Mogamulizumab for adult T-cell leukemia/lymphoma: a literature review

Introduction

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive mature T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) infection (1). HTLV-1 is highly prevalent in southwestern Japan, the Caribbean, Africa, the Middle East, South America, and Papua New Guinea (2). The Shimoyama classification divides ATLL into four subtypes, including acute, lymphoma, chronic, and smoldering. The aggressive ATLL refers to acute, lymphoma, and unfavorable chronic subtypes, while the indolent ATLL refers to favorable chronic and smoldering subtypes.

Despite advances in chemotherapy and allogeneic stem cell transplant (allo-SCT), ATLL remains associated with poor outcomes with rapid progression and a historical median overall survival (OS) ranging from 6 to 13 months in aggressive subtypes (1,2). A retrospective study conducted by our group revealed that 61 patients, with the majority population being Caribbean, were diagnosed with ATLL acute subtype (43.9%), most commonly, followed by lymphoma subtype (36.8%). The OS in acute ATLL was 8.3 months, and in lymphomatous ATLL, 14.3 months (3).

The development of targeted therapies has broadened the treatment landscape, making them a valid therapeutic option for patients with ATLL. C-C chemokine receptor 4 (CCR4) is a G protein-coupled receptor highly expressed on the surface of ATLL cells, making it a therapeutic target of mogamulizumab. CCR4 expression on regulatory T cells creates an immunosuppressive tumor microenvironment for ATLL cells’ proliferation (4). Mogamulizumab, a defucosylated humanized IgG anti-CCR4 monoclonal antibody, is the first CCR4-targeted therapy developed for patients with ATLL. By selectively binding to CCR4 on ATLL cells, mogamulizumab facilitates tumor cell death via antibody-dependent cellular cytotoxicity (ADCC) (2). Meanwhile, mogamulizumab targets and depletes CCR4-positive regulatory T cells, reducing the immunosuppressive tumor microenvironment and enhancing antitumor immune responses (4,5). In the US, mogamulizumab was Food and Drug Administration (FDA)-approved to treat mycosis fungoides and Sezary Syndrome after at least one prior line of systemic therapy in 2018. In Japan, it was approved in 2012 for relapsed/refractory CCR4-positive ATLL and in 2014 for treatment naïve aggressive ATLL when used in combination with chemotherapy (6). We review here the literature on the use of mogamulizumab in ATLL in the context of the recently published phase 2 study of Yoshimitsu et al. (7). We present this article in accordance with the Narrative Review reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0455/rc).

Methods

We retrospectively reviewed clinical trials and retrospective reviews on the use of mogamulizumab in ATLL patients from 2012 to 2025. A comprehensive search for peer-reviewed articles was performed using major medical databases, including PubMed and Google Scholar. Our primary interest was OS, and our secondary interest was progression-free survival (PFS). Search terms used include ATLL, mogamulizumab, CCR4, and HTLV. We reviewed literature published between 1/1/2012 and 12/31/2025. Criteria for selection included ATLL patients treated with mogamulizumab, adults and English literature. Case studies and case reports were excluded. Two authors, C.J. and J.C.W. reviewed the literature independently and consolidated the findings through mutual review. The search strategy is summarized in Table 1.

Clinical efficacy

Frontline therapy

Currently, limited trials (Table 2) have reported the efficacy and survival benefit of mogamulizumab-containing treatment in managing ATLL, especially in the elderly population. Most studies were conducted in Japan due to the high prevalence of HTLV-1 (2). The geographically restricted nature of the studies may limit their applicability to patients from other regions or ethnic backgrounds.

