|
1
|
Singh GK, Das P, Srivastava S, Singh K, Singh V, Barui S, Mulajkar D, Dubey IP. Mycosis fungoides and Sezary syndrome - Simplifying the approach for dermatologists. Part 2: Evaluation, staging, prognosis and treatment. Indian J Dermatol Venereol Leprol 2025; 91:180-187. [PMID: 39912186 DOI: 10.25259/ijdvl_754_2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 07/19/2024] [Indexed: 02/07/2025]
Abstract
Cutaneous T-cell lymphoma is a heterogeneous group of T-cell neoplasms, of which mycosis fungoides and Sezary syndrome are the most common. The prognosis depends on the stage of the disease. The early stage follows a protracted course with a five-year disease-specific survival of greater than 95% and is treated with skin-directed topical therapies, phototherapy, and oral drugs like methotrexate. Advanced disease has a five-year overall survival of less than 25% and requires management by systemic chemotherapeutic agents. This review article is the second part out of the two covering the staging, prognosis, and treatment from a dermatologist's perspective.
Collapse
Affiliation(s)
- Gautam Kumar Singh
- Department of Dermatology, Bharati Vidyapeeth's Medical College, Pune, India
| | - Pankaj Das
- Department of Dermatology, Armed Forces Medical College, Pune, India
| | - Shailendra Srivastava
- Department of Dermatology, Base Hospital Delhi Cantonment and Army College of Medical Sciences, Delhi Cantt, India
| | - Kanwaljeet Singh
- Department of Pathology, Army Hospital, Research and Referral, Kolkata, India
| | - Vikram Singh
- Department of Pathology, Armed Forces Medical College, Pune, India
| | - Sanghita Barui
- Department of Pathology, Base Hospital, Delhi Cantonment and Army College of Medical Sciences, Delhi Cantt, India
| | - Deepak Mulajkar
- Department of Medical Oncology, Army Hospital Research and Referral, Delhi, India
| | - Indra Prakash Dubey
- Department of Nuclear Imaging, Army Hospital Research and Referral, Delhi, India
| |
Collapse
|
|
2
|
Aebischer V, Hahn M, Lenders D, Metzler G, Schaller M, Silber T, Forchhammer S. Clinicopathological characteristics of low-dose methotrexate-induced epidermal dysmaturation: A study of 22 patients. J Dtsch Dermatol Ges 2024; 22:1519-1527. [PMID: 39279548 DOI: 10.1111/ddg.15537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 07/08/2024] [Indexed: 09/18/2024]
Abstract
BACKGROUND AND OBJECTIVE Erosions of the skin and mucous membranes with epidermal dysmaturation are a known side effect of cytostatic chemotherapy regimens and can also be observed during low-dose methotrexate (MTX) therapy. The study aimed to delineate the clinical and histopathological alterations. PATIENTS AND METHODS A database search of the archive for dermatopathology was conducted, identifying 22 patients who developed epidermal dysmaturation on low-dose MTX. Clinical and laboratory changes, along with an array of histologic parameters were analyzed and statistically evaluated using SPSS. RESULTS Patients were predominantly female with a mean age of 69.1 years. The main indications were psoriasis vulgaris and rheumatoid arthritis. Clinically, patients mostly presented erosive plaques at the injection site, on mucosal surfaces, and disseminated lesions. Most patients showed normal laboratory values. Histopathologically, key findings included enlarged keratinocytes with pale cytoplasm and enlarged nuclei with prominent nucleoli, along with the degeneration of the basal layer. Consistent observations in the dermal compartment included infiltration of neutrophilic granulocytes, lymphocytes, and histiocytes. CONCLUSIONS This study proposes clinicopathological criteria for the diagnosis of MTX-associated skin toxicity, aiming to increase awareness among clinicians and pathologists for early diagnosis. Early recognition can prevent potentially life-threatening progression.
Collapse
Affiliation(s)
| | - Matthias Hahn
- Department of Dermatology, Eberhard Karls University, Tübingen, Germany
| | - Daniela Lenders
- Department of Dermatology, Eberhard Karls University, Tübingen, Germany
| | - Gisela Metzler
- Center for Dermatohistology and Oral Pathology Tübingen/Würzburg, Tübingen, Germany
| | - Martin Schaller
- Department of Dermatology, Eberhard Karls University, Tübingen, Germany
| | - Toni Silber
- Department of Dermatology, Eberhard Karls University, Tübingen, Germany
| | | |
Collapse
|
|
3
|
Goel RR, Rook AH. Immunobiology and treatment of cutaneous T-cell lymphoma. Expert Rev Clin Immunol 2024; 20:985-996. [PMID: 38450476 DOI: 10.1080/1744666x.2024.2326035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 02/28/2024] [Indexed: 03/08/2024]
Abstract
INTRODUCTION Primary cutaneous T cell lymphomas (CTCL) are a heterogenous group of non-Hodgkin lymphomas derived from skin-homing T cells. These include mycosis fungoides and its leukemic variant Sezary syndrome, as well as the CD30+ lymphoproliferative disorders. AREAS COVERED In this review, we provide a summary of the current literature on CTCL, with a focus on the immunopathogenesis and treatment of mycosis fungoides and Sezary syndrome. EXPERT OPINION Recent advances in immunology have provided new insights into the biology of malignant T cells. This in turn has led to the development of new therapies that modulate the immune system to facilitate tumor clearance or target specific aspects of tumor biology.
Collapse
Affiliation(s)
- Rishi R Goel
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Immunology and Immune Health (I3H), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Alain H Rook
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| |
Collapse
|
|
4
|
Mocanu M, Procopciuc D, Gheucă-Solovăstru DF, Popescu IA, Olinici DT, Pătrașcu AI, Vâță D, Gheucă-Solovăstru L. An Overview of Methotrexate Indications in Skin Diseases. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1024. [PMID: 39064453 PMCID: PMC11279115 DOI: 10.3390/medicina60071024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 06/14/2024] [Accepted: 06/17/2024] [Indexed: 07/28/2024]
Abstract
Methotrexate is an immunosuppressive drug with remarkable therapeutic results in the treatment of autoimmune and proliferative skin diseases. Although it has been more than half a century since it was first introduced into the therapeutic arsenal of dermatologists, there are currently no standardized therapeutic protocols regarding the prescription of methotrexate in dermatology, with the exception of psoriasis treatment. This review aims to highlight the indications and benefits of methotrexate beyond psoriasis, with a focus on a wide range of inflammatory, vesiculobullous, and proliferative dermatological pathologies.
Collapse
Affiliation(s)
- Mădălina Mocanu
- Department of Dermatology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.A.P.); (L.G.-S.)
- Dermatology Clinic, “St. Spiridon” County Emergency Clinical Hospital, 700115 Iasi, Romania; (D.P.); (D.T.O.); (A.I.P.)
| | - Dorina Procopciuc
- Dermatology Clinic, “St. Spiridon” County Emergency Clinical Hospital, 700115 Iasi, Romania; (D.P.); (D.T.O.); (A.I.P.)
| | | | - Ioana Adriana Popescu
- Department of Dermatology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.A.P.); (L.G.-S.)
- Dermatology Clinic, “St. Spiridon” County Emergency Clinical Hospital, 700115 Iasi, Romania; (D.P.); (D.T.O.); (A.I.P.)
| | - Doinița Temelie Olinici
- Dermatology Clinic, “St. Spiridon” County Emergency Clinical Hospital, 700115 Iasi, Romania; (D.P.); (D.T.O.); (A.I.P.)
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Adriana Ionela Pătrașcu
- Dermatology Clinic, “St. Spiridon” County Emergency Clinical Hospital, 700115 Iasi, Romania; (D.P.); (D.T.O.); (A.I.P.)
| | - Dan Vâță
- Department of Dermatology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.A.P.); (L.G.-S.)
- Dermatology Clinic, “St. Spiridon” County Emergency Clinical Hospital, 700115 Iasi, Romania; (D.P.); (D.T.O.); (A.I.P.)
| | - Laura Gheucă-Solovăstru
- Department of Dermatology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.A.P.); (L.G.-S.)
- Dermatology Clinic, “St. Spiridon” County Emergency Clinical Hospital, 700115 Iasi, Romania; (D.P.); (D.T.O.); (A.I.P.)
| |
Collapse
|
|
5
|
Stuver R, Geller S. Advances in the treatment of mycoses fungoides and Sézary syndrome: a narrative update in skin-directed therapies and immune-based treatments. Front Immunol 2023; 14:1284045. [PMID: 37868986 PMCID: PMC10585160 DOI: 10.3389/fimmu.2023.1284045] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 09/25/2023] [Indexed: 10/24/2023] Open
Abstract
Mycoses fungoides (MF) and Sézary syndrome (SS) are cutaneous T-cell lymphomas that are often challenging to manage given the absence of reliably curative therapies, at times high symptom burden with significant detriment to quality of life, and need for ongoing treatment for disease and symptom control. Recent developments in skin-directed treatments include optimizing the use of existing topical therapies, the introduction of known dermatological agents and treatment modalities for the specific treatment of MF/SS (such as mechlorethamine gel, calcineurin inhibitor creams, and photodynamic therapy), and novel local and topical agents. For advanced disease, dedicated clinical trials have translated to exciting progress, leading to the approval of brentuximab vedotin (2017) and mogamulizumab (2018) for relapsed MF/SS. Additional studies of other active systemic agents, including various cellular therapies, represent further attempts to add to the therapeutic armamentarium in treating MF/SS. In this review, we highlight these recent advancements, ranging from optimization of skin-directed therapies to the introduction of novel systemic agents. We focus on therapies approved in the preceding five years or under investigation in advanced-phase clinical trials.
