INTRODUCTION:Denileukin difitox (DD), a recombinant cytotoxic fusion protein composed of full-length human interleukin-2 (IL-2) conjugated to diphtheria toxin's A and B subunits, has shown activity in patients with relapsed and refractory (R/R) mycosis fungoides and the Sezary Syndrome (MF/SS) whose tumor cells expressed CD25, with response rates of 30-44% in advanced and earlier (Stage I-III) stage patients, respectively. AREAS COVERED:Recently, a newer version of DD with improved purity and bioactivity (DD-cxdl) was developed. A registrational trial of D-cxdl showed similar response rates in R/R MF/SS. The purpose of this review is to describe efficacy and safety data surrounding these medications and highlight the equivalency of these two drugs. EXPERT OPINION:Both DD and DD-cxdl demonstrate activity in R/R MF/SS with higher response rate in tumor and plaque stage disease. Adverse events grade ≥3 included infusion reactions in 8%, elevated hepatic transaminases in 22%, and capillary leak syndrome in 8%. In addition to direct targeting of CD25 expressing tumor cells, both drugs are also capable of depleting immunoregulatory T-cells. A clinical trial of DD-cxdl in Japan showed that responses were independent of CD25 expression, suggesting multiple mechanisms of action for DD-cxdl in MF/SS and potentially other malignancies.

INTRODUCTION:Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma. While MF generally follows an indolent course, a subset of patients will experience progressive and/or treatment-refractory disease. SS is an aggressive cutaneous T-cell lymphoma associated with high morbidity and mortality secondary to immune compromise and opportunistic infection. Although allogeneic hematopoietic cell transplant (allo-HCT) is currently the only available potentially curative treatment modality for MF/SS and is included in the National Comprehensive Cancer Network and the American Society for Transplantation and Cellular Therapy treatment guidelines, there is no published guidance regarding referral criteria, timing and allo-HCT approach to help guide clinicians caring for these patients. METHODS:Delphi survey of 32 specialists in dermatology (n = 9), transplant hematology/oncology (n = 10), nontransplant hematology/oncology (n = 8), and radiation oncology (n = 5) from across the United States. Consensus required agreement of ≥75% of participants. RESULTS:Sixteen consensus statements were generated on 4 topics: 1) criteria for referral for consideration for allo-HCT, 2) allo-HCT preparative regimens and procedures, 3) disease status at the time of allo-HCT, and 4) multidisciplinary management in the pre- and post-transplant settings. CONCLUSION:These clinical practice guidelines provide a framework for decision-making regarding allo-HCT for MF/SS and highlight areas for future prospective investigation.

Penile melanomas (PM) are an exceedingly rare subtype of mucosal melanoma (MM), and we reviewed the clinicopathologic features and molecular profile in 8 PMs. The patient ages ranged from 46 to 78 (mean: 62.8) years with involvement on the glans (n=5; 62.5%), penile urethra (n=2; 25%), and foreskin (n=1, 12.5%). Tumor depth ranged from 1.6 to 10.0 (mean: 5.25) mm. Most of the patients underwent partial penectomy (n=6; 75%) and sentinel lymph node (LN) biopsy N=7; 87.5%). Seven patients had metastatic disease at diagnosis, 6 involving LNs and 1 the adrenal gland, and 4 died of disease with a mean follow-up period of 40.5 (2 to 95) months. Five of 7 (71%) cases identified 15 molecular alterations within KIT , CDKN2A , NF1 , PTEN , and APC (n=2 each), and NRAS , MAP3K1 , CDH1 , MSH6 , and TERT (n=1 each). Two cases were not found to harbor genetic aberrations, and 1 case failed testing. In addition, we reviewed the English literature and included 93 cases with a reported depth of invasion and follow-up. A total of 101 PMs were analyzed for prognostic parameters, and the overall survival was significantly worse in patients with LN metastasis (P=0.0008), distant metastasis (P=0.0016), and greater depth of invasion (P=0.0222) based upon T-stage. While T4 conferred substantially worse survival, the delineation of the survival curves between T2 and T3 was less clear, and combining T2+T3 disease had a strong prognostic impact ( P =0.0024). Prognostic parameters used in the staging of cutaneous melanomas may also be used in PMs. An alternative staging system expanding the inclusion criteria for T2 might provide a more accurate prognostic stratification.

