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Biology and treatment of HTLV-1 associated T-cell lymphomas

Best Practice & Research Clinical Haematology, 1, 26, pages 3 - 14

Adult T-cell leukemia-lymphoma (ATL) is a distinct peripheral T-lymphocytic malignancy associated with human T-cell lymphotropic virus type I (HTLV-1) endemics in several regions of the world including the south-west Japan. The three major routes of HTLV-1 transmission are mother-to-child infections via breast milk, sexual intercourse, and blood transfusions. A HTLV-1 infection early in life, presumably from breast feeding, is crucial to the development of ATL. The estimated cumulative risk of developing ATL among HTLV-1-positive individuals is about 3% after transmission from the mother. The diversity in clinical features and prognosis of patients with this disease has led to its subtype-classification into acute, lymphoma, chronic, and smoldering types defined by organ involvement, lactate dehydrogenase (LDH) and calcium values. For the acute, lymphoma and unfavorable chronic subtypes (aggressive ATL), and the favorable chronic and smoldering subtypes (indolent ATL), intensive chemotherapy followed by allogeneic stem cell transplantation and watchful waiting until disease progression has been recommended, respectively, in Japan. A retrospective analysis suggested that the combination of interferon alpha and zidovudine was promising for the treatment of ATL, especially for leukemic subtypes. There are several new trials for ATL, including a defucosylated humanized anti-CC chemokine receptor 4 monoclonal antibody, histone deacetylase inhibitors, a purine nucleoside phosphorylase inhibitor, a proteasome inhibitor and lenalidomide.

Keywords: ATL, HTLV-1, subtype-classification, molecular epidemiology, multi-step carcinogenesis, treatment strategy, new agent development.

Introduction

Adult T-cell leukemia (ATL) was first described in 1977 by Uchiyama and Takatsuki as a distinct progressive T-cell leukemia of peculiar morphology, so called “flower cells” with a suspected viral etiology because of the clustering of the disease in the southwestern region of Japan [1] . Subsequently, a novel RNA retrovirus, human T-cell leukemia/lymphotropic virus type I (HTLV-1), was isolated from a cell line established from leukemic cells of an ATL patient, and the finding of a clear association with ATL led to its inclusion among human carcinogenic pathogens [2], [3], [4], and [5]. In the mid-1980s and 1990s, several inflammatory diseases were reported to be associated with HTLV-1 including tropical spastic paraparesis (TSP)/HTLV-1-associated myelopathy (HAM), HTLV-1 uveitis and infective dermatitis [6], [7], [8], and [9]. At the same time, endemic areas for the virus and diseases have been found such as the Caribbean islands, tropical Africa, South America, Mid East and northern Oceania [10] . Subsequently, diversity in the clinical features of ATL has been recognized including ATL without leukemic manifestation and nomenclature of adult T-cell leukemia/lymphoma (ATLL) and/or adult T cell leukemia-lymphoma (ATL), and a classification of clinical subtypes of the disease was proposed [11] . This chapter will review the current recognition of ATL focusing on the biology and treatment of the disease.

Recent epidemiological findings of HTLV-1 and ATL in Japan

It has been estimated that there are several tens of million HTLV-1-infected individuals reside in the world, with 1.1 million in Japan, and the annual incidence of ATL is approximately 1,000 in Japan. The annual rate of ATL development among HTLV-1 carriers older than 40 years is estimated at 1.5 per 1000 in males and 0.5 per 1000 in females, and the cumulative risk of ATL development among HTLV-1 carriers is estimated to be 2.5%–5% over the course of a 70-year life span [12] .

Recently, the prevalence of HTLV-1 in Japan as determined by screening of blood donors was surveyed [13] . The seroprevalence of HTLV-1 among 1,196,321 Japanese first-time blood donors from 2006 to 2007 was investigated. A total of 3787 such donors were confirmed to be positive for the anti-HTLV-1 antibody. This resulted in an estimation of at least 1.08 million current HTLV-1 carriers in Japan, which is 10% lower than that reported in 1988. The adjusted overall prevalence rates were estimated to be 0.66% and 1.02% in men and women, respectively. The peak in carrier numbers was found among individuals in their 70s, which is a shift from the previous peak observed in the 1988 database among individuals in their 50s. As compared to the survey in the 1980s, carriers were distributed throughout the country, particularly in the greater Tokyo metropolitan area.

