Treatment Of Early-stage Mycosis Fungoides Research Articles

Effectiveness and tolerability of chlormethine gel for the management of mycosis fungoides: a multicenter real-life evaluation.

Topical chlormethine (CL) is recommended as a first-line treatment for early-stage mycosis fungoides (MF) and in 2017, the European Medicines Agency approved the CL gel formulation to treat adult patients. More recently, to increase patient compliance and adherence, clinicians have developed flexible protocols that allow the concomitant use of CL gel with topical corticosteroids in daily practice regimens. Therefore, sharing real-life data on CL gel use and side effects management may help improve the use of this agent. To expand knowledge about the actual use of CL gel in patients with MF, the present study assessed the improvement of MF skin lesions after CL gel treatment and provided information on the management of cutaneous adverse events (AEs) in a real-life setting. This was an Italian retrospective study conducted among six dermatology referral centers. Patients ≥18 years affected by MF and in treatment with CL gel (160 µ/g), alone or in combination according to routine clinical practice, between December 2019 and December 2021 were considered. The study's primary aim was to evaluate the effectiveness of CL gel in terms of overall response rate (ORR) after 3 months of treatment. A total of 79 patients (61% male) with different stages of MF (84% early stage) were included. CL gel was prescribed mainly in association with topical corticosteroids (66% of patients). ORR after 3 months of treatment was 42%, with no differences between early- and advanced-stage MF. Response rates improved over time up to 97% after 18 months of treatment. Overall, 66 AEs were reported in 67% of patients; most were hyperpigmentation (45%) and irritant contact dermatitis (37%). Six AEs led to treatment discontinuation, and five out of six (83%) patients who reported these events resumed treatment after interruption. No AEs were classified as severe. Our observations support the use of CL gel in patients with early- and advanced-stage MF, making it a valuable treatment option.

Successful Treatment of Early-Stage Mycosis Fungoides With Topical PUVA in Adult Patient: Case Report

Mycosis fungoides is fairly common type of cutaneous T-cell lymphoma with prolonged indolent course. Early-stage MF patch/plaque stage disease (T1/T2) can be treated safely and effectively by Phototherapy. Systemic PUVA and Narrowband UVB widely used with considerable result in MF. Topical PUVA is rarely considered as a phototherapy line in MF. We represent in our patient complete clearance of MF plaque after topical PUVA phototherapy without relapse.

Efficacy of narrowband UVB phototherapy in early-stage mycosis fungoides in Iranian patients.

Narrowband UVB (NB-UVB) has been shown to be effective for the treatment of early mycosis fungoides (MF) in light-skinned patients, but the effect of NB-UVB on patients with darker skin phototypes needs further investigation. The aim of this study was to evaluate the effect of NB-UVB in the treatment of early-stage MF in Iranian patients. In this retrospective study, 24 patients with the diagnosis of early MF (9 stage AI, 15 stage IB) were enrolled. All patients were treated with NB-UVB phototherapy 2-3 times weekly. After achieving complete response, a maintenance treatment was recommended. The response rate, side effects, and recurrence rate in the follow-up period were assessed. The follow-up period was ranged 6 to 24months. Ten patients (41.7%) had complete remission after a mean number of 42.9 treatment and mean cumulative dose of 58.11J/cm2. Twelve patients (50%) had partial response, and 2 patients (8.3%) had no response. After discontinuation of maintenance treatment, 4 of 10 patients (40%) with complete remission relapsed within a mean of 5months. Side effects were limited to erythema (12.5%) and hyperpigmentation (4%). NB-UVB is a safe and effective method for the treatment of early MF, but it seems that more treatment sessions and higher doses of NB-UVB are required for darker skin phototypes.

Randomized Mechlorethamine/Chlormethine Induced Dermatitis Assessment Study (MIDAS) Establishes Benefit of Topical Triamcinolone 0.1% Ointment Cotreatment in Mycosis Fungoides.

