Adult T-cell leukemia-lymphoma (ATL) diagnosis is crucial for effective management of this distinct peripheral T-lymphocytic malignancy, which is associated with human T-cell lymphotropic virus type I (HTLV-1). This consensus statement aims to clarify the diagnostic criteria, prognostic factors, clinical subclassifications, and treatment strategies for ATL, providing a comprehensive guide for clinicians. The diverse clinical presentations and prognoses of ATL necessitate a clear understanding of its subtypes: acute, lymphoma, chronic, and smoldering. While chronic and smoldering ATL are often indolent and managed with observation, aggressive ATL subtypes carry a poor prognosis due to drug resistance, high tumor burden, and severe immunodeficiency. This document, born from discussions at the 13th International Conference on Human Retrovirology: HTLV, offers a standardized approach to Atl Diagnosis and management, incorporating established data and expert consensus. We propose refined response criteria tailored to ATL, drawing from lymphoma and chronic lymphocytic leukemia (CLL) guidelines. Although clinical subclassification is valuable for ATL diagnosis, the heterogeneity within subtypes highlights the need for deeper molecular understanding to refine risk stratification and treatment decisions. This review emphasizes a treatment strategy aligned with clinical subtype and prognostic factors, encompassing watchful waiting, chemotherapy, antiviral therapy, allogeneic hematopoietic stem-cell transplantation (alloHSCT), and targeted therapies, ultimately aiming to improve outcomes in ATL patients through precise ATL diagnosis and risk-adapted management.
DEFINITION OF ATL
Adult T-cell leukemia-lymphoma (ATL) is recognized as a unique type of peripheral T-cell malignancy directly linked to the retrovirus human T-cell leukemia virus type 1 or human T-cell lymphotropic virus type 1 (HTLV-1). For consistent ATL diagnosis and classification, adherence to the WHO classification of ATL, as published in 2001, is recommended.
PROGNOSTIC FACTORS IN ATL
Identifying prognostic factors is paramount for accurate ATL diagnosis and predicting disease course. Extensive research involving 854 patients has pinpointed several major prognostic indicators for ATL. Advanced performance status (PS), elevated lactic dehydrogenase (LDH) levels, age of 40 years or older, involvement of more than three lesions, and hypercalcemia have been consistently identified through multivariate analysis as significant prognostic factors in ATL diagnosis. These factors have been integrated into a risk model to better stratify patients.
Further studies have revealed additional factors associated with a less favorable prognosis in ATL diagnosis, including thrombocytopenia, eosinophilia, bone marrow involvement, elevated interleukin-5 serum levels, C-C chemokine receptor 4 expression, lung resistance–related protein, p53 mutation, and p16 deletion. For chronic ATL specifically, elevated LDH, high blood urea nitrogen, and low albumin levels have been identified as poor prognostic factors via multivariate analysis. Univariate analysis has further indicated that neutrophilia, p16 deletion, and chromosomal deletions detected by comparative genomic hybridization are linked to poorer outcomes in chronic ATL. Conversely, CLL-like morphology in ATL cells has been associated with prolonged transformation-free survival in chronic ATL. Primary cutaneous tumoral type, while often categorized under smoldering ATL, has been identified as a poor prognostic factor in univariate analyses. Integrating these established and emerging prognostic factors may offer a more refined risk stratification approach than the Shimoyama criteria alone, which classifies ATL into four clinical subtypes, although a comprehensive multivariate analysis of these factors remains to be conducted. It is important to note that the relevance of these prognostic factors may evolve with the advent of novel therapeutic strategies, such as antiretroviral therapies, in ATL management.
Comparative data between Japanese ATL patients and those from other regions is limited, with a lack of prospective studies addressing this issue. A retrospective analysis of 89 patients predominantly of Caribbean origin showed a median age at ATL diagnosis of 50 years, slightly younger than the 57 years observed in the Japanese population. However, survival times based on the Shimoyama subclassification appear comparable between Caribbean and Japanese populations (acute: 4 vs 6 months; lymphomatous: 9 vs 10 months; chronic: 17 vs 24 months; and smoldering: 34 months vs > 5 years, respectively). While Caribbean patients with less aggressive subtypes seemed to have poorer outcomes, the statistical significance of this observation is not definitively established.
