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Indication: The topical treatment of stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma in adult patients who have received prior skin-directed therapy
CADTH recommends that Ledaga should not be reimbursed by public drug plans for the treatment of stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma (MF-CTCL) in adult patients who have received prior skin-directed therapy.
MF-CTCL is a type of blood cancer that starts in the skin with visible patches and plaques which are associated with itchiness, pain, or burning. It is estimated that every year there are 5.6 new cases of MF-CTCL per million persons.
Currently, treatments for MF-CTCL work in most but not all patients, and long-term use may cause side effects. Phototherapy is one of the treatments for MF-CTCL, but it is difficult to access for many patients. Unmet needs for patients with MF-CTCL include treatments that can cure MF-CTCL, are easily accessible, and have fewer side effects.
Treatment with Ledaga is expected to cost approximately $2,995 per month.
The CADTH pCODR Expert Review Committee (pERC) recommends that chlormethine gel (160 mcg, 0.02%) should not be reimbursed for the topical treatment of stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma (MF-CTCL) in adult patients who have received prior skin-directed therapy.
pERC could not recommend chlormethine gel be reimbursed because of several important limitations with the reviewed randomized controlled trial (RCT), Study 201 (N = 260), that resulted in a high degree of uncertainty regarding the magnitude of the treatment effect of chlormethine gel. Study 201 was not designed to evaluate the effects of chlormethine gel on health-related quality of life, which was identified by patients as a key outcome of interest. No comparative data were available between chlormethine gel and the current standards of care for early stage MF-CTCL (i.e., phototherapy, topical retinoids, and topical corticosteroids). Although Study 201 found chlormethine gel was noninferior to chlormethine ointment for relieving skin-related signs and symptoms of MF-CTCL, the comparison was relative to an alternative formulation of the treatment that is no longer used in Canada. It is also unknown whether the degree of change on the primary outcome measure that was used in the RCT (the Composite Assessment of Index Lesion Severity [CAILS]) represents a clinically significant improvement because of the lack of a validated estimate of a minimally important difference for the scale. Patients also expressed a desire for treatments with fewer adverse effects. Chlormethine gel was associated with similar percentages of patients who had serious adverse events (10.9% versus 8.7% with chlormethine ointment) and similar withdrawals due to adverse events (21.9% versus 18.1% with chlormethine ointment), with most events being skin-related. pERC concluded that the overall and long-term balance between the potential benefits and harms of treatment with chlormethine gel are highly uncertain because of the limitations with the clinical evidence.
Chlormethine gel (Ledaga) has a Health Canada indication for topical treatment of stage IA and IB MF-CTCL in adult patients who have received prior skin-directed therapy. Chlormethine is a bifunctional alkylating agent that inhibits rapidly proliferating cells. It is available in 60 g tubes containing 160 mcg of chlormethine hydrochloride (equivalent to 0.02% chlormethine) per gram of gel. The gel is applied as a thin film once daily to affected areas of the skin. The product monograph notes that treatment should be stopped for any grade of skin ulceration or blistering, or moderate-to-severe dermatitis (e.g., marked skin redness with edema). Treatment with chlormethine gel can be restarted after the skin-related effects have resolved at a reduced frequency of once every 3 days. If restarted treatment is tolerated for at least 1 week, the frequency of application can be increased to every other day for at least 1 week and then to once-daily application if tolerated.
To make their recommendation, pERC considered the following information:
The information in this section is a summary of input provided by the patient and clinician groups who responded to CADTH’s call for input and from clinical experts consulted by CADTH for the purpose of this review.
Lymphoma Canada, with the collaboration and input of CSPA and CLF, conducted an online survey of cutaneous lymphoma patients from September 2020 to January 2021. Overall, 233 patients with MF-CTCL responded to the survey, of which 210 (90%) were diagnosed with MF-CTCL. Fifty-six (33%) patient respondents indicated they had experience with chlormethine gel.
Patients reported having visible patches or lesions, itchiness, pain or burning of the skin or lesions, plaques, and rash-like skin redness. The patients indicated that even in the early stages of the disease, these symptoms negatively impact their quality of life and mental and emotional well-being, their self-image, family relationships, intimate relationships, and work.
The patients indicated that having a choice in treatment options was extremely important to them. The patients reported that they want treatments that result in longer survival, better quality of life, longer remission, fewer side effects, and easier or faster treatment application. Among the patients who had experience with chlormethine gel, 74% indicated that they would take it again if it were available to them.
