Abstract
Background
Methotrexate (MTX) has been a longstanding therapeutic option for mycosis fungoides (MF); however, data on its real‐world effectiveness remain limited.
Objectives
To evaluate treatment‐related outcomes of oral MTX in patients with early‐ and late‐stage MF.
Methods
This is a retrospective multicentre analysis involving MF subjects from five referral centres for cutaneous lymphomas in Greece. Data regarding the effectiveness and safety were analysed.
Results
In total, 211 MF patients were enrolled (males, 68.3%) with a median (IQR) age of diagnosis at 68.3 (56–75) years. Late‐stage (IIB‐IVB) disease was present in 124 patients (59.3%). MTX monotherapy was administered to 112 (53.1%) patients, with 99 receiving combination regimens with phototherapy, interferon and retinoids. MTX was used as first‐line regimen in 103 (48.9%) cases. An overall response rate (ORR) of 55.5% was observed with 29.9% of patients achieving complete responses. MTX demonstrated greater effectiveness as a first‐line treatment compared to subsequent use with no significant differences between monotherapy and combination therapy. The median time to best response was 3.8 months (IQR 2.3–9.9 months). Patients with erythrodermic disease (Stage III) had better ORRs compared to patients with tumour stage disease (Stage II) (61.1% vs. 44.8% respectively). The progression‐free survival (PFS) varied according to stage, with a median PFS of 17.1 months for early‐stage disease, 5.7 months for Stage IIB disease, 46 months for Stage III and 9.6 months for Stage IV disease (0.7‐.). Serious adverse (Grade 3) events leading to treatment discontinuation occurred in 14 (6.7%) cases. All patients received oral MTX once weekly with a median weekly dose of 15 mg/week (7.5–25).
Conclusions
Our findings support MTX as a viable treatment option for MF, particularly when used in the first‐line setting, offering a favourable benefit/risk profile. Response rates are stage‐dependent, with erythrodermic patients achieving superior and durable responses.
Methotrexate (MTX) has been a longstanding therapeutic option for mycosis fungoides (MF); however, data on its real‐world effectiveness remain limited. This study aimed to assess real‐world outcomes of oral MTX in the treatment of MF. Data from five referral centres for cutaneous lymphoma in Greece were retrospectively reviewed with the baseline‐ and treatment‐related characteristics of patients extracted and analysed accordingly. In total, 211 patients were included in the study. MTX demonstrated greater effectiveness as a first‐line treatment compared to subsequent use with no significant differences between monotherapy and combination therapy. No significant differences were observed between MTX monotherapy and MTX combined with other treatments. Patients with early‐stage disease (IA‐IIA) achieved favourable outcomes along with patients with erythrodermic disease (Stage III). Patients with Stage IV and IIB disease had the worst responses. The presence of the folliculotropic variant of MF did not affect responses to treatment while large cell transformation had a negative impact on responses. Overall, MTX demonstrated acceptable safety and a small amount of patients discontinued the medication due to adverse events. The findings of this large multicentric study support MTX as a viable treatment option for MF, particularly when used in the first line setting, offering a favourable benefit/risk profile. Response rates are stage‐dependent, with erythrodermic patients achieving superior and durable responses.
Why Was the Study Undertaken?
Methotrexate has been a longstanding therapeutic option for mycosis fungoides; however, data on its real‐world effectiveness remain limited.
What Does this Study Add?
In our cohort, methotrexate demonstrated greater effectiveness as a first‐line treatment compared to subsequent use. Patients with erythrodermic disease (Stage III) had better overall response rates compared to patients with tumour stage disease (Stage II). The progression‐free survival varied according to stage, with a median PFS of 17.1 months for early‐stage disease, 5.7 months for Stage IIB disease, 46 months for Stage III and 9.6 months for Stage IV disease (0.7‐.). In total, 26.1% of the patients experienced Grade 1–3 adverse events, with none of them requiring hospitalization or any deaths being recorded during observation. Overall, patients with Stage IV and IIB disease had the worst responses. The presence of the folliculotropic variant of mycosis fungoides did not affect responses to treatment while large cell transformation had a negative impact on responses.
