Subtype Of Cutaneous T-cell Lymphoma Research Articles

Primary Cutaneous CD8+ Aggressive Epidermotropic Cytotoxic T-Cell Lymphoma (PCAECTCL) Descriptors and Clinicopathologic Determinants of Survival: Analysis of a Pooled Database

Introduction: Primary Cutaneous CD8+ Aggressive Epidermotropic Cytotoxic T-cell lymphoma (PCAECTCL) is a rare provisional clinical entity and a subtype of cutaneous T-cell lymphoma. It is characterized by cytotoxic T-cells that primarily involve the epidermis causing rapidly progressive epidermal necrosis and extensive skin ulcers. PCAECTCL is often resistant to conventional chemotherapy and is usually associated with a poor prognosis. We conducted this pooled database analysis to delineate key disease characteristics and clinicopathologic determinants of survival in this rare provisional cutaneous T-cell lymphoma. Methods: To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 128 cases. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assessing the influence of demographic and clinicopathologic factors on overall survival (OS). Results: A total of 128 patients with confirmed PCAECTCL were identified. The median age was 62, with a peak incidence between 60 and 75 years. There was a male predominance with M:F ratio of 1.9. The median duration of symptoms prior to diagnosis was 6 months. Most of the patients presented with stage IIB (75%), followed by IB (13%), IA(7%), IVB(3%), and IIA(1%). Constitutional symptoms (CS), hemophagocytic syndrome, and ulceration/necrosis were present in 6%, 33%, 1.5%, and 45%, respectively. PCAECTCL widely metastasized in 62% of the cases, mainly to mucocutaneous tissues and visceral organs (83%), which included testicles (11%) and CNS (22%). PCAECTCL immunophenotype consisted of: CD2(37%), CD3(99%), CD5(40%), CD7(66%), CD30(16%), CD45RA(77%), CD56(6%), Granzyme B(72%), TIA-1(100%), and a median Ki-67 score of 70%. The median OS of the whole group was 20 months. OS was significantly impacted as age increased from <40 to 40-59 and > 60 (34 vs. 27 vs. 12 months, p=0.0003). Combination chemotherapy and stem cell transplant were statistically superior to no treatment, with a median OS of 17, 50, and 1 months, respectively (p=0.0002). Males tended to have shorter OS than females (13 vs. 24 months). Similarly, the presence of CS tended to have a shorter OS (6 vs. 21 months). OS was not impacted by stage or immunohistochemical features. Conclusions: This study presents updated clinicopathologic data from a pooled cohort of patients with PCAECTCL. It details the features of this rare provisional entity and identifies the clinical, immunohistochemical, and treatment modalities that are major determinants of OS.

HDACi Promotes the Occurrence of Ferroptosis in CTCL

Cutaneous T-cell lymphoma (CTCL) is a type of extranodal non-Hodgkin's lymphoma (NHL), a disease caused by clonal proliferation of T-lymphocytes originating in the skin. CHOP is the classic first-line treatment regimen for PTCL, working best for ALK-positive ALCL, while chemotherapy regimens are not very friendly for CTCL and other subtypes of PTCL. Currently, second-line treatment regimens have shown encouraging results with HDAC inhibitors in PTCL, and the anti-tumor mechanisms of HDAC inhibitors are being explored, including induction of apoptosis, cell cycle arrest inhibition of tumor angiogenesis, and so on. Ferroptosis is a new mode of cell death, which was mainly manifested by mitochondrial membrane lipid peroxidation, ferritin phagocytosis, the release of ferrous ions. And ferrous ions further leads to cellular lipid peroxidation, resulting in cell death. Our study shows that HDACi can significantly enhance ferroptosis inducer-mediated ferroptosis. WB and qPCR showed that ferroptosis-related molecules were significantly downregulated. In the case of HDACi combined with ferroptosis inducer, HDACi significantly enhanced the intensity of ferroptosis, and mitochondrial shrinkage and increased membrane density could be observed under electron microscopy. Intracellular iron content was detected by PGSK probe and detected by co Focused microscopy revealed that the fluorescence signal was significantly attenuated in the combination group. Reactive oxygen species assay indicated a significant increase in intracellular reactive oxygen species level, where we found the presence of ferroptosis in PTCL for the first time. In addition, we found that HDACi combined with ferroptosis inducer could enhance the apoptosis level of lymphoma cells, and the combination group significantly downregulated BCL-2, Caspase3,and significantly upregulated p-H2AX expression compared with the single drug.In terms of cycle arrest, CyclinD1 was significantly down-regulated in the combination group, and flow cytometry results were consistent with the above, while CCK8 and Edu showed significant down-regulation of cell viability and proliferation. SD rat transplantation tumor models showed a significant reduction in tumor volume in the combination group compared to the single agent and control groups, suggesting that HDACI combined with ferroptosis inducer is a promising therapeutic strategy.

