changes in trends were examined using joinpoint regression analysis. The observed survival was estimated by the Kaplan–Meier method. Relative survival was calculated using Ederer II and standardized using the Brenner method and International Cancer Survival Standard (ICSS) group 1 age structure. Stratified by gender, area, and histological type, incidence, mortality, and age of onset trends were observed in Beijing.Results In Beijing, there were 801 new cases and 463 deaths of T-cell lymphoma from 2007 to 2018. Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) was the most prevalent subtype (37.45%), followed by angioimmunoblastic T-cell lymphoma (AITL; 20.35%), NK/T-cell lymphoma (NK/TCL; 17.60%), and anaplastic large cell lymphoma (ALCL; 10.24%). The crude incidence and mortality rates were 0.52 and 0.30 per 100,000 person-years, respectively, whereas the age-standardized incidence and mortality rates (ASIR and ASMR) were 0.35 and 0.18 per 100,000 person-years, respectively. Both ASIR and ASMR were more prevalent in men (0.48 and 0.24 per 100,000) and urban area (0.38 and 0.19 per 100,000) than in women (0.22 and 0.11 per 100,000) and rural area (0.30 and 0.15 per 100,000). The average annual percentage change (AAPC) of ASIR and ASMR was 5.72% (95% confidence interval (CI): 1.79%–9.81%) and 4.35% (95% CI: −0.09%–8.99%), respectively. The age-specific incidence rate increased with age and peaked at the age groups of 10–14 and 80–84. The mean and median age of onset increased between 2007 and 2018. In addition, it decreased after the age of onset was age standardization (β = −0.41, P = 0.26). The 5-year age-standardized relative survival was 39.02% for all patients, 58.14% for NK/TCL, 57.60% for ALCL, 31.38% for AITL, and 29.18% for PTCL-NOS.Conclusions T-cell lymphoma incidence was rising, but survival was dismal in Beijing, indicating the need for improved early diagnosis and standardized treatment.

The clinical features, treatment, and prognostic factors for peripheral T-cell lymphomas: A single-institution analysis of 240 Chinese patients.

This study aimed to analyze the clinical features, treatment, survival, and prognostic factors of Chinese patients with peripheral T-cell lymphoma (PTCL) excluding natural killer/T-cell lymphoma (NKTCL). Data on patients with newly diagnosed PTCLs between January 1, 2006 and December 31, 2017 at our hospital were retrospectively reviewed. Patients with NKTCL were excluded. A total of 240 patients were included. PTCL, not otherwise specified (PTCL-NOS), was the most frequent subtype (42.5%), followed by angioimmunoblastic T-cell lymphoma (AITL) (21.3%), anaplastic lymphoma kinase (ALK)-negative anaplastic large-cell lymphoma (ALK-ALCL) (16.7%), ALK-positive ALCL (ALK+ALCL) (10.8%) and others (8.8%). With a median follow-up of 81.1 months, the 5-year progression-free survival (PFS) and overall survival (OS) rates for all patients were 30.4% (95% CI 25.0%-37.0%) and 48.8% (95% CI 42.6%-55.7%), respectively. On multivariate analysis, no consolidative autologous stem cell transplantation (ASCT) and not achieving complete response after first-line chemotherapy retained independently prognostic value for inferior PFS and OS. Besides, bone marrow involvement and serum albumin level were independent factors for PFS, and Eastern Cooperative Oncology Group performance status ≥2 was significantly predictive of inferior OS. Compared with PTCL-NOS, significantly superior PFS and OS were observed for ALK+ALCL and ALK-ALCL. The survival outcomes with current treatment for most PTCL subtypes are still unsatisfactory. Prospective randomized studies are needed to establish the value of consolidative ASCT in PTCL, and novel therapeutic approaches should be explored.

