Subtype Of T-cell Lymphoma Research Articles

A novel mouse model of cutaneous T-cell lymphoma revealed the combined effect of mogamulizumab with psoralen and ultraviolet a therapy.

Mycosis fungoides (MF) is a subtype of cutaneous T-cell lymphoma (CTCL). Topical or systemic treatment with psoralen, such as 8-methoxypsoralen (8-MOP), followed by ultraviolet A (UVA) irradiation (PUVA therapy) is an effective phototherapy for early-stage MF. However, the efficacy of PUVA therapy for advanced-stage MF is not satisfactory, and the ideal combination partner for PUVA therapy has not yet been found. In this study, we developed a new mouse model of CTCL in which efficacy of PUVA was detected and further evaluated the efficacy of combination treatment of PUVA and mogamulizumab, an anti-CCR4 monoclonal antibody. Cytotoxicity of PUVA therapy against HH cells, a CTCL cell line, was observed in vitro. The cytotoxicity was dependent on both 8-MOP and UVA. Using HH cells, we developed a mouse model in which HH cells were subcutaneously inoculated in the ear. In this model, PUVA therapy suppressed tumour growth with statistical significance, while 8-MOP or UVA alone did not. Combination therapy of PUVA and mogamulizumab showed greater antitumor activity than either monotherapy with statistical significance. In the histological analysis of the tumour tissue, PUVA accelerated tumour necrosis and then induced the infiltration inflammatory cells in the necrotic area, suggesting that these cells served as effector cells for mogamulizumab. This combination therapy is expected to be a beneficial option for CTCL therapy.

Real-life experience of using pegylated liposomal doxorubicin in primary cutaneous T-cell lymphomas.

Mycosis fungoides (MF) is the most prevalent subtype of primary cutaneous T-cell lymphomas (CTCLs). Sézary syndrome (SS) is another entity defined by leukaemic involvement, lymphadenopathy and erythroderma. Pegylated liposomal doxorubicin (PEG-DOXO) is an anthracycline used in the management of advanced primary CTCL, particularly in induction strategies. However, there are limited data on its effectiveness and tolerability in real-life patients. We report 36 patients who received PEG-DOXO for MF or SS in our centre, describing the patients' characteristics, response rates and tolerance to the treatment. The best overall responses were observed for the skin, with lower response rates for nodal involvement and moderate responses for blood disease. The treatment was mainly well tolerated, without severe adverse events, and no cardiotoxicity was observed on cardiac function monitoring.

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.

DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T cells in PTCL-NOS

AbstractPeripheral T-cell lymphomas (PTCLs) are heterogenous T-cell neoplasms often associated with epigenetic dysregulation. We investigated de novo DNA methyltransferase 3A (DNMT3A) mutations in common PTCL entities, including angioimmunoblastic T-cell lymphoma and novel molecular subtypes identified within PTCL–not otherwise specified (PTCL-NOS) designated as PTCL-GATA3 and PTCL-TBX21. DNMT3A-mutated PTCL-TBX21 cases showed inferior overall survival (OS), with DNMT3A-mutated residues skewed toward the methyltransferase domain and dimerization motif (S881–R887). Transcriptional profiling demonstrated significant enrichment of activated CD8+ T-cell cytotoxic gene signatures in the DNMT3A-mutant PTCL-TBX21 cases, which was further validated using immunohistochemistry. Genomewide methylation analysis of DNMT3A-mutant vs wild-type (WT) PTCL-TBX21 cases demonstrated hypomethylation in target genes regulating interferon-γ (IFN-γ), T-cell receptor signaling, and EOMES (eomesodermin), a master transcriptional regulator of cytotoxic effector cells. Similar findings were observed in a murine model of PTCL with Dnmt3a loss (in vivo) and further validated in vitro by ectopic expression of DNMT3A mutants (DNMT3A-R882, -Q886, and -V716, vs WT) in CD8+ T-cell line, resulting in T-cell activation and EOMES upregulation. Furthermore, stable, ectopic expression of the DNMT3A mutants in primary CD3+ T-cell cultures resulted in the preferential outgrowth of CD8+ T cells with DNMT3AR882H mutation. Single-cell RNA sequencing(RNA-seq) analysis of CD3+ T cells revealed differential CD8+ T-cell subset polarization, mirroring findings in DNMT3A-mutated PTCL-TBX21 and validating the cytotoxic and T-cell memory transcriptional programs associated with the DNMT3AR882H mutation. Our findings indicate that DNMT3A mutations define a cytotoxic subset in PTCL-TBX21 with prognostic significance and thus may further refine pathological heterogeneity in PTCL-NOS and suggest alternative treatment strategies for this subset.