40. Clonal evolution of Cutaneous T Cell Lymphoma (CTCL) revealed at single cell resolution

Patients with CTCL subtypes Mycosis Fungoides and Sézary Syndrome (MF/SS) frequently progress to advanced stage disease, which has a 20% 5-year survival. The molecular factors that drive MF/SS progression remain undefined. To address this, we subjected 41 longitudinal tumor samples (peripheral blood, skin and lymph node biopsies, 49-1050 days apart) and matched, purified non-malignant cells from 10 MF/SS patients to single-cell (sc)RNA-seq and exome+whole genome sequencing (eWGS). and patient-specific TCR clonotype assignment (scRepertoire). Clustering and cell type inference of scRNAseq (UMAP/Seurat/singleR) showed canonical CTCL marker genes and high clonal proportions (1-100%) of patient-specific TCR clonotypes. Somatic genome copy number variants (CNV) from scRNAseq (copykat) and eWGS (cnvkit), and deleterious/damaging single nucleotide variants (SNV) (eWGS, GATK/Mutect2) were identified in CTCL versus matched, non-malignant cells. To segregate early genomic events from progression-associated, we developed an integrative analysis pipeline to prioritize somatic CNV/SNV in genes with altered expression in >=30% of patients. This novel approach revealed alterations in NF-KB and T-cell receptor pathways (NFKB2, STAT3/5, TOX) as early events that were maintained in subsequent CTCL samples. We demonstrate gain-of-function activity in a novel-to-CTCL mutation in STAT3. Losses of some chromatin-modifying enzymes (DNMT3A, KDM6B) are early events, while gains of others (EZH2) are acquired with progression. Strikingly, progression-associated mutations were enriched in cell metabolism, growth, and motility genes, some of which are new to MF/SS: HIF1A, ITPR3, GTPase/RAS (IQGAP1/2, RASA1), and PI kinase (AKT1, MTOR, PIK3R1). These findings represent new insights into MF/SS progression and identify new precision medicine targets for currently available therapies.

Genetics Abnormalities with Clinical Impact in Primary Cutaneous Lymphomas.

Simple SummaryThe genetic landscape of cutaneous T-cell lymphomas analyzed by sequencing high throughput techniques shows a heterogeneous somatic mutational profile and genomic copy number variations in the TCR signaling effectors, the NF-κB elements, DNA damage/repair elements, JAK/STAT pathway elements and epigenetic modifiers. A mutational and genomic stratification of these patients provides new opportunities for the development or repurposing of (personalized) therapeutic strategies. The genetic heterogeneity in cutaneous B-cell lymphoma parallels with the specific subtype. Damaging mutations in primary cutaneous diffuse large B-cell lymphoma of the leg type, involving MYD88 gene, or BCL6 and MYC translocations or CDKN2A deletions are useful for diagnostic purposes. The more indolent forms, as the primary cutaneous lymphoma of follicle center cell (somatic mutations in TNFRSF14 and 1p36 deletions) and the cutaneous lymphoproliferative disorder of the marginal zone cells (FAS gene), present with a more restricted pattern of genetic alterations.Primary cutaneous lymphomas comprise a heterogeneous group of extranodal non-Hodgkin lymphomas (NHL) that arise from skin resident lymphoid cells and are manifested by specific lymphomatous cutaneous lesions with no evidence of extracutaneous disease at the time of diagnosis. They may originate from mature T-lymphocytes (70% of all cases), mature B-lymphocytes (25–30%) or, rarely, NK cells. Cutaneous T-cell lymphomas (CTCL) comprise a heterogeneous group of T-cell malignancies including Mycosis Fungoides (MF) the most frequent subtype, accounting for approximately half of CTCL, and Sézary syndrome (SS), which is an erythrodermic and leukemic subtype characterized by significant blood involvement. The mutational landscape of MF and SS by NGS include recurrent genomic alterations in the TCR signaling effectors (i.e., PLCG1), the NF-κB elements (i.e., CARD11), DNA damage/repair elements (TP53 or ATM), JAK/STAT pathway elements or epigenetic modifiers (DNMT3). Genomic copy number variations appeared to be more prevalent than somatic mutations. Other CTCL subtypes such as primary cutaneous anaplastic large cell lymphoma also harbor genetic alterations of the JAK/STAT pathway in up to 50% of cases. Recently, primary cutaneous aggressive epidermotropic T-cell lymphoma, a rare fatal subtype, was found to contain a specific profile of JAK2 rearrangements. Other aggressive cytotoxic CTCL (primary cutaneous γδ T-cell lymphomas) also show genetic alterations in the JAK/STAT pathway in a large proportion of patients. Thus, CTCL patients have a heterogeneous genetic/transcriptional and epigenetic background, and there is no uniform treatment for these patients. In this scenario, a pathway-based personalized management is required. Cutaneous B-cell lymphoma (CBCL) subtypes present a variable genetic profile. The genetic heterogeneity parallels the multiple types of specialized B-cells and their specific tissue distribution. Particularly, many recurrent hotspot and damaging mutations in primary cutaneous diffuse large B-cell lymphoma of the leg type, involving MYD88 gene, or BCL6 and MYC translocations and BLIMP1 or CDKN2A deletions are useful for diagnostic and prognostic purposes for this aggressive subtype from other indolent CBCL forms.

