Treatment Of Cutaneous T-cell Lymphoma Research Articles

The Landscape of Cutaneous T-Cell Lymphoma (CTCL) in the Middle East and North Africa (MENA) and the Establishment of the MENA CTCL Working Group

The high cancer burden in the Middle East and North Africa (MENA region) is coupled with an increasing cancer incidence. While the MENA region constitutes 6% of the world’s population, it remains underrepresented in clinical trials. Cutaneous T-cell lymphomas (CTCLs) represent a heterogeneous group of rare extranodal non-Hodgkin lymphomas with variable clinical presentation. In the MENA region, where darker skin colors are more common than in the West, CTCL generally presents at a younger age and with distinct clinical features that necessitate special expertise and management across disciplines: rare forms of CTCL are more common (hypo- and hyperpigmented MF) and a higher prevalence of pediatric MF is noticed. The multidisciplinary approach to cancer management is growing worldwide and is necessary for the comprehensive management of CTCL. The MENA CTCL group was established with the aim of creating a collaborative environment for the diagnosis and treatment of CTCL in the region. Its first meeting was held in May 2023. The group plans to increase the global representation of the MENA region and establish CTCL registries and patient advocacy groups in the region.

Pegylated interferon-α2a in cutaneous T-cell lymphoma - a multicenter retrospective data analysis with 70 patients.

Interferon-alpha is an important therapeutic option for the treatment of the cutaneous T-cell lymphomas (CTCL). Since the approved recombinant interferon-α-2a(IFN-α2a) has no longer been produced sinceJanuary 2020, pegylated interferon-α2a (pegIFN-α2a) can be used as an alternative treatment, even though it is not approved for the treatment of CTCL. The aim of this multicentre study was to generate comprehensive data on the efficacy and tolerability of pegIFN-α2a in the treatment of CTCL. A multicenter retrospective study was conducted with 70 patients with CTCL from twelve German skin centers. In total, 70 patients were included in the study, with 57.2% male and a mean age of 58.8 ±14.9 years. Mycosis fungoides was present in 71.4% of cases and Sézary Syndrome in 28.6%. An overall response rate of 55.2% was observed with pegIFNα-2a therapy. In 50% of cases, therapy was discontinued after 63.6 ±33.5 weeks. The most common reason for discontinuation was adverse events, which occurred in 68.6% of cases and which were classified as severe in 29.2%. Blood count changes, fatigue and liver toxicity occurred most frequently. Our analysis provides comprehensive data on the efficacy and tolerability of pegIFNα-2a therapy in patients with CTCL. In terms of response rates and side effect profile, pegIFNα-2a appears to be comparable to IFN-α2a therapy.

Role of Retinoids and Their Analogs in the Treatment of Cutaneous T-cell Lymphoma: A Systematic Review.

Biologically active derivatives of vitamin A, known as retinoids, can be used to treat cutaneous T-cell lymphomas. Retinoids and their analogs can modulate cell proliferation, differentiation, and apoptosis, and alter the immune response. This study systematically evaluated the safety, efficacy, and tolerability of retinoids for the treatment of cutaneous T-cell lymphomas and considered its limitations, dosing-side effects, and technique with the intent to provide valuable insights for clinicians and patients regarding the treatment of cutaneous T-cell lymphomas with the retinoids. The literature search is conducted using Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) criteria yielding 16 relevant articles. This study explored the different facets of the role of retinoids in the treatment of cutaneous T-cell lymphomas. In conclusion, the available studies and research have shown that retinoids play an important role in the mild and early stages of cutaneous T-cell lymphoma. However, further investigation is required to explain the mechanism of action of retinoids and the impact of their side effects in patients with cutaneous T-cell lymphoma.

Kinases Inhibitors as New Therapeutic Opportunities in Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of T-cell lymphomas characterised by high relapse rates and no curative treatments unless the allogeneic stem cell transplantation. The main complication in the management of this kind of malignancy is the variability that characterises the genetic and clinical features among the CTCL subtypes. JAK/STAT, MAPK/ERK, PI3K/Akt, and NF-kB are those signalling pathways that are found altered in CTCL and that are responsible for promoting both T-cell malignancy and the pro-tumorigenic microenvironment. Thus, targeting key players of these pathways can be an advantageous therapeutic option for CTCL. In this review, we aim to summarise the different approaches that precisely inhibit the kinases of each cited signalling. JAK inhibitors seem to be the most promising kinase inhibitors for CTCL. However, adverse events have been reported especially in patients with immunosuppression or an underlying autoimmune disease. More studies are needed, especially clinical trials, to investigate the benefits of these drugs for the treatment of cutaneous T-cell lymphomas.

