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Adult T-cell leukaemia lymphoma (ATLL) is an aggressive disease caused by the human T-lymphotropic virus 1 (HTLV-I) with a short survival. Responses to interferon alpha (IFN-α) and zidovudine (AZT) have been documented but not with long-term follow-up. We treated 15 ATLL patients with IFN and AZT. Eleven patients had acute ATLL, two had lymphoma and two smouldering ATLL, with progression. The main features were: organomegaly (14), skin lesions (10), high white blood cell (WBC) count (11) and hypercalcaemia (9). Eleven patients had previously received chemotherapy and one had received an autograft. At the time of the study, seven patients had progressive disease and eight were in partial or complete clinical remission. Responses (PR) lasting 2+ to 44+ months were seen in 67%; 26% did not respond (NR) and one patient was not evaluable. Hypercalcaemia predicted a poor outcome but differences were not significant. Eight of the 15 patients have died 3–41 months from diagnosis. Median survival for the 15 patients was 18 months. Survival of the NR ranged from 4 to 20 months; six PR patients are alive 8–82 months from diagnosis. The differences in survival between NR (median: 6 months) and PR (55% of patients alive at 4 years) were statistically significant (P = 0·002). In conclusion, IFN and AZT improves the outcome of ATLL patients and helps maintain responses.
Adult T-cell leukaemia lymphoma (ATLL) is an aggressive T-cell malignancy aetiologically linked to the human T-lymphotropic virus 1 (HTLV-I) with median survival ranging from 7 to 13 months in both endemic and non-endemic regions (Shimamoto et al, 1990a, b; Shimoyama et al, 1991; Plumelle et al, 1993; Pombo de Oliveira et al, 1995; Matutes & Catovsky, 1998). In the United Kingdom (UK), the disease affects mainly immigrants from the Caribbean basin or Africa and more rarely from other countries (Matutes & Catovsky, 1994). Although the incidence of ATLL among the various T-cell malignancies in the UK is unknown, it is estimated to be around 20 newly diagnosed cases/year (Taylor et al, 2000).
Novel strategies such as the use of unlabelled or radiolabelled anti-CD25 monoclonal antibody (mAb), deoxycoformycin and interferons (IFN) alpha, beta and gamma have also been used, but only occasional patients have achieved a durable response (Tamura et al, 1987; Ichimaru et al, 1988; Waldmann et al, 1988; Mercieca et al, 1994; Waldmann, 1994). Isolated case reports of a response to etoposide monotherapy (Kojima et al, 1993), allogeneic bone marrow transplantation (Ljungman et al, 1994) and, more recently, a case responding to all-trans retinoic acid have been documented (Maeda et al, 2000). Extremely rare spontaneous remissions have been reported (Schnitzer et al, 1983; Mattock et al, 1986).
A preliminary report showed that a combination of IFN-α and zidovudine (AZT) was effective in a single ATLL patient co-infected with HTLV-I and the human immunodeficiency virus (HIV), producing a sustained response (Shibata et al, 1989). Two subsequent studies of a total of 24 ATLL patients further suggested that IFN-α combined with AZT produced a measurable response with 67% (7 out of 24) of the patients achieving a response, 29% of which were considered clinical complete responses (CR) (Gill et al, 1995; Hermine et al, 1995). In the largest study, which included 19 patients, the overall median survival was 3 months and that of the complete and partial responders 13 months versus 1·3 months for the non-responders (Gill et al, 1995). Therefore, it could not be concluded that this drug combination was superior to standard chemotherapy.
We report the response rate, long-term follow-up and survival of 15 ATLL patients treated over a 4 year period with the combination of IFN-α and AZT. This study aimed to (i) determine the efficacy and tolerability of IFN-α combined with AZT in ATLL, and (ii) estimate the response duration and compare survival with the historical series of ATLL treated in the UK during the last 15 years.
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Our findings have extended previous studies (Gill et al, 1995; Hermine et al, 1995) by showing that over two thirds of ATLL patients achieve and/or maintain a response to the combination of IFN and AZT. In our study, all responses qualified as PR but none were complete. However, in our study, responses were only considered as PR or CR when sustained for over 2 months compared with only 1 month in the earlier reports (Gill et al, 1995; Hermine et al, 1995).