For randomized prospective studies, Ishida et al. reported a multicenter, randomized, phase II trial in 2015 in newly diagnosed ATLL in adults aged >20 years (8). The trial compared mogamulizumab in combination with a dose-intensified modified Lymphoma Study Group 15 (mLSG15) chemotherapy protocol, which consists of three chemotherapy regimens, including vincristine, cyclophosphamide, doxorubicin, and prednisone (VCAP); doxorubicin, ranimustine, and prednisone (AMP); vindesine, etoposide, carboplatin, and prednisone (VECP), to chemotherapy alone. The trial enrolled 53 evaluable patients and demonstrated a higher complete response (CR) rate (52%), overall response rate (ORR) (86%) in the mogamulizumab group (n=29), compared to CR rate of 33%, ORR of 75% in the chemotherapy group (n=24). Updated follow-up results in 2018 demonstrated a significantly higher 1-year progression-free survival (PFS) of 47% in the mogamulizumab group compared to 29% in the chemotherapy group. However, the OS was 45% and 50% in the mogamulizumab group and chemotherapy group, with no statistically significant difference between the two groups, likely because the trial was underpowered to detect such a difference (9).

For single-arm, prospective studies, Yoshimitsu et al. conducted a multicenter, single-arm, phase 2 study (7) investigating the efficacy of mogamulizumab in combination with chemotherapy of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as frontline treatment for newly diagnosed ATLL in the elderly patient population. A total of 48 eligible patients (acute ATLL 64.6%, lymphomatous ATLL 18.8%, unfavorable chronic ATLL 16.7%) received 6 cycles of CHOP combined with mogamulizumab every 2 weeks, followed by mogamulizumab monotherapy every 2 weeks for 2 cycles. The study reported a CR rate of 64.6% and an ORR of 91.7%. The 1-year PFS and OS were 36.2% and 66%, respectively. Mogamulizumab-associated cutaneous adverse effects were associated with significantly better OS. The CCR4 mutated (detected in 38% of patients) group appeared to have better PFS and OS; however, the results were not statistically significant. Tanimoto et al. reported a small-size single-arm phase 2 study; a total of 24 newly diagnosed ATLL patients were enrolled, and five patients discontinued the study before receiving mogamulizumab. 19 patients received three cycles of CHOP followed by mogamulizumab as immunological consolidation. The ORR was 87.5% (10). The 1-year OS and PFS were 52.6% and 26.6%, respectively.

A few retrospective studies have demonstrated the benefit of mogamulizumab in the frontline setting. A retrospective study conducted by Shichijo et al. suggested a potential survival benefit of mogamulizumab-containing regimens in the transplant-ineligible population, including elderly patients. The study retrospectively analyzed 39 patients and revealed a significantly better 4-year OS in the mogamulizumab-containing treatment group compared to the chemotherapy-alone group (46.3% vs. 20.6%, P=0.033) (11). In addition, for patients over 65 years old, the 4-year OS was better at 40.4% in the mogamulizumab-containing group compared to 15.4% in the chemotherapy group. This study suggested that a mogamulizumab-containing regimen is a promising strategy for patients who are ineligible for allo-SCT, including the elderly population. Another retrospective study conducted by Hashimoto et al. revealed that among patients older than 70 years and ineligible for allo-SCT, those who received mogamulizumab-containing treatment had a 2-year OS of 45%, while the chemotherapy group’s OS was 34.7% (12).

Relapsed/refractory ATLL

To date, mogamulizumab has not been FDA-approved to treat ATLL in the relapsed/refractory setting. Numerous studies (Table 3) have shown the efficacy of mogamulizumab in treating relapsed/refractory ATLL patients. A multicenter, single-arm, phase II study conducted by Ishida et al. reported an ORR of 50% in the 26 relapsed ATLL patients who received mogamulizumab monotherapy, with a median PFS of 5.2 months and OS of 13.7 months (13).

