Therapy For Cutaneous T-cell Lymphoma Research Articles

Cantharidin overcomes IL-2Rα signaling-mediated vorinostat resistance in cutaneous T-cell lymphoma through reactive oxygen species

BackgroundVorinostat (SAHA) is a histone deacetylase inhibitor that has shown clinical efficacy against advanced cutaneous T-cell lymphoma (CTCL). However, only a subset of patients with CTCL (30–35%) respond to SAHA...

Central hypothyroidism induced by bexarotene preceding graves' disease after interferon therapy for cutaneous t-cell lymphoma

Central hypothyroidism induced by bexarotene preceding graves' disease after interferon therapy for cutaneous t-cell lymphoma

New Genetic Markers of Skin T-Cell Lymphoma Treatment.

Cutaneous T-cell lymphomas (CTCL) can be described as chronic skin inflammation lesions with the content of malignant T cells and they are considered to be T-cell-mediated skin diseases. CD147 is recognized as a 58-kDa cell surface glycoprotein of the immunoglobulin superfamily; it can induce the synthesis of MMPs (matrix metalloproteinases) on the surface of tumor cells where it was originally identified. It can also function in adjacent tumor fibroblasts using CD147-CD147 interactions. The polymorphism rs8259 T/A is situated in the untranslated region (3'UTR) of the CD147 gene. HLA DRB1*1501 takes part in the process of presentation and recognition of different antigens to T cells. It can be expressed by antigen-presenting cells-macrophages, dendritic cells, and B cells. The aim of the study is to test genotype-phenotype associations of both polymorphisms including therapy in a large cohort of CTCL patients. A final total of 104 CTCL patients were enrolled in the study. For the first remission at the clinic department, they were treated by means of local skin-directed therapy, phototherapy, and systemic therapy. Genomic DNA was isolated from peripheral blood leukocytes. A standard technique using proteinase K was applied. The polymorphisms rs8259 T/A (CD147 gene) and rs3135388 (HLA DRB1*1501) were detected through standard PCR-restriction fragment length polymorphism methods. The severity of the disease (patients with parapsoriasis, stages IA and IB, vs patients with stages IIB, IIIA, and IIIB) was associated with the CD147 genotype: the AA variant was 3.38 times more frequent in more severe cases, which reflects the decision on systemic therapy (p = 0.02, specificity 0.965). The AA genotype in the CD147 polymorphism was 12 times more frequent in patients who underwent systemic therapy of CTCL compared to those not treated with this therapy (p = 0.009, specificity 0.976). The same genotype was also associated with radiotherapy-it was observed 14 times more frequently in patients treated with radiotherapy (p = 0.009, specificity 0.959). In patients treated with interferon α therapy, the AA genotype was observed to be 5.85 times more frequent compared to the patients not treated with interferon therapy (p = 0.03, specificity 0.963). The HLA DRB1*1501 polymorphism was associated with local skin-directed therapy of CTCL. The CC genotype of the polymorphism was observed to be 3.57 times more frequent in patients treated with local therapy (p = 0.008, specificity 0.948). When both polymorphisms had been calculated together, even better results were obtained: the AACC double genotype was 11 times more frequent in patients with severe CTCL (p = 0.009, specificity 0.977). The TACT double genotype was associated with local skin-directed therapy (0.09 times lower frequency, p = 0.007, sensitivity 0.982). The AACC genotype was 8.9 times more frequent in patients treated by means of systemic therapy (p = 0.02, specificity 0.976) and as many as 18.8 times more frequent in patients treated with radiotherapy (p = 0.005, specificity 0.969). Thus, the AACC double genotype of CD147 and DRB1*1501 polymorphisms seems to be a clinically highly specific marker of severity, systemic therapy and radiotherapy of patients with T-cell lymphoma. Although genotyping results were not known during the treatment decision and could not modify it, the clinical decision on severity and therapy reflected some aspects of the genetic background of this complicated T-cell-associated disease very well.

Toxicology, pharmacokinetics, and immunogenicity studies of CCR4-IL2 bispecific immunotoxin in rats and minipigs