IntroductionTreatment of early-stage mycosis fungoides (MF) requires safe, skin-directed therapies. Medication side effects can lead to underutilization of effective therapies. The objective of this study was to assess the use of topical triamcinolone 0.1% ointment as a means of reducing contact dermatitis associated with topical mechlorethamine/chlormethine gel for the treatment of MF.MethodsThis prospective, randomized, open-label study evaluated 28 adults with mycosis fungoides who were eligible for treatment with topical mechlorethamine/chlormethine gel from December 17, 2017 to December 23, 2020. Patients were treated for 4 months with clinical follow-up through 12 months. Patients had half of their lesions also treated with topical triamcinolone 0.1% ointment (while the other half were treated with mechlorethamine/chlormethine alone). The study was self-controlled with separate lesions in the same patient receiving each treatment arm. Treatment arms were determined by the flip of a coin.ResultsTwenty-eight patients enrolled (17 men (61%) and 11 women (39%)). Demographics included 25 White, 2 African Americans, and 1 Asian patient. Twenty-five completed the 12-month follow-up. Triamcinolone 0.1% ointment led to increased tolerability of mechlorethamine/chlormethine gel but did not change the efficacy of mechlorethamine/chlormethine. There was a statistically significant 50% decrease in dermatitis (SCORD score) at month 2 in the triamcinolone-treated arm.ConclusionsTopical triamcinolone ointment is a helpful adjuvant therapy when treating patients with topical mechlorethamine/chlormethine gel. It diminishes inflammation and does not reduce efficacy. The peak incidence of dermatitis in the study occurred in the second and third months.Trial RegistrationClinicalTrials.gov identifier, NCT03380026.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-022-00681-6.

Phototherapy as a treatment of early-stage mycosis fungoides and predictive factors for disease recurrence: A 17-year retrospective study.

Mycosis fungoides is the most common form of cutaneous T-cell lymphoma. Narrowband ultraviolet B and psoralen and ultraviolet A are effective treatment options, but studies of their treatment efficacy and disease relapse remain limited. This study aimed (1) to determine the efficacy of narrowband ultraviolet B and psoralen and ultraviolet A as a treatment for early-stage mycosis fungoides and explore the predictive factors for complete remission and (2) to determine the relapse rate and analyze their predictive factors, including the utility of maintenance therapy. This was a retrospective cohort study consisting of 61 patients with early-stage mycosis fungoides (IA - IB) treated with narrowband ultraviolet B or psoralen and ultraviolet A as the first-line therapy from January 2002 to December 2018 at the Division of Dermatology, Ramathibodi Hospital, Bangkok, Thailand. Cox regression analysis and Kaplan-Meier survival curve were performed for the main outcomes. A complete remission was achieved by 57 (93.5%) patients. The median time to remission was 7.80 ± 0.27 months. Types of phototherapy (narrowband ultraviolet B or psoralen and ultraviolet A), age and gender did not associate with time to remission, while the presence of poikiloderma and higher disease stage led to a longer time to remission. The cumulative incidence of relapse was 50.8%. The median time to relapse was 24.78 ± 5.48 months. In patients receiving phototherapy during the maintenance period, a treatment duration longer than six months was associated with a significantly longer relapse-free interval. Narrow-band-ultraviolet B and psoralen and ultraviolet A are effective treatment options for early-stage mycosis fungoides. Maintenance treatment by phototherapy for at least six months seems to prolong remission.

13523 Phototherapy as a treatment of early-stage mycosis fungoides and predictive factors for disease recurrence: A 17-year retrospective study

Background: Mycosis fungoides (MF) can be described as the most common form of cutaneous T-cell lymphoma (CTCL). NB-UVB and PUVA are effective treatment options, but the studies of their treatment efficacy and disease relapse still limited.

A retrospective, descriptive study of patients with Mycosis fungoides treated by phototherapy (oral PUVA, NB-UVB) with a twice-weekly regimen at the Institute of Dermatology, Bangkok, Thailand, with an experiential timeline of 13years.

