Advanced Cutaneous T-cell Lymphoma Research Articles

Adrenal Insufficiency after Long-term use of Topical Glucocorticoids in Patients with Advanced Cutaneous T-cell Lymphomas: A Case Series.

Abstract is missing (Short communication)

[Artículo traducido] Experiencia con bexaroteno en linfoma cutáneo de células T: un estudio del Grupo Español de Linfomas Cutáneos (GELC)

Background and objectivesBexarotene has been approved to treat advanced stage cutaneous T-cell lymphomas (CTCL) since 1999. However, very few data have been published on its long-term safety and efficacy profile. The aim of this study is to determine the tolerability to bexarotene and outcomes by collecting the 2nd largest case series to date on its long-term use vs CTCL. Material and methodThis was a multicenter retrospective review of 216 patients with mycosis fungoides (174), or Sézary syndrome (42) on a 10-year course of bexarotene alone or in combination with other therapies at 19 tertiary referral teaching hospitals. ResultsA total of 133 men (62%) and 83 women (38%) were included, with a mean age of 63.5 year (27–95). A total of 45% were on bexarotene monotherapy for the entire study period, 22% started on bexarotene but eventually received an additional therapy, 13% were on another treatment but eventually received bexarotene while the remaining 20% received a combination therapy since the beginning. The median course of treatment was 20.78 months (1–114); and the overall response rate, 70.3%. Complete and partial response rates were achieved in 26% and 45% of the patients, respectively. Treatment was well tolerated, being the most common toxicities hypertriglyceridemia (79%), hypercholesterolemia (71%), and hypothyroidism (52%). No treatment-related grade 5 adverse events were reported. ConclusionsOur study confirms bexarotene is a safe and effective therapy for the long-term treatment of CTCL.

Clinical and Real-World Effectiveness of Mogamulizumab: A Narrative Review.

Mogamulizumab (MOG) is an antibody targeting the CCR4 receptor, authorized for relapsed or refractory peripheral T-cell (PTCL) and cutaneous T-cell lymphomas (CTCL). Its adoption in guidelines and endorsement by FDA and EMA established it as a systemic treatment, especially for advanced disease stages due to its comparatively lower toxicity. Clinical trials and real-world evidence have underscored its efficacy in advanced CTCLs, including mycosis fungoides and Sézary syndrome; PTCLs; and adult T-cell leukemia/lymphoma (ATLL), showcasing positive outcomes. Notably, the drug has demonstrated significant response rates, disease stability, and extended periods of progression-free survival, suggesting its applicability in cases with multiple treatment lines. Its safety profile is generally manageable, with adverse events (AEs) primarily related to the skin, infusion-related reactions, drug eruptions, autoimmune diseases, and skin disorders. The latter seem to appear as CCR4 can promote the skin-specific homing of lymphocytes, and MOG is directed against this receptor. While combination with immunostimulatory agents like interferon alpha and interleukin 12 has shown promising results, caution is urged when combining with PD1 inhibitors due to the heightened risk of immune-mediated AEs. The introduction of MOG as a systemic treatment implies a significant advancement in managing these diseases, supported by its favorable safety profile and complementary mechanisms.

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.

Experience With Bexarotene to Treat Cutaneous T-Cell Lymphomas: A Study of the Spanish Working Group of Cutaneous Lymphomas

Background and objectivesBexarotene has been approved to treat advanced stage cutaneous T-cell lymphomas (CTCL) since 1999. However, very few data have been published on its long-term safety and efficacy profile. The aim of this study is to determine the tolerability to bexarotene and outcomes by collecting the 2nd largest case series to date on its long-term use vs CTCL. Material and methodThis was a multicenter retrospective review of 216 patients with mycosis fungoides (174), or Sézary syndrome (42) on a 10-year course of bexarotene alone or in combination with other therapies at 19 tertiary referral teaching hospitals. ResultsA total of 133 men (62%) and 83 women (38%) were included, with a mean age of 63.5 year (27–95). A total of 45% were on bexarotene monotherapy for the entire study period, 22% started on bexarotene but eventually received an additional therapy, 13% were on another treatment but eventually received bexarotene while the remaining 20% received a combination therapy since the beginning. The median course of treatment was 20.78 months (1–114); and the overall response rate, 70.3%. Complete and partial response rates were achieved in 26% and 45% of the patients, respectively. Treatment was well tolerated, being the most common toxicities hypertriglyceridemia (79%), hypercholesterolemia (71%), and hypothyroidism (52%). No treatment-related grade 5 adverse events were reported. ConclusionsOur study confirms bexarotene is a safe and effective therapy for the long-term treatment of 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.