Cutaneous T-cell lymphoma: diagnosing subtypes and the challenges.

Cutaneous T-cell lymphoma is a rare type of extranodal non-Hodgkin's lymphoma that primarily affects the skin. The uncertain pathogenesis and variable clinical presentation make the diagnosis and management of cutaneous T-cell lymphoma a challenge. Cutaneous T-cell lymphoma is a chronic, relapsing illness with treatment aimed at symptomatic relief and improving patient related quality of life. Early-stage cutaneous T-cell lymphoma typically follows an indolent course, often being mistaken for benign dermatological conditions which can lead to a diagnostic delay. Advanced stage cutaneous T-cell lymphoma has a poor prognosis with significant morbidity. Accurate diagnosis and early involvement of a specialist team is paramount to ensure correct management and improved patient outcomes. Promising advances are being made to develop novel agents which could improve prognosis and quality of life. This article provides an overview of the two main subtypes of cutaneous T-cell lymphoma: mycosis fungoides and Sézary syndrome. Clinical presentation, histopathological correlation and diagnostic challenges are reviewed alongside example case studies.

Mass Cytometric Analysis of Early-Stage Mycosis Fungoides.

Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma. Early-stage disease is characterized by superficial infiltrates of small- to medium-sized atypical epidermotropic T lymphocytes that are clonal related. Nevertheless, the percentage of atypical T cells is low with many admixed reactive immune cells. Despite earlier studies, the composition and spatial characteristics of the cutaneous lymphocytic infiltrate has been incompletely characterized. Here, we applied mass cytometry to profile the immune system in skin biopsies of patients with early-stage MF and in normal skin from healthy individuals. Single-cell suspensions were prepared and labeled with a 43-antibody panel, and data were acquired on a Helios mass cytometer. Unbiased hierarchical clustering of the data identified the major immune lineages and heterogeneity therein. This revealed patient-unique cell clusters in both the CD4+ and myeloid cell compartments but also phenotypically distinct cell clusters that were shared by most patients. To characterize the immune compartment in the tissue context, we developed a 36-antibody panel and performed imaging mass cytometry on MF skin tissue. This visualized the structure of MF skin and the distribution of CD4+ T cells, regulatory T cells, CD8+ T cells, malignant T cells, and various myeloid cell subsets. We observed clusters of CD4+ T cells and multiple types of dendritic cells (DCs) identified through differential expression of CD11c, CD1a, and CD1c in the dermis. These results indicated substantial heterogeneity in the composition of the local immune infiltrate but suggest a prominent role for clustered CD4–DC interactions in disease pathogenesis. Probably, the local inhibition of such interactions may constitute an efficient treatment modality.

Genetic Landscape of Peripheral T-Cell Lymphoma

Peripheral T-Cell lymphoma (PTCL) comprises a heterogenous group of uncommon lymphomas derived from mature, post-thymic or “peripheral” T- and natural killer cells. The World Health Organization (WHO) emphasizes a multiparameter approach in the diagnosis and subclassification of these neoplasms, integrating clinical, morphologic, immunophenotypic, and genetic features into the final diagnosis. Clinical presentation is particularly important due to histologic, immunophenotypic and genetic variations within established subtypes, and no convenient immunophenotypic marker of monoclonality exists. In recent years, widespread use of gene expression profiling and next-generation sequencing (NGS) techniques have contributed to an improved understanding of the pathobiology in PTCLs, and these have been incorporated into the 2016 revised WHO classification of mature T- and NK-cell neoplasms which now encompasses nearly 30 distinct entities. This review discusses the genetic landscape of PTCL and its role in subclassification, prognosis, and potential targeted therapy. In addition to discussing T-Cell lymphoma subtypes with relatively well-defined or relevant genetic aberrancies, special attention is given to genetic advances in T-Cell lymphomas of T follicular helper cell (TFH) origin, highlighting genetic overlaps between angioimmunoblastic T-Cell lymphoma (AITL), follicular T-Cell lymphoma, and nodal peripheral T-Cell lymphoma with a TFH phenotype. Furthermore, genetic drivers will be discussed for ALK-negative anaplastic large cell lymphomas and their role in differentiating these from CD30+ peripheral T-Cell lymphoma, not otherwise specified (NOS) and primary cutaneous anaplastic large cell lymphoma. Lastly, a closer look is given to genetic pathways in peripheral T-Cell lymphoma, NOS, which may guide in teasing out more specific entities in a group of T-Cell lymphomas that represents the most common subcategory and is sometimes referred to as a “wastebasket” category.

