Mogamulizumab-Associated Myositis With and Without Myasthenia Gravis and/or Myocarditis in Patients With T-Cell Lymphoma

Abstract Mogamulizumab is being increasingly prescribed for the treatment of T-cell lymphomas (MF/SS/ATLL). We conducted a retrospective cohort study to identify muscular immune-related adverse events (irAEs) associated with mogamulizumab in patients with T-cell lymphoma followed at Dana-Farber Cancer Institute from January 2015 to June 2022. We identified 5 cases of mogamulizumab-associated myositis and/or myocarditis (MAM/Mc), 2 additionally affected by myasthenia gravis, among 42 patients with T-cell lymphoma. Three cases experienced mogamulizumab-associated rash (MAR) prior to developing MAM/Mc. The incidence (n = 5/42, 11.9%) of muscular mogamulizumab-associated irAEs may be higher than has been previously reported in clinical trials and may be of late onset (a median of 5 cycles and as late as 100 days from the last infusion). We highlight the utility of IVIG, together with systemic corticosteroids, for the treatment of these potentially fatal side effects associated with mogamulizumab therapy.

Mogamulizumab is a C-C chemokine receptor type 4 (CCR4)-directed monoclonal antibody used for the treatment of relapsed/refractory mycosis fungoides (MF) or Sézary syndrome (SS), and adult T-cell leukemia/ lymphoma (ATLL). From the MAVORIC trial, a fatal event polymyositis and rare reports of myocarditis have been identified. 1 Given the serious nature of these immunerelated adverse event (irAE), we sought to identify the incidence, clinical characteristics, and long-term outcomes of patients with T-cell lymphoma who developed myositis and/or myocarditis.
After approval by the Mass General Brigham Institutional Review Board, including waiver for informed consent given retrospective deidentified data, we performed a search of the Partners Research Patient Data Registry (January 2015-2022; Brigham and Women's Hospital) for patients who received at least one dose of mogamulizumab and had a diagnosis of T-cell lymphoma were included. Data cutoff was June 2022.
After exclusion of duplicate entries and those who never received mogamulizumab, we identified 5 cases of mogamulizumab-associated myositis and/or myocarditis (MAM/Mc) out of 42 T-cell lymphoma patients (38 = MF/SS, 4 = ATLL) followed at our institution (Table 1): case 1, a 72-year-old female with Sézary syndrome; case 2, an 89-year-old-male with leukemic mycosis fungoides; case 3, a 73-year-old-male with Sézary syndrome; case 4, a 56-year-old-female with mycosis fungoides; and case 5, a 65-year-old-female with ATLL (chronic type, with blood, and cutaneous involvement). Of these, 2 patients (cases 1 and 5) also developed seropositive myasthenia gravis (MG) and 3 patients (cases 1, 2, and 3) developed a mogamulizumab-associated rash (MAR) ( Supplementary  Fig. S1). Among cases of MAM/Mc, median of follow-up e695 The Oncologist, 2023, Vol. 28, No. 8 since initiation of mogamulizumab was 18 months (range: 9-42 months). The median onset of MAM/Mc was 168 days (range: 133-241 days) and occurred after a median of 5 cycles (range: 4-6 cycles) of mogamulizumab. In 3 cases (cases 2, 3, and 5), MAM/Mc developed well after discontinuation of mogamulizumab, onset 50-100 days from last infusion. Statins were taken for at least 2 years prior to MAM/Mc in 3 cases (cases 2, 3, and 5). No cases received messenger RNAbased SARS-CoV-2 vaccination within 30 days of MAM/Mc symptom onset (Table 1). No cases reported prior history of autoimmune conditions. Diagnostic evaluation for MAM/Mc involved laboratory analysis, imaging, functional studies, and muscle biopsy when possible ( Table 2). Targeted magnetic resonance imaging (MRI) of the femur in case 1 revealed symmetrical inflammation of proximal muscles. In contrast, whole body positron emission tomography/computed tomography, obtained for restaging of lymphoma, revealed a patchy and multi-focal pattern of muscle inflammation in case 2 ( Supplementary  Fig. S1). Of the 3 patients (cases 1, 2, and 5) that underwent muscle biopsy, only those with image-directed sampling of the muscle identified inflammation ( Supplementary Fig. S1). Cardiac MRI was pursued in 2 (cases 4 and 5) of 3 cases with troponin elevation and diagnostic of myocarditis in case 4 ( Table 2).
At the time of mogamulizumab discontinuation, 4 cases achieved a global response (complete response in cases 1, 2, and 5; partial response in case 3) ( Table 1). The duration of response ranged from 6 to 36 months and ongoing in 2 cases (minimum follow-up of 9 months).