Results from the Cohort Expansion Stage of a Phase I Trial of Tinostamustine Monotherapy in Advanced Haematological Malignancies (NCT02576496): Findings from a Subset of Patients with Cutaneous T-Cell Lymphoma (CTCL)

Background Tinostamustine, a novel alkylating deacetylase inhibitor, improves drug access to cancer cell DNA strands, breaks them and counteracts damage repair. Tinostamustine was well tolerated, with signals of efficacy, during the dose-escalation stage of a Phase I study in patients with relapsed/refractory (R/R) haematological malignancies for whom no standard treatment with proven clinical benefit was available or recommended. Aims Here we report safety and efficacy findings for tinostamustine in an expansion cohort of patients with CTCL from the Phase I study in patients with advanced haematological malignancies. Methods Patients with advanced CTCL (either mycosis fungoides [MF] or Sezary syndrome [SS]), for whom no standard treatment with proven clinical benefit was available or recommended, received the recommended Phase II dose (RP2D) of tinostamustine 80 mg/m 2 (2 patients) and 100 mg/m 2 (11 patients) over 60 minutes on Day 1 of a 21-day cycle. Patients with CTCL who had received ≥1-4 prior standard systemic therapies were eligible to be enrolled into the cohort. Primary objectives included evaluation of overall response and the safety of tinostamustine. Adverse events (AEs) were assessed for severity using US National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE; version 4.03, June 2010) with the exception that assessment of QTc prolongations was based on CTCAE version 5.0. Treatment-related AEs, AEs leading to death, serious adverse events (SAEs), and AEs resulting in trial discontinuation were recorded. Efficacy objectives estimated the overall response rate (ORR; complete response [CR] + partial response [PR]) and clinical benefit rate (CBR; CR + PR + stable disease ≥4 cycles [SD]) of tinostamustine in patients with CTCL. Secondary efficacy variables included progression-free survival (PFS) and overall survival (OS); all outcomes were evaluated from Cycle 3 until progression or toxicity. Results Out of 48 patients with advanced haematological malignancies treated in the expansion-cohort stage of this Phase I study, 13 had CTCL (MF, n=9; SS, n=4; Table). Mean ± standard deviation age was 63.7 ± 12.9 years, 7/13 (53.8%) patients were female and over half of patients had an Eastern Cooperative Oncology Group performance status score of 0. At the end of the study, patients with CTCL had received a median of 5.0 (range 1-8) cycles of tinostamustine. No unexpected AEs were observed following tinostamustine treatment. Treatment-emergent adverse events (TEAEs) occurred in 12/13 (92.3%) patients. Gastrointestinal AEs were observed in 9/13 patients, the majority of which were nausea or vomiting. Haematological AEs, including thrombocytopenia and anaemia, occurred in 8/13 patients. Eleven serious TEAE events that were considered related to tinostamustine occurred in three patients ( Table) and included two events each of thrombocytopenia, neutropenia and leukopenia, and one event each of anaemia, lymphopenia, lichenoid keratosis, acute coronary syndrome, and interstitial lung disease. There were no incidences of QTcF >500 ms or increased >60 ms from baseline. Overall, 3/13 patients (23.1%) discontinued due to progressive disease and 5/13 (38.5%) due to AEs. One patient with MF experienced a fatal TEAE of decreased appetite. 12/13 patients in the safety analysis were evaluated for disease response. 2/12 patients achieved a CR (1 patient with MF, 1 with SS), 4/12 a PR (3 patients with MF, 1 with SS) and 4/12 experienced SD (2 patients with MF, 2 with SS). ORR was 50% (6/12 patients; 95% confidence interval [CI]: 21.1%, 78.9%) and CBR 83.3% (10/12 patients; 95% CI: 51.6%, 97.9%). Median PFS was 7.3 months (95% CI: 3.2, NE months; 6/12 patients progressed) and median OS was not estimable (4/12 patients died). Conclusions Initial results from this expansion cohort of patients with CTCL further demonstrate signals of efficacy in this heavily pre-treated patient population for whom no other standard therapy with proven clinical benefit was available or recommended; an ORR of 50%, with 6/12 patients achieving a CR or PR, and a median progression-free survival of 7.3 months were observed. Tinostamustine was well tolerated, with no unexpected AEs. The principal TEAEs were haematological and gastrointestinal. Funding: Mundipharma Research Limited and Purdue Pharma, LP

