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• W1997409277 abstract "Adult T-cell leukaemia/lymphoma (ATLL) was first identified in Japan in 1977 ( Takatsuki et al, 1977 ; Uchiyama et al, 1977 ). The causative agent, the human T-lymphotropic virus type I (HTLV-I), was isolated 3 years later by Gallo's group from a patient initially diagnosed as having mycosis fungoides but subsequently reclassified as a case of ATLL ( Poiesz et al, 1980 ). Since then much has been discovered about the molecular pathogenesis of the disease. However, ATLL remains difficult to treat, and acute and lymphoma types have an extremely poor prognosis. Although previously restricted to people of Afro-Caribbean descent, cases of ATLL have also been reported in non-endemic areas. There is also a possibility of spread into other populations via blood transfusion as blood donors in the U.K. are currently not screened for the causative virus, the human T-lymphotropic virus type I (HTLV-I). Epidemiological and clinical features of ATLL will be outlined and conventional and novel therapeutic strategies reviewed, including the promising combination of zidovudine and interferon-α. Prevention of infection with HTLV-I will be discussed. HTLV-I is endemic in south-west Japan, the Caribbean basin, the southeastern United States, Central and South America, and areas of Central and West Africa. Isolated cases or small clusters have also been reported from Iran ( Matutes & Catovsky, 1991; Seymour et al, 1994 ), Romania ( Veelken et al, 1996 ), Georgia ( Gurtsevitch et al, 1993 ), southern Italy ( Manzari et al, 1985 ) and the U.K. (in white patients born in the U.K.; Cunningham et al, 1985 ). HTLV-I is also found in intravenous drug abusers (IVDA) ( Robert-Guroff et al, 1984 ) but HTLV-II is much more common in this group and most of the serological reactivity in IVDA is due to HTLV-II ( Lee et al, 1989 ). In endemic areas of Japan, antibodies to HTLV-I are found in 6–37% of healthy adults aged over 40 years ( Yamaguchi, 1994). However, only 2–4% of carriers develop ATLL during a 70-year lifespan ( Murphy et al, 1989 ; Yamaguchi, 1994), amounting to around 700 new cases of ATLL each year in Japan. The incubation period of ATLL is long, ranging from 10 to 30 years, although disease acquired from blood transfusion may occur after shorter periods ( Osame et al, 1986 ; Chen et al, 1989 ). Consequently, ATLL is very rare in children. The median age of onset is lower for Caribbean and African ATLL patients than for Japanese patients (43 v 58 years) ( Matutes & Catovsky, 1991; Yamaguchi, 1994). There is also a preponderance of female ATLL patients amongst Afro-Caribbeans, whereas the disease is commoner in males in Japan (male to female ratio 1.4:1) ( Yamaguchi, 1994). A major route of transmission of HTLV-I is neonatally via breast milk. Transplacental transmission may also occur but is rare ( Komuro et al, 1983 ). Sexual intercourse is another important mode of transmission. HTLV-I appears to be transmitted more efficiently from male to female than vice versa and risk of transmission may be related to viral load ( Kaplan et al, 1996 ). The virus can also be transmitted by whole blood or blood components containing infected T cells such as platelets ( Okochi et al, 1984 ; Osame et al, 1986 ; Chen et al, 1989 ) or by needle sharing by IVDA. There are no reports of transmission via non-cellular blood products ( Okochi et al, 1984 ), highlighting the need for infected cells for transfer, presumably as a result of the cell-associated nature of HTLV-I. Four clinical subtypes of ATLL have been proposed — acute, lymphoma, chronic and smouldering — and their diagnostic criteria are summarized in Table I ( Shimoyama et al, 1991 ). Most cases (81%) present with a leukaemic picture comprising the acute form (about 57% of patients), chronic (19%) and smouldering (5% of patients) ( Shimoyama et al, 1991 ). In the latter two subtypes the disease has an indolent initial course but usually progresses to acute ATLL after a variable period of time. Approximately 19% of patients present with nodal or extranodal disease with no or very minor peripheral blood involvement, lymphoma-type ATLL ( Shimoyama et al, 1991 ). The main clinical manifestations of ATLL are lymphadenopathy (50–80%), hepatosplenomegaly (25–67%), skin lesions (40–60%) and hypercalcaemia (32–63%) ( Kawano et al, 1985 ; Lymphoma Study Group, 1991; Matutes & Catovsky, 1991; Tsukasaki et al, 1993 ; Hanchard, 1996). Osteolytic lesions and central nervous system involvement each occur in around 2.5–10% of cases ( Lymphoma Study Group, 1991; Matutes & Catovsky, 1991). Opportunistic infection