A Multicenter Retrospective Study of Mogamulizumab Efficacy in Adult T-Cell Leukemia/Lymphoma

doi:10.1016/j.clml.2016.09.009

Clinical Lymphoma Myeloma and Leukemia

Volume 17, Issue 1, January 2017, Pages 23-30.e2

https://doi.org/10.1016/j.clml.2016.09.009 Get rights and content

Abstract

Background

Mogamulizumab, a defucosylated humanized monoclonal antibody targeting C-C chemokine receptor 4, recently became available for the treatment of adult T-cell leukemia/lymphoma (ATL). We conducted a multicenter retrospective study of the efficacy of mogamulizumab in ATL treatment in patients on Hokkaido Island, Japan.

Materials and Methods

A total of 125 patients with ATL treated from January 2010 to December 2014 in 20 hospitals affiliated with the Hokkaido Hematology Study Group were enrolled in the present retrospective study.

Results

Of the 125 ATL patients, 62 (46.6%) presented with the acute type, 51 (38.3%) with the lymphoma type, and 12 (9.0%) with the chronic type; the latter group included 7 unfavorable chronic cases. The median age at diagnosis was 68 years (range, 35-86 years). The median survival for those with acute, lymphoma, and unfavorable chronic types was 302, 279, and 921 days, respectively. Advanced age, high lactate dehydrogenase level, poor performance status (3-4), and the existence of B symptoms were unfavorable prognostic factors for overall survival (OS). Survival rate calculated from the day of diagnosis was significantly higher in patients treated with mogamulizumab. The OS of individuals receiving hematopoietic stem cell transplantation (HSCT) was superior to that of the non-HSCT group. The median interval between the last mogamulizumab dose and allogeneic HSCT was 38 days (range, 21-53 days). Of the 22 HSCT recipients who were not treated with mogamulizumab, overall acute graft-versus-host disease (aGVHD) and grade III-IV aGVHD occurred in 12 (54.5%) and 3 (13.6%) patients, respectively. However, overall aGVHD and grade III-IV aGVHD developed in 8 (88.9%) and 3 (33.3%) of the 9 HSCT recipients treated with mogamulizumab, respectively.

Conclusion

Mogamulizumab improves OS in patients with ATL, although its use in HSCT patients might trigger severe GVHD. Determining the optimal pre-HSCT mogamulizumab treatment regimen is thus a priority.

Introduction

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive T-cell neoplasm associated with infection by a specific retrovirus, human T-cell lymphotropic virus type 1 (HTLV1).1, 2, 3 The prognosis of patients with aggressive ATL remains poor, because this hematologic malignancy is often resistant to conventional chemotherapy and frequently leads to opportunistic infections.4, 5, 6 Recently, a multicenter phase III study of dose-intensified multiagent chemotherapy was performed.⁷ Specifically, a regimen of VCAP-AMP-VECP (vincristine, cyclophosphamide, doxorubicin, prednisone; doxorubicin, ranimustine, prednisone; and vindesine, etoposide, carboplatin, prednisone) was shown to be safe in the patient group. However, the overall outcome was not satisfactory, as the progression-free survival rate at 1 year was only 28%, and the overall survival (OS) rate at 3 years was only 24%.

C-C chemokine receptor 4 (CCR4) is expressed on the surface of certain types of T-cell neoplasms; this includes peripheral T-cell lymphoma and its ATL subtype.⁸ Mogamulizumab, a defucosylated humanized monoclonal antibody targeting CCR4, recently became available for the treatment of ATL. In a phase II study, mogamulizumab monotherapy was effective in patients with relapsed ATL and was associated with an acceptable level of toxicity.⁹ Recently, mogamulizumab treatment was successful in a patient with ATL that had relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT).¹⁰ The investigators noted that it is crucial to avoid excessive exacerbation of graft-versus-host disease (GVHD) and preserve the graft-versus-ATL effect during mogamulizumab treatment after allo-HSCT. Accordingly, the drug was approved for use in patients with ATL in Japan in 2012 and is now a promising therapeutic option for these patients. ATL is endemic in some areas of Japan, including Kyushu/Okinawa, south Shikoku, Tokyo, Tohoku, and Hokkaido districts.11, 12 We present the results of a multicenter retrospective study of mogamulizumab efficacy in ATL patients treated in the Hokkaido area.

