Advanced-stage Cutaneous T-cell Lymphoma Research Articles

56 (PB044): Systemic Targeted Therapies in Patients with Relapsed/Refractory Advanced Stage Cutaneous T-cell Lymphoma: A Real-World Single- Centre Case Series

56 (PB044): Systemic Targeted Therapies in Patients with Relapsed/Refractory Advanced Stage Cutaneous T-cell Lymphoma: A Real-World Single- Centre Case Series

Preliminary validation of a novel patient-reported outcomes (PRO) questionnaire for patients with cutaneous T-cell lymphoma: The CTCL-PRO-18.

e23161 Background: Improving quality of life (QoL) is key to clinical decision-making for patients with cutaneous T-cell lymphoma (CTCL). Currently there is no measure of QoL that captures concerns of patients with advanced-stage CTCL. A thematic analysis of interviews with early- and late-stage patients with CTCL identified novel QoL domains. Using these data, we developed questionnaire items for a new QoL measure (CTCL-PRO-18). Methods: Consented patients completed our new survey and previously validated metrics: SF-36, MF/SS-CTCL QoL, VAS-Itch (past 24 hours), Skindex-29, CES-D, and PROMIS™ Sleep Disturbance. Principal component analysis (PCA) with varimax rotation reduced the number of items on our measure; Cronbach’s alpha evaluated the internal-consistency reliability of items that loaded on each component and the overall measure. We examined the construct and convergent validity of the CTCL-PRO-18 using Pearson correlations, and differences in QoL outcomes by patient demographics and disease status using analyses of variance (ANOVA). Results: 82 patients (47 male; 69 white, 11 Black, 2 Hispanic) completed the surveys. The PCA yielded an 18-item, 5-component solution: 6-item self-consciousness; 3-item burden of treatment; 3-item concern about sores; 3-item sleep/fatigue; and 3-item lack of available CTCL resources. The 5 subscales and overall CTCL-PRO-18 measure had acceptably high reliabilities; Cronbach’s alphas ranged from .74 to .93. Correlations between the CTCL-PRO-18 and each of the previously validated measures were statistically significant (P < .005). Correlations between CTCL-PRO-18 and SF-36 (subscales ranged r =-.320 to -.624), CESD ( r= .645), PROMIS™ Sleep Disturbance ( r= .4780), and VAS-Itch ( r= .665) were moderate. Correlations between CTCL-PRO-18 and MF/SS-CTCL QoL ( r= .720) and Skindex-29 ( r= .814) were high. Correlations between the overall CTCL-PRO-18 and each of its subscales were significant (P < .001) and ranged from .571 (Burden of Treatment) to .882 (Self-consciousness). ANOVAs showed no statistically significant gender or racial/ethnic (white vs. Black/Hispanic race/ethnicity) differences in the CTCL-PRO-18 or the 5 component scores. Burden of Treatment scores were significantly lower for patients with no active disease compared with patients with reduced symptoms and active disease (4.9 [SD 3.9], 6.4 [3.2], and 8.2 [3.8], respectively; P = .018). Conclusions: The CTCL-PRO-18 and its 5 subscales had high internal-consistency reliability. Correlations were higher between the CTCL-PRO-18 and other CTCL-relevant measures (Skindex-29, MF/SS-CTCL QoL) than they were between the CTCL-PRO-18 and less CTCL-specific measures, providing preliminary evidence of the construct and convergent validity of the CTCL-PRO-18. Examination of the discriminant validity of this metric is warranted.