is common in ATLL. Strongyloidiasis is frequent and may be associated with hyperinfection and gram-negative bacteraemia, up to 77% of such cases proving fatal ( Pagliuca et al, 1988 ). Strongyloidiasis is associated with both the carrier state and all clinical subtypes of ATLL, suggesting that HTLV-I infection even without ATLL, is associated with an immunodeficient state ( Pagliuca et al, 1988 ; Taguchi et al, 1991 ). Defective T-cell-mediated immunity is demonstrable in healthy carriers of HTLV-I and in ATLL ( Shimoyama et al, 1991 ). Infective dermatitis and development of Pneumocystis carinii pneumonia (PCP) have been described in otherwise healthy carriers of the virus ( Taguchi et al, 1991 ). HTLV-I is tropic for T cells of helper phenotype and associated with loss of cytotoxic and helper function in vitro ( Pagliuca et al, 1988 ). Immunosuppressive factors from ATLL cells have also been implicated in the immunodeficient state ( Shimoyama et al, 1991 ). Viral and fungal infections are also common in ATLL patients. The blood film in ATLL is often pleomorphic with lymphocytes with polylobated nuclei or ‘flower cells’ being the characteristic feature. Such lymphocytes are characteristic of but not specific for ATLL, being found in small numbers in some cases of Sezary syndrome and in healthy carriers of HTLV-I. Lymph node histology usually corresponds to that of a diffuse T-cell non-Hodgkin's lymphoma (NHL), often of immunoblastic or pleomorphic subtype, and is indistinguishable from non-HTLV-I-associated post-thymic NHL. Skin histology is highly variable and is often described as pleomorphic T-NHL ( Whittaker et al, 1993 ). Markers confirm the post-thymic nature of ATLL cells (TdT− CD1a−) and pan-T markers, e.g. CD2 and CD5, are usually positive although CD7 is frequently negative. Around 90% of cases are CD4+ CD8− and rare cases coexpress CD4 and CD8 or are negative for both markers ( Matutes & Catovsky, 1991). The majority of cases express CD25 corresponding to the α-peptide chain of the interleukin-2 receptor (IL-2R). Diagnosis of ATLL depends on the demonstration of HTLV-I antibodies, most commonly by ELISA with confirmatory Western blotting, and the presence of HTLV-I DNA clonally integrated in the cellular DNA of neoplastic T cells. A scoring system based on the presence or absence of typical features associated with ATLL has been developed to aid diagnosis ( Pombo de Oliviera et al, 1995 ). Survival of patients with acute and lymphoma types of ATLL is poor, median survival times amongst 854 patients studied by the Lymphoma Study Group (LSG) being 6.2 months for acute type, 10.2 months for lymphoma type and 24.3 months for chronic type ATLL ( Lymphoma Study Group, 1991). It is therefore important to identify the subtype of disease at diagnosis. However, there may be considerable variation in prognosis even within clinical subtypes, so it is important to identify other prognostic factors. Five features were found by the LSG to be predictive of shortened survival: poor performance status, high lactate dehydrogenase, age > 40 years, increased tumour bulk, and hypercalcaemia ( Lymphoma Study Group, 1991). Recent evidence suggests tumours consisting of clones of cells carrying defective ( Tsukasaki et al, 1997 ) or multiple ( Shimomoto et al, 1996 ) copies of the HTLV-I provirus may be associated with a worse prognosis. Treatment of patients with ATLL remains disappointing. Despite the wide experience of the disease in Japan and the Caribbean, there is no consensus on the best available therapy for ATLL, resulting in the large number of regimens used worldwide ( Kawano et al, 1985 ; Yamaguchi et al, 1986 ; Lofters et al, 1987 ; Lymphoma Study Group, 1991; Shimoyama, 1992; Tsukasaki et al, 1993 ; Taguchi et al, 1996 ; Ljungman et al, 1994 ; Yamaguchi, 1994; Borg et al, 1996 ). Chronic and smouldering ATLL may not require treatment for months or years. For acute and lymphoma-type ATLL, first-line chemotherapy can be initially effective. Single-agent therapy with conventional drugs and regimens without anthracyclines give poor results and complete response (CR) rates < 10% ( Lymphoma Study Group, 1991). The inclusion of anthracyclines improves response rates, and combinations such as CHOP and VEPA (vincristine, cyclophosphamide, prednisolone and adriamycin) are associated with CR rates of 17–22% ( Lymphoma Study Group, 1991; Shimoyama, 1992). The use of multiple agents for induction and of second-generation drugs may raise response rates further, with 42% of patients receiving the LSG 4 protocol, alternating between three different combinations of drugs, achieving CR ( Shimoyama, 