The clinical experts consulted by CADTH noted that current treatments for MF-CTCL have limitations. Unmet needs include treatments that can be curative, easily accessible, and well-tolerated. Topical corticosteroids are not curative, and it is unclear if they can prevent disease progression. Long-term use can cause side effects. Phototherapy may not be accessible to some patients, and it may cause skin atrophy and increased risk of skin cancer. Topical chlormethine causes dermatitis and may not be tolerated, especially when large surface areas are involved. These treatments have efficacy ranging from 60% to 80%, depending on disease severity. Therefore, different treatment options may be required for refractory disease.
The clinical experts anticipated that it is unlikely that chlormethine gel will shift the current treatment paradigm as it is only supplied in 60 g tubes and can only be used for treatment of small surface areas (< 10% body surface area) because of its potential to cause skin irritation. It may be used to treat lesions refractory to topical corticosteroids or when phototherapy is not accessible or is ineffective. The clinical experts identified patients least likely to benefit from chlormethine gel as those with extensive disease (> 20% affected body surface area) or those with tumours.
A group of 5 clinicians, coordinated by Lymphoma Canada, provided input.
The clinicians noted that the addition of effective topical treatment would be useful in the treatment of patients with MF-CTCL. The goals of this topical therapy include disease control, symptom control, and improved quality of life. Importantly, for select skin sites such as the scalp and other hair bearing areas, where application of creams and ointments is difficult, having a gel product that can be applied would be especially useful in the treatment of these patients. Gel is stable, non-greasy, and quick drying formulation that allows for convenient, simple at home administration, and may encourage adherence to treatment. Chlormethine is a useful treatment, but currently rarely used because it is not always available. This option is more convenient than light (phototherapy or photochemotherapy) treatment for patients that live far from a clinic. The clinicians reported that patients who would benefit most from chlormethine gel include adult patients with IA to IIA stages of MF-CTCL with less than 15% body surface area involvement, and patients with select skin sites involved by MF-CTCL (e.g., hair bearing areas).
The key question raised by the Provincial Advisory Group (PAG) was whether use of chlormethine ointment as a comparator to chlormethine gel in the pivotal trial was clinically relevant. Chlormethine ointment is not currently funded or available for use as a treatment in most jurisdictions. In terms of place in therapy, patients enrolled in Study 201 were required to have been treated with at least 1 prior skin-directed therapy. PAG asked if this would apply to routine clinical care. Another question concerned the quantity of chlormethine gel dispensed (60 g tube) and the quantity needed to treat skin lesions.
Study 201 was a randomized, observer-blinded, controlled, multi-centre trial conducted in 13 academic centres across the US. The objective of the study was to investigate the safety and efficacy of chlormethine 0.02% topical gel for patients with early stage MF-CTCL (May 2006 to August 2011). It was designed as a noninferiority trial comparing chlormethine 0.02% gel with chlormethine 0.02% compounded ointment over a 12-month period. Blocked randomization stratified by MF-CTCL stage (IA versus IB, IIA) was performed. In total, 260 patients with biopsy-confirmed stage I or IIA (cutaneous only) MF-CTCL who had received at least 1 prior skin-directed therapy for MF-CTCL were randomized 1:1 to receive treatment with chlormethine 0.02% gel (n = 130) or chlormethine 0.02% ointment (n = 130). All patients completed a washout period of MF-CTCL therapies for 4 weeks before initiating the trial treatments. Patients in both treatment groups were instructed to apply the treatment once daily to specific lesions, or to the total skin surface depending on the extent of body surface area coverage of the patients. The primary efficacy end point of Study 201 was response rate, defined as a greater than or equal to 50% improvement in patients’ CAILS score from baseline to 12 months. A patient was considered a responder if the response was maintained for at least 2 consecutive visits (or at least 28 days). The main secondary efficacy end point was response rate using the Severity-Weighted Assessment Tool (SWAT). Other outcomes were change in total percentage body surface area response rate, time to response, duration of response, time to disease progression, and safety and tolerability.
Most patients were between 18 and 64 years of age and 40.8% were female. Greater than 54% of patients had stage IA disease and 44.2% of patients had stage IB disease at baseline; 2 patients in each treatment group had stage IIA disease at baseline. The most common previously used skin-directed therapy was corticosteroids, used in 86% of patients in both treatment groups.
