The efficacy and safety of mogamulizumab for advanced mycosis fungoides and Sézary syndrome

Mycosis fungoides (MF) and Sézary syndrome (SS) are closely related forms of cutaneous T-cell lymphoma (CTCL), with SS presenting as a leukemic form. MF and SS have an indolent course of disease and affect skin as the primary site. Disease progression causes significant morbidity, and in an advanced stage presents as a multiorgan disease with poor prognosis. Current treatment options include retinoids, interferons, extracorporeal photopheresis, histone deacetylase (HDAC) inhibitors, and single-agent chemotherapy. However, those therapies are effective in only approximately 20–35% of patients, with the responses often not exciding 6 months.¹ The only exception is allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is curative in around half of the cases. Therefore, novel therapies are needed to improve outcomes for patients with advanced MF and SS.

Novel therapies developed in recent years focused on targeting antigens expressed on malignant cells. These treatments include alemtuzumab, an anti-CD52 monoclonal antibody, and brentuximab vedotin, an anti-CD30 antibody-drug conjugate. More recently, mogamulizumab, an antibody targeting the C-C chemokine receptor 4 (CCR4), became available. The treatment was approved by the U.S. Food and Drug Administration and the European Medicines Agency for patients with previously treated MF and SS.

A review of mogamulizumab safety and efficacy by Daniel Lewis and Alain Rook was recently published in Expert Review of Anticancer Therapy.¹

Mechanism of action

Mogamulizumab is a humanized monoclonal antibody against the N-terminal region of CCR4. CCR4, a receptor for C-C chemokine ligand 17 (CCL17) and CCL22, is involved in T-cell migration to the skin. The receptor is highly expressed on malignant T cells, and in MF and SS correlates with advanced or refractory disease and blood involvement.

Mogamulizumab exerts its anti-tumor effect by enhancing antibody-dependent cellular cytotoxicity and depletion of regulatory T cells (Tregs), which improve the endogenous immune response against malignant cells.

Efficacy

An open-label, multicenter phase I dose-finding study investigated mogamulizumab in 41 patients with MF/SS demonstrated promising efficacy and safety.  The maximum tolerated dose was not reached in phase I after administration of mogamulizumab (0.1, 0.3, and 1.0 mg/kg) once weekly for 4 weeks.

The highest 1.0 mg/kg dose was then tested in phase II, in 23 patients with MF and 15 patients with SS, who received mogamulizumab 1.0 mg/kg weekly for 4 weeks, followed by biweekly dosing until disease progression (PD). Another phase II study of 1.0 mg/kg mogamulizumab was conducted in Japanese patients with CCR4+ peripheral T-cell lymphoma (PTCL) and CTCL, including seven MF patients. The efficacy results achieved in both studies are presented in Table 1.

The subsequent, open-label, randomized, multicenter phase III MAVORIC study compared mogamulizumab with vorinostat. Patients with previously treated SS and MF (N = 372) were randomized to

• mogamulizumab (1.0 mg/kg), four weekly doses followed by biweekly dosing for ≤ 12 months or until PD
• vorinostat (400 mg) daily

A total of 136 of 186 patients in the vorinostat arm crossed over to the mogamulizumab arm — 109 due to PD, and 27 due to intolerable toxicity. The efficacy of mogamulizumab (Table 1) was greater than that of vorinostat with overall response rates of 28% vs 5% and progression-free survival 7.7 vs 3.1 months, respectively. The antibody was most active in patients with advanced disease and resulted in responses of 36% in those with MF, and 37% in patients with SS.

Table 1. Efficacy of mogamulizumab in clinical studies in patients with SS and MF

Safety and tolerability

Mogamulizumab showed a manageable safety profile. The most frequent adverse events (AEs) reported in the MAVORIC trial included infusion-related reactions (IRRs), drug eruptions, diarrhea, and fatigue.

Infusion-related reactions

Patients experienced IRRs predominantly during the first couple of doses. Grade 1–2 events occurred in 32% of patients, and Grade 3 in 2% of patients. There were no Grade 4 events. Pretreatment with acetaminophen and diphenhydramine before the first dose of mogamulizumab reduced the incidence of IRRs (32%), compared with patients who were not pretreated (42%).