Unveiling the hidden struggles: Exploring the profound impact of advanced stage cutaneous T-cell lymphoma on quality of life.

Erythrodermic mycosis fungoides and Sézary syndrome are chronic, relapsing-remitting diseases that greatly impacts patients' quality of life (QoL). Mogamulizumab-kpkc (Mogamulizumab) is a novel therapeutic agent for cutaneous T-cell lymphomas with a notable impact on progression-free survival. Qualitative assessment methods allow a broader exploration and greater insight in individual patient experience than quantitative studies. However, there is limited data on the impact of mogamulizumab on health-related QoL. To investigate the impact of erythrodermic cutaneous T-cell lymphoma (E-CTCL) on QoL and the effect of mogamulizumab on the QoL. Semi-structured interview were conducted with seven patients with E-CTCL that were receiving mogamulizumab treatment. Five major themes arose: Diagnosis and the diagnostic delay and uncertainty experienced by participants; Physical functioning due to the high symptom burden; Psychological and social functioning considering the significant impact on daily life; Treatment and the effect of mogamulizumab; and Support by family, friends and health professionals. Mogamulizumab therapy resulted in a significant decrease of symptoms. The small sample size should also be taken into account although data saturation was reached. This study gives a broad insight into the large impact of E-CTCL and the major consequences on the physical functioning as well as on the emotional/psychological and social well-being. Mogamulizumab appears to have a positive effect on symptoms.

O-131 - Genomic abnormalities involving class I HLA are common in advanced cutaneous T-cell lymphoma

O-131 - Genomic abnormalities involving class I HLA are common in advanced cutaneous T-cell lymphoma

O-150 - Allogeneic transplantation in advanced cutaneous T-cell lymphomas (CUTALLO): a propensity score matched controlled prospective study

O-150 - Allogeneic transplantation in advanced cutaneous T-cell lymphomas (CUTALLO): a propensity score matched controlled prospective study

SOHO State-of-the-Art Updates and Next Questions: A Modern Approach to the Systemic Treatment of Advanced CTCL.

The term cutaneous T-cell lymphoma (CTCL) is a general term for T-cell lymphomas that are found primarily in skin. The most common CTCL entities, mycosis fungoides and Sezary syndrome are incurable diseases with a plethora of conventional treatment options. In the past treatment options have been selected primarily according to stage. Given newer targeted therapies with varied response in different body compartments, we suggest a compartment-guided algorithm that may enhance response rates directing the selection of the most efficacious treatment options.

