Table 1.

Clinical trial and real-world studies assessing the efficacy of CL gel

Study	Study type	Patients	Treatment	Main study endpoints	Study details
Clinical trials
Lessin et al. [33]	Randomized, controlled, observer-blinded, multicenter clinical trial (study 201)	N = 260 N = 130 receiving CL gel N = 130 receiving CL ointment	Daily 0.02% CL gel or ointment treatment for up to 12 months No concomitant therapy allowed per trial protocol	The primary endpoint was response, defined as ≥ 50% improvement in baseline CAILS for at least two consecutive visits over ≥ 4 weeks Secondary endpoints included ≥ 50% improvement in mSWAT	Treatment efficacy was assessed every month for the first 6 months, and every 2 months thereafter CR was defined as 100% improvement with a score of 0, and PR as at least a 50% reduction from baseline scores
Geskin et al. [34]	Post hoc analysis of study 201	N = 260 N = 130 receiving CL gel N = 130 receiving CL ointment	Daily 0.02% CL gel or ointment treatment for up to 12 months No concomitant therapy allowed per trial protocol	By-time analysis of clinical response data	The by-time analysis was performed to analyze proportions of patients with clinically responsive disease at each individual visit. This was determined by dividing the number of patients with a response by the total randomized population (n = 130) VGPR was included as a response category; this was defined as ≥ 75% improvement from baseline by CAILS, mSWAT, or BSA
Querfeld et al. [35]	Post hoc analysis of study 201	N = 260 N = 130 receiving CL gel N = 130 receiving CL ointment	Daily 0.02% CL gel or ointment treatment for up to 12 months No concomitant therapy allowed per trial protocol	Response by CAILS, mSWAT, and BSA Time to first response and response trends Relationship between the frequency of gel application and AEs or CAILS responses	Each visit outcome was reported as a separate time point Separate response analyses were done for patients with stage IA or IB–IIA MF VGPR was included as a response category
Querfeld et al. [36]	Extension phase of study 201, using 0.04% CL gel (study 202)	N = 98	Daily CL gel 0.04% treatment for up to 7 months No concomitant therapy allowed per trial protocol	The primary endpoint was response, defined as ≥ 50% improvement in baseline CAILS for at least two consecutive visits over ≥ 4 weeks	The same lesions as evaluated during study 201 were included; if fewer than five original lesions were available, additional lesions could be evaluated if they had been consistently treated during the study 201 period as well
Querfeld et al. [37]	Post hoc analysis of study 201/202	N = 260 from study 201 N = 98 from study 202 N = 58 who received CL ointment in study 201 N = 40 who received 0.02% CL gel in study 201	Daily 0.02% CL gel or ointment treatment for 12 months followed by CL gel 0.04% treatment for up to 7 months No concomitant therapy allowed per trial protocol	Response by CAILS Time-to-response and repeated measures analyses Relationship between the frequency of gel application and AEs or CAILS responses	Each visit outcome was reported as a separate time point VGPR was included as a response category Patients using CL gel since the beginning of study 201 were compared with those who used CL ointment during study 201 and subsequently switched to CL gel during study 202
Real-world studies
Kim et al. [38]	Prospective, observational study with 46 participating centers (PROVe)	N = 298	CL gel (0.02%) treatment for up to 2 years Variable treatment frequency (daily to less than once per week) Concomitant therapy allowed; 77.9% of patients used other skin-directed therapies and 30.2% used systemic therapies	The primary endpoint was the proportion of stage IA–IB patients who received CL gel + topical corticosteroids + other therapies with a ≥ 50% decrease in BSA from baseline to 12 months Secondary endpoints included BSA response at 12 months for all patients, and a by-time analysis of response	All adult (≥ 18) patients with MF who were treated with CL gel were invited to enroll in the study, regardless of how long they had been using the gel, concomitant therapy, or disease stage Patients were monitored during routine clinical practice visits and no specific clinical assessments were mandated BSA was analyzed to assess efficacy, as this was the most frequently used assessment
Prag Naveh et al. [39]	Single-center retrospective analysis of CL gel-treated patients	N = 66	CL gel (0.02%) application frequency was increased gradually to once daily or lower Over time, multiple dosing regimens were used in 13 patients (20%) Concomitant topical corticosteroids in 40% of patients; concomitant systemic treatment in 7% of patients		Time to response was based on assessment of BSA Response was categorized as CR, PR, SD, or PD; ORR was defined as CR + PR Differences between patients with stage IA and stage IB disease were analyzed
Papadavid et al. [40]	Retrospective analysis of CL gel-treated patients	N = 58	CL gel (0.02%) treatment once daily as monotherapy or in combination with other treatment CL gel monotherapy was used by 32 (55.2%) patients		Efficacy was assessed through mSWAT scores, collected at each visit CR was defined as 100% clearance of skin lesions and PR as 50% to < 100% clearance; ORR4 was defined as all patients who maintained a response for at least 4 months ORR and ORR4 were compared between patients with different disease stages, lesion types, and treatment types
Correia et al. [41]	Retrospective analysis of CL gel-treated patients: focus on maintenance therapy	N = 25 active N = 23 maintenance	CL gel (0.02%) treatment 1–4 × per week, depending on disease severity Most patients alternated use of CL gel with topical steroids		Patients were divided into cohorts depending on active vs maintenance therapy Efficacy was assessed through mSWAT scores—two consecutive scores documented at 6-month intervals Change from baseline mSWAT scores over time (≥ 50% reduction was considered a response) Safety, PFS, and quality-of-life scores (DLQI) were also assessed
Koumourtzis et al. [45]	Single-center study of CL gel-treated patients with MF	N = 23	CL gel (0.02%) was initiated once daily and could be scaled down to three times per week
Wehkamp et al. [42]	Retrospective analysis of CL gel-treated patients	N = 18	CL gel (0.02%) was initiated once daily (n = 7) or three to four times per week (n = 11)		Data on treatment regimen and photo documentation of skin findings were available Efficacy was assessed through mSWAT scores, collected every 3 months
Dugre et al. [43]	Retrospective observational analysis of medical records of CL gel-treated patients	N = 14	CL gel (0.02%) treatment three times per week (n = 12) or daily (n = 2)		Data collected for the retrospective observational analysis were BSA or BSA affected by disease, location of the lesions, therapeutic management, effectiveness, and treatment tolerance
Sidiropoulou et al. [44]	Prospective, single-center study of MF skin lesions of CL gel-treated patients	N = 13	CL gel (0.02%) treatment once daily as monotherapy	Histopathologic, immunophenotypic, and molecular changes from baseline to week 4–6 of treatment Potential correlations between clinical, histopathologic, and molecular skin responses were evaluated	Twelve of 13 patients were male; 85% had early stage (≤ IIA) at treatment initiation; 62% had classical MF Median follow-up time was 14 months (range 8–17) Paired skin biopsies were collected at baseline and at 4–6 weeks post-CL gel treatment

AE adverse event, BSA body surface area, CAILS Composite Assessment of Index Lesion Severity, CL chlormethine, CR complete response, DLQI Dermatology Life Quality Index, MF mycosis fungoides, mSWAT modified Severity-Weighted Assessment Tool, ORR overall response rate, ORR4 all patients who maintained a response for at least 4 months, PD progressive disease, PFS progression-free survival, PR partial response, SD stable disease, VGPR very good partial response