Another international, multicenter, open-label, randomized phase II trial conducted by Phillips et al. (14) compared mogamulizumab monotherapy in 47 patients with the investigator’s choice chemotherapy in 24 patients in relapsed/refractory aggressive ATLL. The chemotherapy included pralatrexate, gemcitabine/oxaliplatin (GemOx), and dexamethasone, cisplatin, and cytarabine (DHAP). The mogamulizumab group had a higher median age and performance status (PS) score. The trial demonstrated an ORR of 11% with mogamulizumab versus 0% with the investigator’s choice of chemotherapy, which was much lower than Ishida’s study (13). After post hoc adjustment for PS, mogamulizumab was associated with a statistically significant PFS, with a tolerable safety profile. Several factors may have contributed to the lower ORR in Phillips’s trial. Ishida’s study excluded refractory ATLL patients and assessed ORR at four weeks of treatment, whereas Phillips’s trial evaluated the ORR at eight weeks. Additionally, the patients in Phillips’s trial had more adverse prognostic factors, including older age, poorer PS, and greater bone marrow involvement.

Meanwhile, a multicenter prospective observation study by Yonekura et al. (6) enrolled 101 patients who received a mogamulizumab-containing regimen. Seventeen patients had newly diagnosed ATLL, and 84 patients received previous systemic treatment. The ORR was 65%, the median PFS was 7.4 months, and the OS was 16 months. Of note, no significant difference in OS was observed between patients who underwent allo-SCT and patients who did not undergo allo-SCT.

Real-world and retrospective studies further supported effective mogamulizumab activity in relapsed/refractory ATLL. A retrospective analysis (15) of 24 patients who received mogamulizumab after disease progression reported an ORR of 54.2%. Among the 24 patients, 18 patients received mogamulizumab monotherapy, and 6 patients received mogamulizumab in combination with chemotherapy. 18 patients received chemotherapy without mogamulizumab. A better 1-year OS in patients who received mogamulizumab was observed compared to those without mogamulizumab (47.9% vs. 17.6%, respectively). Similarly, a nationwide registry study from Japan included 315 patients with ATLL and reported a higher 1-year OS in 97 patients treated with mogamulizumab compared with those who did not receive the agent (51.2% vs. 34.0%, P=0.006, respectively) (16). After multivariate analysis, mogamulizumab use was found to be an independent predictor of OS.

Prognostic factors

CCR4 mutation

Gain-of-function mutations in CCR4 are present in approximately 25% of ATLL cases (1) and have been associated with improved responses and survival following mogamulizumab therapy. Fujii et al. evaluated CCR4 N-terminus and C-terminus expression by immunohistochemistry (IHC) in 92 samples and identified that the CCR4 C-terminus status serves as a prognostic marker. Loss of CCR4 C-terminus expression was inversely correlated with the presence of a CCR4 mutation. Amino acid truncation in the C-terminus results in the gain-of-function mutation of CCR4, thus enhancing the binding of mogamulizumab. It is associated with superior survival outcomes in ATLL patients treated with mogamulizumab without allo-SCT (17). The 5-year OS was 72.7% in patients with negative CCR4 C-terminus expression and 8.7% in patients with positive expression.

Sakamoto et al. analyzed tumor samples from 116 ATLL patients (18). For patients who received a mogamulizumab-containing regimen without allo-SCT, the CCR4 mutated group showed significantly improved 5-year OS of 72.2% when compared to 26.2% in the CCR-4 nonmutated group. The gain-of-function mutation of CCR4 appears to impair the CCR4 internalization and result in increased CCR4 expression, thus enhancing the targeted therapy efficacy.

Mogamulizumab-associated cutaneous adverse reactions

Studies have reported that mogamulizumab-associated cutaneous adverse reactions correlate with improved survival, suggesting that immune activation may be linked to treatment efficacy. Shichijo et al. reported that 4-year OS in patients with cutaneous adverse reactions was 100% while patients without skin reactions had OS of 10% [95% confidence interval (CI), 0.6–35.8] (11). Tokunaga et al. had similar findings that the OS in patients who developed cutaneous adverse reactions was significantly longer than in patients without cutaneous adverse reactions. It was suggested that mogamulizumab decreased the regulatory T cell activity (19).