We have developed a diphtheria toxin-based recombinant human CCR4-IL2 bispecific immunotoxin (CCR4-IL2-IT) for targeted therapy of cutaneous T-cell lymphoma (CTCL). CCR4-IL2-IT demonstrated superior efficacy in an immunodeficient mouse CTCL model. Recently, we have compared the in vivo efficacy of CCR4-IL2-IT versus Brentuximab (FDA approved leading drug in CTCL market) in the same immunodeficient mouse CTCL model. The comparison demonstrated that CCR4-IL2-IT was significantly more effective than Brentuximab. In this study, we have performed non-GLP (Good Laboratory Practice) toxicology, pharmacokinetics, immunogenicity studies of CCR4-IL2-IT in both rats and minipigs. CCR4-IL2-IT demonstrated excellent safety profiles in both rats and minipigs. The maximum tolerated dose of CCR4-IL2-IT was determined as 0.4 mg/kg in both rats and minipigs. Complete blood count and chemistry analysis did not show significant difference for all measured parameters between the blood samples of pre-injection versus post-injection from the five-day toxicology studies of CCT4-IL2-IT in both rats and minipigs. Histology analysis did not show difference between the PBS treatment group versus CCR4-IL2-IT treatment group at 50 μg/kg in both rats and minipigs. The half-life of CCR4-IL2-IT was determined as about 45 min in rats and 30 min in minipigs. The antibodies against CCR4-IL2-IT were detected in about two weeks after CCR4-IL2-IT treatment. CCR4-IL2-IT did not induce cytokine release syndrome in a peripheral blood mononuclear cell derived humanized mouse model. The depletion of CCR4+ cell and CD25+ cell (two target cell populations of CCR4-IL2-IT) was observed in minipigs. The excellent safety profile promoted us to further develop CCR4-IL2-IT towards clinical trials.

Role of IL-4 and IL-13 in Cutaneous T Cell Lymphoma.

The interleukins IL-4 and IL-13 are increasingly recognized contributors to the pathogenesis of cutaneous T cell lymphomas (CTCLs), and their role in disease-associated pruritus is accepted. The prevailing Th2 profile in advanced CTCL underscores the significance of understanding IL-4/IL-13 expression dynamics from the early stages of disease, as a shift from Th1 to Th2 may explain CTCL progression. Targeted agents blocking key cytokines of type 2 immunity are established therapeutics in atopic disorders and have a promising therapeutic potential in CTCL, given their involvement in cutaneous symptoms and their contribution to the pathogenesis of disease. IL-4, IL-13, and IL-31 are implicated in pruritus, offering therapeutic targets with dupilumab, tralokinumab, lebrikizumab, and nemolizumab. This review analyzes current knowledge on the IL-4/IL-13 axis in mycosis fungoides and Sezary syndrome, the most common types of CTCL, examining existing literature on the pathogenetic implications with a focus on investigational treatments. Clinical trials and case reports are required to shed light on novel uses of medications in various diseases, and ongoing research into the role of IL-4/IL-13 axis blockers in CTCL therapy might not only improve the management of disease-related pruritus but also provide in-depth insights on the pathophysiologic mechanisms of CTCL.

HyBryte™ use in early-stage cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma (CTCL) is a rare type of non-Hodgkin lymphoma of the skin, where at later stages skin-homing malignant T-cells affect lymph nodes, blood, and visceral organs. Even though early CTCL does not affect survival, it can progress to more advanced stages of disease and have a significant effect on the quality of life of patients. Although expectant management is a treatment consideration in early disease stages, most patients cycle through different skin-directed therapies throughout their lifetime. It can become a challenge to manage the serious and accumulating risk of side effects of these therapies, including various skin cancers and skin damage. Adverse effects from topical therapies limit their long-term utility. Thus, there is an unmet need for well-characterized therapies that have a rapid onset of action and minimal long-term/cumulative side effect profile. Most recently, the results of a Phase 3 study of topical HyBryte™ as a potential treatment for CTCL demonstrated its efficacy and safety profile. This article summarizes what is known about HyBryte™, focuses on its mechanism of action, and highlights its effectiveness, safety, and tolerability in the context of other current FDA-approved topical therapies for CTCL.

Real-World Treatment Patterns and Clinical Outcomes With Brentuximab Vedotin or Other Standard Therapies in Patients With Previously Treated Cutaneous T-Cell Lymphoma in the United States

