Mogamulizumab plus etoposide in the management of mycosis fungoides with blood involvement: a case report

Abstract

Mycosis fungoides (MF) and Sézary syndrome are primary cutaneous T-cell lymphomas with widely varying courses of disease and prognosis. Here, we report the case of a patient with MF with blood involvement who experienced many lines of skin-directed and systemic therapies throughout their disease course. The male patient presented with scaly, itchy, and painful patches on his trunk and upper extremities in 2012 and was diagnosed with MF, which progressed to erythroderma with blood involvement. Various skin-directed therapies were prescribed; however, in 2014, progression of skin lesions ensued. The patient achieved a partial response with methotrexate but discontinued after ~12 months due to elevated transaminases. Following treatment with bexarotene then gemcitabine, CHOP chemotherapy was initiated in December 2019, but, after a period of partial skin response, the patient relapsed with progression of skin lesions. Mogamulizumab was initiated in May 2020 (1 mg/kg intravenously on days 1, 8, 15, and 22 of the first 28-day cycle, then on days 1 and 15 of subsequent cycles) with a good initial response in skin and blood. Disease progression in the skin occurred in December 2020; mogamulizumab was continued, and the patient achieved remission with the addition of etoposide and prednisone in August 2021. Onset of progression occurred in July 2022, which did not respond to repeat combination treatment. In October 2022, the patient was diagnosed with large cell CD30⁺ transformation, and the therapeutic approach was changed to extracorporeal photopheresis, brentuximab vedotin, and topical steroids. The patient died in February 2023 due to sepsis. Our experience adds to the limited evidence that mogamulizumab may be continued in combination with etoposide following disease progression in patients with MF with blood involvement; however, more research is needed on the efficacy and safety of this approach.

Background

Mycosis fungoides (MF) and Sézary syndrome (SS) are types of primary cutaneous lymphoma, a heterogeneous group of T-cell and B-cell non-Hodgkin lymphomas that present in the skin. ¹ Early-stage MF often has a relatively indolent disease course, with possible progression of lesions, whereas progression to or initial presentation with advanced-stage (IIB–IVB) MF or SS confers a worse prognosis, often characterized by significant involvement of the blood, tumors, and/or erythroderma, lymphadenopathy, and shorter survival.^1–4 Patients with early-stage MF are often treated primarily with skin-directed therapies (SDTs), whereas those with more advanced or treatment-refractory MF, or SS, generally require systemic treatment, alone or in combination with SDTs.^1,5

Mogamulizumab is a defucosylated, humanized IgG1 monoclonal antibody against the C-C chemokine receptor 4 (CCR4) approved in Europe in 2018 for the treatment of adult patients with MF or SS who have received at least one prior systemic therapy. ⁶ Binding of mogamulizumab to the N-terminal domain of CCR4, which is expressed on the surface of malignant cells in T-cell lymphomas, leads to antibody-dependent cellular cytotoxicity.^6,7 MAVORIC was an open-label, randomized controlled phase III study comparing mogamulizumab (1.0 mg/kg intravenously (IV) on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) with vorinostat (400 mg/day) in patients with stage IB–IVB histologically confirmed relapsed or refractory MF/SS. ⁸ In the primary analysis, median progression-free survival was 7.7 months in patients receiving mogamulizumab and 3.1 months in those receiving vorinostat (hazard ratio 0.53; 95% confidence interval (CI): 0.41–0.69, p < 0.0001). ⁸ The most common treatment-emergent adverse events of any cause or grade in the mogamulizumab group were infusion-related reactions, drug rash, diarrhea, and fatigue; in the group receiving vorinostat, these were diarrhea, nausea, fatigue, and thrombocytopenia. ⁸

We report the case of a patient with MF with blood involvement, who responded to mogamulizumab after other treatment approaches failed to achieve a stable clinical response. Upon disease progression, mogamulizumab was continued in combination with etoposide and prednisone, leading to remission, before further progression occurred. Extracorporeal photopheresis (ECP) and brentuximab vedotin therapy were initiated before the patient passed away due to sepsis. The reporting of this study conforms to the CARE guidelines. ⁹

Patient information and clinical findings

A male patient in his 50s presented with scaly, itchy, and painful patches on his trunk and upper extremities in 2012 (Supplemental Figure 1). The patient was initially diagnosed with MF in 2012 by a skin biopsy. In 2012, following diagnosis of MF, the patient received several SDTs (methylprednisolone aceponate cream (1 mg/g, once daily), mometasone cream (1 mg/g, once daily), clobetasol cream (0.5 mg/g, once daily), imiquimod cream (50 mg/g, once daily for a 3-week period), and phototherapy (psoralen + ultraviolet light A, three times per week)).