IntroductionMycosis fungoides (MF) and Sezary syndrome (SS) are the most common types of cutaneous T-cell lymphoma. Although many available treatments offer temporary disease control, allogeneic hematopoietic stem cell transplant (allo-HSCT) is the only curative treatment option for advanced stage MF and SS. CAR T-cell therapy is a promising new avenue for treatment.Areas coveredIn this review, we discuss the evidence supporting the use of allo-HSCT for the treatment of MF/SS, including disease status at the time of transplant, conditioning regimen, total body irradiation (TBI), and donor lymphocyte infusion (DLI). We also address the potential role for CAR T-cell therapy in CTCL.Expert opinionAllo-HSCT is an effective treatment for patients with advanced MF and SS. However, significant research is required to determine optimal treatment protocols. Data support the use of reduced-intensity conditioning regimens and suggests that the use of TBI for debulking of skin disease may result in more durable remissions. Donor lymphocyte infusions (DLI) appear to be particularly effective in inducing complete remission in MF/SS patients with relapsed or residual disease. Challenges with CAR-T therapies in T-cell lymphoma include T-cell fratricide due to shared antigens on malignant and nonmalignant T-cells, penetrance into the skin compartment, and CAR-T cell persistence.

Subcorneal pustular dermatosis (SPD) is a rare neutrophilic dermatosis characterized by pustules on the trunk and intertriginous areas. While oral dapsone is the first-line treatment for SPD, alternative options are necessary for patients with glucose-6-phosphate dehydrogenase deficiency, drug hypersensitivity reactions, or refractory disease. To date, no consensus exists regarding next-best agents for SPD. In this report, we present a patient with significant SPD who developed dapsone hypersensitivity syndrome and then was successfully treated with colchicine and adalimumab. We propose that colchicine should be considered as a second-line treatment for SPD and present a therapeutic algorithm for clinicians to utilize when patients are not candidates for dapsone, have side effects requiring drug discontinuation, or have refractory disease.

ABSTRACT:Classic Hodgkin lymphoma (CHL) is a B-cell-derived lymphoma that classically displays a bimodal age distribution. CHL typically involves the mediastinum, lymph nodes, and other visceral organs. CHL is characterized histologically by the presence of a relatively paucicellular neoplastic cell population composed of large atypical cells (including Hodgkin and Reed-Sternberg forms) in a reactive mixed inflammatory background, often with prominent necrosis. CHL rarely occurs in the skin, and the associated mixed inflammatory infiltrate or necrotic appearance can create diagnostic uncertainty. Herein, we report the case of a 31-year-old man presenting with a painful dendritic rash of the anterior chest wall with axillary lymphadenopathy. After multiple nondiagnostic biopsies that revealed largely necrotic material, a chest wall skin biopsy was obtained. The skin biopsy was diagnostic of CHL, based on the presence of large atypical dermal cells, including Hodgkin and Reed-Sternberg forms, which expressed CD15, CD30 and Fascin, in a typical mixed inflammatory and necrotic background. Through the lens of this case, we discuss the characteristics and mechanisms of skin involvement of CHL, and the histopathologic and immunohistochemical pitfalls when considering the rare diagnosis of CHL in the skin.

Allogeneic hematopoietic stem cell transplant (allo-HSCT) has been noted to be a potential curative treatment in cases of advanced-stage mycosis fungoides (MF) or Sezary syndrome (SS). To assess outcomes of allo-HSCT for MF/SS we performed a systematic review and meta-analysis including 15 manuscripts and 557 patients, published from 2010–2023. Meta-analysis revealed 1-year and 3+year overall survival (OS) of 51% (95% CI 39–64%) and 40% (32–49%). Progression-free survival at 1 year and 3+years were 42% (31–53%) and 33% (25–42%). Non-relapse mortality was 18% (13–23%). Relapse occurred in of 47% (40–53%) with a median time to relapse of 7.9 months (range 1.6–24 months). Rates of acute and chronic graft-versus-host disease (GVHD) were 45% (35–55%) and 40% (33–48%). Reduced-intensity conditioning (RIC) was associated with superior OS compared to myeloablative conditioning (MAC) (58% vs. 30%, p < 0.001). Of patients with relapse after allo-HSCT, 46% treated with donor lymphocyte infusion (DLI) achieved complete remission. These data support use of allo-HSCT for treatment of advanced-stage MF/SS and suggest superiority of RIC over MAC. Rates of GVHD were comparable to allo-HSCT in general. The improved OS for RIC and high rate of CR with DLI underscore the importance of the graft-versus-lymphoma effect in allo-HSCT for MF/SS.

