Valchlor® in the Treatment of Lichen Planopilaris and Frontal Fibrosing Alopecia: A Single Arm, Open-label, Exploratory Study.

BACKGROUND: Lichen Planopilaris (LPP) is a lymphocyte-mediated scarring alopecia that frequently is treatment resistance to both topical and systemic therapies. AIMS AND
OBJECTIVES: The object of this pilot study was to assess the effectiveness of topical mechlorethamine 0.016% gel (Valchlor®) in decreasing disease activity in LPP and the related clinical variant frontal fibrosing alopecia (FAA).
METHODS: Twelve patients with biopsy-proven LPP/FAA who failed prior topical or systemic therapy with active disease were included. Participants applied mechlorethamine 0.016% gel to involved areas daily for 24 weeks. Outcome measures included LPP Activity Index (LPPAI) score, Physician Global Assessment (PGA) score, Dermatology Quality of Life Index (DQLI) score, and phototrichograms assessing follicular counts before and after six months of therapy.
RESULTS: LPP Activity Index (LPPAI) before and after treatment was significantly different (5.0 before treatment, 2.0 after treatment; p value=0.006). Mean follicular density and follicular units were unchanged during the treatment period.
CONCLUSION: Treatment with mechlorethamine 0.016% gel for 24 weeks resulted in statistically significant improvement of LLP/FFA with no change in phototrichogram parameters. Treatment duration was limited by high rate of contact dermatitis. Further investigation to optimize dosing frequency and to assess the role of combination topical therapy is needed. Copyright:

INTRODUCTION

Lichen planopilaris (LPP) is a rare, chronic form of lymphocyte-mediated scarring alopecia that predominates in women between the ages of 45 and 70 years. Patients present with discrete patches of hair loss with characteristic perifollicular erythema and scale.[1] Diffuse or localized scalp involvement may be seen. Involvement restricted to the frontal scalp, known as frontal fibrosing alopecia (FFA), shows histological features identical to LPP, as demonstrated in Figure 1 and is considered as a clinical variant with increasing incidence and predominates in postmenopausal females.[23]

Figure 1

Histopathologic features of lichen planopilaris and frontal fibrosing alopecia. (×4, H and E, horizontal sections) intense perifollicular lymphocytic inflammation, lamellar fibrosis, and follicular loss with an infundibular predominance. All study participants had biopsy proven active disease

Disease progression results in irreversible hair loss and has been associated with significant impact on quality of life, depression, and anxiety.[4] Successful treatment of LPP/FFA is postulated to require clearance of the lymphocytic inflammation early in the disease course to prevent irreversible follicular destruction and permanent hair loss.[5]

The current treatment strategies for LPP/frontal alpha asymmetry (FAA) include topical and systemic corticosteroids, immunomodulatory treatments using doxycycline and hydroxychloroquine, and immunosuppressive therapies including methotrexate, mycophenolate mofetil, and cyclosporine.[6] Other therapies such as topical minoxidil or oral finasteride have highly variable responses rates and complete clinical remission is usually not achieved with any of the aforementioned therapies.[7] There remains a critical unmet therapeutic need for alternative therapies to treat LPP.

Valchlor®, a 0.016% gel formulation of mechlorethamine, is the Food and Drug Administration approved for skin directed treatment of Stages I and II-a mycosis fungoides.[89] The potential therapeutic benefit of mechlorethamine 0.016% gel in the treatment of LPP/FAA includes lymphocyte apoptosis through direct cytotoxic effects as well as indirect alterations of the surrounding cytokine milieu. Mechlorethamine 0.016% gel has also been shown to deplete resident Langerhans cells in the epidermis which constitute the main resident population of antigen presenting cells in both the epidermis and hair follicles and may also be a relevant therapeutic target in the treatment of LPP/FAA.[10]

The primary objective of this study was to assess the potential effectiveness of once daily application of mechlorethamine 0.016% gel in decreasing disease activity in patients with LPP and FAA.

METHODS

Study design

This was a single arm, open-label, exploratory study to evaluate the efficacy of mechlorethamine 0.016% gel in the treatment of LPP/FAA over a 24-week treatment period. Participants were screened by the Department of Dermatology at the Mayo Clinic in Florida outpatient clinic and interested qualified participants were consented and offered participation. This pilot study was designed to establish feasibility and proof of concept and did not include randomization or crossover components. Due to the exploratory, pilot nature of this study, this sample size was chosen primarily based on feasibility rather than on formal power calculations. Approval by the Mayo Clinic Institutional Review Board was obtained and all patients provided written informed consent, which was performed according to the Declaration of Helsinki.