Multi-omic studies in Cutaneous T Cell Lymphoma (CTCL) reveal progression-associated alterations in epigenetic and lymphocyte signaling pathways

Abstract Patients with advanced stage CTCL have a 20% 5-year survival rate and molecular factors that drive disease progression are undefined. To address this, we collected 52 longitudinal tumor and normal samples from 10 CTCL patients and subjected them to exome + whole genome (eWGS), single-cell (sc)RNA and TCR sequencing. Clustering and cell-type inference of scRNAseq (UMAP/Seurat/singleR) from 92496 total cells showed canonical CTCL marker genes and high proportions of patient-specific TCR clonotypes. Somatic genome copy number alterations (CNA) and deleterious/damaging single nucleotide variants (SNV) (cnvkit, GATK/Mutect2, copykat, cb_sniffer) were identified. We defined molecular changes associated with progression and/or resistance to therapy (APR) as CNA and SNV detected in samples collected at later timepoints with progression and/or lack of therapy response in >30% of patients. This novel approach identified pathways in chromatin modification, particularly DNA and histone methylation, lymphocyte signaling and transcriptional regulation. A novel-to-CTCL SNV in STAT3 had gain-of-function activity and aberrant genomic binding (CUT&RUNseq). CNA and mutant allele levels correlate with disease progression and therapy response in scRNAseq. Our findings represent new insights into CTCL progression, reveal new markers for response assessment, and identify new targets for therapeutic development. Based on these results, we have initiated two clinical trials at WUSM.

[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.

Abrogation of USP9X Is a Potential Strategy to Decrease PEG10 Levels and Impede Tumor Progression in Cutaneous T-Cell Lymphoma

Advanced-stage cutaneous T-cell lymphomas (CTCL) are notorious for its highly aggressive behavior, resistance to conventional treatments and poor prognosis, particularly when large-cell transformation (LCT) occurs. Paternally expressed gene 10 (PEG10) has been recently proposed as a potent driver for LCT in CTCL. However, the targeting of PEG10 continues to present a formidable clinical challenge that has yet to be addressed. Here we report an important post-translational regulatory mechanism of PEG10 in CTCL. Ubiquitin-specific protease 9X (USP9X), a deubiquitinase, interacted with and deubiquitinated PEG10, thereby stabilizing PEG10. Knockdown of USP9X or pharmacological targeting of USP9X resulted in a prominent downregulation of PEG10 and its downstream pathway in CTCL. Moreover, USP9X inhibition conferred tumor cell growth disadvantage and enhanced apoptosis in vitro, an effect that occurred in part through its regulation on PEG10. Furthermore, we demonstrated that inhibition of USP9X obviously restrained CTCL tumor growth in vivo, and that high expression of USP9X is associated with poor survival in CTCL patients. Collectively, our findings uncover USP9X as a key post-translational regulator in the stabilization of PEG10 and suggest that targeting PEG10 stabilization through USP9X inhibition may represent a promising therapeutic strategy for advanced-stage 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.

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.

P-189 - The impact of advanced-stage cutaneous T-cell lymphoma on quality of life: a qualitative study

P-189 - The impact of advanced-stage cutaneous T-cell lymphoma on quality of life: a qualitative study

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.

Spatially Guided and Single Cell Tools to Map the Microenvironment in Cutaneous T-Cell Lymphoma

Mycosis fungoides (MF) and Sézary syndrome (SS) are two closely related clinical variants of cutaneous T-cell lymphomas (CTCL). Previously demonstrated large patient-to-patient and intra-patient disease heterogeneity underpins the importance of personalized medicine in CTCL. Advanced stages of CTCL are characterized by dismal prognosis, and the early identification of patients who will progress remains a clinical unmet need. While the exact molecular events underlying disease progression are poorly resolved, the tumor microenvironment (TME) has emerged as an important driver. In particular, the Th1-to-Th2 shift in the immune response is now commonly identified across advanced-stage CTCL patients. Herein, we summarize the role of the TME in CTCL evolution and the latest studies in deciphering inter- and intra-patient heterogeneity. We introduce spatially resolved omics as a promising technology to advance immune-oncology efforts in CTCL. We propose the combined implementation of spatially guided and single-cell omics technologies in paired skin and blood samples. Such an approach will mediate in-depth profiling of phenotypic and molecular changes in reactive immune subpopulations and malignant T cells preceding the Th1-to-Th2 shift and reveal mechanisms underlying disease progression from skin-limited to systemic disease that collectively will lead to the discovery of novel biomarkers to improve patient prognostication and the design of personalized treatment strategies.