Factors reportedly associated with the onset of ATL include the following: HTLV-1 infection early in life, increase in age, male sex, family history of ATL, past history of infective dermatitis, smoking of tobacco, serum titers of antibody against HTLV-1, HTLV-1 proviral load and several HLA subtypes [10] and [14]. However, definitive risk factors for the development of ATL among asymptomatic HTLV-1 carriers have not been elucidated. Recently, Iwanaga and colleagues evaluated 1218 asymptomatic HTLV-1 carriers (426 males and 792 females) who were enrolled during 2002–2008 for a prospective study on the development of ATL [15] . The HTLV-1 proviral load at enrollment was significantly higher in males than females (median, 2.10 vs. 1.39 copies/100 peripheral blood mononuclear cells (PBMC)) (P < .0001), in those aged 40 or more years, and in those with a family history of ATL. During the follow-up period, 14 participants developed ATL. Their baseline proviral loads were high (range, 4.17–28.58 copies/100 PBMC). Multivariate Cox regression analyses indicated that not only a higher proviral load but also advanced age, a family history of ATL, and the first opportunity for HTLV-1 testing during treatment for other diseases were independent risk factors for the progression of ATL from a carrier status.

Molecular features of HTLV-1 and ATL

The HTLV-I gene encodes three structural proteins, Gag, Pol and Env, and complex regulatory proteins such as Tax, which not only activates viral replication but also induces the expression of several cellular genes. The expression of the proteins encoded by these cellular genes may enhance the multistep carcinogenesis of ATL. However, the expression including Tax is suppressed in vivo probably escaping from immune surveillance, and appears just after in vitro culture [10] . A new viral factor, HTLV-1 basic Zip factor (HBZ), encoded by minus strand mRNA was recently discovered and is thought to be involved in viral replication and T-cell proliferation [16] . Several isoforms of HBZ transcripts were reported to be steadily expressed in HTLV-1–infected cells and primary ATL cells in contrast to Tax. The functions of these transcripts and putative proteins in the context of cellular transformation are now under investigation.

Prototypical ATL cells have a mature helper T-cell phenotype (CD3+, CD4+, CD8−). Recent studies have suggested that the cells of some ATL patients may be the equivalent of regulatory T cells because of the high frequency of expression of CD25/CCR4 and about half of that of FoxP3 [17] . By Southern blotting for both HTLV-1 integration and T-cell receptor (TCR) gene rearrangement, about 10–20% of ATL cases showed clonal changes during the transformation from indolent to aggressive disease [18] . Oligoclonal expansion of HTLV-1 infected pre-malignant cells was detected in asymptomatic HTLV-1 carriers by HTLV-1 integrated site-specific PCR [19] . Polycomb-mediated epigenetic silencing of miR-31 is implicated in the aberrant activation of NF-kB signaling in ATL cells [20] . A high rate of chromosomal abnormalities has been detected in HTLV-1-infected T-cell clones derived from HTLV-1 carriers [21] . Abnormalities in tumor suppressors such as p53 and p14/p16 are frequent and rare in acute- and chronic-type ATL, respectively, and both are associated with poor prognosis [22] . Chromosomal abnormalities detected by cytogenetics or comparative genomic hybridization are often more complex and more frequent in acute ATL than in chronic ATL, with aneuploidy and several hot spots such as 14q and 3p [23] . Microarray analyses of the transcriptomes of ATL cells at the chronic and acute stages elucidate the mechanism of stage progression in this disease revealed that several hundred genes were modulated in expression including those for MET, a receptor tyrosine kinase for hepatocyte growth factor and cell adhesion molecule, TSLC1 [24] and [25].

In summary, ATL is etiologically associated with HTLV-1. However, HTLV-1 does not carry a viral oncogenes, expression of the virus including Tax appears just after in vitro culture. Integration of the provirus into the host genome is random, and chromosomal/genetic abnormalities are complex: therefore, ATL is regarded as a single HTLV-1 disease entity with diverse molecular features resembling the acute-crisis-phase of chronic myeloid leukemia.

Clinical features and prognostic factors of ATL

ATL patients show a variety of clinical manifestations because of various complications of organ involvement by ATL cells, opportunistic infections and/or hypercalcemia [10], [11], and [26]. These three often contribute to the extremely high mortality of the disease. Lymph node, liver, spleen and skin lesions are frequently observed. Although less frequently, digestive tract, lungs, central nervous system, bone and/or other organs may be involved [26] . Large nodules, plaques, ulcers, and erythrodermas are common skin lesions [27], [28], and [29]. Immune suppression is common. Approximately 26% of 854 patients with ATL had active infections at diagnosis in a prior nationwide study in Japan [14] . The infections were bacterial in 43%, fungal in 31%, protozoal in 18%, and viral in 8% of patients. Individuals with indolent ATL might have no manifestation of the disease and are identified only by health check-ups and laboratory examinations.