CD39/CD73 dysregulation and adenosine metabolism contribute to T-cell immunosuppression in patients with Sézary syndrome

Letter to Blood| January 5, 2023 CD39/CD73 dysregulation and adenosine metabolism contribute to T-cell immunosuppression in patients with Sézary syndrome Yuliya Yakymiv, Yuliya Yakymiv ∗ 1Laboratory of Immunogenetics, Department of Medical Sciences, University of Turin, Turin, Italy https://orcid.org/0000-0002-9598-3462 Search for other works by this author on: This Site PubMed Google Scholar Sara Marchisio, Sara Marchisio ∗ 1Laboratory of Immunogenetics, Department of Medical Sciences, University of Turin, Turin, Italy https://orcid.org/0000-0001-7005-837X Search for other works by this author on: This Site PubMed Google Scholar Erika Ortolan, Erika Ortolan 1Laboratory of Immunogenetics, Department of Medical Sciences, University of Turin, Turin, Italy https://orcid.org/0000-0003-2287-9020 Search for other works by this author on: This Site PubMed Google Scholar Cristiano Bracci, Cristiano Bracci 1Laboratory of Immunogenetics, Department of Medical Sciences, University of Turin, Turin, Italy Search for other works by this author on: This Site PubMed Google Scholar Rebecca Senetta, Rebecca Senetta 2Pathology Unit, Department of Oncology, University of Turin, Turin, Italy Search for other works by this author on: This Site PubMed Google Scholar Maria Rebecca Rumore, Maria Rebecca Rumore 2Pathology Unit, Department of Oncology, University of Turin, Turin, Italy Search for other works by this author on: This Site PubMed Google Scholar Cristian Tampieri, Cristian Tampieri 3Pathology Unit, Department of Medical Sciences, University of Turin, Turin, Italy Search for other works by this author on: This Site PubMed Google Scholar Marianna Fia, Marianna Fia 4Dermatologic Clinic, Department of Medical Sciences, University of Turin, Turin, Italy Search for other works by this author on: This Site PubMed Google Scholar Simone Ribero, Simone Ribero 4Dermatologic Clinic, Department of Medical Sciences, University of Turin, Turin, Italy Search for other works by this author on: This Site PubMed Google Scholar Ada Funaro, Ada Funaro † 1Laboratory of Immunogenetics, Department of Medical Sciences, University of Turin, Turin, Italy https://orcid.org/0000-0001-6341-1817 Search for other works by this author on: This Site PubMed Google Scholar Pietro Quaglino Pietro Quaglino † 4Dermatologic Clinic, Department of Medical Sciences, University of Turin, Turin, Italy Search for other works by this author on: This Site PubMed Google Scholar Blood (2023) 141 (1): 111–116. https://doi.org/10.1182/blood.2022017259 Article history Submitted: May 31, 2022 Accepted: August 14, 2022 Connected Content This is a related article to: CD39-CD73-adenosine effects in Sézary syndrome Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Request Permissions Cite Icon Cite Search Site Citation Yuliya Yakymiv, Sara Marchisio, Erika Ortolan, Cristiano Bracci, Rebecca Senetta, Maria Rebecca Rumore, Cristian Tampieri, Marianna Fia, Simone Ribero, Ada Funaro, Pietro Quaglino; CD39/CD73 dysregulation and adenosine metabolism contribute to T-cell immunosuppression in patients with Sézary syndrome. Blood 2023; 141 (1): 111–116. doi: https://doi.org/10.1182/blood.2022017259 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBlood Search Subjects: Immunobiology and Immunotherapy, Lymphoid Neoplasia TO THE EDITOR: Sézary syndrome (SS) is an aggressive subtype of cutaneous T-cell lymphoma, clinically presenting with erythroderma, lymphadenopathy, and atypical T cells (Sézary cells) in the skin, lymph nodes, and peripheral blood.1,2 As disease progresses, patients with SS develop severe immunodeficiency orchestrated by tumor cells and the tumor microenvironment (TME). This immunodeficiency is worsened by therapy and is responsible for a high incidence of life-threatening infections.3 Overexpression of CD39 and/or CD73 in malignant circulating SS T cells has previously been reported.4,5 Here we follow up on our preliminary data by investigating the functional role of the CD39/CD73 ectoenzymes in generating immunosuppressive extracellular adenosine (ADO) in patients with SS.6,7 Our patient cohort consisted of 11 patients with SS (supplemental Table 1, available on the Blood website). At first encounter and at...