Targeting TAG-72 in cutaneous T cell lymphoma

PurposeCurrent monoclonal antibody-based treatment approaches for cutaneous T cell lymphoma (CTCL) rely heavily on the ability to identify a tumor specific target that is essentially absent on normal cells. Herein, we propose tumor associated glycoprotein-72 (TAG-72) as one such target. TAG-72 is a mucin-associated, truncated O-glycan that has been identified as a chimeric antigen receptor (CAR)-T cell target in solid tumor indications. To date, TAG-72 targeting has not been considered in the setting of hematological malignancies. Experimental designCD3+ cells from patients with CTCL were analyzed for TAG-72 expression by flow cytometry. Immunohistochemistry was used to assess TAG-72 expression in CTCL patient skin lesions and a TAG-72 ELISA was employed to assess soluble TAG-72 (CA 72-4) in patient plasma. TAG-72 CAR transduction was performed on healthy donor (HD) and CTCL T cells and characterized by flow cytometry. In vitro CAR-T cell function was assessed by flow cytometry and xCELLigence® using patient peripheral blood mononuclear cells and proof-of-concept ovarian cancer cell lines. In vivo CAR-T cell function was assessed in a proof-of-concept, TAG-72+ ovarian cancer xenograft mouse model. ResultsTAG-72 expression was significantly higher on total CD3+ T cells and CD4+ subsets in CTCL donors across disease stages, compared to that of HDs. TAG-72 was also present in CTCL patient skin lesions, whereas CA 72-4 was detected at low levels in both CTCL patient and HD plasma with no differences between the two groups. In vitro cytotoxicity assays showed that anti-TAG-72 CAR-T cells significantly, and specifically reduced CD3+TAG-72+ expressing CTCL cells, compared to culture with unedited T cells (no CAR). CTCL CAR-T cells had comparable function to HD CAR-T cells in vitro and CAR-T cells derived from CTCL patients eradicated cancer cells in vivo. ConclusionThis study shows the first evidence of TAG-72 as a possible target for the treatment of CTCL.

Application of Photodynamic Therapy with 5-Aminolevulinic Acid to Extracorporeal Photopheresis in the Treatment of Cutaneous T-Cell Lymphoma: A First-in-Human Phase I/II Study.

Extracorporeal photopheresis (ECP) is a therapeutic modality used for T-cell-mediated disorders. This approach involves exposing isolated white blood cells to photoactivatable 8-methoxypsoralen (8-MOP) and UVA light, aiming to induce apoptosis in T-cells and thereby modulate immune responses. However, conventional 8-MOP-ECP lacks cell selectivity, killing both healthy and diseased cells, and has shown limited treatment efficacy. An alternative approach under investigation involves the use of 5-aminolevulinic acid (ALA) in conjunction with light, referred to as ALA-based photodynamic therapy. Our previous ex vivo studies suggest that ALA-ECP exhibits greater selectivity and efficiency in killing T-cells derived from patients with T-cell-mediated disorders compared to those treated with 8-MOP-ECP. We have conducted a clinical phase I-(II) study evaluating ALA-ECP safety and tolerability in cutaneous T-cell lymphoma (CTCL). Here, 20 ALA-ECP treatments were administered to one CTCL patient, revealing no significant changes in vital signs. Two adverse events were reported; both evaluated by the Internal Safety Review Committee as non-serious. In addition, five conceivable events with mainly mild symptoms took place. During the study period, a 53% reduction in skin involvement and a 50% reduction in pruritus was observed. In conclusion, the results indicate that ALA-ECP treatment is safe and well tolerated.

Matrine Enhances the Antitumor Efficacy of Chidamide in CTCL by Promoting Apoptosis.

