Genomic determinants impacting the clinical outcome of mogamulizumab treatment for adult T-cell leukemia/lymphoma

To identify genomic biomarkers for the outcome of mogamulizumabcontaining treatment, an integrated molecular analysis of adult T-cell leukemia/lymphoma (ATL) was conducted on 64 mogamulizumab-naïve patients. Among driver genes, CCR4 and CCR7 alterations were observed in 22% and 11% of the patients, respectively, both consisting of single nucleotide variants (SNVs)/insertion-deletions (indels) in the C-terminus. Patients with CCR4 alterations or without CCR7 alterations exhibited a more favorable clinical response (complete response [CR] rate 93%, 13/14; P = 0.024, and CR rate 71%, 40/56; P = 0.036, respectively). Additionally, TP53, CD28, and CD274 alterations were identified in 35%, 16%, and 10% of the patients, respectively. TP53 alterations included SNVs/indels or copy number variations (CNVs) such as homozygous deletion; CD28 alterations included SNVs, CNVs such as amplification, or fusion; CD274 alterations included CNVs such as amplification, or structural variants. Univariate analysis revealed that TP53, CD28 or CD274 alterations were associated with worse overall survival (OS hazard ratio [HR] 2.330, 95% confidence interval [CI], 1.183-4.589; HR 3.191, 95% CI, 1.287-7.911; HR 3.301, 95% CI, 1.130-9.641, respectively) but that CCR4 alterations were associated with better OS (HR 0.286, 95% CI, 0.087- 0.933). Multivariate analysis indicated that in addition to performance status, TP53, CCR4 or CD274 alterations (HR 2.467, 95% CI, 1.197-5.085; HR 0.155, 95% CI, 0.031-0.778; HR 14.393, 95% CI, 2.437-85.005, respectively) were independently and significantly associated with OS. The present study contributes to the establishment of precision medicine using mogamulizumab in ATL patients.