What Are the Implications of this Study for Disease Understanding and/or Clinical Care?
Our study suggests that methotrexate is an effective and safe option for patients suffering from mycosis fungoides, especially for those with early‐stage disease (IA–IIA) and for those with Stage III disease.
INTRODUCTION
Cutaneous T‐cell lymphomas (CTCLs) encompass a rare and diverse subset of non‐Hodgkin lymphomas characterized by their unique T‐cell phenotype and clinical manifestations. Mycosis fungoides (MF) and Sézary syndrome (SS) are the most prevalent primary CTCL subtypes. Despite the fact that most patients with early‐stage MF follow an indolent course, patients with late‐stage MF/SS have a poor prognosis. Although there are a number of treatments currently available, achieving and maintaining a durable response remain challenging, particularly for individuals affected by late‐stage MF or SS. 1
Methotrexate (MTX) is a folate antagonist that exerts its therapeutic effects by inhibiting dihydrofolate reductase, an enzyme essential for DNA synthesis. 2 It is one of the major chemotherapeutic choices utilized for the treatment of various malignancies including CTCLs. 3 Despite its widespread use in the management of CTCLs, documentation in literature is quite limited and the reported response rates for MF in the real‐world settings exhibit considerable variability. 4 , 5 , 6
Our study aims to summarize and report the clinical experience of patients with MF who were treated at tertiary experienced centres in Greece and underwent treatment with low‐dose MTX. Furthermore, we aim to identify which patients are most probable to achieve better responses based on our extensive clinical observations.
MATERIALS AND METHODS
We retrospectively reviewed the medical charts of all patients suffering from MF from five referral centres for cutaneous lymphomas in Greece (‘Andreas Sygros Hospital for Skin Diseases, Athens’; ‘Attikon Hospital, Athens’; ‘Laikon Hospital, Athens’; ‘Papageorgiou Hospital, Thessalonki’; and ‘General Hospital of Heraklion, Crete’). Patients were considered candidates to the present study if they met the following eligibility criteria upon entry: a histopathological diagnosis of MF/SS, according to the more recent World Health Organization/European Organization for Research and Treatment of Cancer classification, 7 had received oral ΜΤΧ either as monotherapy or combination therapy for at least 1 month and had more than 6 months of follow‐up. Anonymized data that were extracted from medical records included basic patient demographics, MF histology and the associated immunohistochemical analysis, the polymerase chain reaction (PCR) analysis for T‐cell receptor (TCR)‐γ and TCR‐β gene rearrangements, TNMB stage at the time of diagnosis and at the initiation of MTX, disease duration, number and type of previous treatments and patient status at the end of treatment course. Early‐stage disease was defined as Stages IA–IIA and late‐stage disease as IIB–IVB.
Treatment effectiveness was evaluated with the assessment of the response rates mainly based on the clinical evidence and, when required, histopathological assessment. For the clinical assessment of the skin involvement and disease monitoring, the body surface area (BSA) was utilized as the main measure, due to its availability from all the participating centres. Response rates were determined according to the maximum response and were defined as follows based on BSA and, if involved, the blood and visceral compartment: complete response (CR) (no evidence of disease); partial response (PR) (50% improvement); stable disease (SD) (no more than 50% clinical improvement and no more than 25% clinical worsening); and progressive disease (PD) (more than 25% clinical worsening). Relapses after treatment response were defined by physicians according to clinical and/or histopathological data when needed. The overall response rate (ORR) was defined as the proportion of patients achieving either CR or PR. Treatment failure was defined by the occurrence of any of the following events: (1) no evidence of clinical response (No CR or PR) or (2) serious treatment‐related complications leading to drug discontinuation. All treatment‐related adverse events (AEs) were recorded and assessed at each patient visit and were classified and reported according to the Common Terminology Criteria for Adverse Events (CTCAE) terminology.