CLINICAL SUBCLASSIFICATION FOR ATL DIAGNOSIS
Criteria for ATL Subclassification
For clinical subclassification in ATL diagnosis, we recommend using the Shimoyama criteria for ATL clinical subtype classification, published in 1991. These criteria are foundational for stratifying ATL and guiding treatment approaches.
Required Evaluation for ATL Diagnosis
Peripheral Blood Examination
Crucial for ATL diagnosis, particularly in acute, chronic, or smoldering types with leukemic manifestations, is the examination of peripheral blood. ATL diagnosis relies on the detection of ATL cells in the peripheral blood in these subtypes. Typical ATL cells, often termed “flower cells,” are characterized by markedly polylobated nuclei with homogeneous and condensed chromatin, small or absent nucleoli, and agranular basophilic cytoplasm, considered pathognomonic for ATL diagnosis. However, it’s important to recognize the morphological variability of ATL cells. Even in cases with atypical morphology, the presence of a small percentage of prototype ATL cells in blood films should raise suspicion for ATL diagnosis. This suspicion must be confirmed through mature T-cell phenotype analysis, HTLV-1 serology, and demonstration of monoclonal HTLV-1 provirus. For ATL diagnosis in patients without histologically confirmed tumor lesions, the presence of 5% or more abnormal T lymphocytes in peripheral blood, verified by cytology and immunophenotyping, is required.
Bone Marrow Examination in ATL Diagnosis
While bone marrow aspiration or biopsy is not always mandatory for ATL diagnosis, assessing bone marrow can provide valuable information regarding normal bone marrow elements before initiating therapy. Moreover, bone marrow involvement has been identified as an independent poor prognostic factor in ATL, similar to its significance in peripheral T-cell lymphoma unspecified.
Radiologic Imaging and Endoscopy for ATL Diagnosis
Radiologic imaging, specifically computed tomography (CT) scans of the neck, thorax, abdomen, and pelvis, are essential for ATL diagnosis to detect nodal and extranodal disease sites. Upper gastrointestinal (GI) tract endoscopy with biopsy should be considered, especially in aggressive ATL, due to the frequent involvement of the GI tract. These imaging modalities are also crucial for identifying potential opportunistic infections, such as pneumonia, abscess formation, and intestinal infections like strongyloidiasis and cytomegalovirus, which can complicate ATL diagnosis and management. Central nervous system (CNS) evaluation via radiologic imaging and/or lumbar puncture should be considered in patients presenting with altered consciousness without hypercalcemia to assess for cerebral/meningeal ATL involvement or opportunistic infections.
Biopsy for ATL Diagnosis
When ATL diagnosis cannot be established through peripheral blood examination, or when new lesions appear during watchful waiting in indolent ATL, a biopsy of suspicious lesions is necessary. Commonly involved tissues include lymph nodes, skin, liver, spleen, lung, GI tract, bone marrow, bone, and CNS. For lymph node biopsies, excisional biopsy is recommended over core needle biopsy, mirroring practices in other lymphoma diagnoses. Whenever feasible, obtain sufficient sample for both histopathologic examination and molecular analyses, including Southern blotting or linker-mediated polymerase chain reaction for HTLV-1 provirus integration analysis, to solidify ATL diagnosis and understand its molecular characteristics.
Tumor Markers in ATL Diagnosis
Serum LDH levels serve as a reflection of disease bulk and activity in ATL diagnosis. Similarly, the soluble form of interleukin-2 receptor α-chain is often elevated in patients with aggressive ATL, indolent ATL, and HTLV-1 carriers compared to healthy individuals, potentially offering greater accuracy than LDH in monitoring disease status. These serum markers are valuable for detecting acute transformation of indolent ATL and for early detection of relapse post-therapy. Serum thymidine kinase levels have also emerged as a promising tumor marker in ATL diagnosis. However, current standard practice for ATL diagnosis and management primarily relies on serum LDH levels.