Survival Outcomes of Patients with Mycosis Fungoides Involving the External Ear and Ear Canal.

Mycosis Fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma. Disease involvement of specific locations may be more significant than simply the symptoms associated with that site; it is possible that involvement of certain sites could be associated with poor prognosis. We aimed to evaluate the outcomes of patients with MF with documented involvement of the EAC and external ear. Retrospective analysis. We retrospectively reviewed 40 patients with MF that were treated by otologists between 2012 and 2021. We report the largest series of patients with MF involving the external ear and EAC. Of the 40 patients included in this study, 17 presented with Mycosis Fungoides in the otologic region (MFO). Of these 17 MFO patients, 2/17 had involvement of the external ear only, 3/17 of the EAC only, 11/17 of both the external ear and EAC, and 1/17 of the periauricular skin. Of note, 11/14 (79%) patients presenting with EAC disease died compared to11/26 (42%) of patients without involvement. In addition, eight of the 13 (62%) patients with external ear involvement died compared to 14/27 (52%) of patients without involvement. Ear canal involvement was associated with a statistically significant shorter overall survival duration in patients with MF (p=0.03). Furthermore, disease in the EAC was found to have a hazard ratio value of 2.565 (CI 1.102-5.970). Involvement of the EAC by MF portends a poor prognosis. This finding highlights the need for a more in-depth otologic evaluation of patients with MF. 4 Laryngoscope, 133:1486-1491, 2023.

New insights into the pathogenesis and molecular understanding of cutaneous T-cell lymphomas

The pathogenesis of cutaneous T‑cell lymphomas (CTCL) is still an enigma. Therefore, extensive translational research efforts have been undertaken in recent years to gain further clinical and molecular insights. There is increasing evidence that the different clinical appearance of the CTCL subtypes derives from the assumption that they develop from different skin subpopulations of Tcells. Detection and quantification of the malignant T‑cell clones is crucial for the diagnosis and prognosis of CTCL. Numerous recurrent mutant cellular signalling pathways have been found in recent years. This includes the JAK-STAT, NFκB, T‑cell receptor and MAP kinase signalling pathways, as well as cell cycle control and epigenetics. The most recent analyses imply atumour evolution model with initial copy number variation, like amplification or deletions of specific DNA fragments (CNVs) and only subsequent later single nucleotide variations (SNVs). The crucial question, however, is which CNVs are sufficient to initiate general tumourigenesis? The challenge is to identify possible driver genes. Increasing molecular understanding in CTCL will include new breakthrough therapeutic options in the near future.

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.

Characterization of primary cutaneous T-cell lymphoma following solid organ transplantation.