Collapse
Affiliation(s)
- Robert Stuver
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Shamir Geller
- Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| |
Collapse
|
|
6
|
Mirmovich Morvay O, Ramon M, Khamaysi Z, Avitan-Hersh E. Paediatric Mycosis Fungoides: Clinical Variants, Treatment Modalities and Response to Therapy. Acta Derm Venereol 2023; 103:adv6557. [PMID: 37449370 PMCID: PMC10391534 DOI: 10.2340/actadv.v103.6557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 03/28/2023] [Indexed: 07/18/2023] Open
Abstract
Mycosis fungoides is a rare cutaneous lymphoma in the paediatric population. The aim of this study was to examine the epidemiological, clinical, and histological characteristics, as well as the treatment modalities and response to therapy of paediatric patients with mycosis fungoides. This retrospective cohort study reviewed the records of 37 paediatric patients treated at Rambam Medical Center, Israel, between 2013 and 2021. Extracted data included epidemiology, clinical presentation, histological reports, infiltrate clonality status, treatment modalities and response to therapy. The mean follow-up period was 60 months. All patients were diagnosed with stage IA or IB disease. Folliculotropic mycosis fungoides was the most prevalent variant (49%). Most patients were treated with phototherapy (90%), with a response rate of 85%, and a complete response rate of 55% after the first course. There were no significant differences in response to phototherapy between the folliculotropic or other variants (p = 0.072). Similarly, delayed diagnosis, atopic diathesis, clonality, phototherapy type or number of treatments, were not associated with response to therapy, while protracted phototherapy was associated with prolonged remission. In conclusion, mycosis fungoides in the paediatric population is an indolent disease with a favourable prognosis and potentially prolonged response to phototherapy.
Collapse
Affiliation(s)
| | - Michal Ramon
- Department of dermatology, Rambam Health Care Campus, Haifa, Israel
| | - Ziad Khamaysi
- Department of dermatology, Rambam Health Care Campus, Haifa, Israel
| | | |
Collapse
|
|
7
|
Brazel D, Pinter-Brown L. SOHO State of the Art Updates and Next Questions | A Modern Approach to the Systemic Treatment of Advanced CTCL. CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA 2023; 23:401-409. [PMID: 37061415 DOI: 10.1016/j.clml.2023.03.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 03/02/2023] [Accepted: 03/11/2023] [Indexed: 03/18/2023]
Abstract
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.
Collapse
Affiliation(s)
- Danielle Brazel
- Department of Medicine, University of California Irvine Medical Center, Orange, CA.
| | - Lauren Pinter-Brown
- Department of Medicine, University of California Irvine Medical Center, Orange, CA; Chao Family Comprehensive Cancer Center, University of California Irvine, Orange, CA
| |
Collapse
|
|
8
|
Beyzaee AM, Jahantigh N, Goldust M, Rahmatpour Rokni G, Babaei M, Ghoreishi B, Sadathosseini S. Mycosis fungoides with Psoriasiform plaques: A case report and review of the literature. Clin Case Rep 2023; 11:e6848. [PMID: 36846176 PMCID: PMC9950353 DOI: 10.1002/ccr3.6848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/19/2022] [Accepted: 12/28/2022] [Indexed: 02/27/2023] Open
Abstract
Mycosis fungoides (MF) is the most common variant of primary skin T-cell lymphoma. It typically manifests as an indolent progressing cutaneous eruption with erythematous scaly patches or plaques. Due to the nonspecific pathological findings, it can be easily misdiagnosed as psoriasis. A 34-year-old woman with a history of psoriasiform plaques for 12 years was referred to our dermatology clinic. In the beginning, the diagnosis of psoriasis was made and topical steroids were prescribed: it did not exhibit any clinical improvement. During the visit, skin biopsy was performed and the diagnosis of MF was confirmed. Treatment with PUVA, prednisolon, methotrexate, topical ointment including ucerin, urea, and clobetasol were initiated. Significant improvement in all lesions were observed after 1 month of the treatment, and within a year, the disease improved dramatically after PUVA therapy. In refractory cases of psoriasiform plaques that are progressive and/or ulcerative despite the optimal treatment, biopsy is required and a possible diagnosis of MF should be kept in mind.
Collapse
Affiliation(s)
| | | | - Mohammad Goldust
- Department of DermatologyUniversity Medical Center MainzMainzGermany
| | - Ghasem Rahmatpour Rokni
- Department of Dermatology, Faculty of MedicineMazandaran University of Medical SciencesSariIran
| | - Mahsa Babaei
- Shahid Beheshti University of Medical SciencesTehranIran
| | - Bahare Ghoreishi
- Department of DermatologyMazandaran University of Medical SciencesSariIran
| | | |
Collapse
|
|
9
|
Suggested Guidelines for the Treatment of Mycosis Fungoides in Countries with Limited Resources. Dermatol Res Pract 2023; 2023:1360740. [PMID: 36762366 PMCID: PMC9904957 DOI: 10.1155/2023/1360740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 01/13/2023] [Accepted: 01/17/2023] [Indexed: 02/04/2023] Open
Abstract
The treatment options for mycosis fungoides (MF) have been expanding but unfortunately many of the currently used treatment modalities are unavailable in Egypt and other African/Arab countries. In addition, there is a lack of consensus on the treatment of hypopigmented MF (HMF), which is a frequently encountered variant in our population. We aimed to develop regional treatment guidelines based on the international guidelines but modified to encompass the restricted treatment availability and our institutional experience. Special attention was also given to studies conducted on patients with skin phototype (III-IV). Treatment algorithm was formulated at Ain-Shams cutaneous lymphoma clinic through the collaboration of dermatologists, haematologists, and oncologists. Level of evidence is specified for each treatment option. For HMF, phototherapy is recommended as a first line treatment, while low-dose methotrexate is considered a second line. For early classical MF, we recommend Psoralen-ultraviolet A (PUVA), which is a well-tolerated treatment option in dark phenotype. Addition of either retinoic acid receptor (RAR) agonist and/or methotrexate is recommended as a second line. Total skin electron beam (TSEB) is considered a third-line option. For advanced stage, PUVA plus RAR agonist and/or methotrexate is recommended as first line, TSEB or monochemotherapy is considered a second line option. Polychemotherapy is regarded as a final option. All patients with complete response (CR) enter a maintenance and follow-up schedule. We suggest a practical algorithm for the treatment of MF for patients with dark phenotype living in countries with limited resources.
Collapse
|
|
10
|
Vorontsova AA, Karamova AE. Phototherapy combined with systemic agents for mycosis fungoides. VESTNIK DERMATOLOGII I VENEROLOGII 2022. [DOI: 10.25208/vdv1389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The choice of tactics for managing a patient with mycosis fungoides is determined by the stage of the disease. In the early stages of mycosis fungoides, a treatment approach using external therapy and various ultraviolet irradiation spectra (UVB-311 nm and PUVA therapy) is preferable. With insufficient efficiency and / or short remissions in some patients, it is possible to use combined methods in the early stages: PUVA therapy or UVB-311 nm therapy. in combination with systemic therapy, including interferon (IFN) 2b preparations, methotrexate and retinoids. The results of original studies demonstrate an increase in the overall response rate when combining PUVA therapy with IFN- or retinoids in patients with stages IB-IIB. The effectiveness of combined treatment regimens using UVB-311 nm remains insufficiently studied.
Collapse
|
|
11
|
Parsons MW, Wada DA, Halwani AS, Tao R, Gaffney DK. Improved overall survival over time in advanced stage mycosis fungoides: a cross-sectional study. Leuk Lymphoma 2022; 63:2428-2435. [DOI: 10.1080/10428194.2022.2081322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Affiliation(s)
- Matthew W. Parsons
- Department of Radiation Oncology, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA
| | - David A. Wada
- Department of Dermatology, University of Utah, Salt Lake City, UT, USA
| | - Ahmad S. Halwani
- Division of Hematology, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA
| | - Randa Tao
- Department of Radiation Oncology, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA
| | - David K. Gaffney
- Department of Radiation Oncology, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA
| |
Collapse
|
|
12
|
Yonekura K. Current treatment strategies and emerging therapies for cutaneous lymphoma. J Dermatol 2021; 49:223-231. [PMID: 34958516 DOI: 10.1111/1346-8138.16289] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Revised: 12/09/2021] [Accepted: 12/13/2021] [Indexed: 11/28/2022]
Abstract
Cutaneous lymphoma is generally treated with skin-directed therapies (SDT) during the early and localized stages. For the refractory or advanced stages, systemic therapies are used. Previously, retinoids and interferons were used for SDT-resistant cases. Only a few chemotherapy options were available for more advanced disease. In recent years, many novel agents have been introduced and the strategy for systemic therapy has changed, especially for cutaneous T-cell lymphoma (CTCL). For SDT, helical tomotherapy, a new radiation modality, has been drawing attention as an option for radiotherapy. Targeted therapies such as histone deacetylase inhibitors, mogamulizumab, brentuximab vedotin, and denileukin diftitox are new treatment options. Chemotherapy agents such as gemcitabine and pralatrexate have been introduced; they are expected to have meaningful efficacy as monotherapy. Allogeneic hematopoietic stem cell transplantation is still considered for young patients with advanced CTCL as the only potentially curative treatment.