Introduction/BackgroundPrimary cutaneous anaplastic large-cell lymphomas (pcALCLs) are a type of cutaneous T-cell lymphoma (CTCL) in which CD30 is uniformly expressed. In mycosis fungoides (MF), another CTCL, CD30 is heterogeneously expressed. In ALCANZA, patients with pcALCLs or CD30-positive MF randomized to brentuximab vedotin (BV) vs. physician's choice of methotrexate or bexarotene had significantly improved outcomes, including higher objective response rates (ORR) lasting ≥4 months (ORR4), as well as longer median progression-free survival (PFS) and time to next treatment (TTNT). In this study, we sought to assess the real-world impact of treatment with BV in second or later lines of therapy for CTCL. Materials and MethodsThis retrospective chart review describes patient characteristics, treatment patterns, clinical outcomes, and healthcare resource use (HRU) in patients with pcALCLs or MF previously treated with ≥1 systemic therapy and subsequently treated with BV (n = 139) or other standard therapy (OST; n = 164). ResultsMost patients in the BV cohort (96.4%) received BV as second-line (2L) systemic therapy. The most common OSTs were methotrexate (11.6%), mogamulizumab (9.1%), and bendamustine (9.1%) monotherapies. For 2L BV and OST, median duration of therapy was 8.4 and 5.2 months, real-world ORR was 82.1% and 66.5%, and real-world ORR4 was 42.5% and 25.0%. Real-world 1- and 2-year PFS, TTNT, and OS were significantly longer (all P < .01) and HRU was lower for BV vs. OST. ConclusionThese real-world outcomes are consistent with ALCANZA results, demonstrating favorable outcomes with BV vs. OST in patients with CTCL previously treated with ≥1 systemic therapy.

What Does the Future Hold for Biomarkers of Response to Extracorporeal Photopheresis for Mycosis Fungoides and Sézary Syndrome?

Extracorporeal photopheresis (ECP) is an FDA-approved immunotherapy for cutaneous T-cell lymphoma, which can provide a complete response in some patients. However, it is still being determined who will respond well, and predictive biomarkers are urgently needed to target patients for timely treatment and to monitor their response over time. The aim of this review is to analyze the current state of the diagnostic, prognostic, and disease state-monitoring biomarkers of ECP, and outline the future direction of the ECP biomarker discovery. Specifically, we focus on biomarkers of response to ECP in mycosis fungoides and Sézary syndrome. The review summarizes the current knowledge of ECP biomarkers, including their limitations and potential applications, and identifies key challenges in ECP biomarker discovery. In addition, we discuss emerging technologies that could revolutionize ECP biomarker discovery and accelerate the translation of biomarker research into clinical practice. This review will interest researchers and clinicians seeking to optimize ECP therapy for cutaneous T-cell lymphoma.

O-147 - Real-world outcomes and tolerability of mogamulizumab monotherapy and multimodality therapy for cutaneous T-cell lymphoma: results from a multicenter retrospective cohort study

O-147 - Real-world outcomes and tolerability of mogamulizumab monotherapy and multimodality therapy for cutaneous T-cell lymphoma: results from a multicenter retrospective cohort study

Dimethyl fumarate treatment in relapsed and refractory cutaneous T-cell lymphoma: a multicenter phase 2 study

AbstractTargeted therapies for cutaneous T-cell lymphoma (CTCL) are limited and curative approaches are lacking. Furthermore, relapses and drug induced side effects are major challenges in the therapeutic management of patients with CTCL, creating an urgent need for new and effective therapies. Pathologic constitutive NF-κB activity leads to apoptosis resistance in CTCL cells and, thus, represents a promising therapeutic target in CTCL. In a preclinical study we showed the potential of dimethyl fumarate (DMF) to block NF-κB and, specifically, kill CTCL cells. To translate these findings to applications in a clinical setting, we performed a multicentric phase 2 study evaluating oral DMF therapy in 25 patients with CTCL stages Ib to IV over 24 weeks (EudraCT number 2014-000924-11/NCT number NCT02546440). End points were safety and efficacy. We evaluated skin involvement (using a modified severity weighted assessment tool [mSWAT]), pruritus, quality of life, and blood involvement, if applicable, as well as translational data. Upon skin analysis, 7 of 23 (30.4%) patients showed a response with >50% reduction in the mSWAT score. Patients with high tumor burden in the skin and blood responded best to DMF therapy. Although not generally significant, DMF also improved pruritus in several patients. Response in the blood was mixed, but we confirmed the NF-κB–inhibiting mechanism of DMF in the blood. The overall tolerability of the DMF therapy was very favorable, with mostly mild side effects. In conclusion, our study presents DMF as an effective and excellently tolerable therapeutic option in CTCL to be further evaluated in a phase 3 study or real-life patient care as well as in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT02546440.

CCR4-IL2 bispecific immunotoxin is more effective than brentuximab for targeted therapy of cutaneous T-cell lymphoma in a mouse CTCL model.