This review of cutaneous B-cell lymphoma (CBCL) is focused on the clinical presentation, treatment, and workup of each type of lymphoma. Part 1 is an overview of each of the CBCLs, including clinical presentation, recent advances in the pathobiology, and evidence regarding treatment strategies. Part 2 is a detailed guide to the steps in diagnosis and workup of a newly diagnosed CBCL according to the International Society for Cutaneous Lymphoma/European Organization for Research and Treatment of Cancer and NCCN guidelines.

Mogamulizumab is being increasingly prescribed for the treatment of T-cell lymphomas (MF/SS/ATLL). We conducted a retrospective cohort study to identify muscular immune-related adverse events (irAEs) associated with mogamulizumab in patients with T-cell lymphoma followed at Dana-Farber Cancer Institute from January 2015 to June 2022. We identified 5 cases of mogamulizumab-associated myositis and/or myocarditis (MAM/Mc), 2 additionally affected by myasthenia gravis, among 42 patients with T-cell lymphoma. Three cases experienced -mogamulizumab-associated rash (MAR) prior to developing MAM/Mc. The incidence (n = 5/42, 11.9%) of muscular mogamulizumab-associated irAEs may be higher than has been previously reported in clinical trials and may be of late onset (a median of 5 cycles and as late as 100 days from the last infusion). We highlight the utility of IVIG, together with systemic corticosteroids, for the treatment of these potentially fatal side effects associated with mogamulizumab therapy.

Cutaneous T-cell lymphomas are a clinically and histopathologically heterogenous group of disorders, encountered in dermatologic practice. In this article, we provide a detailed practical guide to the evaluation, diagnosis, and management of common cutaneous T-cell lymphomas. Emphasis is placed on the clinical evaluation including the role of the dermatologist in the accurate assessment of body surface area involvement for disease staging, appropriate biopsy techniques , and key considerations, recent advances in the molecular genetic characteristics of disease, and common treatment approaches.