Statistical analysis
The primary endpoint was MTX effectiveness which was determined as the response rate (PR or CR based on physician's evaluation). Secondary endpoints were the progression‐free survival (PFS) time for the initially responding patients, overall duration of treatment and treatment‐related AEs. Response rates were compared between the different disease subsets with the Pearson's chi‐squared test (for categorical data). The survival analysis was performed using the Kaplan–Meier PFS curves for the responding patients and was compared with the log‐rank test. All statistical analyses were conducted with the Stata statistical software (SE version 11.0, StataCorp LLC, College Station, TX).
RESULTS
Characteristics of the included population
Overall, 211 MF patients met the pre‐specified eligibility criteria for this particular study with their basic clinical and treatment characteristics presented at Table 1. The majority of patients were males (68.3%) and the median (IQR) age at diagnosis of MF was 68.3 (56–75) years. The folliculotropic variant of MF (FMF) was detected in 27 patients (12.8%). No cases of the other two described variants of MF (pagetoid reticulosis and granulomatous slack skin) were found in our cohort.
TABLE 1.
Basic clinical and treatment characteristics.
| Patients characteristics | |
|---|---|
| Patients, n | 211 |
| Age (years), median (IQR) | 68.3 (56–75) |
| Gender, n (%) | |
| Male | 144 (68.3%) |
| Stage at diagnosis, n (%) | |
| Total patients with data, n (%) | 209 (100%) |
| IA | 35 (16.8%) |
| IB | 62 (29.7%) |
| IIA | 9 (4.3%) |
| IIB | 32 (15.3%) |
| IIIA | 46 (22%) |
| IIIB | 5 (2.4%) |
| IVA | 19 (9.1%) |
| IVB | 1 (0.5%) |
| Stage at MTX initiation, n (%) | |
| Total patients with data, n (%) | 209 (100%) |
| IA | 17 (8.1%) |
| IB | 56 (26.8%) |
| IIA | 12 (5.7%) |
| IIB | 46 (22%) |
| IIIA | 49 (23.4%) |
| IIIB | 5 (2.4%) |
| IVA | 23 (11%) |
| IVA1 | 19 (9.1%) |
| IVA2 | 4 (1.9%) |
| IVB | 1 (0.5%) |
| MTX as first‐line systemic therapy, n (%) | |
| Yes | 103 (48.9%) |
| No | 108 (51.1%) |
| Previous treatments | |
| Retinoids | 53 (49.1%) |
| Interferon | 21 (19.4%) |
| Retinoids and interferon | 23 (21.3%) |
| Other | 11 (10.2%) |
| MTX monotherapy, n (%) | |
| Yes | 112 (53.1%) |
| No (combination) | 99 (46.9%) |
| Phototherapy | 31 (14.7%) |
| Interferon | 29 (13.7%) |
| Retinoids | 12 (5.7%) |
| Steroids | 7 (3.3%) |
| Radiotherapy | 6 (2.8%) |
| Other | 14 (6.6%) |
| Side effects, n (%) | |
| Yes | 55 (26.1%) |
| Adverse events leading to treatment discontinuation | 14 (6.7%) |
| Patients with large cell transformation | 41 (19.4%) |
| Folliculotropic subtype of MF | 27 (12.8%) |
Οne hundred twenty‐four patients (59.3%) had late‐stage disease (stages IIB‐IVB), including 46 tumour stages (IIB), at the time of MTX initiation. Overall, 112 (53.1%) patients received MTX as monotherapy, 99 (46.9%) subjects concomitantly received phototherapy (n = 31; 14.7%), interferon‐a (IFN‐a) (n = 29; 13.7%) (25 used interferon alfa‐2b, 4 used pegylated interferon) and retinoids (bexarotene and/or acitretin) (n = 12; 5.7%). MTX was administered as a first‐line regimen in 103 (48.9%) cases. All patients received oral MTX once weekly with a median dose of 15 mg/week (7.5–25).