Immunophenotyping in ATL Diagnosis
Immunophenotyping is a critical component of ATL diagnosis. In most cases, ATL cells exhibit a mature CD4+ T-cell phenotype, expressing CD2, CD5, CD25, CD45RO, CD29, T-cell receptor αβ, and HLA-DR. Characteristically, most ATL cells lack CD7 and CD26 and show reduced CD3 expression. CD52 positivity is common in ATL cells, though some patients may be negative, potentially correlating with CD30 coexpression. For a definitive ATL diagnosis, immunophenotypic analysis of CD3, CD4, CD7, CD8, and CD25 is considered the minimum requirement.
Cytogenetics in ATL Diagnosis
Cytogenetic analysis reveals karyotypic abnormalities, which are more frequent and complex in acute and lymphoma types of ATL compared to the chronic type. Aneuploidy and hotspots such as 14q and 3p are commonly observed. Advanced techniques like array-comparative genomic hybridization have shown that lymphoma-type ATL exhibits more frequent gains at 1q, 2p, 4q, 7p, and 7q and losses of 10p, 13q, 16q, and 18p, while acute-type ATL often shows a gain of 3/3p. Currently, outside of clinical trials, cytogenetic analysis is not routinely required for ATL diagnosis in standard clinical practice.
Molecular Biology of HTLV-1 in ATL Diagnosis
Monoclonal integration of HTLV-1 proviral DNA is a hallmark of ATL diagnosis, as defined by the WHO classification. Integration of defective HTLV-1 into ATL cells occurs in approximately one-third of patients, correlating with clinical subtypes and prognosis. Molecular analysis of HTLV-1 integration is recommended when possible for ATL diagnosis. Southern blotting or polymerase chain reaction can detect viral integration, with PCR offering quantitative capabilities. Seronegativity for HTLV-1 is a valuable tool to differentiate T-cell lymphomas from ATL, as HTLV-1 is not found in lymphoma cells other than ATL. Clinically, ATL diagnosis is primarily based on HTLV-1 seropositivity and histologically or cytologically confirmed peripheral T-cell malignancy. However, rare instances of T-cell lymphomas other than ATL developing in HTLV-1 carriers have been documented, highlighting the importance of comprehensive diagnostic evaluation.
Molecular Biology of Host Genome in ATL Diagnosis
Mutation or deletion of tumor suppressor genes, such as p53 or *p15INK4B/p16INK4A, is observed in roughly half of ATL patients and is associated with clinical subtypes and prognosis. These molecular markers may inform therapeutic decisions, guiding choices between conventional chemotherapy, combination therapy with zidovudine (AZT) and interferon alfa (IFN-α), and alloHSCT. Beyond p53* mutations, IRF-4 expression levels may predict response to AZT and IFN-α combination therapy, adding another layer of molecular insight to ATL diagnosis and treatment planning.
TREATMENT STRATEGIES FOR ATL
Criteria for Treatment Decisions in ATL
Treatment decisions in ATL should be guided by the ATL subclassification, prognostic factors at diagnosis, and response to initial therapy. Prognostic factors include clinical variables like performance status (PS), LDH levels, age, number of involved lesions, and hypercalcemia, as well as molecular factors such as Ki-67 expression, alterations in p53 or *p15INK4B/p16INK4A*, and IRF-4 overexpression.
