Updates in cutaneous lymphoma: evidence-based guidelines for the management of cutaneous lymphoma 2018

In 2003, the British Association of Dermatologists and U.K. Cutaneous Lymphoma Group produced the first guidelines for the management of primary cutaneous T-cell lymphomas (CTCLs).1 These guidelines have been updated recently and are published in this issue of the BJD.2 The authors offer a comprehensive study of primary cutaneous lymphomas, including CTCLs and cutaneous B-cell lymphomas (CBCL). These updated guidelines are presented as a detailed evaluation of all relevant literature with highlighted recommendations and algorithms for practical use in the clinic.

Compared with the 2003 guidelines, this updated version adds guidelines for CBCLs and rare CTCL variants. The treatment options for CTCL include separate recommendations for mycosis fungoides (MF) and Sézary syndrome (SS), which have been made according to disease stage, as the prognosis and the selection of appropriate treatment are based on the stage of disease. Some health economic implications are also presented.

In these updated guidelines, multidisciplinary team (MDT) meetings are considered essential for treatment decisions in all patients with cutaneous lymphoma, as primary cutaneous lymphomas are rare and heterogeneous malignancies that can represent considerable diagnostic and therapeutic difficulties. The National Institute for Health and Care Excellence Improving Outcomes Guidance (IOG) defines whether the patient should be referred to the specialist skin cancer MDT meetings or supranetwork MDT meetings across England. In these MDTs, dermatologists, clinical oncologists, haemato-oncologists and both dermatopathologists and haematopathologists are involved in diagnosis and therapeutic decision making. The IOG recommends that all patients with advanced-stage MF or SS and rare CTCL variants should be reviewed by the supranetwork MDT for treatment options.

Skin-directed therapies, including topical steroids, topical nitrogen mustard, phototherapy and skin radiotherapy, are recommended as first-line options in early stages of MF. The evidence for the efficacy of narrowband ultraviolet B (NB-UVB) is provided, especially for patch stage patients. A retrospective case series has shown that NB-UVB is as effective as psoralen–ultraviolet A (PUVA) for treatment of early-stage MF, with no difference in time to relapse.3

Combination PUVA regimens are not recommended in the algorithm since recent randomized controlled trial (RCT) studies showed that PUVA combined with interferon-alpha or bexarotene does not improve overall response, although the combined regimen may improve the duration of response and can reduce cumulative UVA dose. Total skin electron beam (TSEB) therapy has been studied extensively in CTCL. Recent evidence has shown adequate response rates and duration of response with lower doses of TSEB (10–30 Gy).4

As regards systemic therapies for MF and SS, interferon-alpha has shown overall response rates of greater than 50% and complete response rates of greater than 20%. However, interferon-alpha has not been suggested for use in patients with early-stage MF who are responsive to skin-directed therapies, as there is no evidence that interferon affects long-term outcome. Prospective studies of bexarotene have shown significant efficacy and good duration of response with low rates of disease progression in both early- and late-stage disease. Thus, bexarotene is recommended as the second-line treatment for early-stage MF, and the first-line treatment in advanced-stage MF, following the U.K. consensus guidelines for bexarotene prescribing and management.5

The newly developed antibody therapies for treatment of MF and SS have been appraised in addition to the use of pre-existing antibodies. Antibody therapies were not recommended to be used for patients with early-stage disease. Alemtuzumab remains an important second-line therapeutic option for patients with advanced disease, although recent evidence suggests that alemtuzumab is ineffective in patients with MF with tumours and large cell transformation.6

Brentuximab vedotin, an anti-CD30 antibody–drug conjugate, that targets CD30⁺ malignant T cells is recommended as the second-line treatment option for advanced stages of MF according to the encouraging high response rates in phase II and phase III trials. In a phase III trial (ALCANZA) designed to evaluate single-agent brentuximab vedotin vs. investigator's choice of standard therapies in patients with CD30-expressing CTCL, brentuximab vedotin resulted in a significant improvement in the rate of objective response lasting at least 4 months (56·3% vs. 12·5%), in addition to a prolonged median progression-free survival (16·7 vs. 3·5 months).7 Histone deacetylase inhibitors, the emerging class of epigenetic modifying drugs, are not recommended for early-stage MF but can be effective for patients with resistant/refractory disease and disease in advanced stages.

Systemic chemotherapy is contraindicated for early stages of MF and is only reserved as the third-line treatment for patients for advanced stages with refractory progressive disease, because of the lack of durable responses. Recent studies have shown that first-line chemotherapy was associated with a higher risk of death in MF and SS.8 Recent data also pointed out that more intensive regimens have little clinical benefit over less intensive regimens.

Autologous haematopoietic stem cell transplant (HSCT) is not recommended as a treatment option anymore, as it appears to be associated with rapid relapse. A meta-analysis of HSCT in MF and SS supports the view that allogeneic transplantation provides a better survival and disease-free outcome than autologous transplantation.9 Allogeneic HSCT with reduced intensity conditioning regimens, rather than the myeloablative regimens, is recommended. Better responses are achieved in patients in complete or almost complete remission.

In primary cutaneous CD30 lymphoproliferative diseases, the second most frequent subtype of CTCL, treatment recommendations are based on the European Organisation for Research and Treatment of Cancer, International Society for Cutaneous Lymphomas and United States Cutaneous Lymphoma Consortium consensus statement.10 Brentuximab vedotin has been approved by the U.S. Food and Drug Administration and European Medicines Agency for patients with primary cutaneous anaplastic large cell lymphoma or CD30-expressing MF after at least one prior systemic therapy.

European Organisation for Research and Treatment of Cancer consensus guidelines were referred to for the treatment recommendations for CBCL.11 Separate recommendations have been made for low-grade variants (primary cutaneous marginal zone and follicle centre lymphomas) and high-grade lymphomas (primary cutaneous diffuse large B-cell lymphomas).

In conclusion, the 2018 guidelines offer detailed and useful up-to-date and evidence-based recommendations covering the full spectrum of cutaneous lymphomas. It offers physicians around the world evidence-based guidance for deciding on treatment options. However, there remains much for us to study regarding cutaneous lymphomas. There is a lack of high-quality evidence, with only a few published RCTs to date. Large-scale clinical studies involving international multicentre collaborations are needed.

Conflicts of interest

None to declare.