Methotrexate in mycosis fungoides revisited

Abstract

Primary cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin lymphomas characterized by the accumulation of skin-homing lymphocytes, leading to macular or, in later stages, nodular skin lesions. Mycosis fungoides (MF) is the most common entity among CTCL. Diagnosis is based on clinical features and is supported by histological and molecular biological findings.¹ The treatment of MF, apart from allogenic stem cell transplantation, is palliative; therefore, maintaining quality of life is the primary focus. Topical therapies are the most frequently used first-line treatments, including corticosteroids, chlormethine or UV radiation (nbUVB or PUVA).^{1, 2} If these measures are insufficient, immunomodulatory medications are often introduced combination with UV therapy. Candidate medications are methotrexate (MTX), Interferon alpha (IFN-α) and bexarotene.² Each of them can be combined well with UV treatment. Unfortunately, access to INF-α and bexarotene is currently limited due to logistical and financial reasons. Therefore, MTX often is the only immunomodulatory medication readily available.

For oncologic indications, MTX is typically administered at high doses and functions as an anti-folate antimetabolite. In contrast, low-dose MTX is well established in the treatment of various inflammatory conditions, including psoriasis and rheumatoid arthritis.² Under these circumstances, the mechanism of action might differ: MTX activates the enzyme AICAR, which inhibits AMP deaminase, leading to an accumulation of adenosine.³ The resulting adenosine accumulation in lymphocytes results in reduced proliferation and activity of T cells. In CTCL, MTX is administered at low doses, probably due to its direct impact on T-cell proliferation. There are only a few reports on the current tolerability and efficacy of this medication in this context.²

Nikolaou et al. report a retrospective multicentral series of 211 MF patients in Greece. MTX was administered either as monotherapy (112 patients) or combination therapy with various other treatments including phototherapy (n = 31), INF-α (n = 29; 25 received INF-α 2b,4 received pegylated interferon) and retinoids (n = 12; bexarotene and/or acitretin). MTX was given once weekly with a median oral dose of 15 mg/week, reflecting a low-dose approach.⁴ Unfortunately the patient population is very heterogenous: 124 patients had late-stage disease (IIB-IVB). Moreover, there was no information provided on CD30 expression level within the cohort. First line treatment in patients with early staged MF showed a progression free survival (PFS) of more than a year⁴ which is notably longer than what has been reported in prospective trials such as ALCANZA.

In this multicentre, open-label, randomized trial, oral MTX or oral bexarotene has been used in the control arm to brentuximab and achieved a median PFS of 3.5 months. However, this trial has investigated CD30+ CTCL, including CD30+ lymphoproliferative disorders and CD30+ MF.⁵

Based on the results of the presented retrospective analysis, the use of MTX in early stages of MF seems to be justified by a decent response, good tolerability and a favourable economic load. However, we clearly see that retrospective studies have major limitations concerning disease assessment and lack details of the lymphoma subtypes.

Open access publishing facilitated by Universitat Zurich, as part of the Wiley - Universität Zurich agreement via the Consortium Of Swiss Academic Libraries.

Prof. Dummer has intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, T3 Pharma, MaxiVAX SA, Pfizer and Simcere outside the submitted work. Senior medical advisor Oncobit. Dr. Suter has no COI to declare.