Study subjects

Twelve patients were recruited from the Department of Dermatology at the Mayo Clinic in Jacksonville, FL between May 2018 and February 2019 and referred patients by dermatologists in the Southeastern United States with all screening and follow-up examinations performed at Mayo Clinic in Florida.

Patients with biopsy proven LPP/FAA who failed one prior topical or systemic therapy with evidence of active disease were considered eligible to participate. The presence of active disease was based on a baseline clinical examination showing perifollicular erythema with scaling. Patients with predominance of end-stage scarring hair loss but without significant active erythema were excluded from the study.

No other topical or systemic therapies were permitted during the study and all study participants underwent a 4-week wash out before starting mechlorethamine 0.016% gel therapy. Pregnant or nursing women, active smokers, and those in prior use of systemic immunosuppressive therapies were excluded from participation in the study. Of the 12 study participants who enrolled, one patient had a hair piece applied prior to the week 12 visit. For this one patient, data from the week 4 visit were used, but data from the week 12 and week 24 visits were not used. When considering the remaining 11 patients, for measures that were assessed at both week 12 and week 24 but were missing for week 24 (this occurred for 3 of the 11 patients), these were imputed using the last observation carried forward method.

Treatment regimen

All study participants applied mechlorethamine 0.016% gel to involved areas at night, beginning with three times per week (Monday, Wednesday, and Friday) and subsequently increasing to daily application after 1 month. The total duration of the treatment was 24 weeks. Patients were instructed to first part the hair away from involved area as needed, limit application to areas with alopecia and erythema, apply 30 min after showering or washing, and allow treated areas to dry for 5–10 min before covering with clothing or going to bed. Participants were instructed to wash their hands with soap and water after applying mechlorethamine 0.016% gel.

Outcome measures

Information was collected regarding baseline patient characteristics (age, age at onset, sex, race, diagnosis, medications, and lichen planopilaris activity index [LPPAI] score), at week 12 (missed application information, adverse events, and LPPAI score), and at week 24 (missed application information, adverse events, LPPAI score, dermatology life quality index [DLQI] score, follicular units, mean follicular density, and physician global assessment [PGA]).

The primary outcome measure was LPPAI score, which at weeks 12 and 24 was categorized as nonresponse (reduction of <25% from baseline score), partial response (reduction of between 25% and 85% from baseline score), or complete response (reduction >85% from baseline score).

The LPPAI is a standardized validated quantitative measure of disease activity.[11] LPPAI score (0–10) is calculated as follows: (pruritus + pain + burning)/3+ (scalp erythema + perifollicular erythema + perifollicular scale)/3 + 2.5 (pull test) +1.5 (spreading/2). Symptoms and signs are graded on a 4-point scale with 0 = absent, 1 = mild, 2 = moderate, and 3 = severe. Clinical progression and a positive hair pull test are graded 1 = yes; 0 = no.

Secondary measures of efficacy were mean follicular density and follicular units using phototrichograms, PGA score, and the dermatology quality of life index score before and after 6 months of therapy.

Phototrichograms of all individuals were performed by a single trained evaluator using FotoFinder® video-epiluminescence microscopy (FotoFinder Systems GmbH) in combination with a TrichoScan® (TRICHOLOG GmbH) of a representative area of disease activity using digital software-supported epiluminescence technique that provides the mean follicular density (mean number of follicular units per square cm) in a given area of the scalp. Degree of change in follicular density from baseline to week 12 and week 24 was calculated using both absolute changes (i.e., week 12 minus baseline) and percentage changes.

PGA score used standardized photography compared to the presenting baseline and is scored as-1 = worse (no change to erythema with new areas of alopecia); 0 = no change; 1 = mild improvement (slight reduction in erythema, alopecia not progressive); 2 = moderate (moderate reduction in erythema, alopecia not progressive); 3 = significant improvement (very mild erythema, alopecia not progressive); and 4 = clear (no erythema, alopecia not progressive).

Statistical analysis

Continuous variables were summarized using the sample median and range. Categorical variables were summarized with number and percentage of patients. Comparisons outcomes at both week 12 and week 24 in relation to the baseline time point were made using a paired Wilcoxon signed-rank test. No adjustment for multiple testing was made in these exploratory analyses; P < 0.05 was considered as statistically significant. All statistical tests were two-sided. Statistical analyses were performed using R Statistical Software (version 3.6.1; R Foundation for Statistical Computing, Vienna, Austria).