Allogeneic transplantation in advanced cutaneous T-cell lymphomas (CUTALLO): a propensity score matched controlled prospective study

Advanced-stage cutaneous T-cell lymphomas (CTCLs) are rare, usually refractory, and fatal diseases. Case series have suggested that allogeneic haematopoietic stem cell transplantation (HSCT) might improve the prognosis of advanced-stage CTCLs. The objective of this study was to investigate the effect of allogeneic HSCT compared with non-HSCT therapy on the outcome of individuals with advanced-stage CTCLs. In this prospective, multicentre, matched controlled trial, conducted at 30 hospitals, participants with advanced CTCLs were allocated treatment: if they had an available compatible related donor they were assigned to allogeneic HSCT, or if not they were allocated to non-allogeneic HSCT therapy. Key inclusion criteria were participants aged 18-70 years, with advanced stage mycosis fungoides or Sézary syndrome, and at least one poor prognostic criteria. Participants were excluded if they were not in complete or partial remission of the disease. Propensity score 1:1 matching with replacement (ie, that each participant treated with HSCT was matched to the participant with the closest propensity score treated with non-HSCT therapy, even if they had already been matched) was used to handle confounding factors, with the balance of covariate distribution between HSCT and non-HSCT groups assessed using standardised mean differences. The primary endpoint was progression-free survival in the matched intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02520908), and is currently active but not recruiting. From June 1, 2016, to March 3, 2022, total of 99 participants were enrolled at 17 centres in France. Participants with a sibling or matched unrelated donor were assigned to allogeneic HSCT (HSCT group, n=55 [56%]) and participants without a donor were assigned to non-allogeneic HSCT treatment (non-HSCT group, n=44 [44%]). The median follow-up among survivors was 12·6 months (IQR 11·0-35·2). In the HSCT group, 51 participants (93%) were 1:1 matched to participants from the non-HSCT group. In the intention-to-treat analysis, median progression-free survival was significantly longer in the HSCT group (9·0 months [95% CI 6·6-30·5]) than in the non-HSCT group (3·0 months [2·0-6·3]), with a hazard ratio of 0·38 (95% CI 0·21-0·69; p<0·0001). In the per-protocol population, 40 participants (78%) in the HSCT group had 101 serious events and 29 participants (67%) in the non-HSCT group had 70 serious adverse events. The most common serious adverse event other than graft-versus-host disease in both groups was infections, occurring in 30 participants (59%) in the HSCT group and in 19 participants (44%) in the non-HSCT group. Allogeneic HSCT was associated with significantly longer progression-free survival in participants with advanced-stage CTCLs. These results indicate that allogeneic HSCT treatment should be made available to individuals with high-risk, advanced-stage mycosis fungoides or Sézary syndrome who achieve pre-transplant disease remission. French Ministry of Health, National Cancer Institute, Programme Hospitalier de Recherche Clinique en Cancérologie.

Exploring the Nonlymphocytic Cutaneous Microenvironment in Advanced Cutaneous T-Cell Lymphomas using Single-Cell RNA Sequencing

Exploring the Nonlymphocytic Cutaneous Microenvironment in Advanced Cutaneous T-Cell Lymphomas using Single-Cell RNA Sequencing

Cogent data on allogeneic haematopoietic stem-cell transplantation efficacy in advanced cutaneous T-cell lymphoma

Cogent data on allogeneic haematopoietic stem-cell transplantation efficacy in advanced cutaneous T-cell lymphoma

Evaluating Photopheresis Regimens for Advanced CTCL: The Role of the SARS-CoV-2 Pandemic—A Single-Center Retrospective Study

Extracorporeal photopheresis (ECP) is an established, safe, and effective treatment for cutaneous T-cell lymphoma (CTCL). There is no published literature reviewing the clinical efficacy of ECP at varying frequencies or the ideal duration of therapy. The SARS-CoV-2 pandemic necessitated a reduced frequency of ECP for patients with CTCL at our center. We performed a retrospective chart review of patients with CTCL receiving ECP at the Penn Dermatology Photopheresis Service (PDPS) on March 1, 2020, and followed up their course until January 31, 2021. Our retrospective cohort study suggests that one day of ECP with extending duration between treatments can be considered an alternative maintenance regimen in appropriate patients with stable disease on concomitant multimodality immunomodulatory therapy.