Response to Chlormethine/Mechlorethamine gel Maintenance Treatment Regimen in Patients With Mycosis Fungoides: A Single-center Retrospective Study

BackgroundMycosis fungoides (MF), the most common subtype of Cutaneous T-cell lymphomas, is caused by malignant T-cell proliferations in the skin that can invade blood, lymph nodes, or viscera. Currently, data on efficacy of maintenance therapies in MF are lacking. We developed a unique protocol to use chlormethine/mechlorethamine 0.016% gel formulation as maintenance regimen for MF patients in remission. PurposeTo determine progression-free survival and efficacy of chlormethine/mechlorethamine as maintenance and active treatment regimens for MF. Materials and MethodsA retrospective review of MF patients seen at Thomas Jefferson University from 2012 to 2020 was conducted. Patients of all stages treated with chlormethine/mechlorethamine as maintenance or active treatment with 2 consecutive mSWATs (modified Severity Weighted Assessment Tool) documented were included. Treatment outcomes were assessed by change in mSWAT and progression-free survival. Dermatology Life Quality Index surveys before and after treatment were analyzed. ResultsOf 186 MF patients, 44 met inclusion criteria. Patients on maintenance therapy had a 65.22% progression-free survival rate with median time to progression of 29.45 months. By-time analysis for responders on active and maintenance treatment showed an increased response over time. Peak responses were seen at last mSWAT recorded. Both cohorts experienced improved quality-of-life scores from initiation to discontinuation of chlormethine/mechlorethamine. ConclusionPatients on maintenance and active chlormethine/mechlorethamine treatment regimens demonstrated improvement in mSWAT and quality-of-life. Chlormethine/mechlorethamine treatment showed progression-free survival for a median of 29.45 months, indicating this therapy may be an effective maintenance regimen.

Effect of PUVA and NB-UVB Therapy on the Skin Cytokine Profile in Patients with Mycosis Fungoides.

Background Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma. The aim of the present study was to produce up-to-date information on different phototherapy approaches on skin cytokines in patients with MF. Methods A total of 27 patients with mycosis fungoides were treated with phototherapy: NB-UVB (narrow‐band ultraviolet B therapy) (10 patients) and PUVA (long-wavelength ultraviolet radiation of spectrum A with the use of skin-photosensitizing furocoumarins) therapy (17 patients). Evaluation of the effectiveness of treatment was carried out using BSA (body surface area) and the modified assessment of the severity of the skin lesions scale (mSWAT) used to quantify tumor mass in cutaneous T-cell lymphomas. Average numbers of procedures were 30.2 and 27.8 in the NB-UVB and PUVA groups, respectively. The median total dose of NB-UVB irradiation was 19.9 J/cm2 and PUVA therapy was 104.0 J/cm2. The overall response to therapy including complete and partial remission was 74.9% in the total group; 70% in the NB-UVB group, and 77.7% in the PUVA therapy group. In the obtained biopsies from lesions, surrounding tissue before treatment and skin samples of four healthy volunteers, the concentration of the IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, sCD40L, and TNF-α cytokines was studied. An increase in IL-4 and TNF-α levels was shown in the lesional skin of patients compared to the skin of healthy controls. After the treatment, positive correlations of mSWAT with the levels of IL22, IL33, and TNF-α in the tumor tissue were found. The levels of IL10 and IFN-γ after PUVA treatment were increased in comparison to baseline. There was no difference in cytokine levels before/after NB-UVB therapy.

Sézary Syndrome: Different Erythroderma Morphological Features with Proposal for a Clinical Score System.