ATL cells, so called “flower cells”, are usually detected easily in the blood of affected individuals except in smoldering type, which mainly has skin manifestations and lymphoma type [11] . The histological analysis of aberrant cutaneous lesions or lymph nodes is essential for the diagnosis of the smoldering type with mainly skin manifestations and lymphoma type of ATL, respectively. Because ATL cells in the skin and lymph node can vary in size from small to large and in form from pleomorphic to anaplastic and Hodgkin-like cell with no specific histological pattern of involvement, distinguishing the disease from Sezary syndrome, other peripheral T-cell lymphomas and Hodgkin lymphoma can at times be difficult without examinations for HTLV-1 serotype/genotype [26] .

Hypercalcemia is the most distinctive laboratory abnormality in ATL as compared to other lymphoid malignancies, and is observed in 31% of patients (50% in acute type, 17% in lymphoma type and 0% in the other two types) at onset [11] . Individuals with hypercalcemia do not usually have osteolytic bone lesions. Parathyroid hormone-related protein or receptor activator of nuclear factor kappa B ligand (RANKL) produced by ATL cells is considered the main factor causing hypercalcemia [30] and [31].

The diagnosis of typical ATL is not difficult and is based on clinical features, ATL cell morphology, mature helper-T-cell phenotype and anti-HTLV-1 antibody in most cases [11] . Those rare cases which might be difficult to diagnose can be shown to have the monoclonal integration of HTLV-1 proviral DNA in the malignant cells as determined by Southern blotting. However, its sensitivity is around 5% of ATL cells among normal cells. Furthermore, the monoclonal integration of HTLV-1 is also detected in some HAM/TSP patients and HTLV-1 carriers [32] . After the diagnosis of ATL, subtype-classification of the disease, reflecting prognostic factors, clinical features and natural history of the disease are based on the presence of organ involvement, leukemic manifestation and values for LDH and calcium, is necessary for the selection of appropriate treatment ( Table 1 ) [11] and [33].

Table 1 Diagnostic criteria for clinical subtypes of adult T-Cell leukemia-lymphoma.

  Smoldering Chronic Lymphoma Acute
Anti-HTLV-1 antibody + + + +
Lymphocyte (×103/μUL) <4 ≥4 <4 a
Abnormal T lymphocytes ≥5% d + c ≤1% + c
Flower cells with T-cell marker b b No +
LDH ≤1.5 N ≤2 N a a
Corrected Ca2+ (mEq/L) <5.5 <5.5 a a
Histology-proven lymphadenopathy No a + a
Tumor lesion
Skin and/or lung a a a a
Lymph node No a Yes a
Liver No a a a
Spleen No a a a
Central nervous system No a a a
Bone No No a a
Ascites No No a a
Pleural effusion No No a a
Gastrointestinal tract No No a a

a No essential qualification except terms required for other subtype(s).

b Typical “flower cells” may be seen occasionally.

c If the proportion of abnormal T lymphocytes is less than 5% in peripheral blood, a histologically proven tumor lesion is required.

d Histologically proven skin and/or pulmonary lesion(s) is required if there are fewer than 5% abnormal T lymphocytes in peripheral blood.

HTLV-1, human T-lymphotropic virus type I; LDH, lactate dehydrogenase; N normal upper limit.

With permission from Shimoyama M, Members of the Lymphoma Study Group (1984–1987): Diagnostic criteria and classification of clinical subtypes of adult T-cell leukemia-lymphoma. Br J Haematol 1991; 79:428.

Major prognostic indicators for ATL, elucidated among 854 patients with ATL in Japan by multi-variate analysis were advanced performance status, high LDH level, age of 40 years or more, more than three involved lesions, and hypercalcemia [34] . Additional factors associated with a poor prognosis include thrombocytopenia, eosinophilia, bone marrow involvement, a high interleukin (IL)-5 serum-level, CC chemokine receptor 4 (CCR4) expression, lung resistance-related protein (LRP), p53 mutation and p16 deletion by multivariate analysis [33] . Specific for the chronic type of ATL, high LDH, high blood urea nitrogen (BUN), and low albumin levels were identified as factors for a poor prognosis by multi-variate analysis [10] . Primary cutaneous tumoral type generally included among smoldering ATL had a poor prognosis in a uni-variate analysis [27] .

Recently, a retrospective review of 807 patients in Japan led to a prognostic index for acute- and lymphoma-type ATL based on five prognostic factors; stage, performance status (PS), age, serum albumin and sIL2R. In the validation sample, the index was reproducible with median survival times (MSTs) of 3.6, 7.3, and 16.2 months for patients at high, intermediate, and low risk, respectively [35] . The Japan Clinical Oncology Group (JCOG)-Lymphoma Study Group (LSG) conducted a meta-analysis of three consecutive trials exclusively for aggressive ATL (see below) [36] . OS analysis of a total 276 patients with acute-, lymphoma- or unfavorable chronic-ATL identified two significant prognostic factors, PS and hypercalcemia. In the validation sample, a proposed prognostic index using the two factors into two strata revealed MSTs of 6.3, and 17.8 months for patients at high and low risk, respectively. In both studies, however, the 5-year OS rate was less than 15% even in the low risk group, indicating that they are not sufficient to properly identify non-candidates for allo-HSCT which can achieve a cure of ATL despite considerable treatment-related mortality.

