Smoldering type adult T‐cell leukemia/lymphoma effectively treated with mogamulizumab (anti‐CC chemokine receptor 4 monoclonal antibody)—A case report

Key Clinical Message The use of mogamulizumab needs careful consideration because of severe adverse reactions such as graft‐vs‐host disease. However, refractory specific skin lesions of smoldering type adult T‐cell leukemia/lymphoma can be effectively treated with mogamulizumab when patients have no opportunity to receive hematopoietic stem cell transplantation like our case.


| INTRODUCTION
Adult T-cell leukemia/lymphoma (ATLL) is an endemic disease in southwest Japan and the Caribbean basin caused by human T-lymphotropic virus type 1 (HTLV-1). 1 Skin lesions are treated with skin directed therapy containing topical steroid, ultraviolet, surgery, and radiation. 2 Oral etretinate, or low-dose etoposide and prednisolone are sometimes selected. 3,4 Anti-CC chemokine receptor 4 (CCR4) monoclonal antibody mogamulizumab is also available. We report a case of effectively treated skin lesions of smoldering type ATLL with mogamulizumab.
Two days later from the first mogamulizumab administration, plaques and tumors became flattening and dark reddish-brown (Figure 2A-D). Skin lesions continued to be improved during treatment period ( Figure 2E-H). Modified Severity-Weighted Assessment Tool (mSWAT) score was improved 70 (before the first infusion) to 34 (after the second infusion). As more than 50% of skin lesions were improved, we considered partial response (PR) was achieved. Blood examination revealed normal hematological parameters and liver function during and after the mogamulizumab treatment: hemoglobin 13.5 g/L, WBC 6.5 × 10 9 /L, platelet 300 × 10 9 /L, AST 16 IU/L, ALT 15 IU/L after the first infusion, and hemoglobin 12.3 g/L, WBC 5.7 × 10 9 /L, platelet 237 × 10 9 /L, AST 19 IU/L, ALT 13 IU/L after the final infusion. Renal function was not exacerbated: BUN 15.1 mg/dL, creatinine 1.11 mg/dL, eGFR 49.8 mL/ min/1.73 m 2 after the first infusion, and BUN 22.2 mg/dL, creatinine 1.01 mg/dL, eGFR 55.2 mL/min/1.73 m 2 after the final infusion.

| DISCUSSION
Mogamulizumab highly enhances antibody-dependent cellular cytotoxicity (ADCC) of natural killer cells by binding to CCR4 expressed on tumor cells. 5 Although Mogamulizumab can be used for any subtypes of CCR4 positive ATLL, most cases are for aggressive type. 6 Efficacy of mogamulizumab for skin lesions is comparatively high. Responses according to disease sites are 74.5%-100% for blood, 57.7%-63% for skin, and 25%-31.5% for nodal and extranodal lesions. 7,8 Acute graft-vs-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and cutaneous adverse reactions (CARs) is major adverse events.
Mogamulizumab depletes not only tumor cells but also Foxp3 + regulatory T cells (Tregs) and T cells with Th2 phenotype (Th2-cells) because they also express CCR4 on their surfaces. 9 Depletion of Tregs enhances antitumor immunity, on the other hand, it may cause severe complications such as GVHD. 9 Reduction of Th2-cells results in shifting the Th1/ Th2 balance to the Th1 axis, and it might enhance tissue damage through GVHD. 9 It spends 4 months until the number of Tregs return to baseline level after the last mogamulizumab administration. 10 The rates of acute GVHD are 65.7% for patients who received allo-HSCT within 90 days after the last administration of mogamulizumab, and 28.6% after over 91 days. 9 The shorter interval (<3 months) between the last administration of mogamulizumab and allo-HSCT is highly associated with severe GVHD. 10 In our case, the patient was 77 years old (>70 years old) and had no chance to receive allo-HSCT due to his age even if his illness would have unfortunately become crisis. Therefore, we selected mogamulizumab treatment with not being afraid of the possibility of GVHD.
The frequency of all CARs is 34.3%, and the serious one is 10.7%. 6 Rash, erythema, and pruritus are common CARs. 6 Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are reported in 0.8% and 0.6%, respectively. 6 Histological features of CARs are spongiosis in the epidermis, liquefactive degeneration of basal cells, and heavy lymphocyte infiltration in the upper dermis. 11 Infiltrating lymphocytes are positive for CD3, CD8, granzyme B, perforin, and TIA-1. 11 The overall response rate (ORR) and the overall survival (OS) are better in patients with CARs. 8,11 The ORRs for the patients with and without CARs are 78%-86% and 37%-47%, respectively. 6,11 The OS is significantly longer in patients who experienced CARs (15.7 months) than ones who did not (5.4 months). 8 In our case, PR was achieved, and spongiotic dermatitis with activated cytotoxic T-cells positive for CD8 and granzyme B appeared 10 weeks after from the last administration of mogamulizumab. Furthermore, Foxp3 + Tregs, which had been observed before the mogamulizumab administration, markedly diminished. Depletion of Tregs by mogamulizumab might increase activated cytotoxic T cells and cause CARs. The use of mogamulizumab for patients who have possibility to receive allo-HSCT should be carefully decided owing to the high incidence of GVHD. However, smoldering type ATLL patients with refractory specific skin lesions can be treated with mogamulizumab when they have no plan to receive allo-HSCT due to age or other reasons.