Phototherapy has been a first-line treatment for early-stage mycosis fungoides (MF) since 1976. Oral 8-methoxypsoralen plus ultraviolet A (oral PUVA) and narrow-band ultraviolet B (NB-UVB) are favorable modalities owing to their availability. In previous studies, phototherapy was conducted thrice per week initially, which is not feasible for many patients. To evaluate the initial clinical responses and time to relapse in patients with early-stage MF treated with oral PUVA and NB-UVB at a twice-weekly regimen. We reviewed the records of patients with biopsy-proven MF who received oral PUVA or NB-UVB in 2002-2014. Demographic data, staging, response to initial course of phototherapy, and initial relapse-free interval were collected. Among 70 patients, 14 (20%) and 56 (80%) were treated with oral PUVA and NB-UVB, respectively. The majority had early-stage MF (IA, 22.9%, IB, 57.1%, and IIA, 4.3%). Oral PUVA led to a complete response (CR) in 2 (14.3%) patients and partial response (PR) in 7 (50%) patients; 17 (30.4%) and 25 (44.6%) patients, respectively, achieved CR and PR with NB-UVB. The number of treatments was similar in both groups. The cumulative dose was 520.7J/cm2 for PUVA and 41.6J/cm2 for NB-UVB. There was no initial relapse in the 2 (100%) patients and in 10 (58.8%) patients treated with oral PUVA and NB-UVB at 18months and 9.14months of follow-up, respectively. Patients with early-stage MF can achieve clinical response with oral PUVA and NB-UVB, with a twice per week regimen. The initial relapse-free interval was longer than 1year.

Cost of early-stage mycosis fungoides treatments in Spain.

AimTo identify the most common therapeutic options for the treatment of early-stage mycosis fungoides in Spain, quantify their associated healthcare resource use and costs.MethodsAfter reviewing the literature, a panel of 6 Spanish clinical dermatologists validated the treatments and healthcare resource use through a structured questionnaire. Individual responses were collected, analyzed and presented into a face-to-face meeting in order to reach a consensus. Cost categories considered were: drug acquisition and administration, photo/radiotherapy session and maintenance, clinical follow-up visits and laboratory tests. Costs were expressed in euros from 2018. The Spanish National Health System perspective was considered, taking into account direct health costs and time horizons of 1, 3 and 6 months.ResultsCosts for the skin-directed treatments (SDT) assessed at 1, 3 and 6 months, were: Topical carmustine [€6,593.36, €19,780.09 and €27,592.78]; Phototherapy with psoralens and ultraviolet A light (PUVA) [€1,098.68, €2,999.99 and €3,187.60]; Narrow-band ultraviolet B phototherapy [€1,657.47, €4,842.10 and €4,842.10]; Total skin electron beam therapy (TSEBT) [€6,796.45, €7,913.34 and €7,913.34]. Cost for topical corticosteroids, being considered an adjuvant option, were €17.16, €51.49 and €102.97. Costs for the assessed systemic treatments alone or in combination with SDT at 1, 3 and 6 months, were: Systemic retinoids [€2,026.03, €5,206.63 and €7,426.42]; Systemic retinoids + PUVA phototherapy [€3,066.50, €8,271.26 and €10,046.58]; Interferon alfa + PUVA phototherapy [€1,541.09, €5,167.57 and €6,404.55].ConclusionAccording to the Spanish clinical practice, phototherapies in monotherapy were the treatments with the lowest associated costs regardless of the time horizon considered. TSEBT turned out as the treatment with the highest associated costs when considering 1 month. However, while considering 3 and 6 months the treatment with the highest associated costs was topical carmustine. The results of this analysis may provide critical information to measure the disease burden, to detect unmet medical needs and to advocate towards better treatments for this rare disease.

Revisiting Imiquimod for Treatment of Folliculotropic Mycosis Fungoides: A Case Report and Review of the Literature.

Folliculotropic mycosis fungoides (FMF) is an aggressive variant of mycosis fungoides (MF) characterized by infiltration of the hair follicle epithelium by neoplastic T cells. FMF demonstrates poor response rates to standard skin-directed therapies such as phototherapy and topical corticosteroids. Imiquimod, an immunomodulatory agent that stimulates the antitumor immune response, has been used successfully in treatment of early-stage MF. We report a 21-year-old patient with unilesional FMF who achieved clinical remission with imiquimod application. This case highlights a potential for use of imiquimod as a treatment option for patients with FMF and limited skin involvement.