Early during treatment with the SDTs, the patient developed erythroderma. As a result of this, flow cytometry was conducted to assess for progression in the blood, leading to the identification of B2 blood involvement (CD4⁺/CD26⁻ cell count of 1225/µl (76% of the total leukocyte cell count of 1612/µl)). The patient was therefore diagnosed with MF with blood involvement (T4N0M0B2) following the initial diagnosis of MF in 2012. As the patient had stable disease in the skin and blood compartments, the SDTs were continued following the diagnosis of MF with blood involvement, as clinically warranted and were continued throughout the course of subsequent systemic treatments.

In 2014, physical examination revealed progression of skin plaques into skin tumors, with corresponding emergence of new patches and plaques, suggesting unsatisfactory response to SDT; systemic treatment was therefore initiated. Treatment with methotrexate (10–15 mg/week) was initiated in 2014 and achieved a partial response in the skin (flow cytometry was not conducted at this stage), but concurrent elevated liver transaminase levels resulted in methotrexate being withdrawn after approximately 12 months, in 2015.

After approximately 2–3 months, the patient initiated treatment with bexarotene (150–300 mg/m² once daily) in 2016 and continued to receive this treatment for approximately 2 years. However, in 2018, bexarotene was discontinued because of diffuse joint pain arising from diffuse idiopathic skeletal hyperostosis and disease progression in the form of plaques on the arms and gluteal region.

In 2018, a new biopsy was performed due to skin progression to rule out large cell transformation, and this confirmed histologically that the patient had CD30⁻ MF. Following withdrawal of bexarotene, the patient received five cycles of gemcitabine (1200 mg/m² on days 1, 8, and 15 of each 28-day cycle from March to July 2019) and had a stable disease response. Upon completion of the fifth cycle, the patient developed cough, fever, and dyspnea, with chest X-ray indicating the presence of pneumonitis. Gemcitabine was discontinued in July 2019, and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy was initiated in December 2019.

The patient had a period of partial skin response during administration of CHOP chemotherapy but experienced relapse at completion of the final treatment cycle in March 2020, characterized by progression of skin lesions noted on physical examination. There was an increase in the body surface area affected by plaque and tumors, new tumors had emerged, and the size of the tumors had increased. Flow cytometry revealed atypical T-cell populations (CD4⁺/CD7⁻/CD26⁻) of 17.5%. A summary of the absolute counts of the atypical CD4⁺/CD7⁻/CD26⁻ T-cell populations during 2020−2022 (pretreatment and post-treatment with mogamulizumab) can be found in Table 1.

Table 1.

Absolute counts of atypical T-cells (CD4⁺/CD7⁻/CD26⁻) prior to and following initiation of mogamulizumab in May 2020.

Atypical T-cell populations and CD4/CD8 ratio	Pre-mogamulizumab	Post-mogamulizumab	Post-ECP and brentuximab vedotin
	March 2020	July 2020	November 2022
Atypical T-cell populations (CD4+/CD7−/CD26−)	Atypical T-cell count of 1629/µl (17.5% of the total leukocyte count of 9310/µl)	Atypical T-cell count of 60/µl (0.76% of the total leukocyte count of 7960/µl)	Atypical T-cell count of 3/µl (0.02% of the total leukocyte count of 14,260/µl)
CD4/CD8 ratio	5.75	0.2	0.07

ECP, extracorporeal photopheresis.

Therapeutic interventions and follow-up and outcome

As a number of previous treatments had failed, and the patient had a high skin tumor burden, along with blood and skin involvement, the decision was taken to initiate mogamulizumab (1 mg/kg IV on days 1, 8, 15, and 22 of the first 28-day cycle, then on days 1 and 15 of each subsequent cycle) in May 2020.

Treatment with mogamulizumab was initially associated with a complete response based on improvement of skin lesions on physical examination; in July 2020, the tumors began to reduce in size, and most of the patches and plaques disappeared. There was also a complete response in the blood compartment, with a marked decrease in tumoral cells in blood; in July 2020, flow cytometry revealed that atypical T-cell populations (CD4 ⁺ /CD7⁻/CD26⁻) decreased to 0.76% following initiation of mogamulizumab versus a pre-mogamulizumab value of 17.5% (pre-mogamulizumab value from March 2020, prior to the initiation of mogamulizumab in May 2020; see Table 1).

The patient did not report any adverse or unanticipated events, and the tolerability was favorable. However, in December 2020, physical examination showed progression of skin lesions, with new tumors on the back (approximately 8 × 8 cm ), on both legs and on the fifth toe of the right foot. Despite progression in the skin, disease control in the blood compartment was observed; mogamulizumab was continued, and in August 2021, etoposide (50 mg/day, 3 weeks on, 1 week off) and prednisone (5–60 mg/day) were added to the treatment regimen, based on previously reported use of a combination of mogamulizumab with etoposide.10,11 The patient received six cycles of etoposide and prednisone between August 2021 and January 2022, after which the patient continued to receive mogamulizumab monotherapy. After the first cycle of etoposide, the tumors disappeared, and the patient achieved a complete skin response.