CD38 Targeting in Aggressive, Treatment-Refractory Cutaneous T-Cell Lymphomas

The treatment of advanced-stage cutaneous T-cell lymphomas (CTCL) remains challenging.

Advanced stage cutaneous T-cell lymphoma treated with high-dose external beam radiation therapy: A case report.

The treatment for advanced-stage or refractory cutaneous T-cell lymphoma (CTCL) is largely palliative. Due to the rarity of the disease, there are few randomized controlled trials and large-scale prospective studies. Therefore, the treatment of advanced-stage CTCL remains challenging. A 64-years-old man who had received narrowband UVB phototherapy for several years presented with a generalized rash with widespread polycyclic erosions and painful ulcers on his hands and feet. We restaged him as stage III CTCL. He was treated with high-dose radiation for curative purposes and 3-dimensional conformal radiation therapy to both hands and feet. At the 2-year follow-up after the end of radiotherapy, the irradiated skin had recovered to normal soft, smooth skin with localized fibrosis and hypopigmented skin. He reported an excellent quality of life, and his hands and feet were free to move. CTCL at an advanced stage could require dose escalation with local radiotherapy for curative purposes. High-dose 3-dementional conformal radiation therapy could be effective and has tolerable toxicities.

464 CCR8 is a new therapeutic target in cutaneous T-cell lymphomas

Cutaneous T-cell lymphomas (CTCL) are rare non-Hodgkin lymphomas of skin-tropic T cells. Advanced-stage CTCL are frequently refractory to treatment and early relapses are common. There is a clear unmet need for new treatments with long-term efficacy in CTCL. CCR8 is a chemokine receptor expressed by skin resident memory T cells which are suspected to be the tumor cells of origin in mycosis fungoides. CCR8 is also strongly expressed by tumor-infiltrating Treg involved in immune escape. We combined blood flow cytometry in 13 patients with CTCL and healthy controls, in vitro stimulation of CTCL patients cells, Nanostring gene expression analysis, and single cell RNA sequencing analysis on human CTCL skin to study CCR8 expression and function in CTCL.

Mogamulizumab-Associated Rash (MAR) Correlates with Longer Progression Free Survival in Cutaneous T Cell Lymphoma (CTCL)