Immunosuppression following solid organ transplantation is a known risk factor for the development of posttransplant lymphoproliferative disorders (PTLD). Primary cutaneous T-cell lymphoma (CTCL) occurring in the posttransplant setting is rare, which has made comprehensive understanding of this disease challenging. This study aims to further characterize the spectrum of clinicopathologic features of CTCL in solid organ transplant recipients (SOTR). A retrospective chart review was performed for SOTR who were diagnosed with CTCL at a multi-site academic medical center from January 1, 1998, to December 31, 2013. Eight patients fulfilled the inclusion criteria and were included in this study. Data collected included patient demographics, transplanted organ, the time between transplant and CTCL diagnosis, clinical presentation and rash morphology, a histological subtype of CTCL, immunosuppression regimens, and patient status. Twelve diagnostic skin biopsies for five patients were examined and reviewed by a board-certified dermatopathologist. Six (75%) out of the eight patients were men, two (25%) were women, and the median age was 53 years. The median time from the date of transplant to the diagnosis of CTCL was 8.2 years. Transplanted organs included the liver (4), kidney (3), and heart (1). Clinical presentation varied from papulonodules, comedone-like lesions, intense pruritis, and scaly erythematous eruptions. The most common histologic presentation was folliculotropic mycosis fungoides (FMF) (7/12). Epstein-Barr virus-in situ hybridization (EBV-ISH) was negative in all specimens. We emphasize the rarity of CTCL among SOTR. Although rare in the general population, the FMF subtype appears to be disproportionately seen in SOTR compared with other CTCL.

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.

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.

Lack of PRAME Expression in Cutaneous T-Cell Lymphomas.

Cutaneous T-cell lymphomas (CTCLs) are rare tumors with no established markers that can reliably distinguish between benign and malignant lesions. Preferentially Expressed Antigen in Melanoma (PRAME) is a cancer/testis antigen that is found in many solid and hematologic malignancies. PRAME overexpression typically portends a poor prognosis and lower chemotherapeutic response. To date, no studies have established a role for PRAME in CTCL. An analysis was performed on 47 cases definitively diagnosed as CTCL: 25 cases of mycosis fungoides, 2 of Sezary syndrome, 5 of CD30+ lymphoproliferative disorder, 7 of primary cutaneous anaplastic large T-cell lymphoma, 3 of primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, 1 of subcutaneous panniculitis-like T-cell lymphoma, and 4 of angiocentric T-cell lymphoma. PRAME immunohistochemistry was completely negative in all cases. PRAME expression was not found in any CTCL subtypes, suggesting that the pathogenesis of CTCL is not mediated by PRAME. Further study is required to identify biomarkers that might aid in the diagnosis and prognostication of CTCLs.

Contemporary Treatment Patterns and Response in Relapsed/Refractory Cutaneous T-Cell Lymphoma (CTCL) across Five European Countries.

Simple SummaryRecent studies have mostly focused on the treatment of advanced mycosis fungoides and Sézary syndrome and less on the treatment of relapsed or refractory (R/R) cases of cutaneous T-cell lymphoma (CTCL). There is also a paucity of data on the treatment and outcomes of primary cutaneous anaplastic large cell lymphoma and other rare CTCL subtypes. This European observational study provided real-world data on the current treatments used in the management of CTCL across three lines of therapy. As a result, there was a significant level of heterogeneity in treatment types than expected by European guidelines. These findings highlight the lack of consensus in relapsed CTCL, as well as the urgent unmet treatment needs.The treatment pattern of cutaneous T-cell lymphoma (CTCL) remains diverse and patient-tailored. The objective of this study was to describe the treatment patterns and outcomes in CTCL patients who were refractory or had relapsed (R/R) after a systemic therapy. A retrospective chart review study was conducted at 27 sites in France, Germany, Italy, Spain and the United Kingdom (UK) of patients who received a first course of systemic therapy and relapsed or were refractory. Data were collected longitudinally from diagnosis to first-, second- and third-line therapy. The study included 157 patients, with a median follow-up of 3.2 years. In total, 151 proceeded to second-line and 90 to third-line therapy. In the first line (n = 147), patients were treated with diverse therapies, including single- and multi-agent chemotherapy in 67 (46%), retinoids in 39 (27%), interferon in 31 (21%), ECP in 4 (3%), corticosteroids in 3 (2%) and new biological agents in 3 (2%). In the second line, the use of chemotherapy and retinoids remained similar to the first line, while the use of new biologics increased slightly. In sharp contrast to the first line, combination chemotherapy was extremely diverse. In the third line, the use of chemotherapy remained high and diverse as in the second line. From the time of first R/R, the median PFS was 1.2 years and the median OS was 11.5 years. The presented real-world data on the current treatments used in the management of R/R CTCL in Europe demonstrate the significant heterogeneity of systemic therapies and combination therapies, as expected from the European guidelines.

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.

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.

