Curr Hematol Malig Rep (2012) 7:235–240 T-cell malignancies, including T-cell prolymphocytic leuke- mia, CTCL, and PTCL [26]. The clinical efficacy of pentos- tatin was evaluated in patients with ATL from the 1980s to 1990s, and a phase II study of pentostatin revealed a re- sponse rate of 32 % (10 of 31) in patients with relapsed or refractory ATL [27]. Other drugs that are often used in patients with relapsed or refractory ATL are some combina- tion chemotherapy regimens, including EPOCH (etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubi- cin) and ESHAP (etoposide, methylprednisolone, high-dose cytarabine and cisplatin); however, there is no apparent evidence of an advantage of these combination chemothera- pies over other therapeutic options. In the U.S., pralatrexate and romidepsin have been approved for the treatment of PTCL and can also be used for ATL. The efficacy of these drugs for ATL is not clear because they have been evaluated only in a very limited number of patients (the efficacy of pralatrexate was evaluated in a clinical study in one patient) [28]. CCR4 as a Novel Therapeutic Target Chemokines act as signaling molecules in the migration and tissue homing of various leukocytes. Among them, thymus and activation-regulated chemokine (TARC) and monocyte- derived chemokine (MDC) induce the selective recruitment of distinct subsets of T-cells through triggering of a chemo- kine receptor, CCR4. CCR4 is a seven-transmembrane G- protein coupled receptor and selectively expressed on Th2 cells and regulatory T cells [29, 30]. The expression on normal cells such as Th2 cells can be partly regulated by the ligand, especially MDC [31], while the regulation by the ligands on cancer cells are not yet understood. Ishida et al. analyzed 103 patients with ATL, and found that tumor cells from about 90 % of patients showed CCR4 expression [32]. They also found that patients with CCR4-positive ATL were more likely to have skin infiltration and had a worse out- come than those with CCR4-negative ATL, indicating that CCR4 played an important pathogenetic role in ATL [32]. In addition, Yoshie et al. found that the expression of CCR4 was increased in association of HTLV-1 and showed a relationship to Fra-2/Jun D which induces downstream genes such as c-Myb and SOX4, and MDM2 which pro- motes growth and inhibits apoptosis [33]. CCR4 is also expressed on other types of PTCL (29 % of total cases; PTCL-NOS, 38 %; AITL, 35 %; ALK- ALCL, 67 %; my- cosis fungoides [MF], 41 %) [34]. Jones et al. independently reported that some types of PTCL expressed CCR4, as well [35]. In addition, analysis of 50 patients with PTCL-NOS revealed that CCR4-positive patients had significantly shorter survival than CCR4-negative patients [34]. Nakagawa et al. analyzed 51 patients with PTCL-NOS using the array 237 comparative genomic hybridization technique, and found that patients with PTCL-NOS with genomic aberrations had a significantly higher frequency of CCR4 positivity and a worse outcome than those with PTCL-NOS without genomic aber- rations [36]. These findings resemble those observed in patients with ATL. Although the role of CCR4 in the tumor- igenesis and progression of PTCL-NOS has not been fully elucidated, CCR4 seems to be a promising target molecule in the treatment of PTCL as well as in ATL. Clinical Trials of Mogamulizumab Mogamulizumab/KW-0761 is a humanized monoclonal an- tibody that recognizes the N-terminal region of human CCR4 [37–39]. It is a therapeutic antibody produced using a novel glycoengineering technology that enhances antibody- dependent cellular cytotoxic (ADCC) activity [40]. Mogamu- lizumab and its human-mouse chimeric version, KM2760, showed potent antitumor activity mediated by enhanced ADCC against ATL cell lines and primary ATL cells in vitro and in vivo [39, 41, 42]. A phase I clinical study (0761–0501 Study: Clinical- Trials.gov Identifier NCT00355472) has been conducted in patients with CCR4-positive relapsed PTCL, including ATL [43 ]. The primary objectives of the study were to assess the safety of mogamulizumab, and analyze its maximum toler- ated dose (MTD) and pharmacokinetics. The secondary objectives were to determine the best overall response rate (ORR) and progression-free survival (PFS). Mogamulizu- mab was intravenously administered once a week for 4 weeks at four dose levels (0.01, 0.1, 0.5, and 1.0 mg/kg) according to the conventional 3+ 3 design. Enrolled in the study were 16 patients, of whom 13 had ATL (11 acute type, 2 lymphoma type), 1 had tumor-stage MF, and 2 had PTCL- NOS. All 16 patients receiving mogamulizumab were in- cluded in the safety and efficacy analyses. No dose-limiting toxicity (DLT) was observed in any of the 13 patients who received mogamulizumab at a dose of 0.01–1.0 mg/kg, and thus MTD was not reached. Then, three additional patients were enrolled to receive 1.0 mg/kg, the highest dose. One patient showed grade 4 neutropenia, grade 3 febrile neutro- penia, and grade 3 skin eruption, but these adverse events occurred in only 1 of the 6 patients who received a dose of 1.0 mg/kg, indicating that this drug would be tolerated at least up to 1.0 mg/kg. The best ORR in the total 16 patients was 31 % (of those, 2 had complete response [CR] and 3 had partial response [PR]), and the best ORR was also 31 % in patients with ATL (of those, 2 had CR and another 2 had PR). Pharmacokinetic analysis revealed a plasma mogamu- lizumab trough concentration of 7.5–19.6 μg/mL after the 1st to 4th administration of mogamulizumab at a dose of 1.0 mg/kg. These concentrations were sufficient to kill