Treatment of ATL

Current treatment options for ATL include watchful waiting until the disease progresses, interferon alpha (IFN) and zidovudine (AZT) therapy, multi-agent chemotherapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) and new agents.

Recently, a treatment strategy based on the clinical subtype classification and prognostic factors was suggested as shown in Table 2 [33] .

Table 2 Strategy for the treatment of adult T-Cell leukemia-lymphoma.

Smoldering-or favorable chronic-type ATL
  • Consider inclusion in prospective clinical trials
  • Symptomatic patients (skin lesions, opportunistic infections, etc): consider AZT/IFN or watch and wait
  • Asymptomatic patients: consider watch and wait
Unfavorable chronic- or acute-type ATL
  • If outside clinical trials, check prognostic factors (including clinical and molecular factors if possible):
    • Good prognostic factors: consider chemotherapy (VCAP-AMP-VECP evaluated by a phase III trial against biweekly-CHOP) or AZT/IFN (evaluated by a meta-analysis on retrospective studies)
    • Poor prognostic factors: consider chemotherapy followed by conventional or reduced intensify allo-HSCT (evaluated by retrospective and prospective Japanese analyses, respectively).
    • Poor response to initial therapy: consider conventional or reduced intensity allo-HSCT
Lymphoma-type ATL
  • If outside clinical trials, consider chemotherapy (VCAP-AMP-VECP)
  • Check prognostic factors (including clinical and molecular factors if possible) and response to chemotherapy:
    • Good prognostic factors and good response to initial therapy: consider chemotherapy followed by observation
    • Poor prognostic factors or poor response to initial therapy: consider chemotherapy followed by conventional or reduced intensity allo-HSCT.

Watchful waiting

At present, no standard management for indolent ATL exists. Therefore, patients with the smoldering or favorable chronic type, may survive one or more years without chemotherapy, excluding topical therapy for cutaneous lesions, are observed and therapy is delayed until disease progression [33] . However, it was recently found that the long-term prognosis of such patients was poorer than expected. In a long-term follow-up study for 78 patients with indolent ATL (favorable chronic- or smoldering-type) with a policy of watchful waiting until disease progression at a single institution in Japan, the MST was 5.3 years with no plateau in the survival curve. Twelve patients remained alive for >10 years, 32 progressed to acute ATL, and 51 died [37] .

Chemotherapy

Since 1978, a number of consecutive chemotherapy trials have been conducted for patients newly diagnosed with ATL by the JCOG-Lymphoma Study Group (LSG) ( Table 3 ) [10] . Between 1981 and 1983, JCOG conducted a phase III trial (JCOG8101) to evaluate LSG1-VEPA (vincristine, cyclophosphamide, prednisone, and doxorubicin) vs LSG2-VEPA-M (VEPA plus methotrexate (MTX)) for advanced non-Hodgkin lymphoma (NHL), including ATL [10] . The complete response (CR) rate of LSG2-VEPA-M for ATL (37%) was marginally higher than that of LSG1-VEPA (17%; P = .09). However, the CR rate was significantly lower for ATL than for B-cell NHL and peripheral T-cell lymphoma (PTCL) other than ATL (P < .001). The MST of the 54 patients with ATL was 6 months, and the estimated 4-year survival rate was 8%.

Table 3 Results of sequential chemotherapeutic-trials of untreated patients with ATL (JCOG-LSG).

  J7801 J8101 J8701 J9109 J9303 JCOG9801
LSG1 LSG1/LSG2 LSG4 LSG11 LSG15 mLSG15/mLSG19
Pts. no. 18 54 43 62 96 57 61
CR (%) 16.7 27.8 41.9 28.3 35.5 40.4 24.6
CR + PR (%)       51.6 80.6 72.0 65.6
MST (months)   7.5 8.0 7.4 13.0 12.7 10.9
2 yr. survival (%)       17.0 31.3    
3 yr. survival (%)       10.0 21.9 23.6 12.7
4 yr survival (%)   8.0 11.6        

CR: complete remission, PR: partial remission, MST: median survival time.