Cutaneous T-cell lymphoma (CTCL) encompasses two main subtypes: mycosis fungoides and Sezary syndrome. Global response rates for the systemic treatment of mycosis fungoides and Sezary syndrome are approximately 30% and none of these treatments are thought to be curative. C-C chemokine receptor type 4 (CCR4) and CD25 are encouraging targets for the treatment of CTCL and are individually targeted by mogamulizumab and denileukin diftitox, respectively. We developed a novel CCR4-IL2 bispecific immunotoxin (CCR4-IL2 IT) targeting both CCR4 and CD25. CCR4-IL2 IT demonstrated superior efficacy against CCR4+ CD25+ CD30+ CTCL in an immunodeficient NSG mouse tumor model. Investigative New Drug-enabling studies of CCR4-IL2 IT are ongoing, including Good Manufacturing Practice production and toxicology studies. In this study, we compared the in vivo efficacy of CCR4-IL2 IT versus the US Food and Drug Administration-approved drug, brentuximab, using an immunodeficient mouse CTCL model. We demonstrated that CCR4-IL2 IT was significantly more effective in prolonging survival than brentuximab, and combination treatment of CCR4-IL2 IT and brentuximab was more effective than brentuximab or CCR4-IL2 IT alone in an immunodeficient NSG mouse CTCL model. Thus, CCR4-IL2 IT is a promising novel therapeutic drug candidate for CTCL treatment.

Single-Fraction Radiation Therapy for Localized Cutaneous T-Cell Lymphoma

Mycosis fungoides is the most common type of cutaneous T-cell lymphoma (CTCL). Single-fraction radiation therapy has been used as a skin-targeted therapy to treat localized CTCL lesions. The objective of this study was to investigate the treatment outcomes associated with single-fraction radiation therapy for CTCL. We retrospectively studied the outcomes among patients with CTCL treated with single-fraction radiation therapy at our institution between October 2013 and August 2022. Clinical response (complete response [CR], partial response [PR], or no response [NR]) and retreatment response were evaluated. A total of 242 lesions from 46 patients were analyzed, for an average of 5.3 lesions treated per patient. The majority of lesions presented with a plaque morphology (n=145, 60.0%). All lesions were treated to a dose of 8 Gy in 1 fraction. Median follow-up was 24.6 months (range, 1-88 months). Of the 242 lesions, 36 (14.8%) had an initial PR or NR; all were retreated with the same regimen to the same site at a median interval of 8 weeks. Eighteen of the retreated lesions (50.0%) went on to have a CR. Thus, the overall CR rate for CTCL lesions was 92.6%. No recurrences were noted in the treated areas after achieving CR. Single-fraction radiation therapy to a dose of 8 Gy in 1 fraction to localized areas provided a high rate of complete and durable responses in the affected sites.

New Molecular and Biological Markers in Cutaneous T Cell Lymphoma: Therapeutic Implications.

Cutaneous T cell lymphomas (CTCLs) exhibit a wide variety of clinical features, histologic characteristics, and genetic drivers. We review novel molecular findings that inform our understanding of the pathogenesis of CTCL, with a focus on the tumor microenvironment (TME). There is increasing evidence challenging the model of TCM:mycosis fungoides (MF) and TEM:Sézary syndrome (SS) phenotype. Phylogenetic analysis performed using whole-exome sequencing (WES) raises the possibility that MF can arise without a common ancestral T cell clone. The detection of ultraviolet (UV) marker signature 7 mutations in the blood of patients with SS raises questions about the role of UV exposure in CTCL pathogenesis. There is also increasing interest on the role of the TME in CTCL. Existing therapies such as the RXR retinoid bexarotene and the anti-CCR4 monoclonal antibody mogamulizumab may act through the CTCL TME by impacting the CCL22:CCR4 axis, while cancer-associated fibroblasts (CAFs) in the CTCL TME contribute to drug resistance, as well as a Th2 milieu and tumor growth via secretion of pro-tumorigenic cytokines. Staphylococcus aureus (SA) is a frequent cause of morbidity among CTCL patients. SA may positively select for malignant T cells through adaptive downregulation of alpha-toxin surface receptors and promotion of tumor growth via upregulation of the JAK/STAT pathway. Recent molecular advancements have contributed to our understanding of the pathogenesis of CTCL and shed light into the potential mechanisms of existing therapies. Further understanding of the CTCL TME may fuel the discovery of novel therapies for CTCL.

Mogamulizumab Multimodality Therapy with Systemic Retinoids, Interferon, or Extracorporeal Photopheresis for Advanced Cutaneous T‐Cell Lymphoma

Mogamulizumab is a novel monoclonal antibody designed to target CC chemokine receptor 4 (CCR4), which is expressed by tumor cells in cutaneous T‐cell lymphoma (CTCL). In clinical trials, mogamulizumab monotherapy has demonstrated efficacy in reducing tumor burden in advanced CTCL, particularly in the peripheral blood. In clinical practice at our center, mogamulizumab has been combined with other agents such as systemic interferon, systemic retinoids, and extracorporeal photopheresis for an enhanced synergistic effect. There is limited published research on mogamulizumab combination therapy. This study evaluates the clinical efficacy of mogamulizumab in combination with systemic interferon, retinoids, and/or extracorporeal photopheresis for therapy of CTCL. Nineteen patients on this regimen at our academic center were identified. Treatment response rates, progression‐free survival, duration of response, and adverse effects were characterized by retrospective chart review. All patients on this regimen at our center had an initial partial or complete response. Moreover, responses were durable, and the regimen was well‐tolerated with few grade 3 adverse effects. These results demonstrate the utility of a multimodality approach to the therapy of CTCL with mogamulizumab and warrant further confirmation.