1992). Similar CR rates are reported with MACOP-B and PROMACE, but no one regimen appears superior ( Lymphoma Study Group, 1991; Shimoyama, 1992). However, these improved response rates do not translate into increased survival due to early relapse: median survival times with these regimens are around 6 months ( Lymphoma Study Group, 1991; Shimoyama, 1992). Relapse in ATLL may be due to the rapid acquisition of drug resistance or the presence of residual disease. Neoplastic cells in some cases show over-expression of P-glycoprotein, especially at relapse ( Kuwazuru et al, 1990 ). However, the use of non-cross-resistant agents such as deoxycoformycin ( Yamaguchi et al, 1986 ; Lofters et al, 1987 ) and of alternating schedules of non-cross-resistant multiple drug combinations ( Uozimi et al, 1995 ) have not been associated with increased survival. Similarly, attempts at intensification of therapy have improved response rates (CR rates of around 40%) but have not yet improved prognosis ( Lymphoma Study Group, 1991; Shimoyama, 1992; Taguchi et al, 1996 ), probably attributable to the frequent poor performance status of patients and the increase in infective complications during intensive therapy. As discussed below, improvements in anti-infective prophylaxis may make such approaches safer and the use of growth factors may ameliorate neutropenia. The use of granulocyte colony-stimulating factor (G-CSF) supported an intensive regimen using CHOP followed by etoposide, vindesine, ranimustine and mitoxantrone and produced CR in 36% and PR in 38% of patients ( Taguchi et al, 1996 ). Median survival was 8.5 months but there was no control group treated without G-CSF and little data on incidence of infections. Survival times of CR patients were longer than those of PR patients ( Taguchi et al, 1996 ). The role of high-dose therapy and stem cell rescue in ATLL is as yet unclear. Autologous bone marrow transplantation in ATLL is often precluded by the presence of marrow infiltration, especially in acute-type ATLL, occurring in two-thirds of patients at diagnosis ( Shimoyama, 1992). One patient was successfully treated with myeloablative chemotherapy and G-CSF without stem cell rescue ( Brito-Babapulle et al, 1992 ). Peripheral blood stem cell (PBSC) transplantation is an alternative option in such patients with marrow involvement. Experience with this technique so far is limited but may be encouraged by the recent finding that CD34+ haemopoietic progenitor cells in patients with ATLL are not infected with HTLV-I ( Nagafuji et al, 1993 ). Two patients in one series received BEAC (BCNU, etoposide, cytosine arabinoside, cyclophosphamide) conditioning and PBSC rescue and one of these remains alive with smouldering disease at 18 months post-transplant ( Pawson et al, 1998 ). Few cases of allogeneic transplantation have been reported with little success ( Ljungman et al, 1994 ; Borg et al, 1996 ). Early relapses have been documented and may be due to the infection of donor lymphocytes with HTLV-I from residual host haemopoietic tissue or dead and dying ATLL cells ( Ljungman et al, 1994 ; Miyoshi et al, 1995 ). Other measures important in preventing relapse include central nervous system (CNS) prophylaxis. The CNS appears to be an important site of relapse of ATLL and may act as a sanctuary site. CNS involvement is clinically evident at diagnosis in only 2.5% of patients with all types of ATLL ( Lymphoma Study Group, 1991). In contrast, 11.4% of patients had brain involvement at post-mortem ( Suzumiya et al, 1993 ). In a study of 73 patients with acute and lymphoma-type ATLL, 9/19 patients relapsing at new sites had meningeal relapse and none of these had received prophylactic intrathecal therapy ( Tsukasaki et al, 1993 ). Therefore, cerebrospinal fluid should be analysed at diagnosis and CNS prophylaxis with intrathecal chemotherapy given to all patients with acute and lymphoma-type ATLL. Prevention of infection is extremely important during treatment of acute and lymphoma-type ATLL. Nearly half of 818 patients treated by the LSG developed severe infections which eventually were the main cause of death ( Lymphoma Study Group, 1991). Approximately three-quarters of these infections were bacterial, 10% fungal, 10% viral and 5% protozoal with the lungs being the main focus of infection ( Lymphoma Study Group, 1991; Shimoyama, 1992). Prophylactic use of cotrimoxazole is now routine, but anti-fungal and anti-viral agents should be considered in all patients with acute or lymphoma-type ATLL. Amongst 21 patients receiving prophylactic cotrimoxazole there was only one case of suspected PCP ( Pawson et al, 1998 ) as opposed