In March 2022, the patient experienced a pulmonary embolism, which was determined to be secondary to acute infection with COVID-19 occurring in the same month. The authors attributed the pulmonary embolism to the COVID-19 infection, based on the timing of occurrence and the high frequency of pulmonary embolism cases reported during the COVID-19 pandemic.

The patient remained in complete remission until July 2022, when progression occurred, and a second course of etoposide and prednisone was implemented in combination with mogamulizumab, with a further four cycles administered between July 2022 and October 2022. However, clinical examination showed the disease continued to progress, with new tumors apparent in October 2022; as a result of this progression, mogamulizumab and etoposide were stopped. The patient had tolerated the combination treatment well, with no adverse effects apart from mild neutropenia, observed as a neutrophil count consistently within 1000–1500 cells/µl; this neutropenia had no clinical repercussion and required no further management.

After mogamulizumab and etoposide were stopped in October 2022, a reassessment of the patient was performed, and following a skin biopsy, he was diagnosed with large cell CD30⁺ transformation. As the patient was experiencing rapid disease progression within the skin (blood status unknown, but suspected to be high), treatment with ECP every 2 weeks, combined with brentuximab vedotin (1.8 mg/kg every 3 weeks), and once-daily topical steroid creams were initiated. Despite this combination, progression was observed in the skin, and a positron emission tomography-computed tomography (PET-CT) scan showed new tumors on the skin, scalp, and neck muscles, as well as multiple enlarged axillary and inguinal lymph nodes. In November 2022, flow cytometry revealed atypical T-cell populations (CD4⁺/CD7⁻/CD26⁻) of 0.02% (see Table 1). The patient was admitted to the hospital in February 2023; he died 3 days after admission due to septic shock. The probable origin of the septic shock was determined to be cutaneous or pulmonary; however, due to the severe state of the patient, no radiologic or invasive diagnostic measures were taken to confirm this.

Discussion

In this article, we report a case of a patient with MF with blood involvement refractory to several lines of topical and systemic treatments. Treatment with mogamulizumab monotherapy resulted in improvements in skin lesions for approximately 7 months. Following disease progression, etoposide and prednisone combined with mogamulizumab led to a complete skin response with remission for approximately 11 months from the first cycle. After this period of remission, the patient experienced further progression, which did not respond to further treatment with mogamulizumab in combination with etoposide and prednisone. ECP and brentuximab vedotin therapy were initiated; however, further disease progression occurred before the patient died due to septic shock.

Mogamulizumab has shown efficacy in the treatment of MF and SS, as a monotherapy, ⁸ and a retrospective analysis of etoposide monotherapy in MF also indicated therapeutic value, ¹² providing clinical rationale for their combined use in treatment-refractory patients. Further to the patient described in this case report, other case reports have reported the successful treatment of T-cell lymphomas with mogamulizumab plus etoposide^10,11 Mogamulizumab plus etoposide has been reported to achieve resolution of rash and pruritus, and a rapid decrease in nodular mass size, in a patient with cutaneous nodular mass-type adult T-cell leukemia/lymphoma following prior lines of topical and systemic therapy. ¹¹ Furthermore, a case report described a patient with MF who responded well to etoposide plus mogamulizumab, which was also reported to be well-tolerated. ¹⁰ Similarly, in another case report, successful outcomes were reported in a patient with erythrodermic MF who was treated with mogamulizumab followed by etoposide monotherapy. ¹³

In conclusion, our experience with this patient suggests that mogamulizumab may be continued in combination with other therapies, such as etoposide, following disease progression, with the aim to augment mogamulizumab response. Patients with advanced, treatment-refractory disease represent a high unmet medical need as treatment options become limited. Further evidence for the risk–benefit profile of mogamulizumab in combination with etoposide needs to be established through further clinical trials.

Supplemental Material

sj-jpg-1-tah-10.1177_20406207251388057 – Supplemental material for Mogamulizumab plus etoposide in the management of mycosis fungoides with blood involvement: a case report

Supplemental material, sj-jpg-1-tah-10.1177_20406207251388057 for Mogamulizumab plus etoposide in the management of mycosis fungoides with blood involvement: a case report by Daniel Nieto Rodríguez and Elena Sendagorta in Therapeutic Advances in Hematology

Supplemental Material

sj-jpg-2-tah-10.1177_20406207251388057 – Supplemental material for Mogamulizumab plus etoposide in the management of mycosis fungoides with blood involvement: a case report

Supplemental material, sj-jpg-2-tah-10.1177_20406207251388057 for Mogamulizumab plus etoposide in the management of mycosis fungoides with blood involvement: a case report by Daniel Nieto Rodríguez and Elena Sendagorta in Therapeutic Advances in Hematology