Collapse
Affiliation(s)
- Kentaro Yonekura
- Department of Dermatology, Imamura General Hospital, Kagoshima, Japan
| |
Collapse
|
|
13
|
Podkonjak T, Cranmer H, Scarisbrick J, McCarthy G, Lilley C, Cheng LI. Cost-effectiveness of brentuximab vedotin for the treatment of cutaneous T-cell lymphoma. J Comp Eff Res 2021; 11:193-202. [PMID: 34879742 DOI: 10.2217/cer-2021-0201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: To assess the cost-effectiveness of brentuximab vedotin (BV) versus physician's choice (methotrexate or bexarotene) for treating advanced cutaneous T-cell lymphoma. Materials & methods: A partitioned-survival model was developed from the National Health Service perspective in England and Wales. Model inputs were informed by the ALCANZA trial, real-world UK data, published literature or clinical experts. Results: Over the modeled lifetime, BV dominated physician's choice and provided an additional 1.58 life-years and 1.09 higher quality-adjusted life years with a net cost saving of £119,565. The net monetary benefit was £152,326 using a willingness-to-pay threshold of £30,000/quality-adjusted life year. Results were robust in sensitivity and scenario analyses. Conclusion: BV is a highly cost-effective treatment for advanced cutaneous T-cell lymphoma.
Collapse
Affiliation(s)
| | - Holly Cranmer
- Takeda Pharmaceuticals International Co., London, UK
| | - Julia Scarisbrick
- Department of Dermatology, University Hospital Birmingham, Birmingham B15 2TH, UK
| | | | | | - Lung-I Cheng
- Global Value & Access Oncology, Takeda Pharmaceutical America, Inc., Lexington, MA 02421, USA
| |
Collapse
|
|
14
|
Gorenkova LG, Belousova IE, Kravchenko SK, Kovrigina AM, Sidorova YV, Ryzhikova NV, Lepik EE, Shneyder TV. Modern possibilities of therapy for primary cutaneous T-cell lymphomas: the first results of the use of brentuximab vedotin in the Russian Federation. JOURNAL OF MODERN ONCOLOGY 2021. [DOI: 10.26442/18151434.2021.3.201204] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background. Primary cutaneous T-cell lymphomas are rare heterogeneous group of lymphoproliferative diseases characterized by primarily involving skin and subcutaneous adipose tissue. Half of these cases are mycosis fungoides (MF), for about 25% are cutaneous CD30+ lymphoproliferative diseases (CD30+ LPD): primary cutaneous anaplastic large cell lymphoma (pcALCL) and lymphomatoid papulosis (LyP). During the initiating treatment of patients with MF and Szary syndrome (SS), carried out on the territory of the Russian Federation, for about 30% of patients are resistant to various therapeutic effects, especially in the later stages. The problem of the treatment of CD30+ LPD is extracutaneous dissemination in case of pcALCL, steadily relapsing course of LyP without symptom-free intervals. These characteristics of the therapy of cutaneous lymphomas demand for the need to search for new treatment options. Brentuximab vedotin, according to the results of the international randomized ALCANZA trial, has shown high efficiency in the treatment of cutaneous T-cell lymphoproliferative diseases.
Aim. To evaluate the efficacy of brentuximab vedotin application in patients with cutaneous T-cell lymphomas in adverse risk group received at least one line of systemic therapy.
Materials and methods. The study included 21 patients: 16 men and 5 women. The diagnosis of MF was verified in 8 patients, SS in 5 patients, cutaneous CD30+ LPD in 6 patients (5 patients pcALCL, 1 patient LyP) and a primary cutaneous peripheral T-cell lymphoma, unspecified in 2 patients. The diagnosis of cutaneous T-cell lymphoma was verified on the basis of the anamnesis of the disease, on the character of cutaneous lesions, on histological, immunohistochemical and in some cases on molecular genetic testing of the biopted sample of the skin (the assessment of T-cell receptor gene rearrangement).
Results. The late stages of the disease were diagnosed in 12 of 13 patients with MF/SS. Extracutaneous lesions were diagnosed in 57% of cases. The median of prior lines therapy was 3 (18 variants of treatment). The overall response to the treatment was achieved in 91% of cases (in 19 of 21 patients): the complete remission was obtained in 53% of cases, very good partial remission in 31% of cases and partial remission in 16% of cases. The progression of the disease was determined in 2 patients (after the first and fourth cycles). Some patients with partial remission as a result of therapy using brentuximab vedotin had the additional therapy (radiation therapy, interferon , the cycles of systemic therapy) and these acts gave an option of achieving deeper antitumor response. The early relapse was diagnosed in 2 of 19 patients who had responded to the treatment. The treatment tolerability was acceptable, and the toxicity did not exceed the already known one described in earlier studies. Thus, the stable overall antitumor response had been persisting in 89% of patients (the median of the observation was 10 months).
Conclusion. The use of targeted therapy with brentuximab vedotin gave an option of achieving high treatment results in group of patients with advanced stages of the disease and inefficiency of several lines of therapy.
Collapse
|
|
15
|
Bellinato F, Gisondi P, Girolomoni G. Risk of lymphohematologic malignancies in patients with chronic plaque psoriasis: A systematic review with meta-analysis. J Am Acad Dermatol 2021; 86:86-96. [PMID: 34363908 DOI: 10.1016/j.jaad.2021.07.050] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/01/2021] [Accepted: 07/22/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND The association between chronic plaque psoriasis and lymphohematologic malignancies (LHMs) remains controversial. OBJECTIVE To investigate the risk of LHMs in patients with psoriasis according to the best evidence. METHODS A systematic review and meta-analysis of observational cohort studies was undertaken to assess the association of psoriasis with different LHMs. A literature search for relevant studies was performed on February 28, 2021. The random-effects model in conducting meta-analyses was applied. To evaluate the risk of bias, the Newcastle-Ottawa Scale was employed. RESULTS A total of 25 observational studies were selected, comprising collectively 2,501,652 subjects. A significantly increased risk for LHM (hazard ratio [HR], 1.55; 1.24-2.94) and lymphoma (HR, 1.27; 1.08-1.50) in patients with moderate-to-severe plaque psoriasis compared to the general population was found. In detail, increased risks for Hodgkin lymphoma (HR, 1.71; 1.27-2.30), non-Hodgkin lymphoma (HR, 1.27; 1.08-1.50), multiple myeloma (HR, 1.32; 1.03-1.69), and leukemia (HR, 1.28; 1.00-1.65) were found. The risk of cutaneous T-cell lymphoma was markedly augmented in patients with psoriasis (HR, 6.22; 3.39-11.42). LIMITATIONS Possible ascertainment bias related to the diagnosis of LHMs. CONCLUSION The increased risk of LHMs, particularly cutaneous T-cell lymphoma, in patients with psoriasis could be related to exposure to systemic immunosuppressive therapies, comorbidities, and sustained immune activation, particularly in the skin.
Collapse
Affiliation(s)
- Francesco Bellinato
- Section of Dermatology and Venereology, Department of Medicine, University of Verona, Verona, Italy.
| | - Paolo Gisondi
- Section of Dermatology and Venereology, Department of Medicine, University of Verona, Verona, Italy
| | - Giampiero Girolomoni
- Section of Dermatology and Venereology, Department of Medicine, University of Verona, Verona, Italy
| |
Collapse
|
|
16
|
Mehta-Shah N, Horwitz SM, Ansell S, Ai WZ, Barnes J, Barta SK, Clemens MW, Dogan A, Fisher K, Goodman AM, Goyal G, Guitart J, Halwani A, Haverkos BM, Hoppe RT, Jacobsen E, Jagadeesh D, Lunning MA, Mehta A, Olsen EA, Pro B, Rajguru SA, Shanbhag S, Shaver A, Shustov A, Sokol L, Torka P, Torres-Cabala C, Wilcox R, William BM, Zain J, Dwyer MA, Sundar H, Kim YH. NCCN Guidelines Insights: Primary Cutaneous Lymphomas, Version 2.2020. J Natl Compr Canc Netw 2021; 18:522-536. [PMID: 32380458 DOI: 10.6004/jnccn.2020.0022] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL), and Sézary syndrome (SS) is a rare erythrodermic and leukemic subtype of CTCL characterized by significant blood involvement. Although early-stage disease can be effectively treated predominantly with skin-directed therapies, systemic therapy is often necessary for the treatment of advanced-stage disease. Systemic therapy options have evolved in recent years with the approval of novel agents such as romidepsin, brentuximab vedotin, and mogamulizumab. These NCCN Guidelines Insights discuss the diagnosis and management of MF and SS (with a focus on systemic therapy).
Collapse
Affiliation(s)
- Neha Mehta-Shah
- Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | | | | | - Weiyun Z Ai
- UCSF Helen Diller Family Comprehensive Cancer Center
| | | | - Stefan K Barta
- Abramson Cancer Center at the University of Pennsylvania
| | | | | | - Kristopher Fisher
- St. Jude Children's Research Hospital/The University of Tennessee Health Science Center
| | | | | | - Joan Guitart
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | | | | | - Deepa Jagadeesh
- Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | | | | | | | - Barbara Pro
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | - Satish Shanbhag
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
| | | | - Andrei Shustov
- Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | | | | | | | | | - Basem M William
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | | | | | | | | |
Collapse
|
|
17
|
Sanches JA, Cury-Martins J, Abreu RM, Miyashiro D, Pereira J. Mycosis fungoides and Sézary syndrome: focus on the current treatment scenario. An Bras Dermatol 2021; 96:458-471. [PMID: 34053802 PMCID: PMC8245718 DOI: 10.1016/j.abd.2020.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 11/23/2020] [Accepted: 12/06/2020] [Indexed: 11/28/2022] Open
Abstract
Cutaneous T-cell lymphomas are a heterogeneous group of lymphoproliferative disorders, characterized by infiltration of the skin by mature malignant T cells. Mycosis fungoides is the most common form of cutaneous T-cell lymphoma, accounting for more than 60% of cases. Mycosis fungoides in the early-stage is generally an indolent disease, progressing slowly from some patches or plaques to more widespread skin involvement. However, 20% to 25% of patients progress to advanced stages, with the development of skin tumors, extracutaneous spread and poor prognosis. Treatment modalities can be divided into two groups: skin-directed therapies and systemic therapies. Therapies targeting the skin include topical agents, phototherapy and radiotherapy. Systemic therapies include biological response modifiers, immunotherapies and chemotherapeutic agents. For early-stage mycosis fungoides, skin-directed therapies are preferred, to control the disease, improve symptoms and quality of life. When refractory or in advanced-stage disease, systemic treatment is necessary. In this article, the authors present a compilation of current treatment options for mycosis fungoides and Sézary syndrome.
