Prevalence and implications of mogamulizumab-induced immune-related adverse events in mycosis fungoides/Sézary syndrome; a single-center experience.

To the Editor: We characterized immune-related adverse events (irAEs) in mycosis fungoides (MF)/Sézary syndrome (SS) patients treated with mogamulizumab and investigated the relationship between mogamulizumab associated rash (MAR) and disease outcomes. We performed a retrospective cohort study of patients treated at our center January 1, 2015-July 1, 2022. Analyses of PFS, OS, and time to next treatment (TTNT) each used extended Cox models with a time-dependent covariate of MAR to account for guarantee-time bias.1Cheung K.M. Tsui T.Y.M. Chow J.C.H. Guarantee-time bias in studies on the relationship between immune-related adverse events and antitumor activity.Cancer. 2022; 128: 2549-2550Crossref PubMed Scopus (1) Google Scholar,2Giobbie-Hurder A. Gelber R.D. Regan M.M. Challenges of guarantee-time bias.J Clin Oncol. 2013; 31: 2963-2969Crossref PubMed Scopus (334) Google Scholar Models for PFS and TTNT were stratified by SS/MF/T-stage (T1/2 and T4) to allow for underlying differences in the baseline hazard; the model of OS was stratified by SS/MF/T-stage (T1/2 and T4) and age divided at the median. Fisher's exact and Wilcoxon rank-sum tests were used to compare categorical and continuous patient characteristics, respectively. A total of 41 patients were included (Table I). Median follow-up from the time of mogamulizumab start was 32 months (inverted Kaplan–Meier). Eight patients (19.5%) had infusion reactions. There were a total of 11 serious AEs, 10 were irAEs, and one was an infusion reaction. AEs led to treatment discontinuation in 31.7%. Among those that received at least 3 weeks of treatment (n = 39), the global and skin response rates were 67%: CR 31% (SS = 10 vs MF = 2), PR 36% (SS = 12 vs MF = 2). The blood response rate was 90.9%; median time to relapse in the blood was 24.9 months after CR in blood (95% CI: 14.4-36.6).Table IParticipant demographics and characteristics according to mogamulizumab-associated rash (MAR)MAR?Fisher's Exact P-values∗Benjamini–Hochberg correction with a false discovery rate of .05 does not change statistical significance of reported P-values.AllNoYesN%N%N%Sex.99 Female1946.31346.4646.2 Male2253.71553.6753.8Subtype.48 MF1434.11139.3323.1 SS2765.91760.71076.9Race.52 American Indian12.413.6-- Black512.2310.7215.4 Other12.4--17.7 White3482.92485.71076.9Ethnicity.32 Hispanic12.4--17.7 Non-Hispanic4097.628100.01292.3Stage.4 IA12.4--17.7 IB1024.4932.117.7 IIIA512.2310.7215.4 IIIB24.913.617.7 IV112.413.6-- IVA24.927.1-- IVA11741.51035.7753.8 IVA237.327.117.7T-stage.004 T137.3--323.1 T21843.91657.1215.4 T42048.81242.9861.5N-stage.99 N03790.22589.31292.3 N337.327.117.7 Nx12.413.6--B-stage.19 B01639.01346.4323.1 B1512.227.1323.1 B22048.81346.4753.8∗ Benjamini–Hochberg correction with a false discovery rate of .05 does not change statistical significance of reported P-values. Open table in a new tab Sixteen of 39 patients (41%) developed an irAE. MAR occurred in 33% (n = 13) with a median time to MAR onset of 67 days (range: 21-147 days). MAR had diverse clinical and histologic presentations (Table II). The other irAEs were myositis in 8% (n = 3),3Larocca C.A.T.M. Fisher D.C. Kupper T.S. Successful treatment of mogamulizumab-induced myositis. Oral Presentation at: United States Cutaneous Lymphoma Consortium Annual Meeting. Virtual Platform; June.2021Google Scholar myocarditis (n = 2), myasthenia gravis (n = 1), conjunctivitis (n = 1), polymyalgia rheumatica flare (n = 1), and drug-induced liver failure (n = 1).Table IIClinical features and histologic findings of participants with mogamulizumab-associated rash (MAR)CaseMAR by CTCAE (grade)Clinical morphologyLocationHistologic findingsT-cell cloneMAR onset (days)MAR onset with relation to best skin responseOther AE (grade)1Morbilliform (1)Urticaria (1)Macules and papules; single urticarial plaqueTrunkInterface, Langerhans microabscesses, superficial and mid-dermal perivascular lymphocytic infiltrate, scattered eosinophilsN46BeforeInfusion reaction, (2) ALT elevation (1)2Eczema (2)Eczematous patches and plaquesTrunk, extremitiesSpongiosis, Langerhans