Cutaneous T-cell Lymphoma (CTCL) is a rare group of non-Hodgkin lymphoma originating from the skin, which is characterized by T-cell lymphoproliferative disorders. Chidamide, a Chinese original antineoplastic agent with independent intellectual property rights, and matrine, an extract of Chinese herbal medicine, both have been reported to exert effects on the treatment of tumors individually. However, chidamide combined with matrine has not been tested for the treatment of CTCL. Both HH and Hut78 CTCL cell lines were treated with chidamide (0.4 μmol/L), matrine (0.6 g/L), or chidamide combined with matrine for 24, 48, and 72 h. Cell viability was estimated by MTS assay at each time point. Flow cytometry was then conducted to detect cell apoptosis. The exact mechanism of chidamide combined with matrine on CTCL cells was detected by Western blotting and further validated in xenograft models of NOD/SCID mice. Compared to the single drug, chidamide combined with matrine showed a more significant effect on proliferation inhibition and apoptosis induction on CTCL cells both in vitro and in vivo. The results from the in vitro and in vivo studies suggested that matrine could enhance the anti-tumor effect of chidamide by increasing the protein expression of cleaved caspase- 3 and decreasing the expression of E-cadherin, NF-κB, p-Bad, and Bcl-2 to activate apoptosis. Our data have demonstrated chidamide combined with matrine to exhibit elevated antitumor activity in both CTCL cells and xenograft models of NOD/SCID mice, which may be a potential treatment option for CTCL.

[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.

The effect of UVA light/8-methoxypsoralen exposure used in Extracorporeal Photopheresis treatment on platelets and extracellular vesicles.

Extracorporeal Photopheresis (ECP) is a leukapheresis based treatment for Cutaneous T-Cell Lymphoma, which takes advantage of the cellular lethal effects of UVA light in combination with a photoactivated drug, 8-methoxypsoralen. 25% of patients treated with ECP do not respond to treatment, however the underlying mechanisms for this lack of response remain unknown. Platelets, a rich source of extracellular vesicles (EVs) and key mediators in thromboinflammatory oncological progression, as well as leukocytes, are both processed through ECP and are subsequently transfused back into the patient, delivering potent immunomodulation. The effect of exposing platelets and their EVs directly to Ultra Violet A light (UVA)/8-methoxypsoralen is currently unknown. Platelet-rich plasma (PRP) was isolated from healthy donors and exposed to UVA light and/or 8-methoxysporalen in vitro and platelet activation and aggregation was assessed. EV size and concentration were also characterised by Nanoparticle Tracking Analysis and Flow Cytometry. We found that UVA light and 8-methoxypsoralen treatment in vitro does not induce platelet aggregation or significantly alter levels of the platelet activation markers, soluble P-selectin or platelet factor 4, with circulating levels of small and large EV size and concentration remaining constant. Therefore, utilising the combination of UVA light and 8-methoxypsoralen used in ECP in vitro does not activate platelets or alter important circulating EVs. Further studies will be needed to validate if our observations are consistent in vivo.

JAK Inhibitors in Cutaneous T-Cell Lymphoma: Friend or Foe? A Systematic Review of the Published Literature.

Cutaneous T-cell lymphomas (CTCLs) are a group of lymphoid neoplasms with high relapse rates and no curative treatment other than allogeneic stem cell transplantation (allo-SCT). CTCL is significantly influenced by disruption of JAK/STAT signaling. Therefore, Janus kinase (JAK) inhibitors may be promising for CTCL treatment. This study is a systematic review aiming to investigate the role of JAK inhibitors in the treatment of CTCL, including their efficacy and safety. Out of 438 initially searched articles, we present 13 eligible ones. The overall response rate (ORR) in the treatment with JAK inhibitors in clinical trials was 11-35%, although different subtypes of CTCL showed different ORRs. Mycosis fungoides showed an ORR of 14-45%, while subcutaneous-panniculitis-like T-cell lymphoma (SPTCL) displayed an ORR ranging from 75% to 100%. Five cases were reported having a relapse/incident of CTCL after using JAK inhibitors; of these, three cases were de novo CTCLs in patients under treatment with a JAK inhibitor due to refractory arthritis, and two cases were relapsed disease after graft-versus-host disease treatment following allo-SCT. In conclusion, using JAK inhibitors for CTCL treatment seems promising with acceptable side effects, especially in patients with SPTCL. Some biomarkers, like pS6, showed an association with better responses. Caution should be taken when treating patients with an underlying autoimmune disease and prior immunosuppression.

Real-world evidence of heparin and citrate use in extracorporeal photopheresis: A hypothesis-generating data review of device settings and performance.