Rationale for the Clinical Use of Less Frequent Dosing of Mogamulizumab for T-Cell Lymphomas Using Population Pharmacokinetic and Exposure Response Analysis

▪Background: CC chemokine receptor 4 (CCR4) is expressed on several T cell subsets and is implicated in the pathogenesis of a variety of leukemias and lymphomas. Mogamulizumab is a humanized monoclonal antibody targeting CCR4 receptors and is indicated for treatment of adult patients with cutaneous T-cell lymphoma (relapsed or refractory mycosis fungoides or Sézary syndrome). The objectives of these analyses were to (1) develop a population pharmacokinetics (PPK) model to characterize mogamulizumab PK following administration to subjects who have lymphomas or solid tumors, (2) evaluate patient covariates that influence the variability in PK, (3) simulate mogamulizumab PK at 2 mg/kg every four weeks (Q4W) dosing and compare with the PK at 1 mg/kg every two weeks (Q2W) dosing and (4) assess the exposure-response (ER) relationship between mogamulizumab exposures and adverse events (AEs). A Phase 2 clinical study is ongoing to obtain PK, efficacy, and safety data for 2 mg/kg Q4W dosing (NCT04745234).Methods: Plasma or serum pharmacokinetic data from 525 subjects with cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), adult T-cell leukemia-lymphoma (ATL), or solid tumors were included in this analysis. Mogamulizumab was administered over 0.01 mg/kg to 3 mg/kg dose range as mono- or combination-therapy. Nonlinear mixed effects modeling was used to develop a base PPK model followed by covariate evaluation. Simulations were performed to estimate exposure metrics to support ER analyses and to compare 2 mg/kg Q4W and 1 mg/kg Q2W dosing scenarios following four 1 mg/kg weekly doses in the first cycle of treatment. Comparisons between mogamulizumab exposures and grade 3 and grade 4 AEs were conducted.Results: A two-compartment PPK model with linear elimination and log-normal variability on clearance and the volumes of distribution of the central and peripheral compartments, described the PK data. Body weight, albumin, and tumor type were identified as statistically significant covariates affecting mogamulizumab exposure. Other covariates that were tested but did not demonstrate statistically significant effect on mogamulizumab exposure included age, race, creatinine clearance, degree of CCR4 expression, combination- vs. mono-therapy, CTCL subtype (when applicable), and mild hepatic impairment. The PK simulations demonstrated that the overall exposures (AUC ss) achieved with mogamulizumab 2 mg/kg Q4W dosing were comparable to mogamulizumab 1 mg/kg Q2W dosing, with C max predicted to be 47% greater and C min to be 29% lower. Evaluations of dose and exposure (AUC ss, C max, C min) vs. incidence of grade 3 and grade 4 AEs showed no relationship.Conclusions: The PPK model adequately characterized the mogamulizumab PK over the doses ranging from 0.01 to 3 mg/kg. There was no relationship between the exposure of mogamulizumab and the emergence of grade 3 or grade 4 AEs across the dose range explored. Thus, the mogamulizumab 2 mg/kg Q4W dosing is not expected to lead to increased incidences of grade 3 and grade 4 AEs. From a PK and safety perspective, this analysis supports 2 mg/kg Q4W Mogamulizumab as an appropriate alternative dosing strategy to the approved, 1 mg/kg Q2W, dosing posology in T-cell lymphomas.Acknowledgements: We would like to express special appreciation to Dr. Roland Meier, MD, PhD, for sponsoring this abstract. DisclosuresMehta: Kyowa Kirin: Current Employment. Patel: Kyowa Kirin: Current Employment. Vuppugalla: Kyowa Kirin: Current Employment. Tudor: Kyowa Kirin: Current Employment. Dwyer: Kyowa Kirin: Current Employment; Bristol Myers Squibb: Current Employment. Hruska: Viatris: Current equity holder in publicly-traded company; Viking: Current equity holder in publicly-traded company; Durect: Current equity holder in publicly-traded company; CymaBay: Current equity holder in publicly-traded company; Takeda: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company; Johnson & Johnson: Current equity holder in publicly-traded company; GlaxoSmithKline: Current equity holder in publicly-traded company; Genmab: Current equity holder in publicly-traded company; Gilead: Current equity holder in publicly-traded company; Biohaven: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company; Bristol Myers Squibb: Current equity holder in publicly-traded company; Kyowa Kirin: Current Employment. Marsteller: Kyowa Kirin: Current Employment. OffLabel Disclosure:Yes. Mogamulizumab is a CCR4-directed monoclonal antibody indicated for the treatment of adult patients with relapsed or refractory mycosis fungoides or Sézary syndrome after at least one prior systemic therapy - new dosing regimen under examination.

Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies

Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies