Immunohistochemistry for CCR4 C-terminus predicts CCR4 mutations and mogamulizumab efficacy in adult T-cell leukemia/lymphoma

Abstract

Mogamulizumab targets extracellular N-terminal domain of CCR4, which is expressed in most adult T-cell leukemia/lymphoma (ATL) cases. Recently, we reported that CCR4 C-terminal gain-of-function mutations were frequent in ATL cases, and a subgroup with these mutations who were treated without allogenic hematopoietic stem cell transplantation (HSCT) and with mogamulizumab-containing [HSCT (-) and mogamulizumab (+)] regimens had a superior survival rate. Although these mutations are most likely a biomarker for predicting a strong response to mogamulizumab, their detection is time-consuming and costly. A more convenient screening tool may be necessary in the clinical setting. In this study, the clinicopathological importance of immunohistochemistry for the CCR4 N-terminus (CCR4-N-IHC) and C-terminus (CCR4-C-IHC) was examined in a large ATL cohort (n = 92). We found that CCR4-C-IHC, but not CCR4-N-IHC, was inversely correlated with the CCR4 mutation status. In ATL patients negative for CCR4-C-IHC, a subgroup treated with HSCT (-) and mogamulizumab (+) regimens showed a significantly better prognosis. In addition, CCR4-C-IHC was found to be a useful marker for high-sensitivity screening of the CCR4 mutational status (87%). The present study suggests that CCR4-C-IHC may be useful for identifying ATL patients harboring mutated CCR4 who may benefit from the superior efficacy of mogamulizumab-containing regimens and that CCR4-C-IHC may be a rapid and cost-efficient tool for screening for CCR4 mutation status.

Keywords: ATL; CCR4; immunohistochemistry; mogamulizumab; prognosis.

Figure 1

Representative CCR4 C‐terminus expression in ATL cases with intensities scored 0 (negative, A), 1+ (weak, B), 2+ (moderate, C), and 3+ (strong, D).

Figure 2

Survival of patients with ATL stratified according to CCR4‐C‐IHC findings (negative, 0/1/2+ versus positive, 3+). (A) The 5‐year OS of the 40 patients positive for CCR4‐C‐IHC and 52 patients negative for CCR4‐C‐IHC was 28.0% (95% CI, 13.9–48.3%) and 47.6% (95% CI, 33.2–62.4%), respectively. (B) Among the patients with ATL with an aggressive variant (n = 82), the 5‐year OS of those positive for CCR4‐C‐IHC (n = 34) or negative for CCR4‐C‐IHC (n = 48) was 24.0% (95% CI, 10.5–45.8%) and 42.5% (95% CI, 27.9–58.5%), respectively. (C) Among the 26 patients with ATL who received allogeneic HSCT, the 5‐year survival from the day of allogeneic HSCT in the seven patients positive for CCR4‐C‐IHC and 19 negative for CCR4‐C‐IHC was 33.3% (95% CI, 8.4–73.2%) and 49.4% (95% CI, 27.7–71.3%), respectively. (D) Among the 25 patients with ATL with an aggressive variant who received allogeneic HSCT, the 5‐year survival from the day of allogeneic HSCT in the six patients positive for CCR4‐C‐IHC and 19 negative for CCR4‐C‐IHC was 33.3% (95% CI, 8.4–73.2%) and 49.4% (95% CI, 27.7–71.3%), respectively. (E) Among the 30 patients with ATL who did not receive any MOGA‐containing treatment or allogeneic HSCT, the 5‐year OS in the eight positive for CCR4‐C‐IHC and 22 negative for CCR4‐C‐IHC was not reached and 35.7% (95% CI, 17.5–59.3%), respectively. (F) Among the 24 patients with ATL with an aggressive variant who did not receive any MOGA‐containing treatment or allogeneic HSCT, the 5‐year OS in the six positive for CCR4‐C‐IHC and 18 negative for CCR4‐C‐IHC was not reached and 16.8% (95% CI, 4.5–46.4%), respectively. (G) Among the 36 patients with ATL who received MOGA‐containing treatment but no allogeneic HSCT, the 5‐year survival from the day of the first dose of antibody in the 25 patients positive for CCR4‐C‐IHC and 11 negative for CCR4‐C‐IHC was 8.7% (95% CI, 1.4–38.4%) and 72.7% (95% CI, 41.4–91.0%), respectively. This difference was statistically significant. (H) Among the 33 patients with ATL with an aggressive variant who received MOGA‐containing treatment but no allogeneic HSCT, the 5‐year survival from the day of the first dose of antibody in the 22 patients positive for CCR4‐C‐IHC and 11 negative for CCR4‐C‐IHC was 10.3% (95% CI, 1.7–43.5%) and 72.7% (95% CI, 41.4–91.0%), respectively. This difference was also statistically significant. Survival curves were compared using the log‐rank test, and the P value is indicated in each panel. MOGA, mogamulizumab.