In the intention-to-treat population, the confirmed response rate based on the CAILS score was higher for chlormethine gel than chlormethine ointment (58.5% versus 47.7%); 13.8% and 11.5% of patients in the chlormethine gel and chlormethine ointment treatment groups, respectively, achieved complete response (i.e., no evidence of disease with a 100% improvement). The ratio of the response rate of gel to ointment was 1.23 (95% confidence interval [CI], 0.97 to 1.55), meeting the pre-specified criterion for noninferiority (≥ 0.75 for lower bound of 95% confidence interval [CI]). The SWAT response was 46.9% for chlormethine gel and 46.2% chlormethine ointment. The ratio of response was 1.02 (95% CI, 0.78 to 1.32). Body surface area response was achieved in 44.6% patients treated with chlormethine gel and 43.1% of patients in the chlormethine ointment group, with a ratio of response of 1.03 (95% CI, 0.78 to 1.36). Time to response in the chlormethine gel group was 26 weeks versus 42 weeks in chlormethine ointment group. Response was maintained in 86% of patients in chlormethine gel group and in 82% of patients on the chlormethine ointment group.
During the trial period, 84.4% of patients treated with chlormethine gel and 90.6% of patients treated with chlormethine ointment experienced at least 1 adverse event. Most adverse events in both treatment groups were skin-related. The frequency of skin irritation was higher in the gel group compared with the ointment arm (25.0% versus 14.2%). Serious adverse events occurred in 10.9% and 8.7% of patients in the chlormethine gel and ointment groups, respectively. Approximately 22% of patients in the chlormethine gel group and 18% in the chlormethine ointment group withdrew prematurely for adverse events. During the 12-month trial period and the additional 12-month follow-up period (in the extension study, Study 202), 20 non-melanoma skin cancers were detected in 11 (4.3%) patients, which included 10 basal cell carcinomas (5 occurring in a treatment area), 9 squamous cell carcinomas (1 in a treatment area), and 1 Merkel cell carcinoma (not in treatment area). Eight of these patients developed non-melanoma skin cancer during treatment; 3 additional patients developed non-melanoma skin cancer during the 1-year follow-up period.
The key limitations of Study 201 included the choice of a comparator (chlormethine ointment) that is not part of the current standard of care in Canada, uncertainty regarding the clinical significance of the results, and absence of health-related quality of life outcomes.
No indirect evidence was submitted.
Study 202 was an open-label, single-arm extension study that evaluated the efficacy and safety of a higher concentration of chlormethine gel (0.04%). Patients in Study 201 who had not achieved complete response based on CAILS on either chlormethine gel or chlormethine ointment during Study 201 were eligible to enroll into Study 202. All patients who enrolled into the study received the higher strength of chlormethine gel (0.04%) for up to 7 months, and were followed and evaluated for adverse events and skin cancers during the 7-month study treatment follow-up and for 5 months thereafter. CAILS responses at the end of Study 202, relative to Study 201 baseline showed an overall confirmed response rate of 75.5%, and responses relative to the Study 202 baseline showed a confirmed response rate of 23.5%. Overall, 72.4% of patients in Study 202 had an adverse event and 6.1% had a serious adverse event. The most common adverse events were skin irritation (11.2%), erythema (10.2%), and pruritus (6.1%). A lack of systemic exposure to chlormethine or its degradation product was confirmed in this study.
Cost and Cost-Effectiveness.
CADTH identified the following key limitations with the sponsor’s analysis:
CADTH reanalysis included: updating the prevalence of MF-CTCL, using the proportion of patients eligible for coverage to calculate market size, increasing the daily dose of chlormethine gel, and increasing the duration of phototherapy.
Based on CADTH reanalyses, the budget impact to the public drug plans of introducing chlormethine gel for patients with MF-CTCL is expected to be $2,480,803 in year 1, $8,130,658 in year 2, and $19,702,020 in year 3, for a 3-year total budget impact of $30,313,481. The estimated budget impact is sensitive to the proportion of MF-CTCL patients who are eligible for public drug plan coverage, the daily dose of chlormethine gel, and the price of chlormethine gel.
Dr. Maureen Trudeau (Chair), Dr. Catherine Moltzan (Vice-Chair), Mr. Daryl Bell, Dr. Jennifer Bell, Dr. Kelvin Chan, Dr. Matthew Cheung; Dr. Winson Cheung, Dr. Michael Crump, Dr. Avram Denburg, Dr. Leela John, Dr. Christine Kennedy, Dr. Christian Kollmannsberger, Mr. Cameron Lane, Dr. Christopher Longo, Ms. Valerie McDonald, Dr. Marianne Taylor, and Dr. W. Dominika Wranik
Initial meeting: June 10, 2021
Regrets: None
Conflicts of interest: None
Reconsideration meeting: November 10, 2021
Regrets: None
Conflicts of interest: None
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About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.
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Indication: The topical treatment of stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma in adult patients who have received prior skin-directed therapy
Sponsor: Recordati Rare Diseases Canada, Inc.
Final recommendation: Do not reimburse
Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/
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