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 yearsref;
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 womenref
(approximately 1.5 : 1 male to female ratio).
Aetiology : HTLV-1
infection (identified by Gallo's group in 1980ref).
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 repairref.
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
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 :
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 lobulesref,
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
Southern blot analysis indicates the presence of oligoclonal or monoclonal
proliferation of CD4+ cells that carry the HTLV-1 provirus in
the cellular DNAref.
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 growthref1,
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
a combination of IFN-a
and AZT (zidovudine)
can prolong life expectancy by between 6 months and 2 yearsref1,
Significant responses (66%) in patients, including those who had failed
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 prognosisref.
topoisomerase inhibitors have had 40% response rates in small phase II
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 sourceref.
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 investigationref.
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+
+ 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 lymphomaref.
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
Aneuploidy and multiple chromosomal breaks are associated with an aggressive
Ongoing genetic abnormalities, including defective HTLV-1 integration and
deletion of tumor suppressor genes p15INK4B and p16INK4A, are
associated with a worse prognosisref.