RESULTS

A summary of characteristics at baseline for the 12 study patients is shown in Table 1. Median age at baseline was 66 years (range: 50–82 years), median age at onset was 63 years (range: 42–77 years), all patients were female, and most patients (92%) were white. The most common diagnosis was FAA (n = 7; 58%) followed by LPP (n = 5; 42%).

Table 1

Baseline patient characteristics

Variable	n	Median (minimum, maximum) or number of patients, n (%)
Age at baseline (years)	12	66 (50, 82)
Age of onset (years)	12	63 (42, 77)
Sex (female)	12	12 (100.0)
Race (White)	12	11 (91.7)
Diagnosis
LPP	12	5 (42)
FFA		7 (58)
Taking medication		7 (58.3)
Plaquenil	12	2 (16.7)
Topical corticosteroids		5 (41.7)
Systemic corticosteroids		1 (8.3)
Finasteride		2 (16.7)

LPP – Lichen planopilaris; FFA – Frontal fibrosing alopecia

For the 11 patients who were included in the week 12 and week 24 analyses, information regarding missed applications and actions taken on the study drug is summarized in Table 2. There were a substantial number of missed applications at both weeks 12 and 24 (at least 91% of patients, most with 26–31 missed applications). Eight patients (72.7%) had discontinued study drug at week 12 and by week 24 all patients had discontinued treatment. Adverse event information is shown in Table 3. All patients reported experiencing an adverse event at either week 12 or 24, with the most common one being contact dermatitis (82% at week 12, 100% at week 24).

Table 2

Outcomes

Variable	n	Median (minimum, maximum), n (%), or P
LPPAI score
Baseline	11	5.0 (3, 7)
Week 12	11	3.0 (0, 6)
Percentage change from baseline: (week 12 minus baseline)/baseline ×100	11	-42.9 (-100.0, 33.3)
Nonresponse: >-25%		3 (27.3)
Partial response: -25%--85%		7 (63.6)
Complete response: <-85%		1 (9.1)
P: Week 12 versus baseline		0.014
Week 24	11	2 (0, 5)
Percentage change from baseline: (Week 24 minus baseline)/baseline ×100	11	-66.7 (-100.0, 66.7)
Nonresponse: >-25%		1 (9.1)
Partial response: -25%--85%		8 (72.7)
Complete response: <-85%		2 (18.2)
P: Week 24 versus baseline		0.006
DLQI score
Baseline	11	5 (1, 11)
Week 24	8	3 (0, 11)
Absolute change from baseline: Week 24 minus baseline	8	-2 (-11, 2)
P: Week 24 versus baseline		0.093
Follicular units
Baseline	11	62 (20, 76)
Week 24	8	58 (15, 89)
Absolute change from baseline: Week 24 minus baseline	8	-5 (-16, 19)
Percentage change from baseline: (Week 24 minus baseline)/baseline × 100	8	-9.1 (-25.8, 37.5)
P: Week 24 versus baseline		0.57
Mean follicular density
Baseline	11	44.5 (14.4, 54.6)
Week 24	8	41.6 (10.8, 63.9)
Absolute change from baseline: Week 24 minus baseline	8	-3.2 (-11.5, 13.7)
Percentage change from baseline: (week 24 minus baseline)/baseline×100	8	-9.0 (-25.8, 37.6)
P: Week 24 versus baseline		0.55

P result from a paired Wilcoxon signed-rank test. LPPAI – Lichen planopilaris activity index

Table 3

Adverse events at weeks 12 and 24

Variable	Week 12		Week 24
	n	n (%) or median (minimum, maximum)	n	n (%) or median (minimum, maximum)
Any adverse event		10 (90.9)		11 (100.0)
Ocular mucositis	11	0 (0.0)	11	0 (0.0)
Oral mucositis		0 (0.0)		0 (0.0)
Contact dermatitis		9 (81.8)		11 (100.0)
Severe itching		1 (9.1)		0 (0.0)
Patient withdrew because of contact dermatitis		9 (81.8)		11 (100.0)
Pruritus score	11	8 (4, 10)	11	8 (7, 10)
Topical corticosteroid used		8 (88.9)		10 (90.9)

A summary of study outcomes is shown in Table 2. Regarding the primary outcome measure of LPPAI score, this was significantly lower at both week 12 and week 24 in comparison to baseline (P = 0.014 and P = 0.006, respectively), with median percentage changes of −43% and − 67%, respectively. A representative treatment response at week 12 is shown in Figure 2. When categorizing percentage change in LPPAI score as nonresponse, partial response, or complete response, at week 12, most patients had either a partial response (64%) or a complete response (9%), and by week 24 these responses showed additional improvement (73% partial, 18% complete). DLQI score also showed some degree of improvement from baseline to week 24, however, this difference was not quite statistically significant (median: 5 vs. 3, P = 0.093). There was no noticeable change in follicular units or follicular density from baseline to week 24 (P ≥ 0.55). For the eight patients who were evaluated with the PGA at week 24, 6 (75%) were assessed as “no change,” and 2 (25%) were assessed as “mild improvement.”