Sézary syndrome is a rare subtype of cutaneous T-cell lymphoma characterized by erythroderma, peripheral lymphadenopathies, and circulating atypical cerebriform T-cells. To date, no definite staging system has been developed for these patients. In this retrospective analysis of the archive of the Dermatological Clinic of the University of Turin, Italy, erythrodermic SS patients were classified according to clinical records and photographs into three main presentations: erythematous, infiltrated, or melanodermic. The pattern of erythroderma was found to be associated with disease outcome, as better survivals were recorded in patients with erythematous and infiltrative erythroderma. Patients in the melanodermic group, though less represented in our investigation, seemed to show a worse trend in survival. According to this preliminary evidence, a new prognostic classification, with a revised score specific for Sézary syndrome patients, can be proposed to usefully integrate the current staging system. The correlation displayed in our research will be hopefully confirmed by prospective studies with larger cohorts, with the aim of identifying significant prognostic features in this subset of cutaneous T-cell lymphoma patients.

Histone deacetylase inhibitors as a novel therapeutic approach for pheochromocytomas and paragangliomas.

Epigenetic mechanisms, such as DNA methylation and histone modifications (e.g., acetylation and deacetylation), are strongly implicated in the carcinogenesis of various malignancies. During transcription, the expression and functionality of coding gene products are altered following the histone acetylation and deacetylation. These processes are regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. HDAC inhibitors (HDACis) have been developed as promising therapeutic agents, to limit exposure to traditional and toxic chemotherapies and offer more alternatives for some specific malignant diseases with limited options. Mechanistically, these agents affect many intracellular pathways, including cell cycle arrest, apoptosis and differentiation, and their mechanism of action mainly depends on the type of cancer. Currently, five HDACis have been approved for the treatment of several hematological malignancies (e.g., T-cell lymphoma subtypes and multiple myeloma); while, many of them are tested for further therapeutic indications in solid tumors (e.g., colorectal, thyroid, breast, lung and pancreatic cancer). Herein, we review the literature and gather all available evidence, from in vitro and in vivo data to clinical trial results, that recognizes the antitumor activity of HDACis on pheochromocytomas and paragangliomas; and supports their clinical implementation in the treatment of these rare neuroendocrine tumors at metastatic setting.

POSC49 The Cost-Effectiveness of Brentuximab Vedotin in Frontline Systemic Anaplastic Large Cell Lymphoma in France

Systemic anaplastic large cell lymphoma (sALCL) is a rare type of non-Hodgkin lymphoma and one of the subtypes of peripheral T-cell lymphoma. The objective of this study was to estimate the cost-effectiveness of brentuximab vedotin (BV) in combination with cyclophosphamide, doxorubicin and prednisone (CHP) chemotherapy versus current chemotherapies in France.

Mycosis fungoides and Sézary syndrome : a systematic review

The two main subtypes of primary cutaneous T-cell lymphomas include the most frequent, mycosis fungoides (MF), and the rare leukemic variant, Sézary syndrome (SS). MF presents as cutaneous patches and can progress to plaques, tumors and erythroderma. SS is characterized by the presence of erythroderma, generalized lymphadenopathy and clonal T cells in the peripheral blood, consistent with a poorer prognosis. Histologically, early CTCL lesions are sometimes indistinguishable from more common inflammatory skin diseases and a clinico-pathological correlation is essential for an accurate diagnosis. Except for allogenic stem-cell transplantation, therapy is generally palliative and aims to improve patient quality of life.

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.

OP437 Use Of Real-World Evidence In Survival Analysis Adjusting For Treatment Crossover In Cutaneous T-Cell Lymphoma

Real-World Evidence is useful for validating crossover adjustment approaches, particularly when the adjustment is required because a trial does not accurately reflect a health technology assessment (HTA)-relevant population. We use the MAVORIC trial advanced stage mycosis fungoides and Sézary syndrome cutaneous T-cell lymphoma population and data from the Hospital Episodes Statistics to explore and validate crossover adjustment methods.IntroductionThe MAVORIC trial compared mogamulizumab to vorinostat in patients with mycosis fungoides (MF) or Sézary syndrome (SS), subtypes of cutaneous T-cell lymphoma. However, the treatment comparison within MAVORIC may not represent an HTA relevant population from a UK perspective: (i) 72.6 percent of patients randomized to vorinostat switched to mogamulizumab and (ii) vorinostat is not used in current clinical practice in the UK. This study explores methods to adjust treatment effect estimates using different crossover adjustment methods and Real-World Evidence.This medicine is subject to additional monitoring. This will allow quick identification of new safety information. See www.mhra.gov.uk/yellowcard for how to report side effects.MethodsAn advanced stage (stage ≥IIB MF and all SS) population was included. Three methods were considered for treatment crossover adjustment. A synthetic control arm was created using the Hospital Episodes Statistics (HES) dataset. Predicted survival for the MAVORIC control arm, post-crossover adjustment, was compared to the HES to inform the selection of the appropriate methods for adjustment. A direct comparison between mogamulizumab (reweighted to represent the distribution of MF/SS patients in the HES) and the synthetic control was also conducted.ResultsFollowing crossover adjustment of the vorinostat arm, using the inverse probability of censoring weighting method, the overall survival (OS) hazard ratio (HR) estimate for mogamulizumab vs. vorinostat was 0.45 (95% confidence interval (CI): 0.19, 1.07). This adjustment method was considered the most appropriate based on an assessment of assumptions and a comparison of OS between the adjusted vorinostat data and the HES data. The OS HR estimate for reweighted mogamulizumab vs. synthetic control from HES was 0.33 (CI: 0.21, 0.50).ConclusionsReal World Evidence from the HES database can be used to validate crossover adjustment methods and to better reflect current clinical practice in the UK. Results using both methods support each other.