Other biomarkers

The prospective MIMOGA observational study further identified immune biomarkers associated with a favorable outcome to mogamulizumab treatment, including higher baseline levels of Tax-specific cytotoxic T lymphocytes and a higher percentage of B cells (6). The study also noted that higher soluble interleukin-2 receptor (sIL-2R >20,000 U/mL), higher calcium (Ca >11.0 mg/dL), lower albumin (albumin <3.5 g/dL), and mogamulizumab use <60 days to allo-SCT were associated with worse OS. Shimazu et al. (16) identified that age <70 years, PS of 0–1, corrected calcium level <11 mg/dL, albumin level >3.5 mg/dL, lactate dehydrogenase (LDH) level <265 IU/L, and using mogamulizumab are associated with superior OS.

Safety and toxicity

Mogamulizumab is typically given as 1 mg/kg intravenously weekly for 8 weeks, followed by 1 mg/kg every 2 weeks. The safety and toxicity of mogamulizumab were evaluated in both retrospective and prospective studies. Common adverse events, including infusion-related reactions, rash, lymphopenia, gastrointestinal symptoms, and infections, occurred in 30–40% of patients receiving mogamulizumab (20,21). Tumor lysis syndrome was reported in 2–3% of patients, and rare severe dermatological reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been documented as well (2,4).

With depletion of regulatory T cells, mogamulizumab is associated with immune-related adverse events, including autoimmune hepatitis, myocarditis, myositis, and endocrinopathies. These events have been reported weeks to months after treatment completion, warranting continuous monitoring and avoidance of concurrent use of immunotherapy (22). Infectious complications, including cytomegalovirus (CMV) and hepatitis B reactivation (HBV), have also been described, particularly in highly pretreated patients and those receiving combination chemotherapy (21).

Importantly, the use of mogamulizumab is associated with an increased risk of severe, corticosteroid-refractory acute graft-versus-host disease (GVHD) when administered before allo-SCT (23,24). Retrospective analyses have demonstrated significantly higher non-relapse mortality and inferior OS in patients receiving mogamulizumab before transplantation, particularly when the interval between treatment and transplant is short, such as <50 days. These findings are thought to be associated with prolonged depletion of CCR4-positive regulatory T cells and should be considered carefully when treating transplant-eligible patients.

Conclusions

Mogamulizumab represents one of the most extensively studied targeted therapies for ATLL patients. Its dual mechanism of direct tumor cell death and immune modulation provides a strong biological rationale for its use. The available evidence from phase II trials and retrospective studies suggests that mogamulizumab may offer clinical benefit in ATLL across both frontline and relapsed/refractory settings. Combination regimens may deepen the clinical responses, but the durability of remission remains suboptimal. In addition, the immune-related adverse events and increased risk of severe steroid-refractory GVHD in patients who undergo allo-SCT need further attention.

Despite encouraging outcomes, there are a few important limitations. The current literature on mogamulizumab in ATLL is predominantly derived from Japan, reflecting the geographic concentration of HTLV-1 infection. In critically evaluating the available data, it is important to consider the hierarchy of study designs: randomized controlled trials (RCTs) provide the highest level of evidence but are limited to a single phase II RCT in this disease; single-arm prospective studies offer moderate evidence; and retrospective analyses, while informative, are subject to selection bias and confounding. These limitations should be acknowledged throughout the review when interpreting effect sizes and survival outcomes.

Mogamulizumab has served as the frontline therapy, as a bridge to allo-SCT in transplant-eligible patients, and as salvage therapy in the relapsed/refractory setting. Further large-scale, randomized prospective studies are needed to verify the current findings. Combinations of immune checkpoint inhibitors and emerging novel targeted therapies may represent a promising approach to improve the treatment outcomes in this aggressive disease. CCR-4 mutated status serves as a favorable prognostic factor. Further investigation into molecular and immunologic biomarkers may help to identify the patients most likely to benefit from the targeted therapy.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0455/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0455/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0455/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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