In 1987, JCOG initiated a multicenter phase II study (JCOG8701) of a multiagent combination chemotherapy (LSG4) for advanced aggressive NHL (including ATL). LSG4 consisted of three regimens: (1) VEPA-B (VEPA plus bleomycin), (2) M-FEPA (methotrexate, vindesine, cyclophosphamide, prednisone, and doxorubicin), and (3) VEPP-B, (vincristine, etoposide, procarbazine, prednisone, and bleomycin) [10] . The CR rate for ATL patients was improved from 28% (JCOG8101) to 43% (JCOG8701); however, the CR rate was significantly lower in ATL than in B-cell NHL and PTCL (P < .01). Patients with ATL still showed a poor prognosis, with an MST of 8 months and a 4-year survival rate of 12%.

The first phase II trial (JCOG9109) with a pentostatin, which was considered to be a promising agent showing responses against relapsed/refractory ATL as a single agent, -containing combination (LSG11) as the initial chemotherapy [38] . A total of 62 untreated patients with aggressive ATL (34 acute, 21 lymphoma, and 7 unfavorable chronic type) were enrolled. Among the 60 eligible patients, there were 17 CRs (28%) and 14 partial responses (PRs) (overall response rate [ORR] = 52%). The MST was 7.4 months, and the estimated 2-year survival rate was 17%. The prognosis of patients with ATL remained poor, even though they were treated with a pentostatin-containing combination chemotherapy.

In 1994, JCOG initiated a phase II trial (JCOG9303) of an eight-drug regimen (LSG15) consisting of vincristine, cyclophosphamide, doxorubicin, prednisone, ranimustine, vindesine, etoposide, and carboplatin for untreated ATL [39] . Dose intensification was attempted with the prophylactic use of granulocyte colony-stimulating factor (G-CSF). In addition, non–cross-resistant agents such as ranimustine and carboplatin, and intrathecal prophylaxis with methotrexate and prednisone were incorporated. Ninety-six previously untreated patients with aggressive ATL were enrolled: 58 acute, 28 lymphoma, and 10 unfavorable chronic types. Approximately 81% of the 93 eligible patients responded (75/93), with 33 patients obtaining a CR (35%). The overall survival rate of the 93 patients at 2 years was estimated to be 31%, with an MST of 13 months. Grade 4 neutropenia and thrombocytopenia were observed in 65% and 53% of the patients, respectively, whereas grade 4 non-hematologic toxicity was observed in only one patient.

To confirm whether the LSG15 regimen would be considered as the new standard for the treatment of aggressive ATL, JCOG conducted a phase III trial comparing modified (m)-LSG15 ( Fig. 1 ) with CHOP-14 (cyclophosphamide, hydroxy-doxorubicin, vincristine [Oncovin], and prednisone), both supported with G-CSF and intrathecal prophylaxis [37] . A total of 118 patients were enrolled. The CR rate was higher in the mLSG15 arm than in the CHOP-14 arm (40% vs. 25%, respectively; P = .020). The MST and OS rate at 3 years were 12.7 months and 24% in the mLSG15 arm and 10.9 months and 13% in the CHOP-14 arm {two-sided P = .169, and the hazard ratio was 0.75; 95% confidence interval (CI), 0.50 to 1.13}. In mLSG15 vs. CHOP-14, rates of grade 4 neutropenia, grade 4 thrombocytopenia and grade 3/4 infection were 98% vs. 83%, 74% vs. 17% and 32% vs. 15%, respectively. Three treatment-related deaths (TRDs), two from sepsis and one from interstitial pneumonitis related to neutropenia, were reported in the mLSG15 arm. The longer survival at 3 years and higher CR rate with mLSG15 compared with CHOP-14 suggest that mLSG15 is a more effective regimen at the expense of greater toxicity, providing the basis for future investigations in the treatment of ATL [40] . The superiority of VCAP-AMP-VECP in mLSG15 to CHOP-14 may be explained by the more prolonged, dose dense schedule of therapy in addition to 4 more drugs. In addition, agents such as carboplatin and ranimustine not affected by multidrug-resistance (MDR)-related genes, which were frequently expressed in ATL cells at onset, were incorporated [10] . However, the MST of 13 months in VCAP-AMP-VECP (mLSG15) still compares unfavorably to other hematological malignancies, requiring further effort to improve the outcome.

gr1

Fig. 1 Regimen of VCAP-AMP-VECP in mLSG15. VCAP = vincristine (VCR), cyclophosphamide (CPA), doxorubicin (ADM), prednisone (PSL); AMP = ADM, ranimustine (MCNU), PSL; VECP = vindesine (VDS), etoposide (ETP), carboplatin (CBDCA) and PSL. *MCNU and VDS are nitrosourea and vinca alkaloid, respectively, developed in Japan. A previous study on myeloma described that carmustine (BCNU), another nitrosourea, at 1 mg/kg is equivalent to MCNU at 0.8–1.0 mg/kg. VDS at 2.4 mg/m2 can be substituted for VCR, another vinca alkaloid used in this regimen, at 1 mg/m2 with possibly less myelosuppression and more peripheral neuropathy which can be managed by dose modification.