A computational in silico approach to predict high-risk coding and non-coding SNPs of human PLCG1 gene.

PLCG1 gene is responsible for many T-cell lymphoma subtypes, including peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL), cutaneous T-cell lymphoma (CTCL), adult T-cell leukemia/lymphoma along with other diseases. Missense mutations of this gene have already been found in patients of CTCL and AITL. The non-synonymous single nucleotide polymorphisms (nsSNPs) can alter the protein structure as well as its functions. In this study, probable deleterious and disease-related nsSNPs in PLCG1 were identified using SIFT, PROVEAN, PolyPhen-2, PhD-SNP, Pmut, and SNPS&GO tools. Further, their effect on protein stability was checked along with conservation and solvent accessibility analysis by I-mutant 2.0, MUpro, Consurf, and Netsurf 2.0 server. Some SNPs were finalized for structural analysis with PyMol and BIOVIA discovery studio visualizer. Out of the 16 nsSNPs which were found to be deleterious, ten nsSNPs had an effect on protein stability, and six mutations (L411P, R355C, G493D, R1158H, A401V and L455F) were predicted to be highly conserved. Among the six highly conserved mutations, four nsSNPs (R355C, A401V, L411P and L455F) were part of the catalytic domain. L411P, L455F and G493D made significant structural change in the protein structure. Two mutations-Y210C and R1158H had post-translational modification. In the 5’ and 3’ untranslated region, three SNPs, rs139043247, rs543804707, and rs62621919 showed possible miRNA target sites and DNA binding sites. This in silico analysis has provided a structured dataset of PLCG1 gene for further in vivo researches. With the limitation of computational study, it can still prove to be an asset for the identification and treatment of multiple diseases associated with the target gene.

Antitumor Activity of Dual BCL-2/BCL-Xl Inhibitor Pelcitoclax (APG-1252) in Natural Killer/T-Cell Lymphoma (NK/TCL)