Treatment‐related outcomes
For the whole cohort, a 55.5% ORR was noted: 29.9% of the patients achieved CR and 25.6% achieved PR. MTX was found to be more effective when used as a first‐line rather than as a subsequent agent (p = 0.014). Higher response rates were recorded among patient with Stage I (67.1%) and Stage III disease (61.1%) (Table 2). More patients with Stage IA achieved a response when compared with Stage IB, with 76.5% ORR versus 64.3% respectively. Patients with Stage IV disease had the worst responses with 29.2% of the patients achieving either CR or PR. The subgroup analyses according to stage did not reveal any superiority regarding the effectiveness of combination regimens when compared with MTX monotherapy. For early stages (IA, IB and IIA), responses were observed in 20/31 (64.5%) patients in the monotherapy group versus 35/54 (64.8%) in the combination treatment group (p = 0.978). For Stage IIB 10/21(47.6%) versus 10/25 (40%) of the patients exhibited a response (p = 0.604) and for Stages III and IV 26/46 (56.5%) versus 14/32 (43.8%) (p = 0.267) of the patients respectively. Regarding the combination of MTX with IFN‐a, 16/29 (55.1%) of the patients had a response, with 7/29 (24.1%) patients achieving a CR and 9/29 (31%) PR.
TABLE 2.
Overall responses of patients receiving methotrexate.
| Total patient number | 211 |
| Overall responses (CR + PR) | 117 (55.5%) |
| Complete response (CR) | 63 (29.9%) |
| Partial response (PR) | 54 (25.6%) |
| MTX as first line | 66/103 (56.4%) |
| MTX as subsequent agent (second or third line) | 51/108 (43.6%) |
| MTX monotherapy | 60/112 (53.6%) |
| MTX combination therapy | 57/99 (57.6%) |
| According to MF stage | |
| Stage I | 49/73 (67.1%) |
| Stage IA | 13/17 (76.5%) |
| Stage IB | 36/56 (64.3%) |
| Stage II | 26/58 (44.8%) |
| Stage IIA | 6/12 (50%) |
| Stage IIB | 20/46 (43.5%) |
| Stage III | 33/54 (61.1%) |
| Stage IV | 7/24 (29.2%) |
| Patients with large cell transformation | 11/41 (26.8%) |
| Patients without large cell transformation | 106/170 (62.4%) |
Median (ΙQR) time to best response was 3.8 months (2.3–9.9) months after MTX initiation. For the initial responding patients with available data (n = 108), the median time to relapse was 18.2 months (95% CI: 13.1–25.2), 21.6 months for complete responders (95% CI: 14.7–46) and 11.7 months for partial responders (95% CI: 4.7–18.2) (Figures 1 and 2). Regarding the PFS, statistically significant differences were observed according to the MF stage (p = 0.008). The median PFS was 17.1 (95% CI: 13.6–21.6) months for early‐stage disease, 5.7 months (95% CI: 4–13.1) for IIB disease, 46 months (95% CI: 14.7–57.9) for Stage III and 9.6 months for Stage IV disease (95% CI: 0.7‐.) (Figure 3). The median (IQR) duration of treatment was 7 (3–16) months. The median duration of treatment was 14, 12, 20 and 10 months for Stages I, II, III and IV respectively.
FIGURE 1.
Overall median time to relapse (among initial responders).
FIGURE 2.
Median progression‐free survival time according to initial response.
FIGURE 3.
Median progression‐free survival time according to stage.
In total, 41 (19.4%) patients had MF with large cell transformation (LCT). Those patients demonstrated statistically significantly lower response rates compared to patients with no LCT (RR 62.4% vs. 26.8%, p < 0.001). The presence of the folliculotropic variant of MF in histology did not affect the probability of achieving a response.