Interferon-alpha and zidovudine

In 1995, Gill and associates reported that 11 of 19 patients with acute- or lymphoma-type ATL showed major responses (5 CR and 6 PR) to a combination of IFN and zidovudine (AZT) [41] . The efficacy of this combination was also observed by Hermine and associates; major objective responses were obtained in all five patients with ATL (four with acute type and one with smoldering type) [42] . Although these results are encouraging, the OS of previously untreated patients with ATL was relatively short (4.8 months) compared with the survival of those in the chemotherapy trials conducted by the JCOG-LSG (7–8 months) [43] . Since then, several small phase II studies using AZT and IFN have shown responses in ATL patients. The therapeutic effect of AZT and IFN is not a direct cytotoxic effect of these drugs on the leukemic cells. Enduring AZT treatment of ATL cell lines resulted in the inhibition of a telomerase, reprograming the cells to a p53-dependent senescence [44] .

Recently, the results of a “meta-analysis” on the use of IFN and AZT for ATL were reported [45] . A total of 100 patients received interferon-alpha and AZT as initial treatments. The ORR was 66%, with a 43% CR rate. In this worldwide retrospective analysis, the MST was 24 months and the 5-year survival rate was 50% for first-line IFN and AZT, vs. 7 months and 20% for 84 patients who received first-line chemotherapy. The MST of patients with acute-type ATL treated with first-line IFN/AZT and chemotherapy was 12 and 9 months, respectively. Patients with lymphoma-type ATL did not benefit from this combination. In addition, first-line IFN/AZT therapy in chronic- and smoldering-type ATL resulted in a 100% survival rate at a median follow-up of 5 years. However, because of the retrospective nature of this meta-analysis based on medical records at each hospital, the decision process to select the therapeutic modality for each patient and the possibility of interference with OS by second-line treatment remains unknown. A prospective multicenter phase III study evaluating the efficacy of IFN/AZT as compared to watchful-waiting for indolent ATL is to be initiated in Japan.

Researchers from the UK reported the results of a retrospective analysis in 73 patients with aggressive ATL (acute ATL, 29; lymphoma ATL, 44) and suggested that chemotherapy with concurrent/sequential IFN/AZT as initial treatment might improve survival for both the acute- and lymphoma-types of ATL compared with chemotherapy alone [46] .

Recently, a phase II study of the combination of arsenic trioxide, IFN, and AZT for chronic ATL revealed an impressive response rate and moderate toxicity [47] . Although the results appeared promising, the addition of arsenic trioxide to IFN/AZT, which might be sufficient for the treatment of chronic ATL as described above, caused more toxicities and should be evaluated with caution.

Allogeneic hematopoietic stem-cell transplantation (allo-HSCT)

Hishizawa and coworkers reported the results of a nationwide retrospective study in 386 patients with ATL who underwent allo-HSCT between 1996 and 2005 with several kinds of conditioning regimens [48] . The 3-year OS for the entire cohort was 33% (95% CI, 28%–38%). Multivariable analysis revealed 4 recipient factors for a poor prognosis: older age (>50 years), male sex, status other than CR, and use of unrelated cord blood compared with use of HLA-matched related grafts. Treatment-related mortality was higher among patients given cord blood transplants; disease-associated mortality was higher among male recipients or those given transplants not in remission. Among patients who received related transplants, donor HTLV-1 seropositivity adversely affected disease-associated mortality. Using the same cohort, it was recently found that the development of mild-to-moderate acute GVHD confers a lower risk of disease progression and a beneficial influence on survival among allografted patients with ATL [49] .

In addition to conventional allo-HSCT, Okamura and associates reported the results of consecutive multicenter feasibility studies of reduced-intensity allo-HSCT against ATL [50] . Analysis of the combined data from both studies disclosed that grade I-II acute GVHD was the only factor that favorably affected OS and PFS and the long term prognosis after RIST was promising [51] .

More recently, an expanded cohort of the above studies was analyzed for a comparison of myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) for allo-HSCT [52] . Although no significant difference in OS between MAC and RIC was observed, there was a trend indicating that RIC contributed to a better OS in older patients. Regarding mortality, RIC was significantly associated with ATL-related mortality compared to MAC.

The minimal residual disease after allo-HSCT detected as HTLV-1 proviral load was much less than that after chemotherapy or AZT/IFN therapy, suggesting the presence of a graft-versus-ATL effect as well as graft-versus-HTLV-1 activity [47] .