Retinoids have been reported to be efficacious in patients with sclerodermatous chronic graft-versus-host disease (cGVHD) and enhance T-regulatory cells in GVHD mouse models.1Wolff D. Schleuning M. von Harsdorf S. et al.Consensus conference on clinical practice in chronic GVHD: second-line treatment of chronic graft-versus-host disease.Biol Blood Marrow Transplant. 2011; 17: 1-17https://doi.org/10.1016/j.bbmt.2010.05.011Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar,2Thangavelu G. Wang C. Loschi M. et al.Repurposing a novel anti-cancer RXR agonist to attenuate murine acute GVHD and maintain graft-versus-leukemia responses.Blood. 2021; 137: 1090-1103https://doi.org/10.1182/blood.2020005628Crossref PubMed Scopus (6) Google Scholar However, to our knowledge, there is no literature supporting acitretin as treatment for superficial forms of cutaneous cGVHD. We present a case of extensive Grover’s disease and superficial cutaneous cGVHD treated successfully with acitretin. A 67-year-old male with a history of polycythemia vera, follicular lymphoma, Langerhans cell histiocytosis, histiocytic sarcoma, melanoma, and nonmelanoma skin cancers (NMSC), who underwent allogeneic hematopoietic stem cell transplantation (HSCT) for blastic plasmacytoid dendritic cell neoplasm, developed a diffuse erythematous scaling papular eruption covering his chest and back on day 33 post-HSCT (while on 1 mg twice daily tacrolimus), concerning for acute GVHD (Fig 1) Prednisone 80 mg daily was initiated with significant improvement, but the rash worsened with prednisone taper. On being unable to taper prednisone below 40 mg and tacrolimus 0.5 mg twice daily, ruxolitinib 10 mg twice daily and mycophenolate mofetil 500 mg twice daily were added and he was referred to dermatology. A skin biopsy at day 95 post-HSCT showed suprabasilar acantholysis, consistent with Grover’s disease, without evidence of GVHD. He started super-potent topical corticosteroids and tapered off prednisone and mycophenolate mofetil over 4 weeks. However, the skin eruption significantly flared. Repeat skin biopsy again showed Grover’s disease without GVHD. He started oral doxycycline, topical calcipotriene, and bleach baths. In the absence of GVHD, ruxolitinib was tapered over 4 weeks and tacrolimus discontinued. By day 153 post-HSCT, he started acitretin 10 mg daily and continued topical steroids, due to the severity and persistence of his Grover’s disease. The acitretin helped this initial rash; however, at day 180 post-HSCT, he developed a new skin eruption consisting of asymmetrical facial erythema, induration, and edema and numerous diffuse erythematous scaling papules and plaques coalescing to involve 60% of his body surface area that was clinically distinct from his Grover’s disease (Fig 2). Two skin biopsies were performed on his cheek and trunk. The former showed a vacuolar interface dermatitis of surface and follicular epithelium, and the latter revealed a lichenoid dermatitis with hypergranulosis, hyperkeratosis, and scattered eosinophils, consistent with overlapping acute and chronic lichenoid GVHD. Acitretin was increased to 25 mg daily given potential therapeutic improvement of GVHD in a preclinical model and lack of GVHD involvement of other organs. On day 200 post-HSCT, there was near resolution of inflammation and postinflammatory hyperpigmentation (Fig 3). Acitretin alone was not sufficient to prevent a subsequent GVHD flare, day 256 post-HSCT, likely triggered by donor lymphocyte infusion (day 197 post-HSCT), for which mycophenolate mofetil 500 mg twice daily and prednisone 20 mg was added. He is now day 650 post-HSCT on mycophenolate mofetil 1.5 g, prednisone 7.5 mg, and acitretin 10 mg daily (dose reduced due to dry eyes). To our knowledge, this is the first report of acitretin for treatment of superficial cutaneous GVHD in the literature. Acitretin is a retinoic acid and retinoid X receptor (RXR) agonist. In a murine model of GVHD, a RXR agonist reduced donor T-cell proliferation, generation of proinflammatory Th1 cells, and promotes T-regulatory cell generation and maintenance. Our patient had significant improvement in both GVHD and Grover’s disease within 2 weeks of starting acitretin 25 mg daily. Moreover, acitretin prevents NMSC in high-risk patients so provides further benefit to this patient and potentially other HSCT patients who are at increased risk of skin cancers.3Bavinck J.N. Tieben L.M. Van der Woude F.J. et al.Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study.J Clin Oncol. 1995; 13: 1933-1938https://doi.org/10.1200/JCO.1995.13.8.1933Crossref PubMed Google Scholar This case also highlights the importance of dermatologists’ care of HSCT patients for accurate diagnosis of GVHD and recommendations of potential alternative therapies to traditional immunosuppression. Acitretin may cause dry eyes and elevation in liver enzymes, requiring special caution when used in post-HSCT patients. We recommend further investigation of acitretin, or other retinoids with RXR agonism, for the treatment of superficial forms of GVHD limited to the skin, especially in patients at high risk of cancer relapse or with several NMSCs, both of which could be precipitated by addition of more highly immunosuppressive agents. None disclosed.

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Abstract: There are 2 types of T cells: αβ and γδ T cells, named based on the composition of the T-cell receptor. γδ T cells are rare, making up 0.5%–10% of T cells. Although most leukemias, lymphomas, and immune-mediated conditions derive from αβ T cells, a handful of rare but important diseases are generally derived from γδ T cells, particularly primary cutaneous γδ T-cell lymphoma, hepatosplenic T-cell lymphoma, and monomorphic epitheliotropic intestinal T-cell lymphoma. There are also malignancies that may evince a γδ TCR phenotype, including large granulocytic lymphocyte leukemia, T-cell acute lymphobplastic leukemia (T-ALL), and mycosis fungoides, although such cases are rare. In this article, we will review the genesis of the T-cell receptor, the role of γδ T cells, and the importance of TCR type and methods of detection and outline the evidence for prognostic significance (or lack thereof) in lymphomas of γδ T cells. We will also highlight conditions that rarely may present with a γδ TCR phenotype and assess the utility of testing for TCR type in these diseases.

Introduction. Solid organ transplant graft-versus-host disease (SOT-GVHD) is a rare phenomenon in which recipients of solid organ transplant develop GVHD due to the presence of donor lymphocytes in the graft. SOT-GVHD most often occurs in patients receiving small bowel or liver transplants. Diagnosis is typically via identification of lymphocytic infiltration on histopathology and molecular demonstration of donor T cell chimerism in the target organ. The gastrointestinal (GI) system is the most common target of SOT-GVHD, and one estimate places long-term survival of patients with SOT-GVHD at 20% at 5 years. In this report, we present the case of a patient with sequential kidney and pancreas transplant who developed SOT-GVHD targeting host lymphocytes, skin, and liver, with a long period of stability before treatment with antithymocyte globulin. Peripheral blood chimerism testing was used to track response to therapy. Remarkably, he survived 1.5 years despite recurrent infections before dying of unrelated causes.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a newly described, adult-onset, autoinflammatory disorder caused by somatic mutations in the X-linked UBA1 gene. This syndrome is characterized by fevers, cytopenias, peripherally circulating myeloid and erythroid precursors with cytoplasmic vacuoles and dysplastic changes, pulmonary inflammation, chondritis, vasculitis, and joint pain and swelling.1,2 Nearly all patients with VEXAS present with cutaneous manifestations of the disease, most commonly a robust neutrophilic dermatosis.