microabscesses, dermal lymphohistiocytic infiltrate, lymphocytic exocytosis, epidermotropismN100BeforeNone3Eczema (2)Photosensitivity (1)Psoriasiform plaquesPhoto-distributed--147BeforeFatigue (1)Arthralgias (1)Alopecia (1)4Eczema (3)Photosensitivity (2)Psoriasiform plaquesPhoto-distributedSubacute spongiosis, superficial perivascular lymphocytic infiltrate with numerous eosinophilsY∗T cell clone distinct from previously identified malignant T cell clone.112BeforeNone5Eczema (2)Erythema annulare centrifugumTrunk, extremitiesPsoriasiform dermatitis, spongiotic dermatitis with parakeratosis, superficial polymorphous infiltrate with lymphocytes, plasma cells, and neutrophilsN65BeforeMyositis (3)Dysphagia (2)Generalized muscle weakness (1)Fatigue (3)6Erythroderma (3)Erythroderma with superimposed psoriasiform plaquesDiffuse, including scalpPsoriasiform dermatitis, subacute spongiosis, numerous eosinophilsN119BeforeMyositis (3)Generalized muscle weakness (1)Fatigue (3)7Eczema (2)Alopecia (1)Seborrheic dermatitisHair thinningScalpSpongiotic dermatitis and periadnexal lymphocytic infiltrate, parakeratosisN21BeforeFatigue (1)8Morbilliform (3)LichenoidDiffuseSpongiosis, interface dermatitis, superficial mixed inflammatory infiltrate with numerous neutrophilsN98SimultaneousInfusion reaction (2)Myocarditis (4)Myositis (4)Myasthenia Gravis (4)9Eczema (2)Eczematous plaques and scaling follicular papulesTrunk, extremities, follicular--44BeforeNone10Other (2)Violaceous edematous plaquesTrunk, extremitiesAcanthosis, band-like interstitial and periadnexal lymphohistiocytic infiltrate-35SimultaneousNone11Eczema (2)Chronic Actinic DermatitisPhoto-distributedSuperficial dermal lichenoid and perivascular lymphocytic infiltrateN56BeforeNone12Eczema (2)Photosensitivity (3)Eczematous plaques, scaling follicular papulesSeborrheic dermatitisTrunk, extremities, scalp, follicularPerivascular, perifollicular superficial dermal lymphocytic infiltrate with focal epidermotropism and exocytosisN67SimultaneousNone13Eczema (1)Seborrheic dermatitisScalp--117BeforePolymyalgia Rheumatica (2)∗ T cell clone distinct from previously identified malignant T cell clone. Open table in a new tab There was a statistically significant relationship between MAR and T-stage (P = .004). Global and skin response rates were the same: Response rates were 92% in patients with MAR compared with 54% in patients without MAR (P = .03 for both). Median OS was “not reached” for patients with MAR and was 37 months for patients without MAR. The extended Cox model showed a statistically nonsignificant, 83% reduction in the hazard of death for patients with MAR compared with those who had not yet or never developed MAR (HR (Yes vs No): 0.17, 95% CI: 0.02-1.3, P = .09). There were no differences in PFS, TTNT, or DoR according to MAR status. Among those who achieved a CR in the blood there was no difference in time to relapse in the blood according to MAR status using a stratified Cox PH model (HR (Yes vs No): 1.2, 95% CI: 0.3-4.6, P = .76). Our study showed that MAR is positively associated with overall responses and T4-stage (erythroderma) at the time of treatment, but not disease subtype (MF vs SS) or stage (I-IV). We observed that the incidence of myositis (n = 3/39) is higher than previously observed in the MAVORIC trial (n = 2/320).4Mogamulizumab [package insert]. Kyowa Kirin, Inc, 2018Google Scholar,5Kasamon Y.L. Chen H. de Claro R.A. et al.FDA approval summary: mogamulizumab-kpkc for mycosis fungoides and Sezary syndrome.Clin Cancer Res. 2019; 25: 7275-7280Crossref PubMed Scopus (40) Google Scholar T.S.K. is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers R01 AR065807 and T32 AR007098) and the National Institute of Allergy and Infectious Diseases (grant number R01 AI127654). He is a scientific advisor for Pellis Therapeutics. N.R.L. is a consultant and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback and Synox Therapeutics outside the submitted work. C.L. is supported by the National Cancer Institute (grant number R37 CA252312). She has served on a medical advisory board for Kyowa Kirin. The other authors declare no conflicts of interest with respect to the research, authorship and/or publication of this article.