Adult T-cell lymphoma/leukemia (ATLL)

ADULT T-CELL LYMPHOMA / LEUKEMIA (ATL / ATLL) (HTLV-1⁺) : 4 clinical subtypes according to estent of disease and calcemia and prognoses^{ref1,
ref2,
ref3}

pre-ATL (WBCs = 10,000/mL; variable survival)
leukemic (80%)^ref
lymphomatous ATL (20%) : prominent adenopathy but lacking peripheral blood involvement but also associated with an aggressive course
smoldering ATL (indolent) (WBCs = normal) with < 5% circulating neoplastic cells, skin involvement, and prolonged survival
chronic ATL (mildly aggressive) with lymphocytosis (WBCs > 10,000/mL) and occasionally associated with lymphadenopathy, hepatosplenomagaly, and cutaneous lesions but having an indolent course
acute ATL (highly aggressive, high grade malignancy) (WBCs = 100,000/mL; survival = 6-8 months) : rapidly progressive clinical course, bone marrow and peripheral blood involvement, hypercalcemia with or without lytic bone lesions, skin rash, generalized lymphadenopathy, hepatosplenomegaly and pulmonary infiltrates

Epidemiology : first described in Japan in 1977; in southern Japan, ATL is the most common form of NHL. The lifetime risk of ATL is about 5% in people infected before the age of 20 years^ref; the incidence is approximately 0.1% infected individuals/year. There is a wide disparity in the mean age at diagnosis: 60 years in Japan, but 40 years in the Caribbean and Brazil; the reason for this disparity is unknown. Men are more commonly affected than women^ref (approximately 1.5 : 1 male to female ratio).
Aetiology : HTLV-1

infection (identified by Gallo's group in 1980^ref). Similar to EBV in Burkitt's lymphoma, HTLV-1 may not have direct oncogenic activity but contributes to a multistep process of worsening genetic instability by interfering with mitotic checkpoints or preventing DNA repair^ref.
Pathogenesis : Tax activates the transcription of several pro-proliferation genes (including IL-2, IL-2R, c-fos, GM-CSF, and numerous other genes that promote entry into the cell cycle) by the formation of multiple complexes with p300/CBP and antagonizing the transcriptional activity of p53.
Symptoms & signs : the clinical features of ATL^ref are those of a NHL: malaise, fever, lymphadenopathy, hepatosplenomegaly, jaundice, drowsiness, weight loss, skin lesions, hypercalcemia, lytic bone lesions, and opportunistic infections due to the underlying immunodeficiency. Other features particularly associated with ATL are thirst and skin involvement (nodules, plaques, or a generalised papular rash)
Laboratory examinations :

cytomorphology : the transformed T cell has a characteristic appearance: the nucleus has multiple lobules^ref, giving rise to the epithet "flower cells". Laboratory findings often include hypercalcaemia (which causes the thirst) and high serum concentrations of lactate dehydrogenase and the soluble IL-2Ra chain
Southern blot analysis indicates the presence of oligoclonal or monoclonal proliferation of CD4⁺ cells that carry the HTLV-1 provirus in the cellular DNA^ref. Typically there is a progression from polyclonal to oligoclonal to monoclonal proliferation in vivo, accompanied by a progression to increasing IL-2 independence of cellular growth^{ref1,
ref2,
ref3}
cytogenetics : +3, inv(14)(q11;q32), del(14)(q11-24;q22-32)
immunophenotype CD2⁺3⁺4⁺5⁺7^-8^{-,
rarely +}25⁺

Therapy : the disease often responds initially to standard chemotherapeutic regimens, but early relapse is common, and the disease typically becomes refractory to further chemotherapy after 2-6 months. Recently, considerable progress has been made with the discovery that a combination of IFN-a and AZT (zidovudine) can prolong life expectancy by between 6 months and 2 years^{ref1,
ref2,
ref3}. However, fundamental improvements in the management of this aggressive condition are needed.CHOP-like regimens have had CR rates of 17-22%^ref. Newer or more intensive regimens may be associated with higher CR rates but have not improved prognosis^ref. Supportive care to decrease opportunistic infections and CNS prophylaxis are recommended for the aggressive ATLL^ref. Recent studies using -interferon and zidovudine (AZT) have reported significant responses (66%) in patients, including those who had failed chemotherapy^ref. Nucleoside analogs have had modest response rates of 10-20% in ATLL^ref. Topoisomerase inhibitors. have had 40% response rates in small phase II trials^{ref1,
ref2,
ref3}. Conjugated and unconjugated monoclonal antibodies directed at the IL-2R have activity in ATLL, but how they and other agents should be incorporated into therapy are areas of investigation^ref. > 40 cases of ATLL treated by allogeneic HSCT

from sibling donors have been reported, while there have been only a few cases of unrelated BMT for treatment of this disease. 8 ATLL patients underwent unrelated BMT; 5 received the conventional conditioning regimen consisting of cyclophosphamide and total body irradiation, while three received a reduced-intensity preparative regimen. 2 patients died due to encephalopathy of unknown aetiology on days 10 and 35, and one patient died due to progression of ATLL 25 months after BMT. 5 patients are currently alive and disease-free at a median of 20 months after BMT. Proviral HTLV-I DNA load in peripheral blood mononuclear cells (PBMCs) was assessed in 4 cases before and after BMT. HTLV-I proviral DNA load was reduced significantly after transplantation. Unrelated BMT is feasible for treatment of ATLL. Further studies in a larger number of cases are required to determine the optimal conditioning regimen and stem cell source^ref.
Prognosis : survival is poor with median survivals of 6.2 months for acute leukemia and 10.2 months for lymphoma^ref. The chronic and particularly the smoldering subtypes have a longer survival but can transform into the more acute forms. Poor performance status, high LDH, age above 40 years, tumor bulk, and hypercalcemia are adverse prognostic factors^ref. Aneuploidy and multiple chromosomal breaks are associated with an aggressive course^ref. Ongoing genetic abnormalities, including defective HTLV-1 integration and deletion of tumor suppressor genes p15^INK4B and p16INK4A, are associated with a worse prognosis^ref.

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