Drug eruptions

In the MAVORIC trial, drug eruptions occurred in 24% of patients and were the leading cause of treatment discontinuation (7%). The eruptions usually presented 3–5 months after initiating therapy as a mogamulizumab-associated rash (MAR); however, they can also appear after the therapy.

MAR usually manifests as a papular, morbilliform, or erythematous eruption, but can also appear as a lichenoid, spongiotic, or granulomatous dermatitis. Its histologic features may resemble MF, such as lymphocyte tagging and exocytosis, follicular destruction, and lamellar fibroplasia. However, in contrast to MF, MAR is characterized by inverted CD4:CD8 ratio and retention of CD7 on T cells. Therefore, in difficult cases, high-throughput sequencing of the T-cell receptor can be used to distinguish MAR from residual/recurrent CTCL.

Grade 1–2 eruptions of MAR should be treated with topical steroids, while those of higher grade may require systemic steroids. Although methotrexate may be considered for protracted MAR, the authors recommend avoiding primary immunosuppressants like cyclosporine.

Infections

Infections are the most common cause of mortality in CTCL. In the MAVORIC study, infections occurred in 21% of patients and were the second-most frequent AE leading to treatment discontinuation. Therefore, while on mogamulizumab therapy, patients should be monitored for signs of infection.

The most common infections in the MAVORIC study were upper respiratory tract infections (10%), followed by pneumonia (5%), cellulitis (3%), and sepsis (2%). Two of the infections, pneumonia and sepsis, resulted in deaths in the mogamulizumab treatment group.

The authors highlighted that the combination of CD4+ lymphocytes depletion caused by mogamulizumab, severe immunodeficiency, and bacterial skin colonization in advanced MF/SS, contribute to the heightened risk of infections.

Acute GvHD

As CCR4 is expressed on malignant T cells as well as Tregs, depletion of Tregs with mogamulizumab before allo-HSCT may potentially increase the severity of graft-versus-host disease (GvHD). Studies have demonstrated that Treg counts may remain low for over 6 months and therefore when possible, it is recommended to delay allo-HSCT ≥ 3 months following mogamulizumab therapy and measure Treg before transplantation.

Autoimmune disease

Mogamulizumab depletion of Treg also raises concerns about the induction or worsening of autoimmune diseases. Although routine screening is not recommended, autoimmune AEs should be investigated in suspected cases.

In the MAVORIC trial, Grade ≥ 3 autoimmune AEs were reported in six patients in the mogamulizumab group including hepatitis, myocarditis, pneumonitis, myositis, polymyositis, polymyalgia rheumatica, and Miller-Fisher syndrome. It has been suggested that developing an autoimmune disease during mogamulizumab treatment is associated with a better outcome.

Possible combinations

Immunotherapy

To further stimulate the immune response against malignant cells, mogamulizumab could potentially be combined with other immunotherapies, including the following:

• Interferons
• Interleukin-12
• Toll-like receptor antagonists like imiquimod or resiquimod

However, such an approach can also lead to an increased incidence of AEs, as in the case of mogamulizumab-PD-1 inhibitor combination.

Low-dose total skin electron beam therapy

As the low-dose total skin electron beam therapy has been shown to induce release of tumor-specific antigens, there is a potential of synergy with mogamulizumab. A clinical trial of such combination is planned.

 HDAC inhibitors

Although some data suggest that HDAC inhibitors may decrease responses to mogamulizumab, the findings were not confirmed in the MAVORIC trial, where response rates were similar among patients in the mogamulizumab group (28%) and those who had crossed over from the vorinostat group (30%).

Conclusion

The MAVORIC study, the largest randomized controlled trial in CTCL to date, which enrolled a large number of patients with advanced or relapsed/refractory MF/SS, demonstrated the efficacy and favorable safety profile of mogamulizumab. This novel therapy induced similar response rates to other available therapies, such as romidepsin and vorinostat, but achieved longer duration of response and the most potent responses within the blood compartment. Therefore, authors of the review recommend the use of mogamulizumab in patients with erythroderma and leukemic disease but without infiltrated plaques, tumors, or significant lymphadenopathy. CCR4 mutations are relatively common in MF/SS patients and their impact on response should be investigated. Further studies should also explore the potential of enhanced activity of mogamulizumab in combinations with other immunomodulatory agents, as well as the optimal time for its use as a bridge to allo-HSCT to avoid the development of GvHD.