In total, 55 (26.1%) patients experienced AEs, with 41 experiencing Grade 1 and 2 treatment‐related AEs and 14 patients (6.7%) experienced Grade 3 AEs that led to treatment discontinuation after careful consideration. No Grade 4/5 AEs occurred, with none of the patients requiring hospitalization and no treatment‐related deaths occurred during the observation period. Among the Grade 3 AEs, seven of them included blood toxicities (four lymphopenia only, one thrombocytopenia only and two both lymphopenia and thrombocytopenia) and seven suffered from serious biochemical irregularities (six abnormal liver function tests and one abnormal renal function tests).
DISCUSSION
The treatment landscape for MF has witnessed notable advancements in recent years, marked by the approval of novel therapeutic agents. 3 However, despite these encouraging steps, the choices that are currently available for managing MF patients remain limited. While novel and effective treatments have emerged, they are often accompanied by great costs and can present a financial challenge for both the patients and healthcare systems. 8 , 9 Furthermore, despite the high effectiveness that can be observed with novel therapeutic modalities, not all patients benefit from them with some never achieving a response or experiencing relapses, underscoring the need for further research and development in this field. 10 On the other hand, solid data available for older treatments is still limited. Our study provides large sample, real‐world data on the use of MTX for patients suffering from MF, drawing from the experiences of major referral centres for cutaneous lymphomas from Greece.
Our study revealed a significant therapeutic advantage of MTX in patients with erythroderma where we observed an ORR of 61.1% and a median PFS time of 46 months. These findings are significantly higher compared to response rates reported for novel agents such as mogamulizumab, which had a 23% ORR for patients with Stage III disease in the pivotal randomized control trial. 9 However, our results cannot be directly comparable as response rates in retrospective cohort studies, which reflect real‐world settings and behaviours, often tend to be higher. Nevertheless, our findings are in line with a previous report by Zackheim et al who reported 29 patients with erythrodermic MF treated with MTX, and demonstrated an ORR of 58% with a median freedom from treatment failure of 31 months and a median survival of 8.4 years. 11 A larger retrospective study of 79 MF patients showed an overall ORR of 75% whereas higher rates were presented in Stage II–VI compared to stage I disease. 6 Combining MTX and IFN‐a has been explored as a treatment approach for erythrodermic MF, aiming to achieve synergistic effects and improve therapeutic outcomes. 12 The rationale behind this combination lies in the distinct mechanisms of action of both drugs, which complement each other in targeting different aspects of the disease. MTX inhibits cell division and reduces tumour burden, while IFN‐a enhances the immune response against malignant cells. One prospective study conducted by Aviles et al. on 158 patients demonstrated that the combination of low‐dose MTX and interferon‐alpha‐2a led to a substantial reduction in tumour burden along with an improvement in skin manifestations after a treatment period of 12 months in patients with erythrodermic MF. 13 Other reports have investigated the activity of low‐dose MTX combined with other agents such as retinoids when used as first line treatments, demonstrating favourable results. 14 , 15 In contrast to these data, our study did not reveal superiority in effectiveness for the combination regimens compared to MTX monotherapy, including the combination of MTX and IFN‐a. Nevertheless, we acknowledge that our dataset may be limited for a comprehensive analysis and we advocate for prospective large‐scale multicentric studies to provide more robust data on when, how long and under which specific indications the combination regimens may confer a therapeutic advantage.
Our study also demonstrated high response rates in patients with early‐stage disease, leading to rapid and substantial responses. Currently, there is a lack of consensus and clear guidance regarding treatment options after the failure of skin directed therapies. A multicentric study published by our group in 2020 reported response rates of acitretin at 59.3% and 35.2% for Stages IA and IB, respectively, with a trend towards better response rates when acitretin was used in combination regiments. 16 In our current study we showed that the response rates of MTX in patients with early‐stage disease were higher to those reported for acitretin, whereas combinations did not offer a response advantage. However, direct comparison studies of retinoids and MTX should be conducted to evaluate whether MTX offers a therapeutic advantage in this patient group.