Extracorporeal photopheresis (ECP) is widely used for the treatment of cutaneous T-cell lymphoma, graft-vs-host disease, and other immune-related conditions. To avoid clotting during treatment, the ECP system used must be effectively primed with an anticoagulant. Heparin is the recommended anticoagulant for the THERAKOS CELLEX System, but acid citrate dextrose-A (ACDA) is often used. We compared system performance between these two anticoagulants for this ECP system. Deidentified data for ECP device performance were obtained at each treatment session, from automatically logged Smart Cards or labels completed by device operators. We compared the effects of ACDA or heparin on overall treatment duration, buffy coat (leukocyte) collection time, photoactivation time and the number of alarms and warnings. The variability in these parameters was also assessed. Data from 23 334 treat sessions were analyzed; ACDA was used in 34.4% and heparin in 65.6%. Overall, the ECP procedure duration, buffy coat collection time and photoactivation time were numerically similar regardless of whether ACDA or heparin was used, and regardless of needle mode. Photoactivation time variability was lower with ACDA compared with heparin in all needle modes. Among treatments that were completed automatically without any operator intervention, total treatment duration and photoactivation time were significantly reduced with ACDA use in both the double- and single-needle modes. The data presented indicate that, in both double- and single-needle modes, the THERAKOS® CELLEX® integrated ECP system performed similarly with ACDA compared to heparin, although ACDA demonstrated potential benefits in reducing variability in photoactivation time.

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.

Romidepsin and Afatinib Abrogate Jak–Signal Transducer and Activator of Transcription Signaling and Elicit Synergistic Antitumor Effects in Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphomas (CTCL) are mature lymphoid neoplasias resulting from the malignant transformation of skin-resident T cells. A distinctive clinical feature of CTCL is their sensitivity to treatment with histone deacetylase (HDAC) inhibitors. However, responses to HDAC inhibitor therapy are universally transient and non-curative, highlighting the need for effective and durable drug combinations. Here we demonstrate that the combination of romidepsin, a selective class I HDAC inhibitor, with afatinib, an epidermal growth factor receptor (EGFR) family inhibitor, induces strongly synergistic antitumor effects in CTCL models in vitro and in vivo via abrogation of JAK-STAT signalling. These results support a previously unrecognized potential role for HDAC inhibitor plus afatinib combination in the treatment of CTCL.

A GSH-resistant FK228 analogue containing a stable disulfide bond

FK228 is a potent natural pan HDAC inhibitor approved by the FDA for the treatment of cutaneous T-cell lymphoma as well as peripheral T-cell lymphoma. It is generally believed that the mechanism of FK228 acting on HDACs is by reducing its disulfide bond after entering the cell, and the dithiol group may chelate with Zn2+ and form a weak reversible covalent bond with cysteine in the catalytic pocket of HDACs, therefore inhibiting the activity of HDACs. However, due to the weak stability of the disulfide bond in FK228, it has been difficult to obtain direct evidence for the above conjecture. Thus, improving the stability of the FK228 disulfide bond will help to explore the exact mechanism of FK228. In this study, based on the stability and target-induced covalent properties of the Cysteine-Penicillamine (Cys-Pen) disulfide bond reported previously, the Pen was introduced into the modification of FK228. Specifically, the d-Cys in FK228 was replaced by d-Pen, the total synthetic pathway was optimized, and the novel synthetic FK228 analogue (FK-P) stability was verified. FK-P can also be used as a new drug molecule in the future to participate in the research of related biological mechanisms or the treatment of diseases.

Photochemical Deoxygenative Hydroalkylation of Unactivated Alkenes Promoted by a Nucleophilic Organocatalyst.

The direct utilization of simple and abundant feedstocks in carbon-carbon bond-forming reactions to embellish sp3 -enriched chemical space is highly desirable. Herein, we report a novel photochemical deoxygenative hydroalkylation of unactivated alkenes with readily available carboxylic acid derivatives. The reaction displays broad functional group tolerance, accommodating carboxylic acid-, alcohol-, ester-, ketone-, amide-, silane-, and boronic ester groups, as well as nitrile-containing substrates. The reaction is operationally simple, mild, and water-tolerant, and can be carried out on multigram-scale, which highlights the utility of the method to prepare value-added compounds in a practical and scalable manner. The synthetic application of the developed method is further exemplified through the synthesis of suberanilic acid, a precursor of vorinostat, a drug used for the treatment of cutaneous T-cell lymphoma. A novel mechanistic approach was identified using thiol as a nucleophilic catalyst, which forms a key intermediate for this transformation. Furthermore, electrochemical studies, quantum yield, and mechanistic experiments were conducted to support a proposed catalytic cycle for the transformation.

Multi-functional biotinylated platinum(IV)-SAHA conjugate for tumor-targeted chemotherapy.