There were no differences in the response rate according to whether the patients had or had not received previous chemotherapy. Indeed, 7 out of 10 (70%) responders were previously treated with standard chemotherapy. Similar results were seen in the study by Gill et al (1995) in which 4 out of 7 patients who had received prior chemotherapy benefited from the treatment, including two with CR. Thus, a reduction of the tumour burden with chemotherapy prior to starting IFN and AZT does not preclude achieving or maintaining a response with this combination. Other factors, e.g. degree of organomegaly and lymphocyte count, performance status and LDH levels, did not influence the response. There was a trend for the responders to have normal calcium levels but differences were not statistically significant. Because the majority of patients in the previous reports and in our series were cases with the leukaemia form of ATLL, it cannot be concluded that this schedule is also equally effective in the lymphomatous form of ATLL.
Treatment was well tolerated with no major toxicities. At the dose given here, flu-like symptoms developed during the first weeks of IFN treatment in most patients but subsided with symptomatic therapy. IFN was stopped in one patient owing to depression and alopecia. Among other side-effects, neutropenia, mainly induced by AZT, and subsequent infections were easily controlled with antibiotic therapy and rarely required hospitalization; only a few patients required intermittent use of growth factors, e.g. granulocyte colony-stimulating factor (G-CSF) to improve neutrophil counts. In two patients, the dose of AZT was reduced and both were switched to a combination of AZT and lamuvidine.
ATLL is a lymphoid malignancy with very poor survival ranging from 6 to 13 months in most of the series reported from Japan, the Caribbean and other endemic countries (Shimamoto et al, 1990a, b; Shimoyama et al, 1991; Plumelle et al, 1993; Pombo de Oliveira et al, 1995; Matutes & Catovsky, 1998). This was also apparent in the patients treated with IFN and AZT (Gill et al, 1995; Hermine et al, 1995). Thus, in one study the overall median survival was 3 months, for the responders 13 months and for those responders who had been previously treated with chemotherapy 17·5 months (Gill et al, 1995). The median survival of our 15 patients was 18 months, significantly longer than the 7 months median survival of a historical series of 52 ATLL patients treated in the UK between 1982 and 1995 (Matutes & Catovsky, 1994) and that of other series of patients. Furthermore, responders to IFN and AZT had a significantly better survival (median survival not reached) than the NR (6 months) and those previously treated with this combination (Gill et al, 1995). This might be related to the fact that our patients continued on maintenance treatment with IFN and AZT after achieving a PR, unlike those in the study of Gill et al (1995) in which treatment was stopped.
The mechanism(s) by which IFN and AZT induces and/or maintain responses is unknown. The possibility that AZT could directly act as an anti-retroviral agent has been entertained but this mechanism has not been yet demonstrated. It is known that healthy HTLV-I carriers as well as patients with HTLV-I-induced spastic myelopathy (TSP/HAM) have a strong cytotoxic T-cell (CTL) response against lymphocytes that express the tax protein of HTLV-I and are capable of eliminating such infected cells (Daenke et al, 1996). This is in contrast to findings in ATLL patients in whom the CTL response is poor. Therefore, there is a possibility that the mechanism of action of IFN and AZT is by enhancing the CTL response against the neoplastic and/or normal HTLV-I + lymphocytes.
Although the combination of IFN and AZT clearly improves the outcome of ATLL patients, a search for new therapies or modifications of previous schedules to cure this disease is needed. The fact that responses were mainly seen in patients with low tumour burden following chemotherapy, although with active disease, and that two cases are maintaining a PR with the combination of IFN plus combivir (AZT plus lamuvidine) has prompted us to start a new trial that first considers the use of combination chemotherapy (e.g. 2–6 courses of CHOP and/or until maximal response) to decrease the tumour load. Once the patient achieves PR, they will then receive consolidation and maintenance therapy with a combination of IFN 3–5 MU/d according to tolerance and combivir (lamuvidine 150 mg plus AZT 300 mg) twice daily. Studies investigating the CTL response as well as monitoring residual disease will be carried out in the new trial and hopefully this will shed some light on the mechanism of action of this combination.