The Impact of a Humanized CCR4 Antibody (Mogamulizumab) on Patients with Aggressive-Type Adult T-Cell Leukemia-Lymphoma Treated with Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Although a humanized CCR4 antibody (mogamulizumab) was reported to be effective for refractory adult T-cell leukemia-lymphoma (ATL), several reports regarding the use of mogamulizumab before allo-hematopoietic stem cell transplantation (HSCT) strongly indicated a high incidence of severe acute graft-versus-host-disease (GVHD) and treatment-related mortality (TRM). We retrospectively analyzed nine aggressive-type ATL patients who underwent allo-HSCT at a single institution in Miyazaki from 2006.1.1 to 2015.7.31. Among nine ATL patients, three had used mogamulizumab before treatment with allo-HSCT because of the poor control of refractory ATL. All three patients were treated with four to eight cycles of mogamulizumab. The interval from last administration of mogamulizumab to allo-HSCT was two to five months. All three patients with prior mogamulizumab treatment developed mild-moderate acute GVHD (grade 2) 28, 34, or 40 days after allo-HSCT. Acute GVHD was controlled by prednisolone treatment. Two patients in complete remission before allo-HSCT exhibited relatively prolonged survival (survival rate, 66%). Moreover, one patient developed human T-cell leukemia virus type 1-associated myelopathy-mimicking myelitis at five months after allo-HSCT. In contrast, two of six ATL patients without a history of mogamulizumab use survived (survival rate 33%). Thus, in cases of mogamulizumab use before treatment with allo-HSCT for refractory ATL, an appropriately long interval from the last administration of mogamulizumab to allo-HSCT may be one of factors to reduce TRM by acute GVHD, and to subsequently enhance graft-versus-tumor effects in ATL cases. Furthermore, caution is needed when administering mogamulizumab before allo-HSCT for severe GVHD and TRM.

Fig. 1A

Acute graft-versus-host-disease (GVHD) of skin in case 2. Skin rash was observed on upper and lower extremities, and back at day 34 after treatment with allogeneic hematopoietic stem cell transplantation. Skin biopsy was consistent with acute GVHD (grade 2) (in Fig. 1B). Furthermore, prednisolone ointments resolved the acute GVHD skin lesion.

Fig. 1B

Histological findings of acute graft-versus-host-disease (GVHD) of skin in case 2. Skin biopsy revealed that this lesion had mild, diffuse infiltration of lymphocytes in the upper dermis and basal side of epidermis. Spongiotic changes and individual cell necrosis of epidermal cells were observed, but no massive necrosis of epidermis or subepidermal cleft formation could be found. Moreover, immunohistochemically, infiltrating lymphocytes exclusively contained cCD3-positive T-lymphocytes, and an almost equal volume of CD4- and CD8-positive cells were noted. Only a few CD79a-positive B-lymphocytes were intermingled in one area. This was considered to be grade 2 acute GVHD.

Fig. 2

Clinical course. (2A) Clinical course of case 1. (2B) Clinical course of human T-cell leukemia virus type 1 associated myelopathy-mimicking myelitis in case 2. (2C) Clinical course of case 3. ATL, adult T-cell leukemia-lymphoma; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisolone; HSCT, hematopoietic stem cell transplantation; FLU, fludarabine; BU, busulfan; TBI, total body irradiation; GVHD, graft-versus-host disease; TBI, total body irradiation; CY, cyclophosphamide, sMTX, short-term methotrexate; FK, acrolimus; HLA; human leukocyte antigen; CR, complete remission; PD, progressive disease; PR, partial response; SD, stable disease; PSL, prednisolone; CSP, cyclosporine

Fig. 3

Transient graft-versus-tumor effect (GVT) effect after development of acute graft-versus-host-disease (GVHD) in case 1 (skin nodule of adult T-cell leukemia-lymphoma: day 33→day 58). In case 1, transient GVT during and after acute GVHD (skin, grade 2) was observed. From day 33 to day 58 after treatment with allogeneic hematopoietic stem cell transplantation, skin lesions and lymph node lesions markedly regressed. These findings clearly demonstrated that GVT was induced by acute GVHD.