Proteasome Inhibitors Interact Synergistically with BCL2, Histone Deacetylase, BET, and Jak Inhibitors against Cutaneous T-Cell Lymphoma Cells

Cutaneous T-cell lymphoma (CTCL) is often refractory to treatment at advanced stages with blood involvement ( Dummer et al., 2021 Dummer R. Vermeer M.H. Scarisbrick J.J. Kim Y.H. Stonesifer C. Tensen C.P. et al. Cutaneous T cell lymphoma. Nature Reviews Disease Primers. 2021; 7: 61 Crossref PubMed Scopus (22) Google Scholar ). We have previously revealed the synergistic cytotoxic effects of inhibiting BCL2, HDAC, BET, and/or JAK in patient-derived CTCL cells and CTCL cell lines, suggesting potential advantages of a spectrum of combination treatment strategies for this disease ( Cyrenne et al., 2017 Cyrenne B.M. Lewis J.M. Weed J.G. Carlson K.R. Mirza F.N. Foss F.M. et al. Synergy of BCL2 and histone deacetylase inhibition against leukemic cells from cutaneous T-cell lymphoma patients. Blood. 2017; 130: 2073-2083 Crossref PubMed Scopus (36) Google Scholar , Kim et al., 2018 Kim S.R. Lewis J.M. Cyrenne B.M. Monico P.F. Mirza F.N. Carlson K.R. et al. BET inhibition in advanced cutaneous T cell lymphoma is synergistically potentiated by BCL2 inhibition or HDAC inhibition. Oncotarget. 2018; 9: 29193-29207 Crossref PubMed Scopus (35) Google Scholar , Yumeen et al., 2020 Yumeen S. Mirza F.N. Lewis J.M. King A.L.O. Kim S.R. Carlson K.R. et al. JAK inhibition synergistically potentiates BCL2, BET, HDAC, and proteasome inhibition in advanced CTCL. Blood Adv. 2020; 4: 2213-2226 Crossref PubMed Scopus (19) Google Scholar ). Proteasome inhibitors target multiple pathways including protein degradation to cause cytotoxicity and have been utilized in other hematologic malignancies. They have demonstrated efficacy as a single agent in a small phase II trial of patients with relapsed or refractory CTCL ( Zinzani et al., 2007 Zinzani P.L. Musuraca G. Tani M. Stefoni V. Marchi E. Fina M. et al. Phase II Trial of Proteasome Inhibitor Bortezomib in Patients With Relapsed or Refractory Cutaneous T-Cell Lymphoma. Journal of Clinical Oncology. 2007; 25: 4293-4297 Crossref PubMed Scopus (236) Google Scholar ), as well as in limited combinations during preclinical studies ( Yumeen et al., 2020 Yumeen S. Mirza F.N. Lewis J.M. King A.L.O. Kim S.R. Carlson K.R. et al. JAK inhibition synergistically potentiates BCL2, BET, HDAC, and proteasome inhibition in advanced CTCL. Blood Adv. 2020; 4: 2213-2226 Crossref PubMed Scopus (19) Google Scholar ) and early clinical trials ( Holkova et al., 2017 Holkova B. Yazbeck V. Kmieciak M. Bose P. Ma S. Kimball A. et al. A phase 1 study of bortezomib and romidepsin in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, indolent B-cell lymphoma, peripheral T-cell lymphoma, or cutaneous T-cell lymphoma. Leuk Lymphoma. 2017; 58: 1349-1357 Crossref PubMed Scopus (15) Google Scholar ). Herein, we share our expanded preclinical assessment of the synergistic activity of proteasome inhibitors when used with the BCL2 inhibitor venetoclax, HDAC inhibitor vorinostat, BET inhibitor mivebresib, or JAK inhibitor fedratinib. We reveal that the cytotoxic effects from combination treatment were greater than additive when assessed in patient-derived CTCL cells. Furthermore, we demonstrate an increase in apoptosis pathway activation with combination treatment and explore the gene expression changes underlying these synergistic effects.

