Introduction: Mogamulizumab (moga), an anti-CC chemokine receptor 4 (CCR4) antibody, is approved in Japan for CCR4+ adult T-cell leukemia/lymphoma (ATL) and peripheral and cutaneous T-cell lymphomas (PTCL, CTCL). As moga affects CCR4+ cells, longitudinal changes in these cells and its ligands, CCL17 and 22, are likely to be found with moga treatment and/or associated cutaneous adverse events (cAEs). Although moga's effects on immune cells were previously reported for CTCL (Ni X, et al. Clin Cancer Res. 2015) and solid tumors (Maeda Y, et al. Nature Commun. 2021), differences based on response and a relationship with cAEs were not shown. We analyzed past clinical trials for ATL/PTCL/CTCL to investigate the effects of moga over time on cells and ligands based on response and occurrence of cAEs.

Methods: Cohorts of relapsed or refractory (r/r) ATL, r/r PTCL and r/r CTCL were taken from 6 moga trials. Each cohort was separated by responders (R) (complete response, unconfirmed complete response, partial response) and non-responders (N) (stable disease, disease progression) subpopulations based on best overall response. A linear mixed model (LMM) including subpopulation, time points, and baseline (BL) values in each cohort as fixed effects and subjects as a random effect was used to estimate the differences between subpopulations. Interactions between subpopulations and time points were not included in the LMM as they were not significant. As this was an ad hoc exploratory study, no adjustments were made for multiple testing.

Results: The efficacy analysis set comprised 69 patients (pts) with ATL, 64 with PTCL (31 PTCL-not otherwise specified, 23 angioimmunoblastic T-cell lymphoma, 7 anaplastic large cell lymphoma, 3 transformed mycosis fungoides [MF]), and 221 with CTCL (126 MF, 94 Sézary syndrome, 1 primary cutaneous anaplastic large-cell lymphoma).

The LMM showed changes over time for only the CTCL cohort for lymphocytes (−1174/µL; 95% confidence interval [CI]: −1809, −538.9; p=0.0003), CD4+ cells (−1042/µL; 95% CI: −1694, −309.3; p=0.0019) and CCL17 (−1846 ng/L; 95% CI: −3254, −439.4; p=0.0105) during the observational period. Lymphocyte and CD4+ cell count changes plateaued in R at Week 4 (mean ± standard error [SE], CD4+ cell counts at BL: 3921±879.7/µL; Week 4: 489.8±75.9/µL).

ATL and PTCL showed a different trend at BL. CD4+ cell count differences at BL were far greater for ATL (mean±SE, R: 6754±1723/µL vs N: 1118±276.2/µL) and PTCL (R: 286.3±90.7/µL vs N: 1498±752.4/µL) vs CTCL (R: 3921±879.7/µL vs N: 3268±885.3/µL). No LMM results were obtained for CD4+CD25+FoxP3+ cells, but BL counts for ATL were higher for R than N (R: 3829±1248/µL vs N: 586.6±312.7/µL, p=0.0188, unpaired t-test), with no differences for PTCL or CTCL.

Moga efficacy in the skin was investigated through longitudinal changes in modified Severity-Weighted Assessment Tool (mSWAT) scores. An LMM was obtained for the CTCL cohort, but the interaction term reached p<0.0001. Actual values showed mean mSWAT scores±SE for R were 97.6±6.5 at BL, 71.0±6.2 at Week 4 (% change ± SE from BL: −29.8±3.71%, p<0.0001) and 34.9±4.9 at Week 24 (−62.6±5.26%, p<0.0001), showing response in the blood precedes response in the skin.

An estimated difference of CCL17 serum levels between R and N (−1846.4 ng/L; 95% CI: −3223.6, −439.4) was seen only for CTCL, suggesting CCL17 decreased from BL in response to moga (R: 4028±844.2 ng/L and N: 5425±809.9 ng/L). In r/r ATL at Week 4, CCL17 serum levels increased to 2213±870.8 from 584.9±291.4 ng/L for R and to 1662±913 from 791.5±285.7 ng/L for N. When the association of ligand increase with cAEs occurrence was analyzed, CCL17 % change±SE from BL was higher for pts with cAEs than without (465±135%, p=0.0043; 301±131%, p=0.0545, respectively, one-sample t-test), with a significant change in CCL22 (94±20%, p=0.0004; −0.46±19%, p=0.9815, respectively) at Week 4. No such differences were seen for r/r CTCL.

Conclusions: This analysis shows the effect of moga on CCR4+ cells and its ligands. In CTCL, longitudinal decreases in lymphocyte counts, CD4+ cell counts and CCL17/22 serum levels preceded mSWAT score decrease in R. In ATL and PTCL there are clear differences in BL counts for lymphocytes, CD4+ and/or FoxP3+ cells in R vs N. Additionally, CCL17/22 increases are seen in pts with r/r ATL with cAEs. These results further suggest that moga's effects on CCR4 ligands and the ligands' usefulness as response biomarkers differs between lymphomas.

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2025
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