The development of multi-functional Pt(IV) complexes as chemotherapeutic agents has gained growing attention in medical oncology. However, the design of multi-functional tumor-targeted Pt(IV) complexes with high hydrolytic stability remains challenging. Herein, we have developed a Pt(IV) prodrug conjugated with vorinostat as a multi-functional cancer therapeutic. In this design, the octahedral Pt(IV) prodrug of a DNA damaging anticancer drug cisplatin is tethered to the cancer cell targeting biotin ligand through one of the axial sites and the other axial site of the Pt(IV) center is attached to the anticancer drug vorinostat (also known as SAHA), a histone deacetylase inhibitor (HDACi) approved by the Food and Drug Administration (FDA) for treatment of cutaneous T-cell lymphoma. The designed biotinylated Pt(iv)-SAHA (Biotin-Pt(iv)-SAHA) conjugate is hydrolytically stable but reduced to Pt(II) species under intracellularly relevant conditions and concomitantly releases cisplatin and two of its axial ligands such as SAHA and biotin. The anticancer activity of the conjugate is investigated against a panel of cisplatin-sensitive human cancer cells, including cisplatin-resistant cells. Interestingly, the conjugate exhibited significantly higher cytotoxicity than the clinically approved anticancer drug cisplatin and slightly more cytotoxicity than the HDACi SAHA in all the tested cell lines. By combining the Pt(IV) prodrug of cisplatin with SAHA in the conjugate, synergistic cytotoxicity is achieved. The imaging studies revealed that the conjugate is taken up by cancer cells and shows dose-dependent cell death. The studies on our designed multi-pronged conjugate can be further optimized to enhance its efficacy, paving the way for developing a new class of clinically relevant chemotherapeutic agents.

In silico methods for predicting physico-chemical properties and biological activity of newly synthesized esters of Bexarotene

The synthetic retinoid analogue Bexarotene (Targretin®, Ligand Pharmaceuticals Inc.) belongs to a group of compounds called rexinoids. They possess a specific affinity for the retinoid X receptor. The latter plays a role in the regulation of cell growth and differentiation through their ability to regulate transcription. Bexarotene is approved for the treatment of cutaneous T-cell lymphoma (CTCL), both as an oral and dermal dosage form. A total of 4 new Bexarotene esters were synthesized and an in silico analysis was performed using the OECD QSAR Toolbox, Molinspiration, PreADME/Tox and SwissADME software. The QSAR Toolbox results show that Bexarotene esters possess high metabolic activity with metabolites similar to those of Bexarotene. Alsom a hydrolysis process is observed making the esters act as prodrugs. According to Lipinski’s rule of 5 all four Bexarotene derivatives give 1 violation and therefore have drug-like properties. The Molinspiration and SwissADME software showed affinity of the newly synthesized molecules for nuclear receptors which partly rejects the prodrug theory. After evaluating the pharmacokinetic profile of the esters, it was observed that the molecules present promising intestinal absorption, distribution, metabolism, excretion and toxicity (ADME/T) characteristics. Even though the in silico analysis gave promising results, further investigation is needed.

A Retrospective Study of Extracorporeal Photopheresis (ECP) in Treatment of Cutaneous T-Cell Lymphoma (CTCL) Evaluating Global, Skin and Blood Responses