Background Patients with mycosis fungoides (MF) are at increased risk of developing non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), lung cancer, bladder cancer and melanoma. The characteristics of patients developing these malignancies have not been specifically delineated. In addition, there are no established guidelines for screening MF patients for second malignancies. Materials/Methods We identified 742 patients with MF who developed second malignancies in the Surveillance Epidemiology and End Result-18 database. Results The majority of second malignancy patients were white and male, mean age 55-67 years at diagnosis of MF, and mean age 61-72 years at diagnosis of second malignancy. The majority of patients diagnosed with second malignancies had early stage MF. MF patients with NHL, lung cancer, and bladder cancer tended to be diagnosed at earlier stages of the second malignancy than patients without MF and demonstrated better 5-year overall survival. There was no improvement in stage at diagnosis or survival for MF patients who were diagnosed with melanoma compared to patients without MF. Conclusions Improvements in survival in MF/NHL, MF/lung cancer and MF/bladder cancer patients may reflect differences in disease biology secondary to having MF or the importance of increased contact with the healthcare system. MF/melanoma data suggest that patients require regular pigmented-lesion-focused skin examinations. Tools for screening include regular lymph node examinations, pigmented-lesion-focused examinations and detailed review of systems questions. Smoking cessation counseling is key intervention in this population, as is ensuring that all age- and sex-specific cancer screenings are up-to-date (e.g. lung cancer screening, mammography, and colonoscopy). The utility of regular imaging for second malignancy screening and lab testing such as routine urinalysis requires additional study and expert consensus.

Background: Patients with cutaneous T-cell lymphoma (CTCL) are at a higher risk of developing second malignancies. However, rates of incidence vary significantly across studies. Methods: A systematic review and meta-analysis of articles published between 1950 and 2019 was performed to evaluate the risk of second malignancies in patients with CTCL. Results: We identified 10 eligible studies, including 12 patient cohorts, with 5.9% to 16.8% of patients developing second malignancies. All studies showed a male predominance for patients developing second malignancies. The mean age across the studies ranged from 44.6 to 68.0 years. The time between the diagnosis of CTCL and second malignancy ranged from 2.1 to 5.4 years (mean, 3.29 y; 95% confidence interval [CI], 2.69-5.15). Meta-analysis showed a standardized incidence ratio of 2.18 (95% CI, 1.43-2.93) for all malignancies. The standardized incidence ratios were 15.25 (95% CI, 7.70-22.79) for Hodgkin lymphoma, 4.96 (95% CI, 3.58-6.33) for non-Hodgkin lymphoma, 1.69 (95% CI, 1.18-2.21) for lung cancer, 1.72 (95% CI, 1.18-2.21) for bladder cancer, and 3.09 (95% CI, 1.77-6.43) for melanoma. Conclusions: We find that patients with CTCL are at increased risk of second malignancies, especially Hodgkin and non-Hodgkin lymphoma, lung cancer, bladder cancer, and melanoma. These findings provide evidence of a population at increased risk of malignancy. Early detection may decrease the morbidity burden of second malignancies, thus providing a strong rationale for prospective screening studies. ( J Am Acad Dermatol 2021;85:1418-28.)

Pseudolymphomatous infiltrates associated with angiosarcoma are a rarely reported phenomenon. Recognition of this reactive process is critical to making an accurate diagnosis, both in diagnosing the angiosarcoma and in avoiding an incorrect diagnosis of lymphoma. Here, we present a novel histopathologic pattern, angiosarcoma with a prominently intravascular atypical lymphoid component, mimicking intravascular T-cell lymphoma. Interestingly, serial biopsies in this case revealed a progressive increase in lymphocyte density and intravascular component over time. Despite prior reports of improved progression-free survival and overall survival of patients with pseudolymphomatous angiosarcoma, this patient showed rapid disease progression.