Blue light photodynamic therapy with 5-aminolevulinic acid in refractory mycosis fungoides: A prospective, open-label study
Authors: Kevin J. Severson, Helen J.L. Cumsky, Caitlin M. Brumfiel, Monica C. Janeczek, Brenda F. Ginos, Heidi E. Kosiorek, Jake Besch-Stokes, Meera H. Patel, William G. Rule, David J. DiCaudo, Allison C. Rosenthal, Mark R. Pittelkow, Aaron R. Mangold
Journal: Journal of the American Academy of Dermatology (2021)

To the Editor: Mycosis fungoides (MF) is the most common primary cutaneous lymphoma.1Kim Y.H. Liu H.L. Mraz-Gernhard S. Varghese A. Hoppe R.T. Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression.Arch Dermatol. 2003; 139: 857-866Crossref PubMed Scopus (577) Google Scholar While typically indolent, refractory and progressive disease occurs in approximately 20% and is associated with significant morbidity and higher mortality.1Kim Y.H. Liu H.L. Mraz-Gernhard S. Varghese A. Hoppe R.T. Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression.Arch Dermatol. 2003; 139: 857-866Crossref PubMed Scopus (577) Google Scholar,2Zackheim H.S. Amin S. Kashani-Sabet M. McMillan A. Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival in 489 patients.J Am Acad Dermatol. 1999; 40: 418-425Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar We conducted the first prospective trial, to our knowledge, to assess blue light photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) in MF. This was a single-arm, open-label study in adult patients with biopsy specimen-proven refractory MF. Refractory was defined as failure of ≥2 skin-directed therapies or ≥1 systemic therapy. Patients received blue light ALA-PDT every 4 weeks for up to 6 cycles (weeks 0, 4, 8, 12, 16, and 20). Four dose levels were used: −1 (2-hour incubation), 0 (3-hour incubation), 1 (3-hour incubation plus 1-hour warming), and 2 (4-hour incubation plus 1-hour warming). Doses were initiated at level 0 then subsequently modified based on tolerability and response. Primary end points included Physician Global Assessment (PGA) and Composite Assessment of Index Lesion Severity (CAILS) scores at 24 weeks or 4 weeks after treatment discontinuation. Owing to the hyperpigmenting nature of PDT, ad hoc analysis eliminated hyperpigmentation to generate modified CAILS (mCAILS) scores. Eligibility, exclusion criteria, study design, efficacy and safety assessments, PDT sessions, and statistical analysis are further described in Supplemental Methods 1-6, available via Mendeley at https://data.mendeley.com/datasets/53kf4k8266/1. The study enrolled 11 patients. Individualized demographics, disease characteristics, and outcomes are detailed in Table I. Six patients reached the 24-week end point. Objective response rates across all patients by PGA, CAILS, and mCAILS were 36.4% (95% confidence interval, 10.9%-69.2%), 18.2% (95% confidence interval, 2.3%-51.8%), and 36.4% (95% confidence interval, 10.9%-69.2%), respectively.Table IBaseline demographic and disease characteristics and treatment outcomesPatientAge, ySexTime from diagnosis, yPrevious treatmentsStageTarget lesions, No.SitesHistologyPDT cycles, No.Reason for de-escalationPGA at study completion (best response)CAILS at study completion (best response)Reason for withdrawal167M2.1tCCS, BX, MEM, nbUVBIB2ThighsFT2, 4∗One lesion received 2 treatment cycles, and 1 lesion received 4 cycles.Bullous dermatitisGrade 5 SD (Grade 5 SD)SD (SD)Per patient267M2.0tCCS, nbUVBIA4Thigh, trunkNF1NAGrade 5 SD (Grade 5 SD)SD (SD)AE (bullous dermatitis)330F5.9tCCS, INNIA2ArmFT4Grade 2 painGrade 5 SD (Grade 4 SD)SD (SD)Per patient436M<1tCCS, MEM, nbUVBIB1ArmNF6Grade 2 painGrade 4 SD (Grade 3 PR)SD (SD)NA551F2.3tCCS, MEM, RTIA4FaceFT6Grade 2 painGrade 1 PR (Grade 1 PR)PR (PR)NA656M<1tCCS, INNIA1ButtockNF6NAGrade 3 PR (Grade 3 PR)PR (PR)NA782M9.5tCCS, nbUVBIA4ThighNF3NAGrade 5-SD (Grade 3 PR)SD (SD)Per patient864M13.6tCCS, MEM, nbUVBIA4AbdomenNF3NAGrade 3 PR (Grade 0 CCR)SD (CCR)NA972F21.4tCCS, INN, nbUVB, RTIB4ButtockNF6NAGrade 2 PR (Grade 1 PR)SD (PR)NA1078F9.0tCSS, MEM, BX, ACN, RTIA2Arm, legFT1NAGrade 4 SD (Grade 4 SD)SD (SD)AE (pain)1122F<1tCCS, oCCS, iCCS, INNIB2ArmFT6Grade 2 painGrade 4 SD (Grade 4 SD)SD (SD)NAResponse definitions for CCR, PR, SD, and PD are provided in the Supplemental Methods via Mendeley.ALA-PDT, 5-Aminolevulinic acid photodynamic therapy; ACN, acitretin; AE, adverse event; BX, bexarotene; CAILS, Composite Assessment of Index Lesion Severity; CCR, complete clinical response; F, female; FT, folliculotropic; iCCS, intralesional corticosteroids; INN, imiquimod; M, male; MEM, mechlorethamine; N, no; NA, not applicable; nbUVB, narrowband UVB; No., number; NF, nonfolliculotropic; oCCS, oral corticosteroids; PGA, Physician Global Assessment; PR, partial response; RT, radiation therapy; SD, stable disease; tCCS, topical corticosteroids; Y, yes.