Introduction: Cutaneous T-cell lymphoma (CTCL) is a rare form of T-cell lymphoma involving the skin in early stage, and blood, lymph nodes, and viscera in more advanced stages. Mycosis fungoides (MF) and Sezary syndrome (SS) are the most common subtypes of CTCL. Patients (pts) with advanced stage (AS)-MF and SS can have severe symptoms including erythroderma, pruritus, desquamation, and have a poor quality of life. Extracorporeal Photopheresis (ECP) was approved by FDA for CTCL in 1988. It is the recommended frontline therapy for SS and is also often used in AS-MF. ECP works by immunomodulatory mechanisms and has minimum side effects. However updated data is lacking on the efficacy of contemporary ECP. Most of the studies were published years ago and did not stage pts and evaluate responses using the current criteria. Blood response was not evaluated in most studies. Besides, ECP techniques including the administration of methoxsalen have changed. Seeking to understand the efficacy of ECP in current practice, we conducted a retrospective study including CTCL pts treated with ECP at Moffitt Cancer Center (MCC), FL, USA in the past 13 years. Methods: Pts with MF or SS who started ECP at MCC after Jan. 2010 were included. In our practice, pts are typically started on ECP alone. A systemic therapy is added in ~ 3 months when a pt does not respond. Response in blood and skin were evaluated every 3 months. Results: A total of 39 pts were included. 23 (59%) were male; 31 (82%) were Caucasian, 4 (11%) were African-American. When starting ECP, 33 (89%) had stage III/IV disease; 30 (77%) had erythroderma; 10.3%, 33.3% and 56.4% of pts had B0, B1 and B2 disease, respectively (Table 1). 18 (46.2%) pts achieved a best global response of complete response (CR), and 12 (30.8%) achieved partial response (PR). The median time to first global response was 6.5 months (range 3.2-19.8 months). At 3 months 28 pts were on ECP alone and 11 were on concurrent systemic therapy including: Interferon (4), retinoid acid (3), romidepsin (3), and pralatrexate (1). At 6 months 20 pts were on ECP alone and 19 were on concurrent systemic therapy including interferon (7), retinoid acid (4), Romidepsin (4), and 1 patient for each of mogamulizumab, vorinostat, methotrexate and interferon + retinoid acid. When evaluated at 3 months, the overall response rate (ORR) in skin was 8/39 (20.5%) in the entire cohort, and 5/28 (17.9%) in pts not on concurrent systemic treatment. When evaluate at 6 months the skin response rates were 16 (41.0%) and 9 (45.0%) in pts with and without concurrent systemic treatment, respectively. The ORR in blood at 3 months was 19/39 (48.7%) in the entire cohort and 13/28 (46.4%) in pts on ECP alone; at 6 months, the ORRs in blood were 25/39 (64.1%) and 13/20 (65%), respectively. With a median followup of 43 months, the median PFS was not reached (NR). The 5-year PFS rate was 58%. At the last followup, 7 pts who were on ECP alone were in CR, and 3 in PR. The response rates at 3 months, 6 months and the best response rates were not associated with baseline characteristics including blood stage (B0 vs B1 vs B2), global stage (I/II vs III/IV), and concurrent systemic therapy (p>0.1 for all, table 1, part of the data was not shown). Discussion: Our results showed the contemporary ECP therapy had excellent efficacy in SS and AS-MF (ORR 77%). Many pts achieved durable remission (5-year PFS 58%). However, it took a median of 6.5 months to achieve an objective response. Pts with AS-MF and SS have significant symptoms and poor quality of life. Research is needed to identify treatment combinations with ECP to induce a quicker response. One limitation of our study is, some pts received systemic therapy concurrently with ECP, thus making it difficult to isolate the treatment effect of ECP. As a sensitivity analysis, we evaluated responses of pts on ECP alone in the first 6 months, and in this way decreased the confounding effect. Our study is also limited by the retrospective nature and the limited sample size. Future prospective studies in larger scale are needed to confirm our results.

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.

Development of Bexarotene Analogs for Treating Cutaneous T-Cell Lymphomas.

Bexarotene, a drug approved for treatment of cutaneous T-cell lymphoma (CTCL), is classified as a rexinoid by its ability to act as a retinoid X receptor (RXR) agonist with high specificity. Rexinoids are capable of inducing RXR homodimerization leading to the induction of apoptosis and inhibition of proliferation in human cancers. Numerous studies have shown that bexarotene is effective in reducing viability and proliferation in CTCL cell lines. However, many treated patients present with cutaneous toxicity, hypothyroidism, and hyperlipidemia due to crossover activity with retinoic acid receptor (RAR), thyroid hormone receptor (TR), and liver X receptor (LXR) signaling, respectively. In this study, 10 novel analogs and three standard compounds were evaluated side-by-side with bexarotene for their ability to drive RXR homodimerization and subsequent binding to the RXR response element (RXRE). In addition, these analogs were assessed for proliferation inhibition of CTCL cells, cytotoxicity, and mutagenicity. Furthermore, the most effective analogs were analyzed via qPCR to determine efficacy in modulating expression of two critical tumor suppressor genes, ATF3 and EGR3. Our results suggest that these new compounds may possess similar or enhanced therapeutic potential since they display enhanced RXR activation with equivalent or greater reduction in CTCL cell proliferation, as well as the ability to induce ATF3 and EGR3. This work broadens our understanding of RXR-ligand relationships and permits development of possibly more efficacious pharmaceutical drugs. Modifications of RXR agonists can yield agents with enhanced biological selectivity and potency when compared to the parent compound, potentially leading to improved patient outcomes.