Clonal Evolution of Cutaneous T Cell Lymphoma Revealed at Single Cell Resolution

Background: Patients with Cutaneous T Cell Lymphoma (CTCL) subtypes Mycosis Fungoides and Sézary Syndrome (MF/SS) who progress to advanced stage disease have a 20% 5-year overall survival rate. Current treatments for CTCL range from localized therapies for skin lesions to systemic treatments, including histone deacetylase inhibitors, chemotherapy, and immunotherapy. While many treatments are initially effective, patients often develop resistance to ongoing treatment. Though recent studies have comprehensively profiled the genomic landscape of CTCL, no clear driver mutation has been identified and the molecular factors that drive MF/SS progression remain undefined. To address these outstanding questions, we collected longitudinal tumor and normal samples from 10 MF/SS patients and subjected them to high resolution genome and transcriptome analyses (exome, whole genome and single-cell RNA sequencing, eWGS and scRNAseq) to define the clonal evolution and temporal progression of CTCL. Methods: We collected 52 serial tumor samples (peripheral blood, skin and lymph node biopsies, 49-1050 days apart) and matched, purified non-malignant cells from 10 MF/SS patients (3 - 8 specimens per patient) representative of patients seen at the Washington University School of Medicine Cutaneous Lymphoma clinic (mean age 56.1 years, 50% female, 60% Caucasian and 40% African American). All were diagnosed with advanced MF and/or SS and half of first specimens were collected within 60 days of diagnosis. Subsequent specimens were collected at progression or lack of response to therapy, on average 20 months between specimens (1.4 - 60, SD = 11.8); patients had received 1-11 different CTCL therapies. For eWGS, specimens were purified by flow cytometry as follows, tumor: CD3+CD4+CD7- and normal: CD4+CD7+ (non-malignant T cells) or CD3-CD14+ (monocytes) or CD3-CD56+ (NK cells). Specimens were subjected to scRNAseq, exome sequencing plus low coverage whole genome sequencing (eWGS), and patient specific TCR clonotype assignment (scRepertoire). Results: Clustering and cell type inference of scRNAseq (UMAP/Seurat/singleR) from 92,496 total cells showed canonical CTCL marker genes and high clonal proportions (1-100%) of patient specific TCR clonotypes. Somatic genome copy number variants (CNV) from eWGS (cnvkit) and scRNAseq (copykat) and deleterious/damaging single nucleotide variants (SNV) (eWGS, GATK/Mutect2; scRNAseq, cb_sniffer) were identified in CTCL versus matched, non-malignant cells. To segregate early genomic events from those that were progression-associated, we developed an integrative analysis pipeline to prioritize somatic CNV and SNV that were detected in samples collected at timepoints with lack of response to therapy and/or progression in ≥30% of patients. This novel approach revealed alterations in T-cell activation pathways as early events that were maintained in subsequent CTCL samples. Loss of some chromatin-modifying enzymes were early events, while gains of others (DNMT3A, EZH2, KMT2C) were acquired with therapy resistance/progression (Fig. 1A). Copy number amplifications of STAT3/STAT5 are frequent and we demonstrate a novel-to-CTCL single nucleotide mutation in STAT3 that has gain-of-function activity. Progression-associated genomic changes were enriched in cell cycle (CDK genes), DNA damage/repair (TP53BP1, RAD51C), RAS and Rho signaling pathways, and transcriptional regulators (FOXO genes). Expression of mutant alleles was detectable in scRNAseq and variant levels fluctuated with progression or lack of therapy response (Fig. 1B). Conclusion: To date, there have been limited studies defining temporal changes in the genomes and transcriptomes of CTCL due in part to low tumor burden in the skin and blood. Using innovative sequencing and informatic approaches, we identified recurrent alterations in CDK11A, DNMT3A, EZH2, FOXO1, RAD51C, STAT3/STAT5, and TP53BP1, among others, with clonal evolution in CTCL. Many of these have therapeutic implications. Taken together, these findings represent new insights into MF/SS progression, reveal new markers for response assessment, and identify new targets for therapeutic development. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase I Trial Assessing the Feasibility of Romidepsin Combined with Brentuximab Vedotin for Patients Requiring Systemic Therapy for Cutaneous T-Cell Lymphoma