Expression pattern and diagnostic utility of BCL11B in mature T- and NK-cell neoplasms

BCL11B is an essential transcription factor for T-cell lineage commitment and differentiation, and its dysregulation has been shown to be associated with T-cell tumourigenesis. In this study, we investigated BCL11B expression by immunohistochemical analysis in 120 cases of mature T-cell lymphoma, 34 B-cell lymphomas, 11 NK-cell neoplasms and 17 reactive cutaneous conditions. All cases of mycosis fungoides (n=23), primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (n=8) and T-prolymphocytic leukaemia (n=6) were positive for BCL11B and the staining intensity was higher than that of reactive T-cells. Fourteen of 15 (93%) cases of angioimmunoblastic T-cell lymphoma, 10 of 12 (83%) T-large granular lymphocytic leukaemia and 14 of 20 (70%) peripheral T-cell lymphoma, not otherwise specified, were also positive for BCL11B with an intensity comparable to reactive T-cells. Other T-cell neoplasms were uncommonly positive including one of three (33%) cases of primary cutaneous gamma delta T-cell lymphoma, one of four (25%) cases of subcutaneous panniculitis-like T-cell lymphoma, one of four (25%) cases of hepatosplenic T-cell lymphoma, and one of 20 (5%) cases of anaplastic large cell lymphoma (8 ALK-positive, 12 ALK-negative). T-cells in reactive cutaneous infiltrates were also positive for BCL11B, but staining intensity was much weaker than in mycosis fungoides. All NK-cell (n=11) and B-cell neoplasms (n=34) were negative for BCL11B. In conclusion, BCL11B shows a distinct expression pattern in various T-cell neoplasms. BCL11B appears to have utility as another T-cell marker and may be useful in the differential diagnosis of lymphoid neoplasms.

S229: CHARACTERISATION OF TUMOR MICROENVIROMENT REMODELLING IN THE PROGRESSION OF AITL WITH SINGLE-CELL RNA SEQUENCING AND IMAGING MASS CYTOMETRY

Background: Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma (PTCL). AITL is an aggressive malignancy with a poor prognosis, and its clinical manifestations vary greatly among individuals. The current chemotherapy regimens based on anthracycline show limited efficacy, and there is no best rescue treatment for patients with relapsed and refractory (RR) AITL. In addition, the lack of optimal AITL models in vitro greatly limits the basic research on the mechanism of disease occurrence and progression, and also hinders the development of new drugs and preclinical trials. Aims: Our study aims to deeply analyze the tumor heterogeneity and microenviroment remodelling in the progression of AITL at single cell resolution, discovering key molecules of drug resistance and potential theraputic targets. Methods: We detected fresh lymph node samples from initail diagnosed (ID) and relapsed and refractory (RR) AITL patients using single-cell RNA sequencing (scRNA-seq), combined with imaging mass cytometry (IMC) and whole exome sequencing. scRNA-seq was performed to compare the differential transcriptome expression patterns in ID- and RR-AITL samples. IMC was performed to analyze the spatial position relationship and protein expression characteristics of different subgroups in the tumor microenvironment of AITL. Immunofluorescence staining was conducted to detect the expression of relative markers on tissue microarrays in patients with AITL. In addition, AITL patient-derived organoid model was established to study the regulatory role of YY1 and its inhibitors in relapsed and refractory AITL. Results: We found that RR-AITL samples exhibited significant differences in the tumor microenvironment compared with ID patients. ScRNA-seq analysis revealed that transcription factor YY1 was significantly highly expressed in follicular helper T cells (Tfh) of RR-AITL patients, which promoted the proliferation and drug resistance of AITL cells (Fig A-D), consistent with the results of IMC (Fig E,F). The proportion of CD8+ T cells in the RR-AITL sample was reduced, while the proportion of Treg was increased, as well as the depletion of T cells (Fig G). Furthermore, the stemness of B cells in RR-AITL was enhanced and exhibits significant malignant characteristics (Fig H). We also found decreased interaction in RR-AITL samples. B cells and myeloid subgroups may play important roles in the progression of AITL (Fig I,J). As shown in Fig K, EBV+ B cells exhibited a wider and more distribution in RR-AITL (Fig L). Interestingly, EBV+ endothelial cells were presented in both ID- and RR- samples, while the spatial analysis showed that the distance of EBV+ endothelial cells to B cells in RR-AITL was obviously greater than in ID group, and the distance of Tfh to B cells also showed similar result (Fig M,N). Moreover, for the first time, we established AITL patient-derived organoid models that can be stablely cultured in vitro. On this basis, we could further clarify the important roles of transcription factor YY1 in the drug resistance of AITL, evaluate the cytotoxic effect of YY1 inhibitor NP-001 on AITL tumor cells. Image:Summary/Conclusion: In conclusion, our study revealed the differences between initial diagnosed and relapsed /refractory AITL in terms of tumor microenvironment, single-cell transcriptomes, the spatial distributions of different clusters and their interactions features. YY1 may serve as an novel target for drug resistance for RR-AITL patients. These findings may provide a theoretical foundation for improving the clinical treatment of AITL.