Allogeneic Hematopoietic Cell Transplantation in Advanced Phase Mycosis Fungoides and Sézary Syndrome: A Retrospective Analysis of 57 Consecutive Patients

Background: Advanced stage Mycosis Fungoides (MF) and Sézary Syndrome (SS) are cutaneous T-cell lymphomas (CTCL) associated to dismal prognosis, with 5-year survival rates ranging from 47% for stage IIB to 18% for stage IVA2-IVB and with a high tendency to relapse. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is considered the only curative treatment option. Recently, allo-HCT from haploidentical donor (Haplo-HCT) has been increasingly used also in MF/SS patients. We hereby report an update on long-term outcome of MF/SS patients who underwent allo-HCT at our Center from 2001 to 2022, currently including a larger population with an increased proportion of Haplo-HCT. Methods: We retrospectively collected clinical data of all consecutive patients with MF/SS transplanted at our Center between September 2001 and May 2022. Conditioning was based on reduced intensity (RIC) regimens, including flaudarabine/cyclophosphamide/TBI200, pentostatin/TBI200, and fludarabine/melphalan in transplants from HLA-identical sibling and unrelated donor (UD), and the thiotepa/fludarabine/cyclophosphamide/TBI200 regimen in Haplo setting. GvHD prophylaxis consisted of CsA, MMF and ATG. Post-transplant cyclophosphamide was added in Haplo-HCT. Results: As of August 2022, 57 CTCL patients underwent allo-HCT at our Institution: 22 (38.5%) from a HLA-identical sibling, 13 (23%) from a 10/10 matched UD, 12 (21%) from a 9/10 or 8/10 matched UD, 1 (1.8%) from cord blood, and 9 (15.7%) from a Haplo donor. Median age at transplant was 55 years (range 20-67). Indication for allo-HCT was MF in 36 patients (63%) and SS in 21 patients (37%). Median number of previous treatment lines was 6 (range 2-11) with a median time from diagnosis to transplantation of 46 months (10-274). Disease status at transplant was complete remission (CR) in 14 cases (24.5%), partial remission (PR) in 35 (61.5%) and progressive disease (PD) in 8 (14%). Stem cell source was peripheral blood in 53 patients (92.9%), bone marrow in 3 (5.2%) and cord blood in 1 (1.8%). After a median follow up of 81 months, 30 patients (52%) were alive, of whom 23 (76%) in CR. Acute GvHD occurred in 29 patients (51%; grade III-IV in 13, 23%), while chronic GvHD in 19 (33%; moderate/severe in 10 patients, 17%). Cause of death was disease progression in 17 patients (62.5%), acute GvHD in 4 (15%), infection in 2 (7.5%) and other in 4 (15%). In the whole cohort, 5-yr overall survival (OS) and disease-free survival (DFS) were respectively 57.6% (95% CI 44-71) and 37.9% (95% CI 25-51). According to donor type, 5-yr OS was 69%, 39% and 89% and DFS 57%, 19% and 57% for HLA-identical sibling, UD and Haplo, respectively (Figure 1). 5-yr OS was significantly higher in SS versus MF patients (78% vs 47%, p=0.03) and in patients who were in CR at the time of transplant (100% vs 43.5%, p<0.001). In the Haplo setting,.disease status at transplant was CR in 1 pt and PR in 8. After a median follow-up of 26 months, 7 out of 9 patients (78%) were still alive and in CR. Acute GvHD occurred in 6 patients (66%), grade III-IV in 2 (22%), while chronic GvHD occurred in 3 patients (33%), moderate/severe in 1 (11%). Two patients relapsed at +5 and +2 months, of whom the latter died 157 days after HCT. Conclusions: After a median follow up of more than 9 years for alive patients, we confirm that RIC allo-HSCT is a powerful therapeutic strategy in selected patients with advanced CTCL, and particularly in SS. With the limitation of a shorter follow-up, transplant outcomes following allo-HCT from haploidentical donor appear to be associated with very low toxicity, excellent OS and DFS comparable to HLA-identical sibling transplants. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Near complete responses to concurrent brentuximab vedotin and ultra-hypofractionated low-dose total skin electron beam radiation in advanced cutaneous T-cell lymphoma.