Introduction: Although most patients (pts) with cutaneous T-cell lymphoma (CTCL) have an indolent course, outcomes for advanced stages (≥IIB) are suboptimal (Dummer R, et al. Nat Rev Dis Primers, 2021). A more aggressive approach of combination cytotoxic therapies in CTCL in the past has been shown to result in higher response rates, but sequential therapies have similar disease-free and overall survival and less toxicities (Kaye FS et al, NEJM, 1989). With the advent of several biological agents in CTCL with favorable toxicity profiles compared to cytotoxics, including the CD30-directed antibody-drug conjugate brentuximab vedotin (BV), and HDAC inhibitors (HDACi), rational novel combinatorial approaches may be beneficial as response rates for single agents remain modest. Evidence suggests that HDAC inhibition may upregulate CD30 expression (Hasanali ZS et al, Sci Transl Med, 2015), supporting the combination of the HDACi romidepsin (R) with BV in pts with CTCL. Methods: In this multicenter phase I trial of R+BV, pts age ≥18 with stage ≥IB CTCL, good organ function, ECOG PS≤2, <Grade (G) 2 neuropathy, who required systemic treatment were enrolled irrespective of CD30 expression. A traditional "3+3" design with 4 dose levels (DL -2, -1, 0, & 1) was used to define the maximum tolerated dose (MTD). Prior HDACi or BV use was allowed. Enrollment started at DL 0, with R given at 10mg/m2 on days (D) 1, 8 & 15, and BV at 1.2mg/kg (max. 120mg) on D1 & 15 of a 28 day cycle for ≤16 cycles. At DL 1, the R dose was 14mg/m2, with BV 1.2mg/kg, both on D1 & 15. Dosing in the de-escalation cohorts -1 and -2 was as follows: R 10mg/m2 & BV 1.2mg/kg D1 & 15 (DL-1) or R 10mg/m2 D1, 8 & 15 with BV 0.9mg/kg D1 &15 (DL-2). Once the MTD was established, 9 additional pts were enrolled in an expansion cohort. Response was measured using the Global Response Score (GRS; Olsen EA et al. JCO, 2011) using the mSWAT for skin assessment, and flow cytometry and CT imaging every 3 cycles for assessment of extracutaneous sites. There was a "run-in" phase of treatment with R alone given 14 days prior to D1 (D-14) with skin biopsies taken at baseline and prior to C1D1 to assess changes in CD30 expression. The trial was registered in clinicaltrials.gov (NCT02616965). Results: A total of 15 pts were enrolled (DL0: n=3; DL1: n=3; expansion cohort: n=9). No pts were enrolled in the de-escalation cohorts. No pt in the dose finding cohorts experienced a DLT, and DL1 was determined as the MTD. In the expansion cohort at DL1, 9 pts were enrolled, 1 of which experienced a DLT (G3 fatigue >72h) during cycle 1. Median age was 65 years (range 51-79); 83% (n=12) were male; median ECOG PS 1 (0-2); median prior lines of systemic therapy 2 (0-4), including 2 pts with prior HDACi, and 3 pts with prior BV exposure. All pts had Mycosis fungoides (MF) or Sezary syndrome (SS). Stage at enrollment was stage IB in 2 (13%), IIB in 7 (47%), IVA1 and IVB in 1 each (7% each) and IVA2 in 4 (27%). The most common treatment-related adverse events (AE) were nausea (67%), vomiting, constipation, diarrhea, fatigue, leukopenia, peripheral sensory neuropathy (33% each), gastro-esophageal reflux, dizziness, dysgeusia, transaminitis, headaches, and neutropenia (20% each; see Table 1). No pts experienced ≥G4 AE. The only G3 AEs observed were transaminitis, fatigue and fever (n=1 each), all resolved spontaneously. Response assessment at data cut off on 7/1/22 was available for 11 of 15 pts. The overall response rate (ORR) by GRS was 64% (7/11; 95%CI 35-92%; n=1 CR). Both pts with prior HDACi exposure, and 2 of 3 with prior BV exposure responded. The median change in mSWAT was a decrease of 57% from baseline (range -25 to -100%, Fig 1). At data-cut off, 1 pt remained on treatment, while 7 pts (47%) came off treatment due to progression, 2 (13%) each due to non-adherence related to COVID-19 concerns and toxicities (recurrent thrombophlebitis; fatigue), and 1 (7%) each due to patient preference, provider preference and completion of study treatment after 16 cycles. With a median follow up of 8 months (0.2-38), median progression-free survival was 5.5m, and median OS not reached (1y OS 81%). Conclusion: In this phase I study exploring the combination of R+BV, the regimen was well tolerated and efficacious in MF/SS including heavily pretreated pts with advanced disease and prior exposure to HDACi and BV. Correlative studies, including analysis of changes in CD30 expression after 1 dose of R, and association of response with CD30 expression, are pending. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