The impact of environmental ultraviolet exposure on the clinical course of mycosis fungoides

As phototherapy plays animportant role in the treatment of early-stage mycosis fungoides (MF), it is possible that environmental ultraviolet (UV) exposure affects the natural history of the disease. To assess the impact of environmental UV exposure on the clinical course of MF. The National Solar Radiation Database was used to identify the top and bottom registries for UV exposure from the Surveillance, Epidemiology, and End Results-18 database. Incidence and survival were determined. The high-UVcohort had a 30% lower risk of developing MF than did the low-UV cohort (hazard ratio, 1.3; 95% confidence interval, 1.20-1.41; P<.001). When stratified by stage and race, this difference was appreciable only among those with early-stage disease and white race. There was no difference in survival between the high- and low-UV cohorts (P=.098); however, a small difference was observed among those with early-stage disease and white race, favoring high UV exposure. Retrospective design, use of the National Solar Radiation Database as a surrogate for individual sunlight exposure. It is possible that environmental solar UV exposure may play a role in controlling early-stage MF among patients with photosensitive features.

Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Treatment of early-stage mycosis fungoides: Results from the PROCLIPI study

Treatment of early-stage mycosis fungoides: Results from the PROCLIPI study

Assessment of efficacy of narrow-band ultraviolet B for the treatment of early-stage mycosis fungoides

Objective To evaluate the efficacy of narrow-band ultraviolet B(NB-UVB) for the treatment of early-stage mycosis fungoides (MF). Methods A retrospective study was performed on 98 patients with early-stage MF treated with NB-UVB from January 2003 to December 2013. The rate of and time to recurrence of MF were assessed, and long-term side effects were evaluated in these patients. Results Among 52 patients achieving complete remission, the median number of sessions of NB-UVB radiation was 30 (range, 18- 87), the median cumulative radiation dose was 24.16 J/cm2 (range, 9.11- 108.86 J/cm2), and the median follow-up duration was 41 months (range, 11- 90 months). Relapse occurred in 14 (26.9%) patients with the median time to recurrence being 8.2 months (range, 3- 60 months). The patients suffering from relapse achieved complete remission after treatment with NB-UVB again. Adverse reactions mainly included skin erythema and itching at the early stage of radiation, as well as temporary pigmentation after radiation. Cutaneous carcinoma occurred in none of these patients during 11- 90 months of follow-up. Conclusions NB-UVB phototherapy appeared to be effective for the treatment of early-stage MF, and no cutaneous carcinoma occurred in these patients during the follow-up. Although MF may relapse in some cases, repeated NB-UVB phototherapy is still effective. Key words: Ultraviolet therapy; Treatment outcome; Mycosis fungoides

High Dose Rate (HDR) Brachytherapy for Mycosis Fungoides of the Wrist.

Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma accounting for approximately half of all cutaneous T-cell lymphomas. Radiation therapy is an effective treatment for early stage MF and has been shown to result in long-term disease-free intervals, with even curative potential. Radiation is also effective as palliative treatment for the localized lesion resistant to the topic or other treatments. In the current study, we report using high dose rate (HDR) radiation treatment for a patient with resistant mycosis fungoides involving the wrist. We report a convenient treatment with an ideal radiation dose distribution, and a excellent clinical outcome.

Phototherapy for mycosis fungoides.

Both phototherapy and photochemotherapy have been used in all stages of mycosis fungoides since they improve the symptoms and have a favourable adverse effect profile. We performed an extensive search of published literature using keywords like "phototherapy", "photochemotherapy", "NBUVB", "PUVA", "UVA1", "mycosis fungoides", and "Sezary syndrome", and included systematic reviews, meta-analysis, national guidelines, randomized controlled trials (RCTs), prospective open label studies, and retrospective case series. These were then arranged according to their levels of evidence. Five hundred and forty three studies were evaluated, of which 107 fulfilled the criteria for inclusion in the guidelines. Photochemotherapy in the form of psoralens with ultraviolet A (PUVA) is a safe, effective, and well tolerated first line therapy for the management of early stage mycosis fungoides (MF), that is, stage IA, IB, and IIA (Level of evidence 1+, Grade of recommendation B). The evidence for phototherapy in the form of narrow-band UVB (NB-UVB) is less robust (Level of evidence 2++, Grade of recommendation B) but may be considered at least as effective as PUVA in the treatment of early-stage MF as an initial therapy. In patients with patches and thin plaques, NB-UVB should be preferentially used. PUVA may be reserved for patients with thick plaques and those who relapse after initial NB-UVB therapy. For inducing remission, three treatment sessions per week of PUVA phototherapy or three sessions per week of NB-UVB phototherapy may be advised till the patient achieves complete remission. In cases of relapse, patients may be started again on PUVA monotherapy or PUVA may be combined with adjuvants like methotrexate and interferon (Level of evidence 2+, Grade of recommendation B). Patients with early-stage MF show good response to combination treatments like PUVA with methotrexate, bexarotene or interferon-α-2b. However, whether these combinations hold a significant advantage over monotherapy is inconclusive. For late stage MF, the above-mentioned combination therapy may be used as first-line treatment (Level of evidence 3, Grade of recommendation C). Currently, there is no consensus regarding maintenance therapy with phototherapy once remission is achieved. Maintenance therapy should not be employed for PUVA routinely and may be reserved for patients who experience an early relapse after an initial course of phototherapy (Level of evidence 2+, Grade of recommendation B). Bath-water PUVA may be tried as an alternative to oral PUVA in case the latter cannot be administered as the former may show similar efficacy (Level of evidence 2-, Grade of recommendation C). In pediatric MF and in hypopigmented MF, both NB-UVB and PUVA may be tried (Level of evidence 3, Grade of recommendation D).

