This international Phase II study, conducted at 22 centers, randomized (2:1 ratio) 71 patients with R/R ATL with at least one prior line of therapy to either mogamulizumab (n=47) or investigator choice chemotherapy (n=24: GemOx=21; pralatrexate=2; DHAP=1). Transmission, replication, and oncogenesis of HTLV-1 in adult T-cell leukemia/lymphoma (ATL). Transmission of infected CD4+CD25+FOXP3+ cells occurs vertical and horizontal routes to a new host. Reverse transcribed HTLV-1 DNA is integrated into the DNA of host cells. and direct cell-to-cell contact and mitosis drives viral replication leading to a clonally diverse population of infected cells. Two transcription regulators, Tax and the HTLV-I basic leucine zipper factor (HBZ) are essential for oncogenesis. Tax up-regulates the P13K/AkT and NFB pathways including through IL-15, and down-regulates p53. HBZ up-regulates TGF, FOXP3, and the C-C chemokine receptor HMOX1 4 (CCR4) while down-regulating INF, IL-2, and TNF. After decades of complex interactions between these molecules, together with the acquisition of new mutations, immune dysregulation, and host-specific factors, ATL develops in 2-5% of carriers. The defucosylated monoclonal antibody mogamulizumab binds CCR4 leading to enhanced antibody-dependent cellular cytotoxicity (ADCC). An estimated 10-15 million people worldwide are infected with HTLV-1.9 The virus is transmitted vertically (breast milk) and horizontally (sexual contact, blood products), infecting primarily mature CD4+ T cells with a CD25+FOXP3+ regulatory T-cell (Treg) Tazarotene phenotype.11 Direct cell-to-cell contact is necessary for the infection of new T cells, while the expansion of the HTLV-1 proviral load is achieved by proliferation of infected T cells, which leads to a clonally diverse neoplastic population11 (Figure 1). Extensive molecular aberrations in HTLV-1-infected T cells, often accumulating over decades, lead to the development of ATL in approximately 3-5% Tazarotene of seropositive carriers. HTLV-1 induced leukemogenesis is a complex, multistep process, driven by Tax and HBZ. Tax-induced upregulation of IL-15, IL-15R, and EZH-2 leads to chronic inflammation and polycomb repressive complex 2 (PRC2) hyperactivation, with genome-wide H3K27me3 accumulation.12 Expression of HBZ by HTLV-1 infected T cells results in increased proliferation, impaired apoptosis, and disruption of genomic integrity.13 Analysis of the somatic mutation landscape of ATL reveals common mutations at and mLSG15 in the randomized front-line study.21 In this context, the study by Phillips em et al /em .8 aimed to determine if the incremental, but encouraging, outcome improvements with mogamulizumab in Japanese ATL could be replicated in non-Japanese ATL. This international Phase II study, conducted at 22 centers, randomized (2:1 ratio) 71 patients with R/R ATL with at least one prior line of therapy to either mogamulizumab (n=47) or investigator choice chemotherapy (n=24: GemOx=21; pralatrexate=2; DHAP=1). The primary objective of the study was confirmed overall response rate (cORR), defined as a response sustained for 8 weeks. In the Tazarotene mogamulizumab arm, cORRs by investigator and independent review were 15% and 11%, respectively, notably inferior to that of the Japanese registration study.3 Remarkably, the cORR in the investigators choice arm was 0%. Concordant with the Japanese Phase II study, the best responses Tazarotene to mogamulizumab by compartment were in blood (54%, all CR) and skin (44%), with no CR in lymph nodes. Responses were observed in all clinical subtypes. Given the study design, with 18 out of 24 patients (75%) on the investigator choice arm crossing over to the investigational arm, it was not possible to assess any OS benefit from mogamulizumab. Median PFS was poor in each arm (0.93 months for mogamulizumab em vs /em . 0.88 months for chemotherapy), much worse than the Japanese pivotal study (PFS, 5.2 months; OS, 14.4 months).3 The authors concluded that the inclusion of primary refractory patients, stricter cORR criteria (8 weeks em vs /em . 4 weeks), and a higher incidence of poor baseline prognostic factors may account for the inferior efficacy of mogamulizumab in this trial compared to the Japanese studies. In addition, 40% of the patients on the mogamulizumab arm of this trial had received prior zidovudine/interferon-Alpha (IFN) therapy, whereas no patient had received it in the Japanese studies, suggesting that mogamulizumab may be less effective after zidovudine/IFN failure. Key differences in disease biology between western and Japanese ATL may also explain differences in response. For example, the presence of CCR4 gain-of-function mutations that have been associated with better outcomes following mogamulizumab therapy in some studies22 were not assessed. Despite the somewhat disappointing results, this is an important study because it gives us the first prospective cohort of homogeneously-treated, non-Japanese ATL individuals, and it defines an important, if still inadequate, benchmark for mogamulizumab with this patient population. The study also exemplifies the futility Tazarotene of standard salvage chemotherapy in R/R ATL, highlighting the importance of ATL patients having access to investigational therapies. Finally, clinically meaningful improvements were obvious actually after individuals experienced progressed per protocol, underlining.