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 :

leukocytosis (40,000-70,000/ml)
anemia < 8 g/d
thrombocytopenia < 50,000/ml
leukemic cells in 80-90% of cases
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, +7, +21, X-, inv(14)(q11;q32), del(14)(q11-24;q22-32)
immunophenotype CD2⁺3⁺4⁺5⁺7^-8^{-,
rarely +}25⁺ (T_reg origin ??)

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.

a combination of IFN-a and AZT (zidovudine) can prolong life expectancy by between 6 months and 2 years^{ref1,
ref2,
ref3}. Significant responses (66%) in patients, including those who had failed chemotherapy^ref.
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.
topoisomerase inhibitors have had 40% response rates in small phase II trials^{ref1,
ref2,
ref3}
allogeneic HSCT from sibling donors : > 40 cases of ATLL 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.
immunotherapy :

mAbs :

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.
alemtuzumab ^ref

188 HLA class I-restricted candidate peptides were sequenced from 3 ATL-derived cell lines. In accordance with the restrained expression of HTLV-I viral RNA in these cell lines, there were no HTLV-I-encoded peptides among these candidates. Based on the differential expression between ATL cells and normal CD4⁺ T cells, 10 novel peptides were selected as T cell epitopes of overexpressed source proteins. RT-PCR analysis revealed that 5 source proteins including PRAME, a known tumor-testis antigen, were highly expressed in the majority of 16 ATL cases. Furthermore, PRAME-specific CTLs in vitro from an HLA-B62⁺ healthy donor could be induced that showed specific cytotoxicity against HLA-B62⁺ PRAME⁺ ATL cells^ref

IFN-a + arsenic trioxide (ATO) : in 7 patients with relapsed/refractory ATL (4 acute and 3 lymphoma). 4 patients exhibited a clear initial response (1 complete remission and three partial remissions). Yet, the treatment was discontinued after a median of 22 days because of toxicity (3 patients) or subsequent progression (4 patients). 6 patients eventually died from progressive disease (5 patients) or infection (1 patient), but the remaining patient is still alive and disease free at 32 months. Pharmacokinetic studies showed that maximum arsenic blood levels (median 0.46 mM) were slowly achieved (8-15 days)^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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