to four confirmed cases, one fatal, amongst 29 patients with ATLL treated without prophylaxis ( Kawano et al, 1985 ). Stools from all patients should be screened at diagnosis of ATLL and any patients positive for Strongyloides treated with thiabendazole which should then be continued prophylactically throughout chemotherapy. The use of CMV-negative blood and blood products should be considered in CMV-negative patients. Novel treatments in ATLL include new topoisomerase inhibitors, monoclonal antibodies, interferons (IFNs) and zidovudine, and lamivudine. MST-16, a topoisomerase II inhibitor, and irinotecan, a topoisomerase I inhibitor, have been associated with 40% response rates in small phase II trials ( Ohno et al, 1993 ; Ichihashi et al, 1992 ; Tsuda et al, 1994 ). Conjugated and unconjugated monoclonal antibodies against the α-chain of the IL-2 and IFNs-α, -β and -γ have induced long-term survival in a few patients but overall survival is only 50% at 5 months ( Greene et al, 1986 ; Tamura et al, 1987 ; Ezaki et al, 1991 ; Waldman et al, 1993 ; Waldman, 1996). Recently, two groups have reported use of IFN-α in combination with zidovudine (AZT) ( Gill et al, 1995 ; Hermine et al, 1995 ; Bazarbachi & Hermine, 1996); major responses occurred in 19/29 (66%) patients and CRs were seen in patients with both acute and lymphoma-type ATLL. Although overall survival in one study was poor (median survival 3 months), many patients had poor performance status at the start of therapy ( Gill et al, 1995 ), and amongst previously untreated patients studied by the Hermine's group, 7/10 patients were alive with a median follow-up of 15 months ( Hermine et al, 1995 ; Bazarbachi & Hermine, 1996). It is particularly encouraging that four patients in whom prior cytotoxic therapy had failed had major responses ( Gill et al, 1995 ). The mechanism of action of the combination of AZT and IFN and the synergism between these agents is uncertain. Viral replication was not thought to be necessary for leukaemogenesis in ATLL making an antiretroviral mechanism unlikely. An immunological effect is possible, since IFN may induce the expression of viral or major histocompatibility antigens at the cell surface. AZT can exert cytostatic effects by terminating DNA replication. Unfortunately, this novel treatment does not cure ATLL. Relapses occur even in some patients on therapy ( Bazarbachi & Hermine, 1996). Cross-resistance with conventional chemotherapy has not been observed and acute ATLL could be treated with AZT and IFN followed by combination chemotherapy as remission consolidation treatment. Alternatively, AZT and IFN could be used as maintenance therapy after induction with conventional agents and such an approach is currently being tested in a multicentre trial in the U.K. As long as the treatment of ATLL remains unsuccessful, effort should be directed into prevention of the disease. At the moment, this is only possible by prevention of HTLV-I infection. Vertical transmission of the retrovirus is reduced by avoidance of breastfeeding or, if this is not feasible, stopping breastfeeding before 6 months of age (5% risk of transmission) as opposed to a risk of about 20% if breastfeeding is continued for 12 months or more ( de The & Kazanji, 1996). Follow-up and counselling of sexual contacts of infected individuals and screening of blood donors reduce horizontal transmission of HTLV-I/II. Testing blood donations for antibodies to HTLV-I/II is currently mandatory in Japan, the United States and Canada — all countries where the seroprevalence is higher than in Britain (0.017% in the United States compared with 0.005% in the U.K.) ( Brennan et al, 1993 ). Testing of blood donors is not currently performed in the U.K. because of the high cost of screening in relation to the low prevalence of HTLV-I/II infection ( Dalgleish, 1993; Brennan et al, 1993 ), but this issue is controversial ( Pagliuca et al, 1995 ). Screening is compulsory in France where prevalence of infection amongst donors (0.004–0.011%) is similar to that in the U.K. ( Coste et al, 1990 ; Courouce et al, 1993 ), and is also obligatory in Sweden ( Giesecke, 1995) and the Netherlands where the seroprevalence is lower than in the U.K. (0.002%) ( Vrielink et al, 1995 ). Vaccines against HTLV-I/II are under development ( de The & Kazanji, 1996), and with greater understanding of the molecular pathophysiology of ATLL intensive treatment schedules may eventually be obsolete." @default.
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• W1997409277 title "MANAGEMENT OF ADULT T-CELL LEUKAEMIA/LYMPHOMA" @default.
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