Figure 2

(a) Baseline presentation of frontal fibrosing alopecia with moderate erythema and perifollicular scaling. (b) Week 12 posttreatment. Marked reduction of erythema with stability of frontal hairline

DISCUSSION

To the best of our knowledge, this is the first clinical trial to assess the efficacy of mechlorethamine 0.016% gel in the treatment of patients with LPP/FAA. By week 12 and week 24, there was a statistically significant decrease in the LLPAI, the primary outcome measure of disease activity [Table 2]. Quantitatively, there was also no change in mean number of follicular units or mean follicular density from baseline to week 24 in a representative target area of disease activity, as illustrated in a representative example in Figure 3.

Figure 3

(a) Pretreatment baseline with follicular density of 52.4/cm2. Note prominent perifollicular scaling. Solid blue dot represents anatomic reference point for TrichoScan®. (b) Week 24 posttreatment endpoint with follicular density of 63.9/cm2. There is minimal perifollicular scaling and hair growth

Despite these favorable outcome measures, there was no statistically significant improvement of DLQI and PGA was assessed as no change in the majority (75%) of patients. This discordance many reflect the poor long term tolerability of treatment with mechlorethamine 0.016% gel.

While all patients were able to titrate to daily application in the 1st month of the study with no adverse advents, by week 12, 82% developed dermatitis. This could not be cleared with daily application of low-potency corticosteroids specified by the study protocol. Re-challenge with mechlorethamine 0.016% gel resulted in immediate flaring even with once weekly application characteristic of acute contact rather than irritant dermatitis.

The observed rate of acute contact dermatitis is significantly higher than previously reported rates with mechlorethamine 0.016% gel[12131415] and may reflect the anatomic site of application as well as the preexisting inflammation activity in LPP/FAA predisposing to antigen priming and contact dermatitis development. Additional study is needed to see if less frequent dosing or combination dosing with mechlorethamine 0.016% gel in combination with high potency topical corticosteroids can minimize the intensity of contact sensitization to allow for longer term application and improved tolerability.

The clinical improvement seen with mechlorethamine 0.016% gel may be due to not only lymphocytic depletion but also as indirect effect of the development contact sensitization. The immunomodulatory effects of contact sensitization have been well described in alopecia areata and are postulated to involve the induction of lymphocyte tolerance due to antigenic competition.

Despite the majority of patients discontinuing therapy at week 12, there was no immediate flaring and continued clinical improvement was seen at week 24. This suggests that treatment with mechlorethamine 0.016% gel may be disease modifying, although a longer follow-up period would be needed to more conclusively establish this trend.

The main limitation of this study includes small sample, lack of ethnic diversity, and the inclusion of both LPP and FAA patients which may not have identical pathogenic mechanisms and responses to treatment. It is also possible that the treatment duration and tolerability could have been improved with the concomitant use of higher potency topical corticosteroids which was deferred to avoid confounding the assessment of the therapeutic efficacy of mechlorethamine 0.016% gel alone.

CONCLUSION

This pilot study established that treatment with mechlorethamine 0.016% gel after 24 weeks resulted in statistically significant improvement (73% partial response and 18% complete response) using LLPAI score with no change in follicular density measured quantitatively through digital image analysis. The treatment duration was limited by a high rate of contact dermatitis reactions generally occurring by week 12 with all patients discontinuing treatment by week 24. As existing therapeutic options for LPP/FAA have limited therapeutic efficacy, treatment with mechlorethamine 0.016% gel may be reasonable in patients with severe and refractory disease or as a short-term topical adjunct to patients on oral therapy. Further investigation is needed to optimize the dosing frequency and to assess the role of combination therapy using high potency topical corticosteroids or topical calcineurin inhibitors in improving long-term tolerability and extending the treatment duration.

Financial support and sponsorship

This investigator initiated study was funded by an unrestricted grant from Helsinn Therapeutics.

Conflicts of interest

This investigator initiated study was funded by an unrestricted grant from Helsinn Therapeutics.