Table 1. Recommended Strategy for the Treatment of ATL
| Smoldering- or favorable chronic-type ATL |
|---|
| Consider inclusion in prospective clinical trials |
| Symptomatic patients (skin lesions, opportunistic infections, etc.): consider AZT/IFN-α or watch and wait |
| Asymptomatic patients: consider watch and wait |
| Unfavorable chronic- or acute-type ATL |
| Recommend: inclusion in prospective clinical trials |
| 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 randomized phase III trial against biweekly CHOP) or AZT/IFN-α (evaluated by a retrospective worldwide meta-analysis) |
| Poor prognostic factors: consider chemotherapy followed by conventional or reduced-intensity allogeneic HSCT (evaluated by retrospective or prospective Japanese analyses, respectively) |
| Poor response to initial therapy with chemotherapy or AZT/IFN-α: consider conventional or reduced-intensity allogeneic HSCT |
| Lymphoma-type ATL |
| Recommend: inclusion in prospective clinical trials |
| If outside clinical trials, consider chemotherapy (VCAP-AMP-VECP) |
| Check prognostic factors and response to chemotherapy (including clinical and molecular factors if possible): |
| Favorable prognostic profiles and good response to initial therapy: consider chemotherapy |
| Unfavorable prognostic profiles or poor response to initial therapy with chemotherapy: consider conventional or reduced-intensity allogeneic HSCT |
| Options for clinical trials (first line) |
| Test the effect of up-front allogeneic HSCT |
| Test promising targeted therapies such as arsenic trioxide + IFN-α, bortezomib + chemotherapy, or antiangiogenic therapy |
| Consider a phase II global study testing pegylated IFN and AZT |
| Options for clinical trials (relapse or progressive disease) |
| Test the effect of promising targeted therapies such as arsenic trioxide and IFN-α, bortezomib, a purine nucleotide phosphorylase inhibitor, histone deacetylase inhibitors, monoclonal antibodies, antiangiogenic therapy, and survivin, β-catenin, syk, and lyn inhibitors, etc. |
| Consider conventional or reduced-intensity allogeneic HSCT when possible |
Abbreviations: ATL, adult T-cell leukemia-lymphoma; AZT, zidovudine; IFN-α, interferon alfa; VCAP-AMP-VECP, vincristine, cyclophosphamide, doxorubicin, and prednisone; doxorubicin, ranimustine, and prednisone; and vindesine, etoposide, carboplatin, and prednisone; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; HSCT, hematopoietic stem-cell transplantation.
Current Treatment Options for ATL
Chemotherapy for ATL
A phase III study indicates that the vincristine, cyclophosphamide, doxorubicin, and prednisone (VCAP); doxorubicin, ranimustine, and prednisone (AMP); and vindesine, etoposide, carboplatin, and prednisone (VECP) regimen is superior to biweekly cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in newly diagnosed acute, lymphoma, or unfavorable chronic ATL, albeit with higher toxicities. The complete response (CR) rate was significantly higher in the VCAP-AMP-VECP arm compared to the biweekly CHOP arm (40% vs 25%, P = .020). Overall survival (OS) at 3 years was 24% in the VCAP-AMP-VECP arm and 13% in the CHOP arm (P = .085). However, the median survival time of 13 months remains unfavorable compared to other hematologic malignancies. The improved efficacy of VCAP-AMP-VECP over biweekly CHOP may be attributed to the prolonged, dose-dense schedule and the incorporation of drugs like carboplatin and ranimustine, which are less affected by multidrug resistance mechanisms often present in ATL cells at diagnosis. Intrathecal prophylaxis, used in both arms of the phase III study, should be considered for aggressive ATL patients, even without CNS symptoms, as CNS relapse is a significant risk after chemotherapy.
IFN-α and AZT Therapy for ATL
Numerous phase II studies using AZT and IFN-α have shown responses in ATL patients. High doses of both agents are recommended (6 to 9 million units of IFN-α combined with daily divided AZT doses of 800 to 1,000 mg/d). However, long-term responses to AZT/IFN-α therapy seem to be primarily observed in patients with wild-type p53 and low IFN regulatory factor 4 expression.