Section snippets

Data Collection

A total of 125 patients with ATL treated from January 2010 to December 2014 in 20 hospitals affiliated with the Hokkaido Hematology Study Group were enrolled in the present retrospective study. The institutional review board of the coordinating center (Sapporo Medical University School of Medicine) and each of the participating hospitals according to their institutional policies approved the present study. Aggressive ATL subtypes (acute, lymphoma, and unfavorable chronic type ATL) were defined

Patient Characteristics

The characteristics of the 125 patients are summarized in Table 1. One half of the patients were men, and the median age of the patients was 68 years (range, 35-86 years). Of the 125 patients, 62 (49.6%) presented with acute type ATL, 51 (40.8%) with the lymphoma type, and 12 (9.6%) with the chronic type (including 7 with an unfavorable chronic type). Also, 104 patients (83.2%) had Ann Arbor stage III/IV disease, and 37 patients (29.6%) had a poor ECOG PS of ≥ 3 (no data regarding stage were

Discussion

The aim of the present study was to evaluate the therapeutic efficacy of mogamulizumab for treatment of ATL in the clinic. To the best of our knowledge, this is the largest retrospective study of its kind of ATL. Although most clinical studies exclude unfit patients, the present study showed that mogamulizumab was associated with a favorable prognosis even when administered to “high-risk” ATL patients. We found that advanced age, high LDH level, poor ECOG PS, and existence of B symptoms were

Conclusion

In our study, the probability of OS for patients who received mogamulizumab tended to be better than that for patients who did not. A concern also exists that the use of mogamulizumab for HSCT patients might cause severe GVHD. The clinical benefit of mogamulizumab as salvage therapy should therefore be determined in future prospective studies.

Disclosure

The authors declare that they have no competing interests.