A prospective study by Chmielowska et al compared the use of MTX with the use of IFN‐a in late stages of MF and SS. Better outcomes were observed with interferon with the main limitation of the study its small participant number (n = 43). 17 Despite that our study did not include any comparison group with the other available systemic choices such as retinoids, IFN‐a or extracorporeal photopheresis (ECP), the low rate of adverse reactions, simple therapeutic scheduling, low cost and the lack of need for patients to move to specialized centres as required with ECP suggest that MTX could be a primary treatment choice for early‐stage patients who have failed to topical treatments, as well as for those with erythrodermic disease.
Patients with tumour stage (IIB) disease had the lowest response rates compared to the other stages with no systemic involvement (IA–IIIA), suggesting that tumour stage may be a negative prognostic factor for response to MTX. Interestingly, our study also showed that LCT, which usually accompanies the progression to tumorous lesions, is a negative predictor of response to treatment with MTX. Although the number of patients included in our study is relatively low, our findings are consistent with previous reports, showing low response rates of MTX in patients with LCT. In 2017 the pivotal Phase III ALCANZA trial compared the efficacy and safety of brentuximab vedotin to physician's choice of MTX or bexarotene in previously treated CD30‐positive MF patients. 18 The study demonstrated the superiority of brentuximab vedotin over MTX showing significant improvements across all primary and secondary endpoints. It is worth noting that there is also limited available data supporting a provoking role of MTX in the development of LCT in MF. 19 Our study echoes these findings underlying the need for further investigation and the development of alternative treatment strategies for patients with CD30‐positive LCT.
CONCLUSIONS
In conclusion our study offers valuable insights into real‐world response rates among MF patients treated with MTX. We conclude that, in general, MTX can be considered as a safe, well‐tolerated treatment option with favourable therapeutic outcomes in MF patients. We recommend its use as monotherapy for refractory early‐stage disease and in cases with erythroderma. For patients with LCT, alternative treatments should be considered. Given the indolent nature of MF, MTX should be considered the standard therapy for patients in this setting. However, we emphasize the need for further research, particularly for large prospective multicentre studies, to provide more comprehensive and definite guidance on MF treatment strategies.
AUTHOR CONTRIBUTIONS
Conceptualization: V.N., A.P., SE. KK., E.G., L.M., M. S., A. S. and E. P. Data curation and analysis: E.P., A.T., IA. K., A.P., K.L., A.V., AI. D., A.D., S.K., A.V, I.K., M.K., E.L., V.P. and A.T. Supervision: V.N., A.P., SE. KK., E.G., L.M., M. S., A. S. and E. P. Writing‐original draft: V.N., E.P., A.T., IA. K. and S.K. Writing‐review and editing: V.N., E.P., A.T., IA. K., A.P., M.S., SE. KK., L.M., E.G., K.L., A.V., AI. D., A.D., S.K., A.V, I.K., M.K., E.L., V.P., A.T., A. S. and E. P.
FUNDING INFORMATION
No funding was received for this particular manuscript. The publication of the article in OA mode was financially supported by HEAL‐ Link.
CONFLICT OF INTEREST STATEMENT
There are no potential conflicts of interest associated with this particular manuscript.
ETHICAL APPROVAL
Ethical approval was given by the hospital ethics committee.
Nikolaou V, Panou E, Tsimpidakis A, Koumprentziotis I‐A, Patsatsi A, Siakantaris M, et al. Effectiveness and safety of methotrexate in the treatment of mycosis fungoides: Real‐world data from a multicentre study. J Eur Acad Dermatol Venereol. 2025;39:1442–1448. 10.1111/jdv.20350
Linked article: R. Dummer et al. J Eur Acad Dermatol Venereol 2025;39:1374–1375. https://doi.org/10.1111/jdv.20789.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.