Collapse
Affiliation(s)
- José Antonio Sanches
- Dermatology Clinic Division, Faculty of Medicine, Hospital das Clínicas, Universidade de São Paulo, São Paulo, SP, Brazil.
| | - Jade Cury-Martins
- Dermatology Clinic Division, Faculty of Medicine, Hospital das Clínicas, Universidade de São Paulo, São Paulo, SP, Brazil
| | | | - Denis Miyashiro
- Dermatology Clinic Division, Faculty of Medicine, Hospital das Clínicas, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Juliana Pereira
- Hematology Clinic Division, Faculty of Medicine, Hospital das Clínicas, Universidade de São Paulo, São Paulo, SP, Brazil
| |
Collapse
|
|
18
|
Sethi TK, Montanari F, Foss F, Reddy N. How we treat advanced stage cutaneous T-cell lymphoma - mycosis fungoides and Sézary syndrome. Br J Haematol 2021; 195:352-364. [PMID: 33987825 DOI: 10.1111/bjh.17458] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
T-cell lymphomas (TCLs) constitute a rare subset of non-Hodgkin lymphomas, with mycosis fungoides/Sézary syndrome (MF/SS) being the most common subtype of cutaneous TCLs (CTCLs). Considered an incurable but treatable disease, MF/SS management presents several challenges including diagnostic delays, debilitating effect on patients' quality of life, need for several lines of therapies, multidisciplinary care and cumulative drug toxicities limiting duration of use. The present review intends to provide an overview of the recent advances in our understanding of the biology of CTCL and how these are being leveraged to provide additional treatment options for management of advanced and recurrent disease. In addition, the discussion of the different modalities of treatment is summarised to further outline the importance of multidisciplinary care and early referral to CTCL centres.
Collapse
Affiliation(s)
- Tarsheen K Sethi
- Division of Hematology, Yale University School of Medicine, New Haven, CT, USA
| | - Francesca Montanari
- Division of Hematology, Yale University School of Medicine, New Haven, CT, USA
| | - Francine Foss
- Division of Hematology, Yale University School of Medicine, New Haven, CT, USA
| | - Nishitha Reddy
- Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, TN, USA
| |
Collapse
|
|
19
|
Mycosis Fungoides and Sézary Syndrome: An Integrative Review of the Pathophysiology, Molecular Drivers, and Targeted Therapy. Cancers (Basel) 2021; 13:cancers13081931. [PMID: 33923722 PMCID: PMC8074086 DOI: 10.3390/cancers13081931] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/09/2021] [Accepted: 04/12/2021] [Indexed: 12/29/2022] Open
Abstract
Simple Summary In the last few years, the field of cutaneous T-cell lymphomas has experienced major advances. In the context of an active translational and clinical research field, next-generation sequencing data have boosted our understanding of the main molecular mechanisms that govern the biology of these entities, thus enabling the development of novel tools for diagnosis and specific therapy. Here, we focus on mycosis fungoides and Sézary syndrome; we review essential aspects of their pathophysiology, provide a rational mechanistic interpretation of the genomic data, and discuss the current and upcoming therapies, including the potential crosstalk between genomic alterations and the microenvironment, offering opportunities for targeted therapies. Abstract Primary cutaneous T-cell lymphomas (CTCLs) constitute a heterogeneous group of diseases that affect the skin. Mycosis fungoides (MF) and Sézary syndrome (SS) account for the majority of these lesions and have recently been the focus of extensive translational research. This review describes and discusses the main pathobiological manifestations of MF/SS, the molecular and clinical features currently used for diagnosis and staging, and the different therapies already approved or under development. Furthermore, we highlight and discuss the main findings illuminating key molecular mechanisms that can act as drivers for the development and progression of MF/SS. These seem to make up an orchestrated constellation of genomic and environmental alterations generated around deregulated T-cell receptor (TCR)/phospholipase C, gamma 1, (PLCG1) and Janus kinase/ signal transducer and activator of transcription (JAK/STAT) activities that do indeed provide us with novel opportunities for diagnosis and therapy.
Collapse
|
|
20
|
Topical and Systemic Formulation Options for Cutaneous T Cell Lymphomas. Pharmaceutics 2021; 13:pharmaceutics13020200. [PMID: 33540765 PMCID: PMC7913115 DOI: 10.3390/pharmaceutics13020200] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 01/27/2021] [Accepted: 01/28/2021] [Indexed: 11/17/2022] Open
Abstract
Although various anti-cutaneous T-cell lymphoma (CTCL) therapies are available for clinical use, appropriate chemotherapy lines for the treatment of CTCLs have yet to be established. Therefore, to date, various clinical trials for the treatment of advanced CTCLs are ongoing. In this review, we evaluate the therapeutic options that are available in clinical practice for treatment of early- and advanced-stage CTCLs (targeted therapies, histone deacetylase (HDAC) inhibitors, retinoids, interferons, cytotoxic drugs, etc.). We also examine clinical trials of novel regimens for the treatment of CTCLs.
Collapse
|
|
21
|
Kamijo H, Miyagaki T. Mycosis Fungoides and Sézary Syndrome: Updates and Review of Current Therapy. Curr Treat Options Oncol 2021; 22:10. [PMID: 33415447 DOI: 10.1007/s11864-020-00809-w] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/20/2020] [Indexed: 12/12/2022]
Abstract
OPINION STATEMENT While most patients with early-stage mycosis fungoides (MF) follow an indolent course, patients with advanced-stage MF/Sézary syndrome (SS) have a poor prognosis with a median survival of less than 5 years. Although there are a number of treatments currently available, achieving and maintaining a durable response remain challenging, especially in advanced-stage MF/SS. The choice of frontline therapy is dependent on the stage of disease. For early-stage MF, the treatment concept is to control skin lesions mainly by skin-directed therapies, such as topical therapies, phototherapies, and radiotherapies. For advanced-stage MF/SS, systemic treatments by biological or targeted therapies including bexarotene and interferon either alone or in combination are tried first, with more immunosuppressive chemotherapies being reserved for refractory or rapidly progressive disease. Recent improvements in biological or targeted therapies include brentuximab vedotin and mogamulizumab. When biopsy samples have 10% or more CD30-positive malignant cells, brentuximab vedotin, an anti-CD30 antibody conjugated to monomethyl auristin E, can be a desirable treatment option. For cases with blood involvement, mogamulizumab, an antibody binding to C-C chemokine receptor 4, is effective with high response rates. In the refractory setting, alemtuzumab, histone deacetylase inhibitors, pralatrexate, gemcitabine, and doxorubicin are considered as the treatment option. Because only allogeneic hematopoietic stem cell transplantation can offer a chance of cure with durable complete remission, advanced-stage patients with a markedly short life expectancy should be evaluated for eligibility. Given that there are few randomized controlled studies in the literature, it is necessary to investigate which therapy is preferable for each patient with MF/SS by comparative prospective trials.
Collapse
Affiliation(s)
- Hiroaki Kamijo
- Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Tomomitsu Miyagaki
- Department of Dermatology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
| |
Collapse
|
|
22
|
Ohtsuka M, Hamada T, Miyagaki T, Shimauchi T, Yonekura K, Kiyohara E, Fujita H, Izutsu K, Okuma K, Kawai K, Koga H, Sugaya M. Outlines of the Japanese guidelines for the management of primary cutaneous lymphomas 2020. J Dermatol 2020; 48:e49-e71. [PMID: 33245165 DOI: 10.1111/1346-8138.15707] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 10/31/2020] [Indexed: 01/06/2023]
Abstract
Since the publication of the Japanese "Guidelines for the management of cutaneous lymphomas" in 2011, the World Health Organization (WHO) classification of hematolymphoid neoplasms and the WHO-European Organisation for Research and Treatment of Cancer classification for primary cutaneous lymphomas were updated and a number of novel systemic drugs for cutaneous T-cell lymphoma had been approved in Japan. In 2020, we revised the Japanese guidelines for the management of cutaneous lymphomas with consideration of the recent advances in the understanding of the pathophysiology and classification of cutaneous lymphomas together with the update of treatment strategies reflecting the advent of novel drugs. In addition to a brief explanation of epidemiology, diagnosis, staging system, prognosis and management of each subtype of cutaneous lymphomas, the recommendations for nine clinical questions regarding treatment options that can vary even among experts are also described. A systematic review process and determination of recommendations in answer to each clinical question have been performed in accordance with the Grading of Recommendations, Assessment, Development and Evaluation scheme by a multidisciplinary expert panel consisting of dermatologists, a hematologist and a radiation oncologist. In this article, we present the outlines of the revised Japanese "Guidelines for the management of cutaneous lymphomas".