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A recent retrospective analysis examined 64 patients with relapsed/refractory ATL who received salvage chemotherapy. The median OS in patients who received (N = 33) and did not receive (N = 31) mogamulizumab were 382 and 240 days, respectively (P = .03).22 Another retrospective study examined 29 transplant-ineligible patients with ATL.
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However, recent clinical studies of Mogamulizumab, a humanized anti-CCR4 monoclonal antibody used for leukemia and lymphoma treatment, showed the development of graft-versus-host disease (GVHD) and other severe adverse drug reactions in some patients. These findings suggest that patients receiving anti-CCR4 therapy should be carefully monitored for adverse events [133,134]. The FOXP3 transcription factor, the specific marker of Tregs, is regarded as a self-antigen.
Adjuvants are substances used to enhance the efficacy of vaccines. They influence the magnitude and alter the quality of the adaptive immune response to vaccine antigens by amplifying or modulating different signals involved in the innate immune response. The majority of known adjuvants have been empirically identified. The limited immunogenicity of new vaccine antigens and the need for safer vaccines have increased the importance of identifying single, well-defined adjuvants with known cellular and molecular mechanisms for rational vaccine design. Depletion or functional inhibition of CD4⁺CD25⁺FoxP3⁺ regulatory T cells (Tregs) by molecular adjuvants has become an emergent approach in this field. Different successful results have been obtained for specific vaccines, but there are still unresolved issues such as the risk of autoimmune disease induction, the involvement of cells other than Tregs and optimization for different conditions. This work provides a comprehensive analysis of current approaches to inhibit Tregs with molecular adjuvants for vaccine improvement, highlights the progress being made, and describes ongoing challenges.
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Interestingly cutaneous reactions appear to correlate with ORR and OS and are therefore a likely reflection of antibody efficacy. Another important point to note is that patients treated with MOGA followed by allogeneic stem cell transplantation (HSCT), have a significantly higher rate of severe acute GVHD and transplant related mortality rate, which may impact overall survival [136,137]. Time between MOGA treatment and HSCT appears to be crucial for acute GVHD incidence.
Following approval in 1997 of the anti-CD20 antibody rituximab for the treatment of B-NHL and CLL, many other unconjugated IgG1 MAbs have been tested in pre-clinical and clinical trials for the treatment of lymphoid neoplasms. Relatively few have been approved however and these are directed against a limited number of target antigens (CD20, CD52, CCR4, CD38, CD319). We review here the known biological properties of these antibodies and discuss which factors may have led to their success or may, on the contrary, limit their clinical application. Common factors of the approved MAbs are that the target antigen is expressed at relatively high levels on the neoplastic targets and their mechanism of action is mostly immune-mediated. Indeed most of these MAbs induce ADCC and phagocytosis by macrophages, and many also activate complement, leading to target cell lysis. In contrast direct cell death induction is not a common feature but may enhance efficacy in some cases. Interestingly, a key factor for the success of several MAbs appears to be their capacity to skew immunity towards an anti-tumour mode, by inhibiting/depleting suppressor cells and/or activating immune cells within the microenvironment, independently of FcγRs. We also expose here some of the strategies employed by industry to expand the clinical use of these molecules beyond their original indication. Interestingly, due to the central role of lymphocytes in the control of the immune response, several of the antibodies are now successfully used to treat many different autoimmune diseases and have also been formally approved for some of these new indications. There is little doubt that this trend will continue and that the precise mechanisms of therapeutic MAbs will be further dissected and better understood in the context of both tumour immunology and autoimmunity.
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This treatment may be followed by allogeneic stem cell transplantation. A further therapeutic option consists of the monoclonal anti-CCR4 antibody mogamulizumab, which has demonstrated global response rates of between 43% and 64% in different studies, with an increase in median survival of 142 days compared to the standard therapies in the retrospective study published by Iyama et al [5,6,19]. However, this treatment may give rise to excess mortality in the event of subsequent allograft, with onset of severe GvHD [6,20,21].
Adult T-cell leukemia/lymphoma (ATLL) is a hematological malignancy associated with chronic HTLV-1 infection.
To describe skin lesions in ATLL.
A descriptive, retrospective study between 1996 and 2016, including all patients diagnosed with ATLL at Saint-Louis Hospital (Paris, France).
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La leucémie/lymphome à cellules T de l’adulte (ATLL) est une hémopathie maligne liée au virus HTLV1.
Analyser l’atteinte cutanée au cours de l’ATLL.
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Trente-sept patients ont été inclus. Parmi eux, 15 (41 %) avaient une atteinte cutanée de la maladie, présente dès le diagnostic chez deux tiers d’entre eux. Les formes d’ATLL chez les patients ayant une atteinte cutanée se répartissaient en forme lymphomateuse (n = 5), forme chronique (n = 4), forme indolente (n = 4), forme aiguë (n = 2). Plusieurs types de lésions cutanées coexistaient chez la moitié des patients. Elles se répartissaient en nodules/tumeurs (n = 8), plaques (n = 7), papules multiples (n = 6), macules (n = 4), purpura (n = 2). Parmi les 15 patients avec atteinte cutanée, la survie médiane des formes lymphomateuses et aiguës était significativement inférieure à celle des formes chroniques et indolentes (8,7 mois versus 79 mois, p = 0,003).
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Original StudyA Multicenter Retrospective Study of Mogamulizumab Efficacy in Adult T-Cell Leukemia/Lymphoma

Abstract

Background

Materials and Methods

Results

Conclusion

Introduction

Section snippets

Data Collection

Patient Characteristics

Discussion

Conclusion

Disclosure

Blood

Lancet Oncol

Blood

Blood

Biol Blood Marrow Transplant

Cell

Blood

Biol Blood Marrow Transplant

Monoclonal integration of human T-cell leukemia provirus in all primary tumors of adult T-cell leukemia suggests causative role of human T-cell leukemia virus in the disease

Proc Natl Acad Sci U S A

Japan Clinical Oncology Group (JCOG) prognostic index and characterization of long-term survivors of aggressive adult T-cell leukaemia-lymphoma (JCOG0902A)

Br J Haematol

Recent advances in the treatment of adult T-cell leukemia-lymphomas

Cancer Sci

Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma: a report from the Lymphoma Study Group (1984-87)

Br J Haematol

VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801

J Clin Oncol

Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome

Clin Cancer Res

Original Study
A Multicenter Retrospective Study of Mogamulizumab Efficacy in Adult T-Cell Leukemia/Lymphoma