It remains unclear which type of allo-HSCT (myeloablative or reduced intensity conditioning) is more suitable for the treatment of ATL. Furthermore, selection criteria with respect to responses to previous treatments, sources of stem cells and HTLV-1 viral status of the donor, remain to be determined. Recently, a patient in whom ATL derived from donor cells developed four months after transplantation of stem cells from a sibling with HTLV-I was reported [53] . To evaluate the efficacy of allo-HSCT more accurately, especially in view of a comparison with intensive chemotherapy alone, a prospective multicenter phase II study of mLSG15 chemotherapy followed by allo-HSCT is ongoing (JCOG0907).

New agents for ATL

Purine analogs

Several purine analogs have been evaluated for ATL. Among them, pentostatin (deoxycoformycin) has been most extensively evaluated as a single agent and in combination as described above [38] .

Other purine analogs clinically studied for ATL are fludarabine and cladribine. Fludarabine is a standard treatment for B-cell chronic lymphocytic leukemia and other lymphoid malignancies. In a phase I study of fludarabine in Japan in which 5 ATL patients and 10 B-CLL patients with refractory or relapsed-disease were enrolled [54] , 6 grade 3 non-hematological toxic events were observed among the ATL patients. A PR was achieved only in one of the 5 ATL patients and the duration was short. Cladribine is among the standard treatments for hairy cell leukemia and other lymphoid malignancies. A phase II study of cladribine for relapsed/refractory aggressive-ATL in 15 patients revealed only one PR  [55] .

Histone deacetylase inhibitor

Gene expression governed by epigenetic changes is crucial to the pathogenesis of cancer. Histone deacetylases (HDACs) are enzymes involved in the remodeling of chromatin, and play a key role in the epigenetic regulation of gene expression. Several classes of HDAC inhibitor (HDACI) have been found to have potent anticancer effects in preclinical studies. HDACIs such as vorinostat (suberoylanilide hydroxamic acid; SAHA), romidepsin (depsipeptide) and panobinostat (LBH589) have also shown promise in preclinical and/or clinical studies against T-cell malignancies including ATL [56] . Vorinostat and romidepsin have been approved for cutaneous T-cell lymphoma (CTCL) by the Food and Drug Administration in the USA. LBH589 has a significant anti-ATL effect in vitro and in mice [54] . However, a phase II study for CTCL and indolent ATL in Japan was terminated because of severe infections associated with the shrinkage of skin tumors and formation of ulcers in patients with ATL. Further study is required to evaluate the efficacy of HDACIs for PTCL/CTCL including ATL.

Monoclonal antibodies

Monoclonal antibodies (MoAb) and toxin fusion proteins targeting several molecules expressed on the surface of ATL cells and other lymphoid malignant cells, such as CD25, CD2, CD52 and chemokine receptor 4 (CCR4), have shown promise in clinical trials.

Because most ATL cells express the alpha-chain of IL-2R (CD25), Waldmann et al. treated patients with ATL using monoclonal antibodies to CD25 [57] . Six (32%) of 19 patients treated with anti-Tac showed objective responses lasting from 9 weeks to longer than 3 years. One impediment to this approach is the quantity of soluble interleukin-2 receptor (IL-2R) shed by the tumor cells into the circulation. Another strategy for targeting IL-2R is conjugation with an immunotoxin (Pseudomonas exotoxin) or radioisotope (yttrium-90). Waldmann et al. developed a stable conjugate of anti-Tac with yttrium-90. Among the 16 patients with ATL who received 5- to 15-mCi doses, 9 (56%) showed objective responses. The responses lasted longer than that obtained with unconjugated anti-Tac antibody [58] and [59].

Siplizumab is a humanized MoAb targeting CD2 and showed efficacy in a murine ATL model. Phase I dose-escalating study of this agent in 22 patients with several kinds of T/NK-cell malignancy revealed six responses (two CR in large granulocyte lymphocyte [LGL] leukemia, three PR in ATL and one PR in CTCL). However, four patients developed EBV-associated lymphoproliferative disorder (LPD) [60] . The broad specificity of this agent may eliminate both CD4- and CD8-positive T cells as well as NK cells without effecting B cells and predispose individuals to the development of EBV LPD.