Background: Mogamulizumab-kpkc (mogamulizumab) is an anti-CCR4 monoclonal antibody approved for relapsed/refractory mycosis fungoides (MF) or Sézary syndrome (SS). In the Phase III MAVORIC trial comparing mogamulizumab to vorinostat, mogamulizumab-associated rash (MAR) was reported in 25% of patients (pts) and was more common in responders than in non-responders. Since then, several small case series have suggested that MAR is associated with response to the drug and prolonged remission. Methods: We collected retrospective data from 8 academic centers on pts diagnosed with CTCL as defined by 2018 WHO-EORTC classification, who received at least one dose of mogamulizumab from 1/1/2000 to 1/31/2022. Primary endpoints were PFS and overall survival (OS) as calculated by Kaplan-Meier, compared with log rank test. Secondary endpoint was response to mogamulizumab in accordance with ISCL/EORTC 2011 criteria. MAR was graded with NCI CTCAE version 5.0. Categorical variables were compared between groups using Fisher test. Quantitative variables are presented with means and standard deviation or median and interquartile range (IQR). Univariate analysis was performed to calculate the hazard ratios (HR) for PFS. Results: A total of 159 pts were included in analysis: 80 (50%) pts had a diagnosis of MF, 67 (42%) had SS, and 11 (7%) had other CTCLs. Median age was 70 (IQR 59.5-76), 65 (41%) were female, 124 (78%) were non-Hispanic Caucasian, 22 (14%) were Black. Median of prior lines of therapy was 3 (0-14). ECOG was 0-1 in 80% of pts at start of mogamulizumab. Majority of pts (70%, n=111) had advanced stage disease (Stage III or IV). Extranodal disease other than skin was present in 111 (70%) and LDH was elevated in 80 (50%) of pts. MAR occurred in 72 (45%) pts. Majority of rash was grade 1-2 (76%, n=55) but 14% (n=10) developed grade 3 rash. Median time to onset was 3.7 months (mo) (IQR 2.1, 7.6) and median time to resolution was 4.3 mo (IQR 1.4, 7.5). Skin biopsy was obtained in 51 of 72 pts who developed MAR. Histologic patterns ranged from spongiotic/psoriasiform (40%, n=29), interface (19%, n=14), lichenoid (28%, n=20), granulomatous (7%, n=5) or a combination of patterns. Location of rash occurred in extremities (78%, n=56), trunk (69%, n=50), face/scalp (39%, n=28), buttocks/groin (8%, n=6) or combination of places. Of the pts who developed MAR, 24 (33%) were treated with topical steroids, 13 (18%) with systemic steroids, 16 (42%) with both topical and systemic steroids and 12 (17%) with other therapies, while 4 (6%) did not receive any treatment. Median follow up was 20.9 mo, IQR: (12.0, 38.4). Median PFS was 30.5 mo (95% CI: 27.0 mo to not reached) for pts who developed MAR vs. 8.6 mo (95% CI: 5.7-20.9) for those who did not (HR=0.38, 95% CI: 0.24-0.62, p<0.0001). Three-year OS for pts with MAR vs. those without was 84% vs 55% (HR 0.3, 95% CI: 0.14-0.63, p=0.0008). Complete remission (CR) was higher in pts with MAR (64%; n=46) than those who did not develop MAR (26%; n=23). Overall response rate (ORR) was also higher in those with MAR vs those without, 85% (n=61) vs. 54% (n=47), p<0.0001. Odds ratio of CR in pts with MAR was 4.64 (95% CI: 2.37-10.25), p<0.0001. CR and partial remission (PR) in the blood were the most predictive of longer PFS on univariate analysis with HR of 0.05 (95% CI: 0.02, 0.14, p<0.001) and 0.07 (95% CI: 0.03, 0.20, p<0.001), respectively. Advanced stage CTCL at the start of mogamulizumab was also associated with improved PFS compared with early stage, HR 0.61 (95% CI: 0.37, 1.00), p=0.05. At last follow-up, mogamulizumab had been discontinued in 114 pts due to rash (n=38), immune event (n=2), progression (n=56) or other adverse outcome (n=22). Mogamulizumab was held in 40 pts with drug rash. Of the pts who permanently discontinued mogamulizumab due to rash, 16 of 38 pts (42%) remain off systemic therapy at last follow up with ongoing response; median time off of systemic therapy for these pts was 7.8 mo (IQR: 6.1, 16.5). Conclusions: The development of MAR in patients with CTCL is associated with higher rates of CR and ORR and significantly longer PFS and OS. CR/PR response in blood were associated with improved PFS. Additionally, 40% of patients who developed MAR and discontinued mogamulizumab had ongoing responses without additional systemic therapy. Rash may be a surrogate marker of favorable outcome with mogamulizumab. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Skin dose distributions between Stanford and rotational techniques in total skin electron therapy (TSET).