Collapse
Affiliation(s)
- Mikio Ohtsuka
- Department of Dermatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Toshihisa Hamada
- Department of Dermatology, Takamatsu Red Cross Hospital, Takamatsu, Japan
| | - Tomomitsu Miyagaki
- Department of Dermatology, St Marianna University School of Medicine, Kawasaki, Japan
| | - Takatoshi Shimauchi
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kentaro Yonekura
- Department of Dermatology, Imamura General Hospital, Kagoshima, Japan
| | - Eiji Kiyohara
- Department of Dermatology, Osaka University School of Medicine, Suita, Japan
| | - Hideki Fujita
- Department of Dermatology, Nihon University School of Medicine, Tokyo, Japan
| | - Koji Izutsu
- Department of Hematology, National Cancer Center Hospital, Tokyo, Japan
| | - Kae Okuma
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Kazuhiro Kawai
- Department of Dermatology, Kido Hospital, Niigata, Japan
| | - Hiroshi Koga
- Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Makoto Sugaya
- Department of Dermatology, International University of Health and Welfare, Narita, Japan
| |
Collapse
|
|
23
|
Abstract
Cutaneous T-cell lymphomas are a heterogeneous collection of non-Hodgkin lymphomas that arise from skin-tropic memory T lymphocytes. Among them, mycosis fungoides (MF) and Sézary syndrome (SS) are the most common malignancies. Diagnosis requires the combination of clinical, pathologic, and molecular features. Significant advances have been made in understanding the genetic and epigenetic aberrations in SS and to some extent in MF. Several prognostic factors have been identified. The goal of treatment is to minimize morbidity and limit disease progression. However, hematopoietic stem cell transplantation, considered for patients with advanced stages, is the only therapy with curative intent.
Collapse
Affiliation(s)
- Cecilia Larocca
- Department of Dermatology, Brigham and Women's Hospital, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA.
| | - Thomas Kupper
- Department of Dermatology, Brigham and Women's Hospital, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA
| |
Collapse
|
|
24
|
Koźmiński P, Halik PK, Chesori R, Gniazdowska E. Overview of Dual-Acting Drug Methotrexate in Different Neurological Diseases, Autoimmune Pathologies and Cancers. Int J Mol Sci 2020; 21:ijms21103483. [PMID: 32423175 PMCID: PMC7279024 DOI: 10.3390/ijms21103483] [Citation(s) in RCA: 161] [Impact Index Per Article: 32.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 05/08/2020] [Accepted: 05/12/2020] [Indexed: 02/07/2023] Open
Abstract
Methotrexate, a structural analogue of folic acid, is one of the most effective and extensively used drugs for treating many kinds of cancer or severe and resistant forms of autoimmune diseases. In this paper, we take an overview of the present state of knowledge with regards to complex mechanisms of methotrexate action and its applications as immunosuppressive drug or chemotherapeutic agent in oncological combination therapy. In addition, the issue of the potential benefits of methotrexate in the development of neurological disorders in Alzheimer’s disease or myasthenia gravis will be discussed.
Collapse
|
|
25
|
Wu JH, Cohen BA, Sweren RJ. Mycosis fungoides in pediatric patients: Clinical features, diagnostic challenges, and advances in therapeutic management. Pediatr Dermatol 2020; 37:18-28. [PMID: 31630432 DOI: 10.1111/pde.14026] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Mycosis fungoides (MF) is the most common primary cutaneous lymphoma in pediatric patients. Given the indolent nature of MF, symptoms often present in childhood but may not be diagnosed as MF until adulthood. Delayed diagnosis is associated with poor long-term prognosis. Thus, increased clinician recognition and accurate diagnosis of early-stage MF in pediatric patients is critically important. In this review, we summarize the clinical features of the most common pediatric MF subtypes and highlight important differences between pediatric and adult MF. Moreover, we reviewed all pediatric MF case series published between 2008 and 2018 to analyze treatment modalities and identify emerging therapies. As treatment of pediatric MF is complex, selection of therapy varies significantly depending upon the specific clinical characteristics, disease severity, and patients' preferences.
Collapse
Affiliation(s)
- Julie H Wu
- Memorial Sloan Kettering Cancer Center, New York, New York
| | - Bernard A Cohen
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ronald J Sweren
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| |
Collapse
|
|
26
|
Lebas E, Chapelier C, Quatresooz P, Seidel L, Nikkels AF. Exploratory Assessment of Oxygen Flow-Assisted Cutaneous Administration of Methotrexate for Superficial Basal Cell Carcinoma, Mycosis Fungoides, and Extramammary Paget Disease. J Invest Dermatol 2019; 140:583-592. [PMID: 31513804 DOI: 10.1016/j.jid.2019.08.443] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 08/22/2019] [Accepted: 08/23/2019] [Indexed: 12/19/2022]
Abstract
The molecular weight of methotrexate (MTX) makes cutaneous penetration difficult. Oxygen flow could enhance the skin permeation of MTX diluted in the proprietary LP3 carrier system. This pilot study aims to assess the efficacy, safety, and tolerance of oxygen flow-assisted LP3-MTX3% for treating superficial skin cancers. Patients with superficial basal cell carcinoma (n = 12), extramammary Paget disease (n = 5), classic mycosis fungoides (MF; n = 10), and folliculotropic MF (n = 6) were included in the study and were treated with four weekly applications of oxygen flow-assisted LP3-MTX3%. Photographs and biopsies were performed before and one month after treatment. At one month after treatment, the mean superficial basal cell carcinoma erythema-crusting-thickness clinical score, the extramammary Paget disease erythema-oozing-scaling/hyperkeratosis-pain/pruritus clinical score, and the modified composite assessment of index lesion severity classic MF and folliculotropic MF scores were improved by 77.5% ± 17.1% (P < 0.0001), 66.7% ± 22.9% (P = 0.011), 51.3% ± 32.2% (P = 0.0007), and 27.8% ± 32.0% (P = 0.086), respectively. At one month after treatment, histology revealed partial and total clearances for superficial basal cell carcinoma (1/12, 11/12), extramammary Paget disease (4/5, 1/5), classic MF (8/10, 2/10), and folliculotropic MF (6/6, 0/6). Tolerance was excellent and no pain was observed. MTX was never detectable in serum at baseline and 1, 2, 3, 8, 24, 48, and 72 hours post-treatment. In conclusion, the interesting therapeutic efficacy of oxygen flow-assisted LP3-MTX3% for treating superficial basal cell carcinoma, extramammary Paget disease, and MF lesions prompts further studies on a larger scale.
Collapse
Affiliation(s)
- Eve Lebas
- Department of Dermatology, CHU of Sart Tilman, University of Liège, Liège, Belgium
| | - Corinne Chapelier
- Department of Dermatology, CHU of Sart Tilman, University of Liège, Liège, Belgium
| | - Pascale Quatresooz
- Department of Pathology, CHU of Sart Tilman, University of Liège, Liège, Belgium
| | - Laurence Seidel
- Department of Biostatistics, CHU of Sart Tilman, University of Liège, Liège, Belgium
| | - A F Nikkels
- Department of Dermatology, CHU of Sart Tilman, University of Liège, Liège, Belgium.
| |
Collapse
|
|
27
|
Ramelyte E, Dummer R, Guenova E. Investigative drugs for the treatment of cutaneous T-cell lymphomas (CTCL): an update. Expert Opin Investig Drugs 2019; 28:799-809. [PMID: 31398295 DOI: 10.1080/13543784.2019.1654995] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction: Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of skin-homing T-cell neoplasms, which represent approximately 75% of all primary cutaneous lymphomas. Mycosis fungoides and Sézary syndrome are the most common CTCL. Early stage disease follows a protracted course, carries a 5-year disease specific survival of 97% and can be treated with skin-directed therapies. Widespread, advanced disease has a 5-year OS of less than 25% and necessitates systemic treatment. Allogeneic stem cell transplantation is a potentially curative treatment option for advanced CTCL, however, transplant-related morbidity and mortality must be considered and a risk-benefit assessment performed on individual basis. Areas covered: Herein, we provide a review of investigative drugs in early-stage trials for the treatment of cutaneous CTCL, including topically applied immunomodulators such as replicating herpes virus or toll-like receptor 7/8 agonist resiquimod and systemic therapies with monoclonal antibodies, such as anti-CD47, recombinant cytotoxic interleukin 2 fusion protein anti-KIR3DL2 antibody and anti-miR-155 antibody. Expert Opinion: Among the reviewed drugs, resiquimod shows promising clinical efficacy with good tolerability in early CTCL. In refractory or relapsed disease, intratumoral anti-CD47-, anti-CCR4- and anti-KIR3DL2-antibodies show high response rates, however, latter two also show considerable toxicity. Larger trials are needed to better evaluate the discussed therapies.
Collapse
Affiliation(s)
- Egle Ramelyte
- Department of Dermatology, University Hospital of Zurich , Zurich , Switzerland.,Faculty of Medicine, University of Zurich , Zurich , Switzerland
| | - Reinhard Dummer
- Department of Dermatology, University Hospital of Zurich , Zurich , Switzerland.,Faculty of Medicine, University of Zurich , Zurich , Switzerland
| | - Emmanuella Guenova
- Department of Dermatology, University Hospital of Zurich , Zurich , Switzerland.,Faculty of Medicine, University of Zurich , Zurich , Switzerland
| |
Collapse
|
|
28
|
Khan S, Sawas A. Antibody-Directed Therapies: Toward a Durable and Tolerable Treatment Platform for CTCL. Front Oncol 2019; 9:645. [PMID: 31417860 PMCID: PMC6683760 DOI: 10.3389/fonc.2019.00645] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 07/01/2019] [Indexed: 12/31/2022] Open
Abstract
Cutaneous T-cell lymphomas (CTCL) are a rare group of heterogeneous disorders characterized by cutaneous involvement of monoclonal T-lymphocytes. Although indolent at early stages, CTCL can confer significant morbidity, and mortality when advanced. There is an unmet need for tolerable and durable treatments with antibodies recently gaining promise. Here we review approved systemic therapies and discuss select antibodies in development.