A recent worldwide meta-analysis of AZT/IFN for ATL in 209 patients treated between 1994 and 2006 revealed promising results. Among patients receiving first-line AZT/IFN-α therapy, the response rate was 66%, with 43% achieving CR. The median survival time for first-line AZT/IFN-α treated patients was 24 months, and the 5-year OS rate was 50%, compared to 7 months and 20%, respectively, in patients receiving first-line chemotherapy. For acute-type ATL, median survival times with first-line AZT/IFN-α and chemotherapy were 12 and 9 months, respectively. Notably, achieving CR with first-line AZT/IFN-α led to prolonged survival of over 10 years in 70% of the study population and 75% of the acute-type ATL subgroup. However, lymphoma-type ATL patients did not appear to benefit from AZT/IFN-α therapy. First-line AZT/IFN-α therapy in chronic- and smoldering-type ATL resulted in 100% OS at a median follow-up of 5 years. While AZT/IFN-α shows promise in indolent ATL compared to watchful waiting, selection bias cannot be excluded. These findings suggest that AZT/IFN-α therapy yields high response and CR rates, particularly in acute, chronic, and smoldering ATL, leading to prolonged survival in a considerable proportion of patients. Despite the retrospective nature of this analysis, the results are promising, and further comparative studies between AZT/IFN-α and chemotherapy in acute ATL are warranted.
alloHSCT for ATL
alloHSCT is emerging as a promising treatment for younger patients with aggressive ATL. Despite higher treatment-related mortality observed in a retrospective multicenter analysis, the estimated 3-year OS rate of 45% is encouraging, potentially reflecting a graft-versus-ATL effect. A phase I trial of alloHSCT with reduced-intensity conditioning for ATL also showed promising results. Minimal residual disease after alloHSCT, as measured by proviral load, was significantly lower compared to chemotherapy or AZT/IFN-α therapy, suggesting a graft-versus-ATL effect and graft-versus-HTLV-1 activity. The optimal type of alloHSCT (myeloablative or reduced-intensity conditioning) for ATL remains uncertain. Myeloablative alloHSCT, but potentially not reduced-intensity conditioning alloHSCT, might be considered for progressive disease at relapse and at initial diagnosis. Further research is needed to define selection criteria regarding response to prior treatments, stem cell sources, and donor HTLV-1 viral status.
Required Pretreatment Evaluation for ATL
ATL diagnosis relies on HTLV-1 seropositivity and histologically or cytologically confirmed peripheral T-cell malignancy, according to the WHO classification. In uncertain cases, Southern blot hybridization for monoclonal integration of HTLV-1 provirus can aid diagnosis, although it has a sensitivity threshold of approximately 5% monoclonal ATL cells in peripheral blood mononuclear cells or fresh biopsy.
Traditionally, indolent ATL (chronic or smoldering types) has been managed similarly to CLL, with watchful waiting until disease progression. In Japan Clinical Oncology Group (JCOG)–Lymphoma Study Group trials for aggressive ATL, previously untreated patients with acute-, lymphoma-, or unfavorable chronic-type ATL were eligible. Unfavorable chronic-type ATL was defined by at least one of low serum albumin, high LDH, or high blood urea nitrogen concentration, demonstrating a prognosis similar to acute- or lymphoma-type ATL when treated with chemotherapy. Trial eligibility criteria also included no prior chemotherapy, age 15-69 years, and Eastern Cooperative Oncology Group PS of 0-3, or 4 due to hypercalcemia, along with specific organ function criteria.
Supportive Care in ATL Management
Sulfamethoxazole-trimethoprim and antifungal agents are recommended for Pneumocystis jiroveci pneumonia and fungal infection prophylaxis, respectively, in JCOG trials. While cytomegalovirus infection is common in ATL, routine ganciclovir prophylaxis is not generally recommended. Antifungal prophylaxis may not be critical in patients not receiving chemotherapy. Strongyloides prophylaxis with agents like ivermectin or albendazole should be considered in patients with a history of exposure to the parasite, especially from tropical regions. Corticosteroids and proton pump inhibitors can precipitate fulminant Strongyloides infestation, warranting testing before their use in endemic areas. Strongyloides infection may increase the risk of subsequent ATL development. Therefore, Strongyloides prophylaxis in HTLV-1 carriers, though not yet proven to prevent ATL, may be a consideration. Hypercalcemia in aggressive ATL should be managed with disease-directed therapy, hydration, and bisphosphonate therapy.