Total skin electron therapy (TSET) has proven to be one of the most effective treatments for advanced-stage cutaneous T-cell lymphoma. Two most used techniques are the Stanford six-field and rotational techniques. This study compares patient skin dose distributions as a function of depth between these two techniques. The EGSnrc system was used to simulate electron beams and calculate patient dose distributions. The calculations assumed the same patient standing on a platform, and the patient's different postures were ignored for the Stanford technique in the comparison of dose distributions. The skin doses were analyzed as a function of skin depth-dose coverage and evaluated using dose-volume-histograms (DVH). The comparisons were performed in three realistic clinical settings in which dual-field were used for patients treated at extended distances of 316 and 500cm, and a single field was used at 700 cm. In all cases the realistic patient treatment beam delivery geometry was simulated. Although small dose differences were observed in some local areas, no clinically significant differences were found in the patient 3D dose distributions between the Stanford and rotational techniques. Virtually the same DVH curves between two the techniques were observed for mean dose to skin depth of 0-5, 5-10, and 10-15 mm from the skin surface, respectively. It is found that the skin depth dose coverage is 2 mm shallower for patient treatment at 500cm compared to at 316cm due to the additional air attenuation. However, very similar dose coverage and uniformity can be achieved at these two different extended treatment distances by adjusting the thickness of acrylic scatter plate. Adequate thickness of a scattering plate improves the skin dose uniformity. Both the Stanford and rotational techniques deliver very similar skin dose coverage in DVH plots, and only small differences are seen in local areas. It is worth to emphasize that the DVH is a graphical representation of the distribution of dose within a structure, and it does not contain spatial information. Therefore, comparison of entire skin dose using DVH may mask some variations at different locations of the surface area. In addition, the comparison did not consider different patient postures of the Stanford technique. Including the different patient postures in the calculation may affect the result of doses to the limbs.

Continuous low-dose gemcitabine in primary cutaneous T cell lymphoma: A retrospective study.

The aim of our retrospective study was to evaluate the efficacy of a continuous therapy with a lower dosage of gemcitabine compared to those usually administered in patients with cutaneous T cell lymphomas (CTCL). Twenty-two patients received different dosages of gemcitabine. Dosage and schedule of the drug were chosen on the basis of clinical features. Gemcitabine was given at 1000 mg every 15 days in 13 patients (four mycosis fungoides [MF], nine Sezary syndrome [SS]); at 1000 mg at days +1, +8, +15 in six cases (three MF, three SS). All patients had been previously treated: four patients had received both skin directed and systemic treatments. Eighteen patients had received photopheresis, IFN, chemotherapy and immunotherapy. The objective response rate (CR + PR) among all patients was 54.5% (12 of 22 patients) with a CR of 4.5% (one of 22 patients) and a PR of 50% (11 of 22 patients). Patients with SS had an ORR of 61.5% (eight of 13 patients) with one CR (7%) and seven PR (53.8%); patients with MF showed an ORR of 55.6% (five of nine patients) but no patients experienced CR (0%). The schedule with the highest efficacy and the lowest toxicity profile was 1000 mg every 15 days. Median progression free survival and overall survival in all patients were 17 and 45 months respectively. Gemcitabine was generally well tolerated. We have demonstrated that a much lower dose of gemcitabine (1000 mg once every 15 days) in patients with advanced-stage and refractory CTCL can lead to a durable response, with tolerable and manageable adverse effects.

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.

New biotherapies for the treatment of cutaneous T-cell lymphomas

Most cutaneous lymphomas are cutaneous T-cell lymphomas, and the most common form is mycosis fungoides. Sézary syndrome is a leukemic form of cutaneous T-cell lymphoma which is characterized by erythroderma and the presence of blood tumor cells. The only potential cure of cutaneous T-cell lymphomas remains allogeneic stem cell transplantation. However, monoclonal antibodies have led to a substantial progress in the treatment of advanced-stage cutaneous T-cell lymphomas. Some of them, such as mogamulizumab (anti-CCR4 monoclobal antibody) or brentuximab vedotin (anti-CD30 coupled to monomethylauristatin E, antibody drug conjugate) have shown efficacy in international randomized controlled studies. Lacutamab, an anti-KIR3DL2 monoclonal antibody, is currently tested in an international, prospective phase 2 trial in cutaneous T-cell lymphomas and peripheral T-cell lymphomas. Finally, immune checkpoint inhibitors have shown clinical benefit in open-label phase 2 studies in cutaneous T-cell lymphomas. This review focuses on the new biotherapies currently used in cutaneous T-cell lymphomas.