Collapse
Affiliation(s)
- Shaheer Khan
- Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, The New York Presbyterian Hospital, College of Physician and Surgeons, New York, NY, United States
| | - Ahmed Sawas
- Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, The New York Presbyterian Hospital, College of Physician and Surgeons, New York, NY, United States
| |
Collapse
|
|
29
|
Denis D, Beneton N, Laribi K, Maillard H. Management of mycosis fungoides-type cutaneous T-cell lymphoma (MF-CTCL): focus on chlormethine gel. Cancer Manag Res 2019; 11:2241-2251. [PMID: 30962713 PMCID: PMC6433101 DOI: 10.2147/cmar.s138661] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Mycosis fungoides (MF) is a low-grade cutaneous lymphoma accounting for more than half of primary cutaneous T-cell lymphomas (CTCLs). Due to the rarity of CTCL, randomized studies are lacking, and treatment is based mainly on the recent published European Organisation for Research and Treatment of Cancer guidelines. Basically, early-stage MF is treated with skin-directed treatments, whereas advanced-stage MF requires more aggressive therapies. Among the skin-directed therapies, nitrogen mustard has been used for more than 50 years. A gel formulation was developed recently, showing a slight decrease in efficacy, counterbalanced by better tolerance (essentially due to a decrease in delayed hypersensitivity reactions). This review aims to summarize the current management of MF and the role of chlormethine gel in the treatment of the disease.
Collapse
Affiliation(s)
- Daphné Denis
- Dermatology Department, Centre Hospitalier Le Mans, Le Mans, France,
| | - Nathalie Beneton
- Dermatology Department, Centre Hospitalier Le Mans, Le Mans, France,
| | - Kamel Laribi
- Haematology Department, Centre Hospitalier Le Mans, Le Mans, France
| | - Hervé Maillard
- Dermatology Department, Centre Hospitalier Le Mans, Le Mans, France,
| |
Collapse
|
|
30
|
Wain T, Venning VL, Consuegra G, Fernandez‐Peñas P, Wells J. Management of cutaneous T‐cell lymphomas: Established and emergent therapies. Australas J Dermatol 2019; 60:200-208. [DOI: 10.1111/ajd.13011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 01/28/2019] [Indexed: 01/04/2023]
Affiliation(s)
- Thevaki Wain
- Department of Dermatology Westmead Hospital SydneyNew South Wales Australia
| | - Victoria L Venning
- The Skin Hospital WestmeadNew South Wales Australia
- Faculty of Medicine University of Sydney Sydney New South Wales Australia
| | - Germana Consuegra
- Department of Dermatology Westmead Hospital SydneyNew South Wales Australia
- Faculty of Medicine University of Sydney Sydney New South Wales Australia
| | - Pablo Fernandez‐Peñas
- Department of Dermatology Westmead Hospital SydneyNew South Wales Australia
- The Skin Hospital WestmeadNew South Wales Australia
- Faculty of Medicine University of Sydney Sydney New South Wales Australia
| | - Jillian Wells
- Department of Dermatology Westmead Hospital SydneyNew South Wales Australia
- Faculty of Medicine University of Sydney Sydney New South Wales Australia
| |
Collapse
|
|
31
|
Querfeld C, Zain J, Rosen ST. Primary Cutaneous T-Cell Lymphomas: Mycosis Fungoides and Sezary Syndrome. Cancer Treat Res 2019; 176:225-248. [PMID: 30596221 DOI: 10.1007/978-3-319-99716-2_11] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Mycosis fungoides and Sézary syndrome are the most common subtypes of all primary cutaneous lymphomas and represent complex diseases that require a multidisciplinary assessment by dermatologists, oncologists, and pathologists. Staging and work-up are critical to guarantee an optimal treatment plan that includes skin-directed and/or systemic regimens depending on the clinical stage, tumor burden, drug-related side effect profile, and patient comorbidities. However, there is no cure and patients frequently relapse, requiring repeated treatment courses for disease control. The study of the tumor microenvironment and molecular mechanisms of these rare neoplasms may assist in the development of new immune therapies providing promising treatment approaches tailored for patients with relapse/refractory disease.
Collapse
Affiliation(s)
- Christiane Querfeld
- Division of Dermatology, City of Hope, 1500 E. Duarte Road, Duarte, CA, 91010, USA.
- Department of Hematology/Hematopoietic Cell Transplantation, Duarte, USA.
- Department of Pathology, Duarte, USA.
- Toni Stephenson Lymphoma Center, City of Hope National Medical Center, Duarte, CA, USA.
| | - Jasmine Zain
- Department of Hematology/Hematopoietic Cell Transplantation, Duarte, USA
- Toni Stephenson Lymphoma Center, City of Hope National Medical Center, Duarte, CA, USA
| | - Steven T Rosen
- Department of Hematology/Hematopoietic Cell Transplantation, Duarte, USA
- Toni Stephenson Lymphoma Center, City of Hope National Medical Center, Duarte, CA, USA
| |
Collapse
|
|
32
|
Prince HM, Querfeld C. Integrating novel systemic therapies for the treatment of mycosis fungoides and Sézary syndrome. Best Pract Res Clin Haematol 2018; 31:322-335. [PMID: 30213403 DOI: 10.1016/j.beha.2018.07.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 07/11/2018] [Accepted: 07/12/2018] [Indexed: 11/26/2022]
Abstract
Novel systemic therapies are generally prescribed to patients with advanced-stage disease or those with early-stage disease refractory to skin-directed therapies. In general, systemic chemotherapy should be reserved for patients who fail to respond to biological agents. Such biological agents include interferon alfa, bexarotene, histone deacetylase inhibitors (vorinostat, romidepsin), brentuximab vedotin and mogamulizumab. Extracorporeal photopheresis is particularly effective for patients with Sézary Syndrome. Allogeneic transplantation is becoming increasing used for younger patients. Novel agents in advanced development include the monoclonal antibody IPH4102,duvelisib,and the new modified formulation of denileukin diftitox. The choice of agents for patients is typically a balance of patient factors (age, co-morbidities, geographic location), relative efficacy and toxicity.
Collapse
Affiliation(s)
- H Miles Prince
- Epworth Healthcare and Sir Peter MacCallum Department of Oncology, University of Melbourne, 140 Clarendon Street, East Melbourne, Victoria, Australia.
| | - Christiane Querfeld
- City of Hope National Medical Center, Beckman Research Institute, 1500 E. Duarte Road, Duarte, CA 91010, USA.
| |
Collapse
|
|
33
|
Erraji H, Ramid H, Hali F, Chiheb S. Le méthotrexate en monothérapie dans le traitement du mycosis fongoïde : expérience du service de dermatologie de Casablanca. Ann Dermatol Venereol 2018. [DOI: 10.1016/j.annder.2018.03.066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
|
|
34
|
Abstract
PURPOSE OF REVIEW Cutaneous T-cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma. Globally, the most common subtypes of CTCL are mycosis fungoides and Sézary syndrome. CTCL can confer significant morbidity and even mortality in advanced disease. Here we review the current and potential future treatments for advanced-stage CTCL. RECENT FINDINGS Heterogeneity of treatment choice has been demonstrated both in US and non-US centers. Systemic treatment choice is currently guided by prognostic features, incorporating stage, immunophenotypic and molecular findings, and patient-specific factors such as age and comorbidities. Randomized controlled studies are uncommon, and the literature is composed predominantly of retrospective, cohort, and early-phase studies. International consensus guidelines are available; however, the lack of comparative trials means that there is no clear algorithmic approach to treatment. This review article reports on the systemic treatment options in current use for advanced CTCL, and on the possible future therapies, acknowledging that an algorithmic approach is not yet forthcoming to guide treatment prioritization.
Collapse
|
|
35
|
Wain T, Pavli A, Wells J, Fernandez-Peñas P. The efficacy and safety of methotrexate versus interferon in cutaneous T-cell lymphomas. J DERMATOL TREAT 2018; 29:715-719. [PMID: 29455635 DOI: 10.1080/09546634.2018.1441492] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
OBJECTIVES Methotrexate (MTX) and interferon (IFN) have been used in the treatment of cutaneous T-cell lymphomas (CTCL) of various subtypes. We review our experience of MTX and IFN use in our patients with CTCL at a tertiary hospital. MATERIALS AND METHODS Medical records of patients over 4 years were reviewed. We describe the dosages, time to response, response rates, side effects, progression rate, and reasons for discontinuation. RESULTS Response rate was significantly higher in the IFN group than MTX group (86.67% and 47.4% respectively, p = .01). Disease progression occurred 57.89% in the MTX group whilst only 26.67% progressed with IFN therapy. Patients taking IFN therapy experienced proportionally more side effects of any type than those undertaking MTX treatment (86.67% vs. 47.37%, odds ratio 7.22). However, discontinuation rate in the IFN group (26.67%) was much lower than in the MTX arm (89.47%). CONCLUSIONS The most significant finding of this study was that patients with CTCL treated with IFN had a better response rate and significantly shorter response time compared with those treated with MTX. Additionally, patients had less disease progression on IFN than with MTX regardless of subtype of T-cell lymphoma and stage of disease.