RESPONSE CRITERIA IN ATL
Consistent response criteria are essential for uniform interpretation in ATL clinical trials due to the complex presentation of ATL, often with both leukemic and lymphomatous components. Most current ATL trials utilize response criteria proposed by JCOG since 1991. International consensus meetings have suggested modifications to the JCOG criteria, aligning with later criteria for CLL and NHL. Complete remission (CR) is defined as the disappearance of all clinical, microscopic, and radiographic evidence of disease. Lymph node criteria include regression to normal size (≤ 1.5 cm greatest transverse diameter) and reduction to ≤ 1.0 cm for previously involved nodes (1.1-1.5 cm). Given the presence of flower cells in HTLV-1 carriers, CR is considered attained if less than 5% abnormal lymphocytes remain and the absolute lymphocyte count, including flower cells, is below 4 × 109/L. Unconfirmed CR is defined for patients with ≥ 75% tumor reduction but residual mass, also requiring an absolute lymphocyte count below 4 × 109/L. Partial response (PR) is defined as ≥ 50% reduction in measurable disease and ≥ 50% reduction in peripheral blood abnormal lymphocyte counts, without new lesions. Progressive disease (PD) in peripheral blood is defined by ≥ 50% increase from nadir in flower cells and an absolute lymphocyte count ≥ 4 × 109/L. PD or relapse in other lesions is defined by ≥ 50% increase in measurable disease or new lesions (excluding skin). Stable disease is defined as not meeting CR/PR or PD criteria. CR, unconfirmed CR, PR, and stable disease require these criteria to be met for at least 4 weeks.
Table 2. Response Criteria for Adult T-Cell Leukemia-Lymphoma
| Response | Definition | Lymph Nodes | Extranodal Masses | Spleen, Liver | Skin | Peripheral Blood | Bone Marrow |
|---|---|---|---|---|---|---|---|
| Complete remission* | Disappearance of all disease | Normal | Normal | Normal | Normal | Normal† | Normal |
| Uncertified complete remission* | Stable residual mass in bulky lesion | ≥ 75% decrease‡ | ≥ 75% decrease‡ | Normal | Normal | Normal† | Normal |
| Partial remission* | Regression of disease | ≥ 50% decrease‡ | ≥ 50% decrease‡ | No increase | ≥ 50% decrease | ≥ 50% decrease | Irrelevant |
| Stable disease* | Failure to attain complete/partial remission and no progressive disease | No change in size | No change in size | No change in size | No change in size | No change | No change |
| Relapsed disease or progressive disease | New or increased lesions | New or ≥ 50% increase§ | New or ≥ 50% increase§ | New or ≥ 50% increase | ≥ 50% increase | New or ≥ 50% increase‖ | Reappearance |
| Not assessable |
*Require each criterion to be present for a period of at least 4 weeks.
†Provided that < 5% flower cells remain and absolute lymphocyte count, including flower cells, is < 4 × 109/L.
‡Calculated by the sum of the products of the greatest diameters of measurable disease.
§Defined by ≥ 50% increase from nadir in the sum of the products of measurable disease.
‖Defined by ≥ 50% increase from nadir in the count of flower cells and an absolute lymphocyte count, including flower cells, of > 4 × 109/L.
Recently, revised response criteria for lymphoma have incorporated positron emission tomography (PET), especially for CR assessment. While various lymphomas, including peripheral T-cell lymphomas, can be [18F]fluorodeoxyglucose avid, PET results in ATL response assessment have not yet been reported. The utility of PET or PET/CT in ATL response assessment requires prospective evaluation. In the interim, PET or PET/CT should be considered for response evaluation when tumorous lesions are fluorodeoxyglucose avid at diagnosis.
ISSUES FOR FUTURE INVESTIGATIONS IN ATL
Targeted Therapy for ATL
Several novel agents targeting ATL are under investigation. A promising targeted therapy is the combination of arsenic trioxide and IFN-α, which targets both Tax and the nuclear factor-κB pathway. This combination has demonstrated clinical efficacy in relapsed/refractory ATL and is currently being evaluated in untreated patients. Monoclonal antibodies against molecules expressed on ATL cells and other lymphoid malignancies, such as CD25, CD2, CD52, and chemokine receptor 4, are showing promise in clinical trials. Histone deacetylase inhibitors like vorinostat, romidepsin, and panobinostat also exhibit promise in preclinical and clinical studies for T-cell malignancies, including ATL. Pralatrexate, a novel antifolate, and forodesine, a purine nucleotide phosphorylase inhibitor, are potential new agents with potent preclinical activity in T-cell malignancies including ATL. Other potential therapies under investigation include bortezomib with high-dose CHOP chemotherapy and antiangiogenic therapies. Microarray analysis has identified survivin, β-catenin, syk, and lyn as potential therapeutic targets.