All cases made a complete recovery following treatment with intravenous immunoglobulin (IVIG) and systemic corticosteroids (Table 1). IVIG was added given lack of clinical improvement on high dose systemic corticosteroids in the first 2 cases and was associated with the first signs of patient-reported improvement in respiratory strength (case 1) and dysphagia (cases 1 and 2) within 2 days of administration. Given this favorable response, IVIG was added irrespective of response to systemic corticosteroids in subsequent cases at the time of MAM/Mc diagnosis.
We report 5 cases of immune-mediated myositis with and without seropositive myasthenia gravis and/or myocarditis in patients with T-cell lymphoma (MF/SS/ATLL). The most frequent toxicities of mogamulizumab therapy are infusion reactions and cutaneous eruptions. 2,3 MAM/Mc is reportedly rarer but a potentially fatal toxicity. In a phase II trial, 1/37 patient developed myositis (grade 3) after 7 cycles. 4 In the MAVORIC trial, 1/184 patient developed MAM after 4.5 months (grade 5); the patient died from respiratory muscle failure and pneumococcal pneumonia. 2,5 Another MAVORIC patient developed myositis (grade 3) and myocarditis after 5 months. 2,5 In our center, the incidence of MAM/Mc (n = 5/42, 11.9%) is higher than what has previously been reported. Similarly, our 5 cases presented 4-8 months after starting treatment with mogamulizumab. Interestingly, 2 of our cases (cases 2 and 3) had been off mogamulizumab for 1-2 months prior to the onset of MAM/Mc due to extensive MAR. Another patient (case 5) had been off mogamulizumab for 3 months prior to the onset of MAM/Mc with MG due to elevated liver enzymes.
We hypothesize that MAM/Mc is a result of the drug's effect on regulatory T cells (T reg ), which also express CCR4. 3 Mogamulizumab depletes T regs and potentially disinhibits autoreactive T cells, leading to adverse events that mirror T-cell-mediated autoimmune syndromes. 3 IrAEs observed in MAVORIC include rash, hepatitis, myocarditis, myositis, pneumonitis, polymyalgia rheumatica, and Miller-Fisher syndrome. 2,5 The incidence and spectrum of mogamulizumab-associated irAEs remains poorly characterized as it is currently prescribed much less frequency than immune checkpoint inhibitors (ICIs). However, given its potential to decrease T reg cells, it is being increasingly studied in combination with ICIs across tumor types, which is cause for heightened awareness of these potentially fatal irAEs. Mortality risk is driven by the potential for involvement of respiratory and bulbar muscles, increased risk of infection, and concomitant myocarditis. It is also important to screen for MG (in patients that develop neuromuscular symptoms), which has not been previously reported with mogamulizumab, but frequently overlaps with ICI-induced myositis. We recommend MAM/Mc be treated according to expert consensus guidelines for the management of ICI-myositis. 6 We highlight the utility of IVIG for MAM/Mc, which parallels the known efficacy of IVIG for corticosteroid-refractory dermatomyositis and polymyositis. 7 Risk factors for the development of MAM/Mc are unknown but may be unique to TCL patients with cutaneous disease. While MAM/Mc patients have a distinct clinicopathologic presentation from dermatomyositis, the presence of active skin inflammation, either due to TCL or MAR, may unmask shared antigens between the skin and muscle tissue. Early data, including our cases, suggests that the induction of these immune-mediated toxicities may correlate with durable complete anti-tumor responses. 8,9 We report 5 cases of immune-mediated myositis with and without seropositive myasthenia gravis and/or myocarditis in patients with T-cell lymphoma (MF/SS/ATLL) treated with mogamulizumab. IVIG, together with systemic corticosteroids, provided safe and effective control of these potentially fatal toxicities. Future research should explore the risk factors associated with the development of these mogamulizumab-associated irAEs, in addition to determining the best treatment strategies to mitigate these irAEs.

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The Oncologist, 2023, Vol. 28, No. 8 The Olsen criteria was used to assess MF/SS response. The Tsukasaki criteria was used to assess ATLL response.

Prior Presentation
Two of the cases in this manuscript were presented at the United States Cutaneous Lymphoma Consortium Annual Virtual Workshop on June 26, 2021.

Data Availability
The data underlying this article will be shared on reasonable request to the corresponding author.