Review of the Treatment of Mycosis Fungoides and SéZary Syndrome : A Stage-Based Approach

Mycosis fungoides (MF) and Sézary Syndrome (SS) are the most common subtypes of cutaneous T-cell lymphomas. Most of patients have indolent and incurable course of disease. Therefore, treatment should be reaching the optimal benefit with minimizing the toxicity as much as possible. To achieve this aim, the management should follow a -stage-based-approach. Treatment of early-stage MF (IA-IIA) involves skin-directed therapy (SDT) including topical corticosteroids, phototherapy, topical chemotherapy, topical retinoids and radiotherapy. For aggressive/recalcitrant early-stage MF or advanced-stage MF, systemic therapy should be considered including interferone-alpha, oral retinoids including bexarotine and more recently acitretin, histone deacetylase inhibitors (HDACi), fusion toxin denileukin diftitox and chemotherapy drugs. Combined drug regimens can be considered in some situations to get the synergistic effect while lowering the individual drug's doses on the other hand. By exception of aggressive stages, chemotherapy should always come after other systemic drugs have been tried or contraindicated. Novel drugs should be considered in situations when all systemic drugs have failed.

Biochemical Changes Observed After PUVA Versus PUVA Plus Methotrexate Therapy in Mycosis Fungoides Using Synchrotron Infrared Microspectroscopy

Mycosis fungoides (MF) is the most common type of cutaneous T cell lymphoma in which the distinction between early stage MF and other inflammatory dermatosis remains difficult. Twenty patients of early stage MF and nine patients with psoriasis and lichen planus were included in this study. Ten MF patients were treated with psoralen plus UVA (PUVA) and the other 10 MF patients were treated with PUVA plus methotrexate (MTX) until complete clinical remission. Synchrotron infrared microspectroscopy (SIRM) found that MF lesions were biochemically different compared to inflammatory diseases. After treating MF with either therapeutic modality, the lymphocytic count decreased significantly in both the epidermis and dermis (P < 0.001) but no biochemical changes were observed in the remaining lymphocytes after treatment, indicating the disease process was slowed by treatment but not eradicated. In conclusion SIRM is a promising method for distinguishing MF from other inflammatory diseases such as psoriasis and lichen planus. A significant reduction in lymphocyte count indicated that PUVA therapy is an effective treatment for early stage MF, and MTX could be reserved for more advanced cases that are not PUVA responsive. However, SIRM evidence of persistent disease suggests that maintenance therapy is recommended after clinical remission.