Prevention of ATL
Preventing HTLV-1-associated ATL involves two key steps. The first is preventing HTLV-1 infection itself, successfully implemented in some endemic regions of Japan through blood donor screening and discouraging breastfeeding by HTLV-1 carrier mothers. The second step, preventing ATL development in HTLV-1 carriers, is less established, partly because only about 5% of carriers develop ATL, and risk factors remain unclear. A nationwide cohort study in Japan (Joint Study of Predisposing Factors for ATL Development) is ongoing to investigate these factors.
Clinical Trials for ATL
Clinical trials have been crucial to advances in ATL treatment, including chemotherapy, AZT/IFN-α, and alloHSCT. The proposed treatment strategy stratified by subclassification and prognostic factors requires ongoing clinical trials to ensure continuous updates and evidence-based practice guidelines.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS
Conception and design: Kunihiro Tsukasaki, Olivier Hermine, Ali Bazarbachi, Juan Carlos Ramos, Deirdre O’Mahony, Achiléa L. Bittencourt, Kensei Tobinai
Administrative support: Olivier Hermine, Lee Ratner, William Harrington Jr, John E. Janik, Graham P. Taylor, Kazunari Yamaguchi, Toshiki Watanabe
Collection and assembly of data: Kunihiro Tsukasaki, Olivier Hermine, Ali Bazarbachi, Juan Carlos Ramos, Deirdre O’Mahony, Achiléa L. Bittencourt, Atae Utsunomiya, Kensei Tobinai
Data analysis and interpretation: Kunihiro Tsukasaki, Olivier Hermine, Ali Bazarbachi, Lee Ratner, Juan Carlos Ramos, Deirdre O’Mahony, John E. Janik, Achiléa L. Bittencourt, Kazunari Yamaguchi, Atae Utsunomiya, Kensei Tobinai, Toshiki Watanabe
Manuscript writing: Kunihiro Tsukasaki, Olivier Hermine, Ali Bazarbachi, Lee Ratner, Juan Carlos Ramos, William Harrington Jr, Deirdre O’Mahony, John E. Janik, Achiléa L. Bittencourt, Graham P. Taylor, Kazunari Yamaguchi, Atae Utsunomiya, Kensei Tobinai, Toshiki Watanabe
Final approval of manuscript: Kunihiro Tsukasaki, Olivier Hermine, Ali Bazarbachi, Lee Ratner, Juan Carlos Ramos, William Harrington Jr, Deirdre OMahony, John E. Janik, Achiléa L. Bittencourt, Graham P. Taylor, Kazunari Yamaguchi, Atae Utsunomiya, Kensei Tobinai, Toshiki Watanabe
Acknowledgments
We thank our other colleagues who provided input into the consensus report: Yoji Ishida, Atsushi Wake, Ryuji Tanosaki, Takashi Ishida, Masamichi Hara, Kyarin Kou, Kazuo Tamura, Naokuni Uike, Jun Okamura, Tetsuya Eto, Hiroshi Kikuchi, Eisaburo Sueoka, Takuya Fukushima, Shigeki Takemoto, Kisato Nosaka, Kimiharu Uozumi, Masato Masuda, and Edgar M. Carvalho.
published online ahead of print at www.jco.org on December 8, 2008.
Supported in part by the intramural Research Program of the National Cancer Institute, National Institutes of Health.
Presented in part at the 13th International Conference on Human Retrovirology: HTLV, May 22-25, 2007, Hakone, Japan, and the 49th Annual Meeting of the American Society of Hematology, December 8-11, 2007, Atlanta, GA.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