Abstract 944: Loss of Ripk3 signaling promotes T cell lymphoma development in Tet2 deficient mice

Abstract The TET2 gene is commonly mutated in multiple hematological malignancies and is frequently associated with poor prognosis. TET2 mutations are also found to occur in healthy individuals with no apparent hematological disease. A common factor observed between such individuals and those with the disease is the presence of increased inflammation and cytokine signature. A key mediator of inflammation and cytokine-induced necroptosis and metabolic signaling is the receptor-interacting protein kinase 3 (Ripk3). Ripk3 plays important tumor-promoting and suppressive roles in multiple cancers. Compared to bone marrow (BM) cells isolated from wild-type mice, higher levels of Ripk3 activity can be detected in Tet2-/- BM cells. Based on the evidence that Tet2 mutations alone are insufficient and are known to cooperate with other mutations for full-blown malignant transformation, we hypothesize that loss of Ripk3 signaling might promote the transformation of Tet2 mutant HSPCs To test our hypothesis we crossed Tet2 conditional knockout (Tet2fx/fx Mx1-Cre+) mice with Ripk3-/- mice to generate Tet2 and Ripk3 compound knockout (Tet2-/-Ripk3-/-) mice. We performed in vitro colony assays and in vivo engraftment and reconstitution assays on Bone marrow mononuclear cells (BM-MNC) derived from Tet2-/-Ripk3-/- and Tet2-/- mice. Our results indicate that TNF-α stimulation confers a significant hematopoietic advantage to Tet2-/- HSPCs which is abolished upon loss of Ripk3. Moreover, while Tet2-/- BM-MNC has significantly higher reconstitution ability in vivo, the additional loss of Ripk3 led to reduced engraftment and reconstitution that was comparable to WT BM-MNC. Given that TNF-α stimulation promotes Ripk3 activation, our results indicate that the TNF-RIPK3 signaling axis is essential in conferring enhanced hematopoietic fitness of Tet2-/- HSPCs.Tet2-/-Ripk3-/- mice developed aggressive tumors by 12-15 months of age as characterized by profound hepatosplenomegaly and lymphadenopathy, with substantial lymphocytosis, neutrophilia, anemia, and thrombocytopenia. There was extensive infiltration of tumor cells in the liver and spleen in diseased Tet2-/-Ripk3-/- mice. There was a marked expansion of both CD4+PD1+CXCR5+ follicular T helper cells (Tfh) and CD4+PD1+ peripheral T helper cells (Tph), indicating the development of a T cell lymphoma in the Tet2-/-Ripk3-/- mice. Additionally, disease characteristics including the reduced surface expression of CD3 in the tumor cells, increased levels of classical Th cytokines in the serum, as well as the presence of heterogeneous populations of cells within the tumor tissues recapitulate the pathological features of angioimmunoblastic T cell lymphoma (AITL). We are currently investigating Ripk3 signaling in the tumor cells of AITL patients and whether we can treat such aggressive fatal diseases by reactivating Ripk3 signaling. Citation Format: Kanak Joshi, Shuchi Zinzuwadia, Ryan Mack, Lei Zhang, Shanhui Liu, Mark Sellin, Wei Wei, Peter Breslin, Ameet R. Kini, Jiwang Zhang. Loss of Ripk3 signaling promotes T cell lymphoma development in Tet2 deficient mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 944.

