Adult T-Cell Leukemia-Lymphoma
Summary of Key Points
Virology and Pathogenesis
• HTLV-I is reverse-transcribed into DNA and randomly integrated into the host cell.
• The HTLV-I genome encodes two unique regulatory proteins—Tax and Rex—responsible for viral expression and cellular transformation. Tax trans-activates viral and cellular genes that could be involved in the pathogenesis of ATL. HTLV-I basic leucine zipper (HTLV-I bZIP; HBZ) is an antisense transcript of HTLV-I, is steadily expressed in ATL cells, and interacts with several host genes and suppresses the activity of Tax.
Epidemiology
• A major cluster of HTLV-I–infected individuals and patients with ATL exists on the southwest coast of Japan, where approximately 1.1 million people are infected with the virus.
• Other clusters have been noted in the Caribbean islands (African), tropical Africa (African), South America (Mongoloid), and northern Oceania (Melanesian).
• HTLV-I is transmitted from mother to child through breast-feeding, by sexual contact, and by blood-borne transmission.
• The estimated cumulative risk of the development of ATL in HTLV-I–positive individuals is about 3% after transmission from their mothers.
Clinical Manifestations
• Patients with ATL show diverse clinical features, and four clinical subtypes have been recognized: acute, lymphoma, chronic, and smoldering.
• The typical manifestations of acute-type ATL include circulating neoplastic cells in the peripheral blood, generalized lymph node swelling, hepatosplenomegaly, skin involvement, opportunistic infections, and hypercalcemia.
Diagnosis
• ATL is suspected when the aforementioned characteristic clinical manifestations and/or the cytologic findings of leukemic cells in the peripheral blood are recognized.
• Morphologic and immunophenotypic analyses of neoplastic cells in peripheral blood or tumor lesions and a serologic assay against HTLV-I are required for the clinical diagnosis of ATL.
• The demonstration of the monoclonal integration of HTLV-I proviral DNA in the neoplastic cells can lead to a definite diagnosis of ATL.
Treatment and Prevention
• An accurate diagnosis of the clinical subtype is vital for appropriate decisions regarding treatment.
• Intensive chemotherapies combining agents used in the treatment of non-Hodgkin lymphoma (NHL) are usually given to patients with the acute or lymphoma subtype of ATL; however, most patients with ATL do not achieve cure with current chemotherapy regimens.
• Further efforts to incorporate promising or new, innovative treatment modalities, such as interferon/zidovudine therapy, new anticancer agents, monoclonal antibody therapy, molecular-targeting therapy, and allogeneic hematopoietic stem cell transplantation (allo-HSCT), are needed for the establishment of risk-adopted therapy.
• Prevention of HTLV-I infections has been achieved in some endemic areas by screening for HTLV-I among blood donors and recommending mothers who are carriers to refrain from breast-feeding. Prevention of ATL among HTLV-I carriers has not been achieved, although several risk factors have been identified.
1. Which is not a significant prognostic factor for ATL?
2. Which is not a treatment strategy for ATL?
3. Which is not a factor for the multiple-step carcinogenesis of ATL?
1. Answer: A. Hypercalcemia, advanced performance status, older age, and a high LDH value as well as the total number of total involved lesions were identified as independent poor prognostic factors in an analysis of more than 800 patients in a Japanese nationwide survey. A high WBC count associated with mainly leukemic manifestation is observed not only in acute-type Adult T-cell leukemia-lymphoma (ATL) but also in chronic-type ATL with an indolent clinical course. Furthermore, lymphoma-type ATL without leukemic manifestation shows an aggressive course similar to the acute type.
2. Answer: C. Intensive chemotherapy such as VCAP-AMP-VECP and allogeneic hematopoietic stem cell transplantation are recommended for the treatment of aggressive ATL, including the acute and lymphoma types, based on prospective studies and retrospective analyses, respectively. Interferon-α alone showed some activity against ATL, including the chronic type. However, a combination of interferon-α and zidovudine resulted in a better durable response against the leukemic form of ATL, including the chronic type, in a worldwide-retrospective analysis. Watchful waiting is recommended for the treatment of indolent ATL, including smoldering type and favorable chronic type ATL, similar to the strategy for nonadvanced chronic lymphocytic leukemia.
3. Answer: A. Most of the ATL patients were breast-fed, and most of their mothers were HTLV-I carriers. Females predominate among HTLV-I carriers, and males predominate among ATL patients. The multiple-step carcinogenesis of ATL is associated with the accumulation of genetic abnormalities in the host genome, including tumor-suppressor gene mutations. Mutations in the HTLV-I genome are not frequent and not associated with ATL development. In contrast, induction of a mutator phenotype by Tax in the infected cells appears to play an important role.