▪Natural killer/T-cell lymphoma (NK/TCL) is one of the most common subtypes (10.4%) of peripheral T-cell lymphoma, which in turn accounts for 10% to 15% of all cases of non-Hodgkin lymphoma. NK/TCL occurs more frequently in Asia and Latin America than other regions, and although associated with Epstein-Barr virus (EBV) infection, NK/TCL has an unclear pathogenesis of genetic and molecular alterations. Asparaginase-based chemotherapy regimens are frequently used, typically with unsatisfactory outcomes. Novel targeted therapies, such as histone deacetylase (HDAC) inhibitors and programmed death-1 antibodies, are reported effective either as single agents or in combination with other agents. Studies have also shown that EBV-positive NK/TCL cell lines are B-cell lymphoma-extra large (BCL-xL) dependent. Other preclinical experiments have shown that BH3-mimetic drugs targeting BCL-xL-induced cell death in NK/TCL cell lines were effective in NK/TCL xenograft models. BCL-xL inhibitors have shown narrow therapeutic windows in clinical trials because of dose-limiting on-target thrombocytopenia. Pelcitoclax (APG-1252) is a novel dual BCL-2/BCL-xL inhibitor under clinical development for solid tumors. As a result of its unique prodrug design, APG-1252 can overcome the undesired platelet toxicity. This study evaluated the potential antitumor effect of APT-1252 in preclinical models of NK/TCL. Cell-based antiproliferation studies showed activity of APG-1252 and its more potent metabolite APG-1252-M1 toward NK/TCL cell lines that overexpressed BCL-xL. Half-maximal inhibitory concentrations (IC 50) for APG-1252 in SNK-1, SNK-6, and SNK-8 (EBV-positive NK/TCL) cell lines were 2.652 ± 2.606 µM, 1.568 ± 1.109 µM, and 0.557 ± 0.383 µM, respectively. Corresponding values for APG-1252-M1 were 0.133 ± 0.056 µM, 0.064 ± 0.014 µM, and 0.020 ± 0.008 µM, respectively. Mechanistic studies demonstrated that APG-1252 and APG-1252-M1 disrupted the complex of BCL-xL/BCL-2-associated X protein (Bax) and BCL-xL/BCL-2 homologous antagonist killer protein (Bak) in SNK-6 cells, thereby liberating these proapoptotic proteins and further activating downstream apoptosis pathways by cleaving poly-ADP ribose polymerase-1 (PARP-1) and caspase-3. In an SNK-6 xenograft model, administration of APG-1252 at 65 mg/kg and 100 mg/kg either twice or once weekly resulted in significant antitumor effects, with tumor growth rate (T/C%) values ranging from 13.7% to 30.7%. Furthermore, the combination of APG-1252 with HDAC inhibitor chidamide or DDGP (dexamethasone, cisplatin, gemcitabine, and pegaspargase) chemotherapy demonstrated synergistic effects. Pharmacokinetic assessment in mice showed that APG-1252 had a long half-life in plasma (127 hours) and tumor tissues (25.2 hours), justifying intermittent dosing schedules used in vivo. Importantly, the transformation of APG-1252 to APG-1252-M1 was 16 times higher in tumor tissues compared to plasma (22% vs. 1.3%) after administration of APG-1252, thereby suggesting that APG-1252 can reduce platelet toxicity caused by APG-1252-M1 in plasma. In conclusion, APG-1252 has promising antitumor effects in NK/TCL, either as a single agent or in combination with an HDAC inhibitor or chemotherapy. These findings provide evidence to further evaluate APG-1252 as a potential treatment for NK/TCL. DisclosuresWang: Ascentage Pharma Co., Ltd., Shanghai: Current Employment, Current equity holder in publicly-traded company. Liang: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Ming: Ascentage Pharma Co., Ltd., Shanghai: Current Employment, Current equity holder in publicly-traded company. Rui: Ascentage Pharma Co., Ltd., Taizhou: Current Employment, Current equity holder in publicly-traded company. Tang: Ascentage Pharma Co., Ltd., Taizhou: Current Employment, Current equity holder in publicly-traded company. LV: Ascentage Pharma Co., Ltd., Shanghai: Current Employment, Current equity holder in publicly-traded company. Ge: Ascentage Pharma Co., Ltd., Shanghai: Current Employment, Current equity holder in publicly-traded company. Zhang: Ascentage Pharma Co., Ltd., Taizhou: Current Employment, Current equity holder in publicly-traded company. Wang: Ascentage Pharma Co., Ltd., Taizhou: Current Employment, Current equity holder in publicly-traded company. Shang: Ascentage Pharma Co., Ltd., Shanghai: Current Employment, Current equity holder in publicly-traded company. Yang: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Zhai: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.

Narrowing of the Racial Disparities Gap in Survival of Patients with Mycosis Fungoides: A Longitudinal Analysis of the SEER Database (1988 to 2011)