Collapse
Affiliation(s)
- Thevaki Wain
- a Department of Dermatology , Westmead Hospital , Sydney , Australia
| | - Alexandra Pavli
- a Department of Dermatology , Westmead Hospital , Sydney , Australia
| | - Jillian Wells
- a Department of Dermatology , Westmead Hospital , Sydney , Australia
| | - Pablo Fernandez-Peñas
- a Department of Dermatology , Westmead Hospital , Sydney , Australia.,b Sydney Medical School , University of Sydney , Sydney , Australia
| |
Collapse
|
|
36
|
Janiga J, Kentley J, Nabhan C, Abdulla F. Current systemic therapeutic options for advanced mycosis fungoides and Sézary syndrome. Leuk Lymphoma 2018; 59:562-577. [PMID: 29308723 DOI: 10.1080/10428194.2017.1347650] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common cutaneous T-cell lymphomas (CTCLs). Both lack curative options, and advanced-stage carries a poor prognosis. Whilst there are a number of treatments available, achieving and maintaining a durable remission remains challenging. We review current systemic treatment options as monotherapy for advanced-stage MF (IIB-IV), appraising their mechanism of action, analyzing their efficacy, and describing toxicities. Individually, reported overall response rates (ORR) vary widely in the literature and duration of responses are typically short, ranging from 7.5 to 22.4 months. Combined therapy is frequently used in an effort to boost responses, although prospective studies comparing combinations to single agent therapies are rarely conducted. While recent translational research has led to increased understanding of the immunopathogenesis of MF and SS and the development of new treatments, current standard of care therapies are not curative and have low ORR for advanced-stage disease.
Collapse
Affiliation(s)
- Jenna Janiga
- a Stritch School of Medicine , Loyola University , Chicago , IL , USA
| | - Jonathan Kentley
- b Department of Dermatology , Royal London Hospital, Barts Health NHS Trust , London , UK
| | - Chadi Nabhan
- c Cardinal Health Specialty Solutions , Waukegan , IL , USA
| | - Farah Abdulla
- d Department of Medicine, Section of Dermatology , University of Chicago Medicine and Biological Sciences , Chicago , IL , USA
| |
Collapse
|
|
37
|
Geskin L, Malone DC. An exploratory cost-effectiveness analysis of systemic treatments for cutaneous T-cell lymphoma. J DERMATOL TREAT 2017; 29:522-530. [DOI: 10.1080/09546634.2017.1412064] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Larisa Geskin
- Department of Dermatology, Columbia University Medical Center, New York, NY, USA
| | | |
Collapse
|
|
38
|
Wilcox RA. Cutaneous T-cell lymphoma: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol 2017; 92:1085-1102. [PMID: 28872191 DOI: 10.1002/ajh.24876] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 07/27/2017] [Indexed: 12/12/2022]
Abstract
DISEASE OVERVIEW Cutaneous T-cell lymphomas are a heterogenous group of T-cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS). DIAGNOSIS The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multi-disciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or blood involvement are generally approached with biologic-response modifiers or histone deacetylase inhibitors prior to escalating therapy to include systemic, single-agent chemotherapy. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.
Collapse
Affiliation(s)
- Ryan A. Wilcox
- Division of Hematology/Oncology; University of Michigan Comprehensive Cancer Center; Ann Arbor Michigan 48109-5948
| |
Collapse
|
|
39
|
Prince HM, Kim YH, Horwitz SM, Dummer R, Scarisbrick J, Quaglino P, Zinzani PL, Wolter P, Sanches JA, Ortiz-Romero PL, Akilov OE, Geskin L, Trotman J, Taylor K, Dalle S, Weichenthal M, Walewski J, Fisher D, Dréno B, Stadler R, Feldman T, Kuzel TM, Wang Y, Palanca-Wessels MC, Zagadailov E, Trepicchio WL, Zhang W, Lin HM, Liu Y, Huebner D, Little M, Whittaker S, Duvic M. Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet 2017; 390:555-566. [PMID: 28600132 DOI: 10.1016/s0140-6736(17)31266-7] [Citation(s) in RCA: 386] [Impact Index Per Article: 48.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 03/01/2017] [Accepted: 03/14/2017] [Indexed: 12/26/2022]
Abstract
BACKGROUND Cutaneous T-cell lymphomas are rare, generally incurable, and associated with reduced quality of life. Present systemic therapies rarely provide reliable and durable responses. We aimed to assess efficacy and safety of brentuximab vedotin versus conventional therapy for previously treated patients with CD30-positive cutaneous T-cell lymphomas. METHODS In this international, open-label, randomised, phase 3, multicentre trial, we enrolled adult patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma who had been previously treated. Patients were enrolled across 52 centres in 13 countries. Patients were randomly assigned (1:1) centrally by an interactive voice and web response system to receive intravenous brentuximab vedotin 1·8 mg/kg once every 3 weeks, for up to 16 3-week cycles, or physician's choice (oral methotrexate 5-50 mg once per week or oral bexarotene 300 mg/m2 once per day) for up to 48 weeks. The primary endpoint was the proportion of patients in the intention-to-treat population achieving an objective global response lasting at least 4 months per independent review facility. Safety analyses were done in all patients who received at least one dose of study drug. This trial was registered with ClinicalTrials.gov, number NCT01578499. FINDINGS Between Aug 13, 2012, and July 31, 2015, 131 patients were enrolled and randomly assigned to a group (66 to brentuximab vedotin and 65 to physician's choice), with 128 analysed in the intention-to-treat population (64 in each group). At a median follow-up of 22·9 months (95% CI 18·4-26·1), the proportion of patients achieving an objective global response lasting at least 4 months was 56·3% (36 of 64 patients) with brentuximab vedotin versus 12·5% (eight of 64) with physician's choice, resulting in a between-group difference of 43·8% (95% CI 29·1-58·4; p<0·0001). Grade 3-4 adverse events were reported in 27 (41%) of 66 patients in the brentuximab vedotin group and 29 (47%) of 62 patients in the physician's choice group. Peripheral neuropathy was seen in 44 (67%) of 66 patients in the brentuximab vedotin group (n=21 grade 2, n=6 grade 3) and four (6%) of 62 patients in the physician's choice group. One of the four on-treatment deaths was deemed by the investigator to be treatment-related in the brentuximab vedotin group; no on-treatment deaths were reported in the physician's choice group. INTERPRETATION Significant improvement in objective response lasting at least 4 months was seen with brentuximab vedotin versus physician's choice of methotrexate or bexarotene. FUNDING Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd), Seattle Genetics Inc.
Collapse
Affiliation(s)
- H Miles Prince
- Division of Cancer Medicine, Peter MacCallum Cancer Centre, The University of Melbourne, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia; Epworth Healthcare, The University of Melbourne, Melbourne, VIC, Australia.
| | - Youn H Kim
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford, CA, USA
| | - Steven M Horwitz
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Reinhard Dummer
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
| | - Julia Scarisbrick
- Department of Dermatology, University Hospital Birmingham, Birmingham, UK
| | - Pietro Quaglino
- Department of Medical Sciences, Dermatologic Clinic, University of Turin, Turin, Italy
| | | | - Pascal Wolter
- Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium
| | - Jose A Sanches
- Department of Dermatology, University of São Paulo Medical School, São Paulo, Brazil
| | - Pablo L Ortiz-Romero
- Department of Dermatology, University Hospital 12 de Octubre, Institute i+12 Medical School, University Complutense, Madrid, Spain
| | - Oleg E Akilov
- Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Larisa Geskin
- Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Dermatology, Columbia University, New York, NY, USA
| | - Judith Trotman
- Department of Haematology, Concord Repatriation General Hospital, University of Sydney, Concord, NSW, Australia
| | - Kerry Taylor
- ICON Cancer Care, South Brisbane, QLD, Australia
| | - Stephane Dalle
- Department of Dermatology, Hospices Civils de Lyon, Claude Bernard Lyon 1 University, Lyon, France
| | - Michael Weichenthal
- Department of Dermatology, University Hospital of Schleswig-Holstein, Kiel, Germany
| | - Jan Walewski
- Maria Sklodowska-Curie Institute and Oncology Centre, Warsaw, Poland
| | | | | | - Rudolf Stadler
- University Clinic for Dermatology, Johannes Wesling Medical Centre, Minden, Germany
| | - Tatyana Feldman
- John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ, USA
| | - Timothy M Kuzel
- Division of Hematology/Oncology/Cell Therapy, Department of Medicine, Rush University, Chicago, IL, USA
| | | | | | - Erin Zagadailov
- Millennium Pharmaceuticals Inc, Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA
| | - William L Trepicchio
- Millennium Pharmaceuticals Inc, Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA
| | - Wenwen Zhang
- Millennium Pharmaceuticals Inc, Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA
| | - Hui-Min Lin
- Millennium Pharmaceuticals Inc, Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA
| | - Yi Liu
- Millennium Pharmaceuticals Inc, Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA
| | - Dirk Huebner
- Millennium Pharmaceuticals Inc, Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA
| | - Meredith Little
- Millennium Pharmaceuticals Inc, Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA
| | - Sean Whittaker
- St John's Institute of Dermatology, Guys and St Thomas NHS Foundation Trust, London, UK
| | - Madeleine Duvic
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| |
Collapse
|
|
40
|
Warren RB, Weatherhead SC, Smith CH, Exton LS, Mohd Mustapa MF, Kirby B, Yesudian PD. British Association of Dermatologists' guidelines for the safe and effective prescribing of methotrexate for skin disease 2016. Br J Dermatol 2017; 175:23-44. [PMID: 27484275 DOI: 10.1111/bjd.14816] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/29/2016] [Indexed: 12/25/2022]
Affiliation(s)
- R B Warren
- The Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester Academic Health Science Centre, Manchester, M6 8HD, U.K
| | - S C Weatherhead
- Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, U.K
| | - C H Smith
- St John's Institute of Dermatology, Guy's and St Thomas NHS Foundation Trust, London, SE1 9RT, U.K
| | - L S Exton
- British Association of Dermatologists, Willan House, 4 Fitzroy Square, London, W1T 5HQ, U.K
| | - M F Mohd Mustapa
- British Association of Dermatologists, Willan House, 4 Fitzroy Square, London, W1T 5HQ, U.K
| | - B Kirby
- St Vincent's University Hospital, Elm Park, Dublin, Ireland
| | - P D Yesudian
- Glan Clwyd Hospital, Sarn Lane, Rhyl, LL18 5UJ, U.K
| |
Collapse
|
|
41
|
Cutaneous Lymphoma—Inpatient Considerations. CURRENT DERMATOLOGY REPORTS 2017. [DOI: 10.1007/s13671-017-0173-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
|
|
42
|
Apoptosis Induction and Gene Expression Profile Alterations of Cutaneous T-Cell Lymphoma Cells following Their Exposure to Bortezomib and Methotrexate. PLoS One 2017; 12:e0170186. [PMID: 28107479 PMCID: PMC5249051 DOI: 10.1371/journal.pone.0170186] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 12/30/2016] [Indexed: 01/11/2023] Open
Abstract
Mycosis fungoides (MF) and its leukemic variant Sézary syndrome (SS) comprise the majority of CTCL, a heterogenous group of non-Hodgkins lymphomas involving the skin. The CTCL’s resistance to chemotherapy and the lack of full understanding of their pathogenesis request further investigation. With the view of a more targeted therapy, we evaluated in vitro the effectiveness of bortezomib and methotrexate, as well as their combination in CTCL cell lines, regarding apoptosis induction. Our data are of clinical value and indicate that the bortezomib/methotrexate combinational therapy has an inferior impact on the apoptosis of CTCL compared to monotherapy, with bortezomib presenting as the most efficient treatment option for SS and methotrexate for MF. Using PCR arrays technology, we also investigated the alterations in the expression profile of genes related to DNA repair pathways in CTCL cell lines after treatment with bortezomib or methotrexate. We found that both agents, but mostly bortezomib, significantly deregulate a large number of genes in SS and MF cell lines, suggesting another pathway through which these agents could induce apoptosis in CTCL. Finally, we show that SS and MF respond differently to treatment, verifying their distinct nature and further emphasizing the need for discrete treatment approaches.