International Society for Cutaneous Lymphomas Pandemic Section (ICLYPS) analysis of cutaneous T-cell lymphoma outcomes during the COVID-19 pandemic: A retrospective cohort study

To the Editor: Outcomes of patients with cutaneous T-cell lymphoma (CTCL), a diverse group of non-Hodgkin lymphomas, during the COVID-19 pandemic are unknown. Patients with CTCL require active management and rely on various local and systemic therapies administered in-hospital or in-office, representing an increased risk for contracting COVID-19. There are no established maintenance protocols for cutaneous lymphomas. The COVID-19 pandemic served as an “experiment of nature” to understand the effects of reduced regimens and maintenance therapy. The professional societies developed emergency guidelines for the management of patients with cutaneous lymphomas during the pandemic to ensure patient safety.1Zic J.A. Ai W. Akilov O.E. et al.United States Cutaneous Lymphoma Consortium recommendations for treatment of cutaneous lymphomas during the COVID-19 pandemic.J Am Acad Dermatol. 2020; 83: 703-704Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,2Papadavid E. Scarisbrick J. Ortiz Romero P. et al.Management of primary cutaneous lymphoma patients during COVID-19 pandemic: EORTC CLTF guidelines.J Eur Acad Dermatol Venereol. 2020; 34: 1633-1636Crossref PubMed Scopus (11) Google Scholar The International Society for Cutaneous Lymphomas created an International Cutaneous Lymphomas Pandemic Section to collect data to assess the impact of these guidelines. Using these data, we can determine if these measures were effective in preventing COVID-19 infection, what the impact was of maintenance therapy, and how delays in treatment affected disease outcomes in CTCL patients. We performed a retrospective analysis of data from the electronic medical records at 9 international academic medical centers in 7 countries from March to October 2020, including 149 patients, actively managed with an established diagnosis of cutaneous lymphoma. Patient demographics, date of diagnosis, staging details, treatment details, delays or changes to treatment regimens, disease outcomes, and COVID-19 disease history including the source of transmission were recorded (Fig 1). Treatment was delayed for 53.0% of patients for a mean of 3.2 months (range: 10 days-10 months). Adjusting for age, race, biological sex, COVID-19 status, and disease stage, treatment delay was associated with a significant risk of disease relapse or progression across all stages (odds ratio 5.00; 95% confidence interval [2.38, 11.0], P value < .001) and, for each additional month that a patient experienced treatment delay, the odds of disease progression increased by 37.0% (odds ratio 1.37; 95% confidence interval [1.14, 1.70], P value < .001) (Table I). A total of 28 (18.8%) patients with CTCL were diagnosed with COVID-19, none acquired from outpatient office visits. Patients who contracted COVID-19 did not have a statistically significant increase in odds of disease progression compared to COVID-19–negative patients (odds ratio 0.41; 95% confidence interval [0.15, 1.08], P value = .07).Table IDemographic and outcomes by treatment delay statusTreatment delay (n = 79) N (%)No treatment delay (n = 70) N (%)Total (N = 149) N (%)Age Mean6459 Median (IQR)65 (53, 78)62 (48, 72) Range28, 9522, 88Biological sex Male43 (54.4)40 (57.1)83 (55.7) Female36 (45.6)30 (42.9)66 (44.3)Race White60 (75.9)44 (62.9)104 (69.8) Black/African American8 (10.1)19 (27.1)27 (18.1) Other/unknown/declined11 (13.9)7 (10.0)18 (12.1)Stage IA-IIA40 (50.6)37 (52.9)77 (51.6) IIB11 (13.9)12 (17.1)23 (15.4) IIIA-IIIB4 (5.1)2 (2.8)6 (4.0) IVA1 (SS)19 (24.1)16 (22.9)35 (23.5) IVA2-IVB3 (3.8)3 (4.3)6 (4.0) PC CD30+ LPD2 (2.5)0 (0.0)2 (1.3)COVID-19 status Positive18 (22.8)10 (14.3)28 (18.8) Negative61 (77.2)60 (85.7)121 (81.2)Length of treatment delay (mo) Mean3.200.00 Median (IQR)3.00 [1.05, 4.00]0.00 [0.00, 0.00] Range0.30, 10.000.00, 0.00 Unknown20Outcomes Improvement of disease5 (6.3)10 (14.3)15 (10.1) Stable disease15 (19.0)36 (51.4)51 (34.2) Disease progression/relapse52 (65.8)22 (31.4)74 (49.7) Deceased7 (8.9)2 (2.9)9 (6.0) Open table in a new tab Based on the results of this study, we conclude the following:1.Adequate safety measures and protocols can prevent transmission of COVID-19 at physicians' offices as no outpatient office-acquired infections were reported.2.Patients with cutaneous lymphomas who develop COVID-19 do not have worse outcomes than expected according to their risk factors.3.As the pandemic continues, our data reveals the need to re-evaluate the initial recommendations made by the USCLC and EORTC-CLTG, and it provides reassurance that our current COVID-19–conscious management practices are safe and effective.4.Delays in therapy lead to adverse clinical outcomes and should be avoided, as the risk of contracting COVID-19 in the outpatient setting did not outweigh the risk of morbidity and mortality due to disease progression.5.Ensuring continuity of treatment and maintenance therapy appears critical to avoiding disease progression, underscoring the importance of maintenance therapy for CTCL. None disclosed.