Broad band UVA: a possible reliable alternative to PUVA in the treatment of early‐stage mycosis fungoides

UVA1 phototherapy was found to induce marked improvement in skin lesions of patients with stages IA and IB mycosis fungoides (MF). Broad band UVA (BB-UVA) is composed of 80.1% UVA1, with similar mechanisms of action. Our aim was to evaluate the efficacy of BB-UVA in the treatment of early-stage MF. Thirty patients with early stage MF were included. They were divided into two equal groups receiving either BB-UVA at 20 J/cm2/ session or PUVA three times/week for 40 sessions. Clinical and histopathological evaluations were performed before and after therapy in addition to immunohistochemical measurement of CD4+ cells and Bcl-2. Patients were followed up for an average duration of 36 months. Comparable clinical and histopathological improvement was noted in MF patients in both groups. Clinical improvement graded 'Excellent' was achieved in 33% of patients in the BB-UVA versus 13.3% in the psoralen and UVA (PUVA) group. Long-term follow-up indicated superiority of BB-UVA over PUVA. BB-UVA group showed a more rapid clearance rate, shorter time to achieve complete clearance, a longer disease-free interval and lower relapse rate. The use of BB-UVA in the treatment of early-stage MF is comparable or even superior to PUVA regarding efficacy and remission periods.

Narrowband Ultraviolet B Phototherapy of Early Stage Mycosis Fungoides in Korean Patients

BackgroundNarrowband UVB (NBUVB) is currently used to treat early mycosis fungoides (MF). There are a number of reports on the efficacy and safety of NBUVB in Caucasians, but little data is available for Asians.ObjectiveThis study was designed to evaluate the effectiveness and safety of NBUVB for early stage MF in Korean patients.MethodsWe enrolled 14 patients (12 men, 2 women; age range, 10~64 years) with clinically and histologically proven MF. Three patients were stage IA, and the others were stage IB. The patients received NBUVB phototherapy three times a week. The starting dose was 70% of the minimal erythema dose and was increased in 20 percent increments if the previous treatment did not cause erythema. Clinical response, total number of treatments, total cumulative dose, duration of remission and side effects were investigated.ResultsEleven of 14 patients (78.6%) achieved complete remission within a mean of 15.36±5.71 weeks (range, 5~27 weeks), 31.0±7.4 treatments (range, 16~39 treatments) and a mean cumulative UVB dose of 31.31±12.16 J/cm2 (range, 11.4~46.8 J/cm2). Three of the 14 patients (21.4%) achieved a partial remission. After discontinuation of treatment, 6 of 11 patients (54.5%) with complete remission relapsed after a mean of 8.5±4.09 months. No serious adverse effects were observed except for hyperpigmentation (7/14, 50%).ConclusionOur data suggest that NBUVB therapy is safe and effective for the treatment of early stage MF in Korean patients.

P99 Broadband UVA versus PUVA in the treatment of early stage mycosis fungoides: a comparative study

Background Mycosis fungoides (MF) is the most common type of cutaneous-T-cell lymphoma, with no established consensus for its treatment [1]. The standard treatment for early stage MF is PUVA [2]. UVA1 phototherapy was found to induce marked improvement in skin lesions of patients with stages IA and IB MF. Broad band UVA is composed of 80.1% UVA1, with similar mechanisms of action [3]. Aim of work The aim of the present work was to compare the efficacy of PUVA versus broad band UVA as a substitute to UVA1 in the treatment of early stage MF (IA, IB, IIA). Patients and methods; Thirty patients with early stage MF (IA and IB) were included in this prospective, randomized clinical trial. They were randomly divided into two equal groups; group A (15 patients receiving PUVA) and group B (15 patients receiving BBUVA at 20 J/cm2/session). The patients received three sessions/week for 13 weeks i.e. forty sessions. The patients were compared regarding clinical, histopathological, immunohistochemical (By measuring the bcl-2 level) and overall responses. Results Among each of the two groups, there was statistically significant improvement in the clinical, histopathological, immunohistochemical and overall responses. However there was no statistically significant difference between both groups in any of the aspects with comparable overall success rates; (93.3%) in the PUVA group and (80%) in the BBUVA group. Excellent overall response rates was higher in the BB-UVA group (41.7%) versus (14.3%) in the PUVA group, but still with no statistically significant difference (P=0.117). As regards the side effects encountered in both groups; there was no statistically significant difference in the rates of tanning, pruritus, appearance of new lesions, photosensitivity or dryness. However discomfort was significantly higher among the BB-UVA group (P=0.032) and nausea was significantly higher among the PUVA group (P=0.003). Conclusion BB-UVA is a new, yet promising therapeutic modality in the treatment of early stage MF, as it is comparable to PUVA, as regards both the efficacy and safety. It could substitute the use of UVA1 in the treatment of early stage MF.