Introduction: Mycosis Fungoides (MF) is the most common subtype of cutaneous T-cell lymphomas. Prior Studies have identified Black race as a risk factor for earlier age at diagnosis, more advanced stages at time of diagnosis and poor prognosis in patients with MF. Data examining differences in racial disparities outcomes over time are limited.Objective: This retrospective analysis aims to examine if the racial disparities in survival outcomes of MF patients have improved over time.Subjects and Methods: Using the United States Surveillance, Epidemiology and End Results (SEER) 1988-2011 public use database, we examined survival patterns for patients with MF (with the code of 9700) between 1988 and 2011. Cases were divided into three cohorts based on the year of diagnosis; “1988 - 1995”, “1996 - 2003”, and “2004 - 2011”. Univariable and multivariable analysis were conducted to assess for factors significantly associated with the overall survival. The nonparametric estimates of the survival distribution function, Kaplan and Meier survival curves, and Cox proportional hazards model were used to investigate the factors affecting the survival time.Results: From 1988 to 2011, a total of 2896 cases of MF were identified with a median follow-up of 60 months. The difference in the survival time between the years of diagnosis 1988-1995 and 2004-2011 is significant (p-value=0.05). The parameter estimate of the Cox proportional hazards model for the “1988-1995” and the “2004-2011” period as a reference is also significant (p-value = 0.024) and the hazard ratio (HR) is 1.407, which means that patients diagnosed in 1988-1995 were 1.4 times likely to die from the disease compared to the patients diagnosed in 2004-2011 (i.e. patients in 1988-1995 were more likely to not survive than in 2004-2011) (Table 1 and 2). There is no significant difference in the survival of the patients between “1996-2003” and “2004-2011” (p-value 0.998), Cox model estimate is not significant (p-value = 0.178), and the HR is 0.94 (Table 1 and 2). For the time period 1988-1995, the survival of Black patients was inferior to White (p= 0.0339), Asians (p=0.001), and other races (p=0.0011); Figure 2 and Table 3. For the time period 1996-2003, there was no difference in survival across races (p-value=0.7599); Figure 3 and Table 3. For the time period of 2004-2011, survival of Black patients was similar to White (p-value=1) but again inferior to Asian (p-value=0.05) and other races (p-value=0.09); Figure 4 and Table 3. Across the entire time period of 1998-2011, the survival of Black patients was inferior to White (Chi-square=6.59 and p-value=0.0084); Figure 5. The survival gap between Black and White patients seems to be obliterated in subsequent; “1996 - 2003” and “2004 - 2011” vs 1988-1995 (Figures 3 and 4) due to improvements in survival of Black patients over time (Figure 6) while the survival of White patients remained rather steady over time (Figure 7).Conclusions: Our study demonstrated that Black race was significantly correlated with poorer survival in patients with MF. The etiology of this poorer prognosis can be related to access to medical care, socioeconomic disparities, or possibly difference in disease biology and immune response. Despite the persistent pattern of lower survival across all time periods, the gap in survival between White and Black races seems to be narrowing overtime. [Display omitted] DisclosuresWilliam: Dova Pharmaceuticals: Research Funding; Incyte: Research Funding; Kyowa Kirin: Consultancy; Merck: Research Funding; Guidepoint Global: Consultancy.

Single-Cell Sequencing Technology Reveals the Heterogeneity of the Immune Microenvironment and Key Molecules of Drug Resistance in Angioimmunoblastic T-Cell Lymphoma

Objective: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. Our study aims to deeply analyze the tumor heterogeneity and clonal evolution of AITL, discovering key molecules of drug resistance and potential theraputic targets.Methods:We detected fresh lymph node samples from newly diagnosed and relapsed/ refractory AITL patients using single-cell RNA sequencing, combined with imaging mass cytometry (IMC) and whole exome sequencing. IMC was performed to analyze the spatial position relationship and protein expression characteristics of different subgroups in the tumor microenvironment of 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:ScRNA-seq revealed the significant differences in the tumor microenvironment of newly diagnosed and RR-AITL patients (Fig A,B). B cells and myeloid subgroups may play important roles in the development of AITL (Fig C). Transcription factor YY1, highly expressed in follicular helper T cell (Tfh) of RR-AITL patients, promoted the proliferation and drug resistance of AITL cells (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,H). Furthermore, the stemness of B cells in RR-AITL was enhanced and exhibits significant malignant characteristics (Fig C,I-K). We also found decreased interaction in RR-AITL samples (Fig L,M). Moreover, for the first time, we established AITL patient-derived organoid models that can be stablely cultured in vitro (Fig N). 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.Conclusion:In conclusion, our study revealed the differences between newly diagnosed and relapsed /refractory AITL in terms of immune microenvironment, single-cell transcriptomes, and signal pathway activation. 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. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Preliminary Results from a Phase I Study of HMPL-523, a Selective Oral Syk Inhibitor, in Patients with Relapsed or Refractory Lymphoma