Patients with advanced stage mycosis fungoides (MF) or Sézary syndrome (SS) have a poor prognosis. Despite many available active single agents for CTCL treatment, high remission rates and long-lasting responses are rarely achieved in advanced CTCL [1]. Therefore, it is important to find more effective strategies, e.g. combination therapy, which could enhance efficacy by targeting key pathways in a synergistic or additive manner. We report on three patients with tumor stage MF (IIB) with fast response and very good partial remission due to induction with BV with 1.8 mg/kg dose concurrently in combination with ultra-hypofractionated low dose TSEBT.

Single-cell RNA sequencing unveils the communications between malignant T and myeloid cells contributing to tumor growth and immunosuppression in cutaneous T-cell lymphoma

Cutaneous T cell lymphoma (CTCL) is characterized by the accumulation of malignant T cells in the skin. However, advanced CTCL pathophysiology remains elusive and therapeutic options are limited due to the high intratumoral heterogeneity and complicated tumor microenvironment (TME). By comparing the single-cell RNA-seq (scRNA-seq) data from advanced CTCL patients and healthy controls (HCs), we showed that CTCL had a higher enrichment of T/NK and myeloid cells. Subpopulations of T cells (CXCR3+, GNLY+, CREM+, and MKI67+ T cells), with high proliferation, stemness, and copy number variation (CNV) levels, contribute to the malignancy of CTCL. Besides, CCL13+ monocytes/macrophages and LAMP3+ cDC cells were enriched and mediated the immunosuppression via inhibitory interactions with malignant T cells, such as CD47-SIRPA, MIF-CD74, and CCR1-CCL18. Notably, elevated expressions of S100A9 and its receptor TLR4, as well as the activation of downstream toll-like receptor and NF-κB pathway were observed in both malignant cells and myeloid cells in CTCL. Cell co-culture experiments further confirmed that the interaction between malignant CTCL cells and macrophages contributed to tumor growth via S100A9 upregulation and NF-kb activation. Our results showed that blocking the S100A9-TLR4 interaction using tasquinimod could inactivate the NF-κB pathway and inhibit the growth of CTCL tumor cells, and trigger cell apoptosis. Collectively, our study revealed a landscape of immunosuppressive TME mediated by interactions between malignant T cells and myeloid cells, and provided novel targets and potential treatment strategies for advanced CTCL patients.

Drug library screening identifies histone deacetylase inhibition as a novel therapeutic strategy for choriocarcinoma.

Choriocarcinoma is a rare and aggressive gynecological malignancy. The standard treatment is systemic chemotherapy as choriocarcinoma exhibits high chemosensitivity. However, refractory choriocarcinoma exhibits chemoresistance; thus, the prognosis remains very poor. This study aimed to identify novel therapeutic agents for choriocarcinoma by utilizing a drug repositioning strategy. Three choriocarcinoma cell lines (JAR, JEG-3, and BeWo) and a human extravillous trophoblast cell line (HTR-8/SVneo) were used for the analyses. The growth inhibitory effects of 1,271 FDA-approved compounds were evaluated in vitro screening assays and selected drugs were tested in tumor-bearing mice. Functional analyses of drug effects were performed based on RNA sequencing. Muti-step screening identified vorinostat, camptothecin (S, +), topotecan, proscillaridin A, and digoxin as exhibiting an anti-cancer effect in choriocarcinoma cells. Vorinostat, a histone deacetylase inhibitor, was selected as a promising candidate for validation and the IC50 values for choriocarcinoma cells were approximately 1 μM. RNA sequencing and subsequent pathway analysis revealed that the ferroptosis pathway was likely implicated, and key ferroptosis-related genes (i.e., GPX4, NRF2, and SLC3A2) were downregulated following vorinostat treatment. Furthermore, vorinostat repressed tumor growth and downregulated the expression of GPX4 and NRF2 in JAR cell-bearing mice model. Vorinostat, a clinically approved drug for the treatment of advanced primary cutaneous T-cell lymphoma, showed a remarkable anticancer effect both in vitro and in vivo by regulating the expression of ferroptosis-related genes. Therefore, vorinostat may be an effective therapeutic candidate for patients with choriocarcinoma.