DOT1L inhibition does not modify the sensitivity of cutaneous T cell lymphoma to pan-HDAC inhibitors in vitro.

Cutaneous T-cell lymphomas (CTCLs) are a subset of T-cell malignancies presenting in the skin. The treatment options for CTCL, in particular in advanced stages, are limited. One of the emerging therapies for CTCL is treatment with histone deacetylase (HDAC) inhibitors. We recently discovered an evolutionarily conserved crosstalk between HDAC1, one of the targets of HDAC inhibitors, and the histone methyltransferase DOT1L. HDAC1 negatively regulates DOT1L activity in yeast, mouse thymocytes, and mouse thymic lymphoma. Here we studied the functional relationship between HDAC inhibitors and DOT1L in two human CTCL cell lines, specifically addressing the question whether the crosstalk between DOT1L and HDAC1 observed in mouse T cells plays a role in the therapeutic effect of clinically relevant broad-acting HDAC inhibitors in the treatment of human CTCL. We confirmed that human CTCL cell lines were sensitive to treatment with pan-HDAC inhibitors. In contrast, the cell lines were not sensitive to DOT1L inhibitors. Combining both types of inhibitors did neither enhance nor suppress the inhibitory effect of HDAC inhibitors on CTCL cells. Thus our in vitro studies suggest that the effect of commonly used pan-HDAC inhibitors in CTCL cells relies on downstream effects other than DOT1L misregulation.

Synthetic Hypericin Photodynamic Therapy for Cutaneous T-Cell Lymphoma

Synthetic Hypericin Photodynamic Therapy for Cutaneous T-Cell Lymphoma

Concomitant Inhibition of FASN and SREBP Provides a Promising Therapy for CTCL.

Simple SummaryThe biosynthesis of fatty acids catalysed by FASN plays an important oncogenic role in various malignancies but has not been reported in CTCL yet. Here, we show that FASN is highly expressed in both cell lines and primary cells from CTCL patients. The inhibition of FASN impairs cell viability, survival, and proliferation. FASN expression is partly controlled by SREBP, and dual inhibition of FASN and SREBP enhances the impairment of cell proliferation. Overall, our data suggest that the combination of FASN and SREBP inhibitors could be a promising novel strategy in CTCL therapy.Cutaneous T cell lymphoma (CTCL) is a group of non-Hodgkin’s primary cutaneous T cell lymphomas, with Mycosis Fungoides and Sézary syndrome (SS) being the two most common subtypes. Fatty acid synthase (FASN) is a crucial enzyme that catalyses the biosynthesis of fatty acids, which has been reported to play an oncogenic role in various malignancies but not in CTCL so far. Herein, we show that FASN is highly expressed in CTCL cell lines and in peripheral blood mononuclear cells (PBMCs) from CTCL patients, while it is not in PBMCs from healthy individuals. The inhibition of FASN in CTCL cell lines impairs cell viability, survival, and proliferation, but, interestingly, it also increases FASN expression. However, inhibiting sterol regulatory element binding protein (SREBP), a transcription factor that promotes the expression of FASN, partially reversed the upregulation of FASN induced by FASN inhibitors. Thus, the combination of FASN and SREBP inhibitors enhanced the effects on both CTCL cell lines and PBMCs from SS patients, where a valid inhibition on cell proliferation could be verified. Importantly, compared to non-malignant cells, primary malignant cells are more sensitive to the inhibition of FASN and SREBP, making the combination of FASN and SREBP inhibitors a promising novel therapeutic strategy in CTCL.