Tre-O2-10 - Ifosfamide and etoposide in advanced-stage, relapsed or refractory primary cutaneous T-cell lymphomas

Prolonged complete remissions (CRs) are rare in advanced-stage cutaneous T-cell lymphomas (CTCLs). Ifosfamide + etoposide (I+E) have been used to treat lymphomas, combined with platinum-based agents in Hodgkin disease or non-Hodgkin lymphomas including peripheral T-cell lymphomas. Monoclonal antibodies have induced long-term remissions in CTCL but are usually poorly effective in transformed disease Allogeneic haematopoietic stem cell transplantation (alloHSCT) holds a potential for cure but relies on the existence of a pretransplant CR, which may require the use of chemotherapeutic regimens. To our knowledge, to date there are no published data on I+E efficacy and tolerance in advanced refractory CTCL. We performed a retrospective monocentre study on 28 patients with mycosis fungoides (MF, n=15) or Sézary syndrome (SS, n=13) treated with I+E between 2012 and 2019. In this study, I+E showed antitumor activity in these heavily pretreated patients with CTCL, with an ORR of 43%, and no significant difference between the full-dose and reduced-dose regimens in terms of ORR or SAE frequencies, indicating that the reduced regimen may be a suitable option in fragile patients. In conclusion, I+E is a valuable therapeutic option in patients with advanced, refractory CTCL.

Bio-O2-05 - Epigenetic modifiers can alter telomerase expression and clonogenic capacities of Sézary cells

Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphomas (CTCL) for which current available treatments do not provide long-term responses. Two epigenetic-modulating agents belonging to the family of histone deacetylase inhibitors (HDACi), vorinostat and romidepsin are FDA approved for advanced stage CTCL. However, the rationale for using such therapies in SS and their biological impact are not well defined. The majority of cancer cells achieve proliferative immortality by activating or upregulating the normally silent human Telomerase Reverse Transcriptase (<i>hTERT</i>) gene. Sezary cells do not escape to this phenomenon. As the <i>hTERT</i> promoter is rich in CpG, we investigated the contribution of epigenetic mechanisms in its re-expression. We analyzed <i>hTERT</i>-promoter methylation status in CTCL cells compared to healthy cells. Nine CTCL cell lines including, five SS cell lines were experimentally investigated (HuT78, the unique commercial SS cell line and four newly developed SS cell lines from our laboratory (PMID: 33106625). Gene-specific methylation analyses revealed a common promotor hypermethylation pattern exclusively observed in tumor cells. We explored <i>hTERT</i> promoter methylation status under the pressure of a demethylating agent approved for the treatment of several hematological disorders (5-azacytidine) by comparison with clinically approved HDACi (romidespin and vorinostat). Surprisingly, romidespin, vorinostat or 5-azacytidine could each reduce <i>hTERT</i> expression level without altering the methylation status of <i>hTERT</i> promoter. To go further, we analyzed the functional effect of the aforementioned epidrugs on the clonogenic capacities of Sézary cells using the soft agar assay. Our data revealed that, besides <i>hTERT</i> downregulation, epidrugs reduced the proliferative and the tumor formation capacities in Sézary cells <i>in vitro</i>. Our first report on <i>hTERT</i> promotor methylation status in CTCL suggests that <i>hTERT</i> promotor methylation status is a hallmark of neoplastic CTCL cells. Our results also provide evidence for functional consequences of epidrugs treatments on tumor formation capacities in Sézary cells <i>in vitro</i>. Indeed, the present investigation states that Sézary cells' clonogenic capacity correlates well with <i>hTERT</i> expression level under epigenetic drugs pressure. The present findings represent a step forward towards a better understanding of the relationship between targeting epigenetic modifiers in a cell-context–dependent manner and the response generated at the cellular levels.