Background: Spleen tyrosine kinase (Syk) plays an integral role in B-cell receptor signaling critical in the development and survival of several subtypes of lymphoma. HMPL-523 is a selective, oral Syk inhibitor that has shown strong anti-tumor efficacy in xenograft models of B-cell and T-cell lymphoma. HMPL-523 had a manageable safety profile and demonstrated anti-tumor activity in a phase I study of lymphoma patients in China (NCT02857998). Here, we report the safety and preliminary anti-tumor activity of HMPL-523 in the dose escalation phase of a phase 1 study of relapsed/refractory lymphoma patients in the United States and Europe (NCT03779113).Methods: The primary objectives of the phase I study were to evaluate the safety and tolerability of HMPL-523 and to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). Secondary objectives were to assess the pharmacokinetics (PK) and evaluate the preliminary efficacy of HMPL-523. Eligible patients had histologically confirmed lymphoma, exhausted all approved therapy options, and had good organ function, including creatinine clearance ≥ 40 ml/min by Cockcroft-Gault, absolute neutrophil count ≥ 1000/µL, platelet count ≥ 50,000/µL, and hemoglobin ≥ 8.0 g/dL. Dose escalation was performed according to a 3+3 study design. Treatment emergent adverse events (AEs) were assessed per NCI CTCAE v5.0. Treatment responses were assessed by Lugano criteria at weeks 8, 16, and 24, and then every 12 weeks. Patients received HMPL-523 treatment daily in 28-day cycles until disease progression or unacceptable toxicity.Results: As of July 15, 2021, 21 patients had been enrolled and dosed with HMPL-523 at one of six dose levels (100 to 800 mg once daily). Baseline tumor subtypes included Hodgkin lymphoma (HL; n=5); diffuse large B-cell lymphoma (DLBCL; n=4); follicular lymphoma (FL; n=4); marginal zone lymphoma (MZL; n=2); and 1 patient each with mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mixed HL/DLBCL, and Richter's transformation. Patients were predominantly Caucasian (90.5%) and male (71.4%). The median age was 61 years (range 27 to 89 years) and 71.4% had an ECOG performance status of 1. The median lines of prior therapy was 4 (range 2 to 17). The majority of patients had prior anti-CD20 antibody exposure (71.4%), and four patients (19%) received prior Bruton tyrosine kinase inhibitors.Five patients continue to receive study treatment. The most frequently reported treatment emergent AEs were aspartate aminotransferase increase (23.8%), anemia (23.8%), neutropenia (19%), hyponatremia (19%), creatinine increase (19%), and nausea (19%). The most common grade ≥ 3 AEs were neutropenia (14.3%), hyponatremia (14.3%), and anemia (9.5%). Three dose limiting toxicities were observed: 1 in the 100 mg cohort (grade 3 confusion) and 2 in the 800 mg cohort (grade 3 fever and grade 3 alanine aminotransferase increase). The dose was deescalated to 700 mg, which was determined to be the MTD and RP2D.Among 17 efficacy evaluable patients, 2 patients (1 HL, 1 FL) dosed at 600 mg and 800 mg (reduced to 600 mg due to toxicity) achieved complete response, and 1 patient (dose increased from 400 to 600 mg) achieved partial response (FL). Stable disease was observed in 5 (29.4%) patients (2 DLBCL, 1 MCL, 1 SLL, 1 PTCL). At steady state, HMPL-523 showed approximately dose proportional PK over the daily dose range of 100 to 700 mg.Conclusions: HMPL-523 was well tolerated at all dose levels within the range of 100 mg to 700 mg and demonstrated proof of activity at dose levels of 400 mg or higher in heavily pre-treated patients. The dose expansion phase of the study will evaluate safety and efficacy in patients with multiple subtypes of B-cell and T-cell lymphoma at the RP2D of 700 mg. Updated safety, PK, and anti-tumor activity will be presented. DisclosuresStrati: Astrazeneca-Acerta: Research Funding; Roche-Genentech: Consultancy. González-Barca: Roche: Honoraria, Other: Travel; Kyowa Kirin: Consultancy; EUSA Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel; Takeda. Abbvie: Honoraria. Taszner: Roche, Takeda: Consultancy, Other: Travel. Pillai: HUTCHMED: Current Employment. Chien: HUTCHMED: Current Employment, Current equity holder in publicly-traded company. Nanda: HUTCHMED: Current Employment, Current equity holder in publicly-traded company, Other: Travel. Rudinski: HUTCHMED: Current Employment. Jayaprakash: HUTCHMED, Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Ended employment in the past 24 months; Astrazeneca: Current equity holder in publicly-traded company. Hahka-Kemppinen: HUTCHMED: Current Employment, Current holder of individual stocks in a privately-held company; Eli Lilly: Current holder of individual stocks in a privately-held company. Kania: HUTCHMED: Current Employment, Current equity holder in publicly-traded company.