∗ One lesion received 2 treatment cycles, and 1 lesion received 4 cycles. Open table in a new tab Response definitions for CCR, PR, SD, and PD are provided in the Supplemental Methods via Mendeley. ALA-PDT, 5-Aminolevulinic acid photodynamic therapy; ACN, acitretin; AE, adverse event; BX, bexarotene; CAILS, Composite Assessment of Index Lesion Severity; CCR, complete clinical response; F, female; FT, folliculotropic; iCCS, intralesional corticosteroids; INN, imiquimod; M, male; MEM, mechlorethamine; N, no; NA, not applicable; nbUVB, narrowband UVB; No., number; NF, nonfolliculotropic; oCCS, oral corticosteroids; PGA, Physician Global Assessment; PR, partial response; RT, radiation therapy; SD, stable disease; tCCS, topical corticosteroids; Y, yes. No patients experienced complete remission or progressive disease. Median time to best treatment response occurred at 8 weeks by PGA, 8.3 weeks by CAILS, and 12.0 weeks by mCAILS. Patients who completed ≥2 treatment cycles exhibited higher response rates (44.4% by PGA and mCAILS and 22.2% by CAILS). Objective response rates by PGA, CAILS, and mCAILS according to the number of treatments received are represented in Fig 1. Study results are further detailed in Supplemental Fig 1 and Supplemental Tables I and II. An example of 1 patient's partial clinical response is depicted in Supplemental Fig 2. All treatment-related adverse events were classified as grade 1 or 2 reactions and included pain, pruritus, bullous dermatitis, ulceration, and induration (Supplemental Table III). Our results indicate this standardized ALA-PDT regimen was well tolerated and moderately successful in treating refractory MF. Response rates increased when ≥2 cycles were administered and plateaued after 5 cycles. Time to best treatment response in our cohort suggests patients may achieve clinical benefit after 3 cycles of ALA-PDT. If no improvement is experienced after 3 months, clinicians should consider alternate therapy. The value of treatment beyond 6 cycles is unknown; however, disease stability may occur in those who respond and are treated for 5 to 6 cycles of therapy. Treatment success in our study was lower compared with 2 similar trials of PDT in MF, which reported response rates of 75% to 92%.3Fernandez-Guarino M. Harto A. Perez-Garcia B. Montull C. De Las Heras E. Jaen P. Plaque-phase mycosis fungoides treated with photodynamic therapy: results from 12 patients.Actas Dermosifiliogr. 2010; 101 ([in Spanish]): 785-791Crossref PubMed Scopus (0) Google Scholar,4Quereux G. Brocard A. Saint-Jean M. et al.Photodynamic therapy with methyl-aminolevulinic acid for paucilesional mycosis fungoides: a prospective open study and review of the literature.J Am Acad Dermatol. 2013; 69: 890-897Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar However, we used a different light source (blue vs red light), sensitizing agent (ALA vs methyl-aminolevulinic acid), and response criteria. Our PDT study is the only one, to our knowledge, to use the CAILS scoring system, which is considered the gold standard for lesional assessment.5Olsen E.A. Whittaker S. Kim Y.H. et al.Clinical end points and response criteria in mycosis fungoides and Sezary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the cutaneous lymphoma task force of the European Organisation for Research and Treatment of Cancer.J Clin Oncol. 2011; 29: 2598-2607Crossref PubMed Scopus (510) Google Scholar Five patients did not complete all 6 cycles of ALA-PDT, which may partially explain reduced response rates. Future randomized trials directly comparing ALA-PDT vs methyl-aminolevulinic acid -PDT in the treatment of refractory MF are warranted. Dr Mangold is an investigator for multiple studies in mycosis fungoides sponsored by Solagenix, MiRagen, Sun Pharma, and Elorac, and also serves on an advisory board for Kirin. Authors Severson, Brumfiel, Ginos, Kosiorek, Besch-Stokes, and Patel, and Drs Cumsky, Janeczek, Rule, DiCaudo, Rosenthal, and Pittelkow have no conflicts of interest to declare.