The pathogenesis of ATLL is not completely understood. Extensive studies have revealed that HTLV-1 transactivator/transcriptional activator (Tax) plays a critical role in the transformation of virus-infected cells. Tax is thought to be a potent oncoprotein, as it results in immortalization of human primary T-cells and Tax transgenic mice malignancy. Tax enhances viral replication through transactivation of the viral promoter, the 5′ long tandem repeat (LTR), results in activation of the nuclear factor kappa-B (NF-kB) pathway, interferes with cell cycle regulators, induces aneuploidy and DNA damage, and impairs DNA repair. Thus, Tax is thought to play a key role in the pathogenesis of ATLL (Matsuoka and Jeang 2011).

HTLV-1 bZIP factor (HBZ) is coded for by the minus strand of the HTLV-1 provirus and can be found in all ATLL cells (Satou et al. 2006). HBZ protein was originally reported to suppress Tax-mediated viral transcription; however, HBZ RNA has also been shown to promote cell proliferation. Importantly, HBZ transgenic mice developed CD4/forkhead box protein-3 (Foxp3)-positive T-cell lymphoma, resembling the immunophenotype and clinical features of human ATLL. These findings suggest that HBZ is a critical factor in leukemogenesis. The proposed model for the interplay between Tax and HBZ is that Tax is needed to initiate the transformation of HTLV-1-infected cells, while HBZ is required to maintain the transformed phenotype in ATLL (Matsuoka and Jeang 2011).

The determinants of ATLL progression in HTLV-1 carriers have been investigated in many epidemiological and clinical studies. In Japanese cohorts, the average age at diagnosis is about 65 years (Yamada et al. 2011), significantly greater than in the Jamaican cohort, who present in their mid-forties, suggesting that other host and environmental factors may also be involved in ATLL pathogenesis (Hanchard 1996). The age at the time of HTLV-1 infection is also a critical factor in ATLL development, as ATLL rarely develops in HTLV-1 carriers who acquired infection through horizontal transmission. Several studies have examined host genetic factors, including HLA haplotypes, due to the observation that patients with ATLL were more likely to have a family history of ATLL when compared with the general population. The frequency of HLA-A*26, HLA-B*4002, HLA-B*4006, and HLA-B*4801 alleles was significantly higher in ATLL patients than in HTLV-1 asymptomatic carriers in Japan (Yashiki et al. 2001). In the Miyazaki cohort, HTLV-1 carriers with a higher anti-HTLV-1 titer and lower anti-Tax reactivity were at greatest risk of developing ATLL (Hisada et al. 1998), and higher HTLV-1 proviral load was a significant risk factor for progression from asymptomatic HTLV-1 carrier status to ATLL. A nationwide prospective study of HTLV-1 carriers in Japan was initiated to identify the determinants of ATLL development. Fourteen subjects out of 1,218 asymptomatic carriers developed ATLL, and all of the 14 subjects had higher baseline proviral loads, whereas there were no cases of ATLL among those with a baseline proviral load of less than 4 copies/100 peripheral blood mononuclear cells (Iwanaga et al. 2010).

The prognosis for patients with acute and lymphoma subtypes of ATLL remains poor, even with chemotherapy or allogeneic hematopoietic stem cell transplantation (alloHSCT). With currently best available chemotherapy in one series (Tsukasaki et al. 2007), the rate of complete response (CR) was 40 % and overall survival (OS) at 3 years was 24 %. The median survival time (MST) is 13 months.

In a previous study, in which Japanese patients with ATLL were followed for a total duration of 7 years, the 4-year survival rates for chronic and smoldering sub-types were 26.9 and 62.8 %, respectively, with a MST of 24.3 months for the chronic sub-type (Shimoyama 1991). Therefore, the chronic and smoldering subtypes of ATLL are characterized by an indolent clinical course and are usually managed by observation or “watchful waiting” until disease progression to acute crisis, which is similar to the approach to the management of chronic lymphoid leukemia or smoldering myeloma. However, a recent report with long-term follow-up of these indolent sub-types of ATLL (chronic and smoldering) revealed that the MST was 4.1 years and the estimated 5-, 10-, and 15-year survival rates were 47.2, 25.4, and 14.1 %, respectively (Takasaki et al. 2010), which were poorer than expected. These findings suggest that even patients with indolent forms of ATLL should be carefully observed in clinical practice, and further research is needed to improve the management of these patients.

The results of a phase III randomized control trial suggest that the vincristine, cyclophosphamide, doxorubicin, and prednisone (VCAP); doxorubicin, ranimustine, and prednisone (AMP); and vindesine, etoposide, carboplatin, and prednisone (VECP) regimens show no benefit over biweekly cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in newly diagnosed acute, lymphoma, or unfavorable chronic subtypes of ATLL in terms of OS, primary study endpoint, or progression-free survival (Tsukasaki et al. 2007). However, the rate of CR was higher in the VCAP-AMP-VECP arm than the biweekly CHOP arm (40 vs 25 %, respectively; P = 0.020). OS at 3 years was 24 % in the VCAP-AMP-VECP arm and 13 % in the CHOP arm (P = 0.085). Nonetheless, the MST of 13 months still compares unfavorably to other hematological malignancies.

Allogeneic HSCT (alloHSCT) has been explored as a promising alternative therapeutic modality that can provide long-term remission in a proportion of patients with ATLL (Choi et al. 2011; Hishizawa et al. 2010; Utsunomiya et al. 2001). In a recent large nationwide retrospective analysis, investigators compared outcomes of 386 patients with ATL who underwent alloHSCT. After a median follow-up of 41 months, 3-year OS for the entire cohort was 33 % (Hishizawa et al. 2010). Another retrospective study based on 294 ATLL patients who received alloHSCT revealed that the development of mild-to-moderate acute GVHD confers a lower risk of disease progression and a beneficial influence on survival (Kanda et al. 2012), which is indicative of a graft-versus-ATLL effect. Another large retrospective analysis of alloHSCT for ATLL (n = 586) in Japan revealed no significant difference in OS between myeloablative conditioning (MAC) and reduced intensity conditioning (RIC). There was a tendency toward better OS in older patients receiving RIC (Ishida et al. 2012). The number of ATLL patients eligible for allogeneic transplantation is few because of older age at presentation and the low rate of CR. Selection criteria for alloHSCT for patients with ATLL remain to be determined.

Results of a recent meta-analysis on the use of AZT/IFN for 254 ATLL patients worldwide showed that the treatment of ATLL patients with AZT and IFN resulted in better response and prolonged OS (Bazarbachi et al. 2010). Two hundred and seven patients received AZT/IFN therapy. In these patients, 5-year OS rates were 46 % for 75 patients who received antiviral therapy (P = 0.004). In acute ATLL, achievement of complete remission with antiviral therapy resulted in 82 % 5-year survival. These results suggest that the treatment of ATLL using AZT/IFN results in high response and CR rates except for lymphoma type of ATLL, resulting in prolonged survival in a significant proportion of patients. Although this is a retrospective analysis, the results seem to be promising, and further studies comparing AZT/IFN-α and conventional chemotherapy or alloHSCT are warranted.

The prevention of ATLL mostly relies on the prevention of HTLV-1 transmission as previously described. Another strategy could be the prevention of ATLL development among HTLV-1 carriers. Despite the prolonged carrier status before ATLL development, there are no interventions exploiting this window of opportunity to treat ATLL. This is partly because only approximately 10 % of HTLV-1 carriers develop HTLV-1-related disease in their lifetime. Careful risk–benefit analysis including the acceptability of side effects during interventions is needed.