Collapse
|
|
43
|
Abstract
Mycosis fungoides is the most common primary cutaneous T-cell lymphoma. The approach to diagnosis and further follow-up is outlined. Evidence for interventions is based classically on a Tumor Node Metastasis Blood TNMB “stage-based” approach. The treatment options in India are limited. The options as per risk stratification and prognostic index are discussed. Early stages and low-risk patients can be managed with expectant policy or skin-directed therapies including topical steroids and phototherapy; intermediate-risk patients can be opted for interferons or retinoids or low dose methotrexate along with radiotherapy including total skin electron beam therapy while high-risk patients are managed most often with single agent or multiagent palliative chemotherapy. Patients who are intermediate- or high-risk need management by a multispecialty team at tertiary care centers.
Collapse
|
|
44
|
Virmani P, Hwang SH, Hastings JG, Haverkos BM, Kohnken B, Gru AA, Mishra A, Fabbro SK, Horwitz SM, Porcu P. Systemic therapy for cutaneous T-cell lymphoma: who, when, what, and why? Expert Rev Hematol 2016; 10:111-121. [DOI: 10.1080/17474086.2017.1270201] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Affiliation(s)
- Pooja Virmani
- Department of Medicine, Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Susan H. Hwang
- Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH, USA
| | - Justin G. Hastings
- Department of Internal Medicine, Division of Dermatology, The Ohio State University, Columbus, OH, USA
| | | | - Becca Kohnken
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
- Department of Veterinary Biosciences, Ohio State University, Columbus, OH, USA
| | - Alejandro A Gru
- Department of Pathology, University of Virginia, Charlottesville, VA, USA
| | - Anjali Mishra
- Department of Internal Medicine, Division of Dermatology, The Ohio State University, Columbus, OH, USA
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Stephanie K. Fabbro
- Department of Internal Medicine, Division of Dermatology, The Ohio State University, Columbus, OH, USA
| | - Steve M. Horwitz
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Pierluigi Porcu
- Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH, USA
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| |
Collapse
|
|
45
|
Ma H, Abdul-Hay M. T-cell lymphomas, a challenging disease: types, treatments, and future. Int J Clin Oncol 2016; 22:18-51. [PMID: 27743148 PMCID: PMC7102240 DOI: 10.1007/s10147-016-1045-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 09/26/2016] [Indexed: 02/06/2023]
Abstract
T-cell lymphomas are rare and aggressive malignancies associated with poor outcome, often because of the development of resistance in the lymphoma against chemotherapy as well as intolerance in patients to the established and toxic chemotherapy regimens. In this review article, we discuss the epidemiology, pathophysiology, current standard of care, and future treatments of common types of T-cell lymphomas, including adult T-cell leukemia/lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large-cell lymphoma, aggressive NK/T-cell lymphoma, and cutaneous T-cell lymphoma.
Collapse
Affiliation(s)
- Helen Ma
- Department of Internal Medicine, New York University, New York, NY, USA
| | - Maher Abdul-Hay
- Department of Internal Medicine, New York University, New York, NY, USA. .,Perlmutter Cancer Center, New York University, New York, NY, USA.
| |
Collapse
|
|
46
|
How I treat mycosis fungoides and Sézary syndrome. Blood 2016; 127:3142-53. [DOI: 10.1182/blood-2015-12-611830] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 04/12/2016] [Indexed: 12/11/2022] Open
Abstract
AbstractMycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma variant and is closely related to a rare leukemic variant, Sézary syndrome (SS). MF patients at risk of disease progression can now be identified and an international consortium has been established to address the prognostic relevance of specific biologic factors and define a prognostic index. There are a lack of randomized clinical trial data in MF/SS and evidence is based on a traditional “stage-based” approach; treatment of early-stage disease (IA-IIA) involves skin directed therapies which include topical corticosteroids, phototherapy (psoralen with UVA or UVB), topical chemotherapy, topical bexarotene, and radiotherapy including total skin electron beam therapy. Systemic approaches are used for refractory early-stage and advanced-stage disease (IIB-IV) and include bexarotene, interferon α, extracorporeal photopheresis, histone deacetylase inhibitors, and antibody therapies such as alemtuzumab, systemic chemotherapy, and allogeneic transplantation. However, despite the number of biologic agents available, the treatment of advanced-stage disease still represents an unmet medical need with short duration of responses. Encouragingly, randomized phase 3 trials are assessing novel agents, including brentuximab vedotin and the anti-CCR4 antibody, mogamulizumab. A broader understanding of the biology of MF/SS will hopefully identify more effective targeted therapies.
Collapse
|
|
47
|
Erythrodermic mycosis fungoides treated with low-dose methotrexate and 311 nm UV-B: A case report with 3-year follow up and literature review. DERMATOL SIN 2016. [DOI: 10.1016/j.dsi.2015.07.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
|
|
48
|
Mycosis fungoides: therapeutic difficulties. Postepy Dermatol Alergol 2016; 32:404-8. [PMID: 26759552 PMCID: PMC4692811 DOI: 10.5114/pdia.2014.44005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Accepted: 01/19/2014] [Indexed: 11/17/2022] Open
|
|
49
|
Panoptic clinical review of the current and future treatment of relapsed/refractory T-cell lymphomas: Cutaneous T-cell lymphomas. Crit Rev Oncol Hematol 2016; 99:228-40. [PMID: 26811014 DOI: 10.1016/j.critrevonc.2015.12.018] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 11/12/2015] [Accepted: 12/23/2015] [Indexed: 11/24/2022] Open
Abstract
Primary cutaneous T-cell lymphomas (CTCLs), such as mycosis fungoides and Sézary syndrome, are a rare group of non-Hodgkin lymphomas, usually treated using a multimodal approach. Unfortunately, many patients go on to develop relapsed/refractory disease. Systemic treatment for relapsed/refractory CTCL has historically relied on chemotherapies and interferons, and while active, responses are often short-lived. Three drugs are now approved in the US to treat relapsed/refractory CTCL including the oral retinoid, bexarotene, and histone deacetylase inhibitors, romidepsin and vorinostat. Although response rates are typically <35%, romidepsin and vorinostat can induce some durable responses in heavily pretreated patients and alleviate bothersome symptoms, such as pruritus. New studies indicate that the anti-CD30 antibody-drug conjugate brentuximab vedotin, anti-CCR4 antibody mogamulizumab, and fusion protein immunotoxin A-dmDT390-bisFv(UCHT1) may be particularly active in this setting. In this paper, we present an exhaustive review of the clinical data on current and possible future drug treatment options for relapsed/refractory CTCL.
Collapse
|
|
50
|
Wilcox RA. Cutaneous T-cell lymphoma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol 2016; 91:151-65. [PMID: 26607183 PMCID: PMC4715621 DOI: 10.1002/ajh.24233] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 11/03/2015] [Indexed: 12/11/2022]
Abstract
DISEASE OVERVIEW Cutaneous T-cell lymphomas are a heterogenous group of T-cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS). DIAGNOSIS The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral, or blood involvement are generally approached with biologic-response modifiers or histone deacetylase inhibitors before escalating therapy to include systemic, single-agent chemotherapy. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.
Collapse
Affiliation(s)
- Ryan A. Wilcox
- Division of Hematology/Oncology, University of Michigan Cancer Center, 1500 E. Medical Center Drive, Room 4310 CC, Ann Arbor, MI 48109-5948
| |
Collapse
|