Abstract CT215: LB1901: A phase 1, open-label, multicenter, multicohort study of CD4-targeted chimeric antigen receptor T cells (CD4-CAR-T) in relapsed or refractory T-cell lymphoma (TCL)

Abstract Background: Disease relapse is common with peripheral T-cell lymphomas (PTCL) or cutaneous T-cell lymphomas (CTCL). Adoptive immunotherapy with CD19 directed CAR-T cells is a standard option for B cell lymphoid malignancies in the relapsed setting. This study assesses the safety and preliminary efficacy of CD4 targeting autologous CAR-T, LB1901, in patients (pts) with CD4+ relapsed or refractory (R/R) TCL. A pre-clinical study showed LB1901 exhibited potent anti-tumor activity without off-target effects (Zeng 2021). Methods: This is a phase 1, open-label, multicenter, multicohort study of LB1901 (NCT04712864; currently enrolling). Eligible pts are ≥18 years with histologically confirmed CD4+ PTCL-NOS (not otherwise specified); or CD4+ AITL (angioimmunoblastic T-cell lymphoma); or CD4+ CTCL (either MF [mycosis fungoides] or SS [Sézary syndrome]). In Part A (dose escalation), pts with SS must have ≤2,000 circulating Sézary cells/µL to ensure safety of pts with higher disease burden. In Part B, pts with &amp;gt;2,000 Sézary cells/µL is allowed. CD4 expressed on tumor cells must be confirmed within 3 months prior to apheresis. Other inclusion criteria include: R/R disease with ≥2 prior lines of systemic antineoplastic therapy; for pts with PTCL-NOS or AITL, ≥1 measurable lesion according to IWG Response Criteria (Cheson 2014) and for pts with CTCL, ≥stage IIB on TNMB-ISLC/EORTC staging system; identified HSCT donor available prior to enrollment (in the event of severe recurrent infections and prolonged lymphopenia for which pt may need an allogeneic HSCT as a safety rescue); and ECOG status of 0 or 1. Response will be evaluated based on IWG response criteria for PTCL and Global Composite Response for CTCL (Olsen 2007). The study will be conducted in 2 parts (Part A: dose escalation and Part B: dose expansion). Three dose levels (0.3 X 106, 1.0 X 106, and 3.0 X 106 CAR+ viable T cells/kg) will be evaluated (N=3-6 for each dose level) with an optional dose level minus 1 (0.1 X 106 CAR+ viable T cells/kg). Part B will include 2 cohorts, PTCL and CTCL (N=12-20 for each), after the recommended dose for expansion (RDE) has been identified in Part A. Enrolled pts will undergo apheresis for PBMC collection. LB1901 will be manufactured from autologous CD8+ T cells. Pts may receive optional bridging therapy and receive lymphodepleting chemotherapy with fludarabine 30mg/m2/day and cyclophosphamide 300mg/m2/day (Flu-Cy), for 3 days followed by LB1901. Primary endpoints are incidence, duration, and severity of AEs and laboratory abnormalities (Parts A and B) and DLT at each dose level (Part A). Secondary endpoints include overall response rate; duration of response; CAR-positive T cell counts and CAR transgene level in blood; and presence of anti-CAR antibody response. Exploratory endpoints include preliminary efficacy, pharmacokinetics, and CD4+ T cell counts. Citation Format: Swaminathan P. lyer, David G. Maloney, Nora Bennani, Auris Huen, Muhammad Akram, Soo Kim, Chuan Wang, Zhiyin Liang, Henry Castro, Lida Pacaud, Mehdi Hamadani. LB1901: A phase 1, open-label, multicenter, multicohort study of CD4-targeted chimeric antigen receptor T cells (CD4-CAR-T) in relapsed or refractory T-cell lymphoma (TCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT215.