CC chemokine receptor 4 (CCR4) is expressed on normal T helper type and regulatory T (Treg) cells and on certain types of T-cell neoplasms [17] . KW-0761, a humanized anti-CCR4 MoAb, with a defucosylated Fc region, exerts strong antibody-dependent cellular cytotoxicity (ADCC) due to increased binding to the Fcγ receptor on effecter cells. A phase I study of dose escalation with four weekly intravenous infusions of KW-0761 in 16 patients with relapsed CCR4-positive T cell malignancy (13 ATL and three PTCL) revealed that one patient, at the maximum dose (1.0 mg/kg), developed grade (G) 3 dose-limiting toxic effects, namely skin rashes and febrile neutropenia, and G4 neutropenia [61] . Other treatment-related G3-4 adverse events were lymphopenia (n = 10), neutropenia (n = 3), leukopenia (n = 2), herpes zoster (n = 1), and acute infusion reaction/cytokine release syndrome (n = 1). Neither the frequency nor severity of these effects increased with dose escalation or the plasma concentration of the agent. The maximum tolerated dose was not reached. No patients had detectable levels of anti-KW-0761 antibody. Five patients (31%; 95% CI, 11%–59%) achieved objective responses: 2 complete (0.1; 1.0 mg/kg) and 3 partial (0.01; 2 at 1.0 mg/kg) responses. Three out of 13 patients with ATL (31%) achieved a response (2 CR and 1 PR). Responses in each lesion were diverse, i.e. good in PB (6 CR and 1 PR/7 evaluable cases), intermediate in skin (3 CR and 1 PR/8 evaluable cases) and poor in LN (1 CR and 2 PR/11 evaluable cases). KW-0761 was well tolerated at all the doses tested, demonstrating potential efficacy against relapsed CCR4-positive ATL or PTCL.

A subsequent phase II study of the agent given once per week for 8 weeks at 1.0 mg/kg to patients with relapsed, aggressive CCR4-positive ATL was conducted [62] . Objective responses were noted in 13 of 26 evaluable patients, including eight CRs, with an overall response rate of 50% (95% CI, 30%–70%). Median progression-free and overall survival were 5.2 and 13.7 months, respectively. The most common adverse events were Lymphocytopenia (95%), infusion reactions (89%) and skin rashes (63%), which were manageable. Based on the results, this agent was approved by the Ministry of Health, Labor and Welfare in Japan. Further investigation of KW-0761 for treatment of ATL and other T-cell neoplasms is ongoing including a randomized phase II trial of VCAP-AMP-VECP (mLSG15) ± mogamulizumab for untreated aggressive ATL.

Other agents

Lenalidomide is an immunomodulatory agent, and was approved for multiple myeloma and myelodysplastic syndromes associated with 5q deletions. Recently, a phase I study of lenalidomide in patients with relapsed advanced ATL or PTCL was conducted in Japan [63] . Based on the development of two DLTs (platelets <10,000/uL and Grade 3 fatigue in one patient and Grade 3 prolongation of QTc interval in one patient), 25 mg daily per 28-day cycle was regarded as the MTD. Among the nine ATL patients, three achieved partial responses (PR) with a hematological complete response in two patients, including the disappearance of skin lesions in one patient. Among the four PTCL patients, one achieved a PR. Based on the preliminary evidence of antitumor activity in ATL patients, a phase II study in patients with relapsed ATL has been started in Japan.

Bortezomib, a proteasome inhibitor, that has exhibited preclinical and clinical activity against T-cell malignancies including ATL, is now under clinical trials for relapsed ATL in Japan [64] . Other potential drugs for ATL include, pralatrexate, a new agent with clinical activity in T-cell malignancies including ATL [65] and [66]. Pralatrexate is a novel anti-folate with improved membrane transport and polyglutamylation in tumor cells and high affinity for the reduced folate carrier (RFC) highly expressed in malignant cells, and was approved by the FDA for peripheral T-cell lymphoma in 2009.

Prevention

Two steps should be considered for the prevention of HTLV-1-associated ATL. The first is the prevention of HTLV-1 infections. This has been achieved in some endemic areas in Japan by screening for HTLV-1 among blood donors and asking mothers who are carriers to refrain from breast feeding. For several decades, before initiation of the interventions, the prevalence of HTLV-1 had declined drastically in endemic areas in Japan, probably because of birth cohort effects [13] . The elimination of HTLV-1 in endemic areas is now considered possible due to the natural decrease in the prevalence as well as intervention of transmission through blood transfusion and breast feeding. The second step is the prevention of ATL among HTLV-1 carriers. This has not been achieved partly because only about 5% of HTLV-1 carriers develop the disease in their life time although several risk factors have been identified by a cohort study of HTLV-1 carriers as described above [15] . Also, no agent has been found to be effective in preventing the development of ATL among HTLV-1 carriers.

Conflict of interest

Kunihiro Tsukasaki received research grants from Celgene and Mundipharma.

Kensei Tobinai received research grants from Merck, Celgene, Kyowa-Kirin, Janssen Pharmaceuticals, and Mundipharma.

Role of the funding source

This work was supported in part by the National Cancer Center Research and Development Fund (23-A-17).

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Footnotes

a Department of Hematology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan

b Department of Hematology, National Cancer Center Hospital, Tsukiji, Tokyo, Japan

Corresponding author. Tel.: +81 4 7133 1111; Fax: +81 4 7134 6922.