Treatment of ATLL remains a challenge for the clinician. Patients usually do not respond or have only transient responses to chemotherapy regimens that are effective in aggressive lymphomas.25
The chemoresistance of this disease likely relates to multiple mechanisms including over‐expression of the multi‐drug resistance protein, TP53
mutations and dysregulation of a variety of cellular (onco)‐genes in the leukaemic cells.26
The largest experience on the results of treatment comes from Japan. A few studies suggest that intensive induction therapy with growth factors support yields a higher response rate. However, most of the patients relapse and overall survival is not improved.27
Results are limited and disappointing with purine analogues such as pentostatin (2′‐deoxycoformycin) and inhibitors of topoisomerase I and II28
and arsenic trioxide.
Monoclonal antibodies against the IL‐2 receptor (anti‐Tac), either labelled or unlabelled (daclizumab), have been used, particularly in patients with relapsed or refractory disease, but their efficacy appear to be limited, with some patients achieving partial responses and complete responses being rare.29,30
Data with a monoclonal antibody against CD52 (alemtuzumab, MabCampath), which has shown remarkable activity in T‐PLL, are scanty and limited to single case reports or reports of a few patients.31,32
However, some of the responders to this antibody were resistant to antiretroviral treatment and had TP53
The role of antibody therapy to eliminate minimal residual disease or for consolidation and maintenance of responses has not been explored.
During the last decade, a major advance on the management of ATLL came with the use of an antiretroviral—zidovudine—combined with interferon alpha. Following the two initial phase II studies that showed a high response rate in previously untreated patients,33,34
two prospective trials in France and in England confirmed the efficacy of this combination, with response rates ranging from 65% to 92% and with more than half of the patients achieving a complete response.35,36
In addition, the British study showed an improvement in overall survival compared with historical controls (median 18 months) and a significant longer survival in the responders (55% of patients alive at 4 years) versus non‐responders (median survival 6 months).35
The mechanism of action of zidovudine has been debated, as to whether it acts through inhibition of HTLV‐I replication or has a direct antiproliferative effect on the cells. A recent study has shown that in vitro long‐term treatment of HTLV‐I‐positive cell lines and fresh ATLL cells with zidovudine results in the inhibition of telomerase function, with the cells becoming senescent rather than apoptotic; such a long exposure leads to the reactivation of normal TP53
function. Furthermore, it would appear that lack of mutation of the TP53
gene predicts for response to zidovudine. Thus, in a retrospective study, patients carrying a wild‐type TP53
gene responded to this agent, while no responses were seen in patients with a mutated gene.37,38
Stem‐cell transplantation has been used in young ATLL patients in an attempt to improve and prolong response. In most of these studies, the patients received grafts from HLA identical siblings.39,40
A recent study used grafts from unrelated donors in 8 patients41
; 5 of these were alive at the time of the report. Median disease free survival was 16.5 months and the overall median survival 20 months. The main causes of mortality or failure of this procedure in these patients were transplantation complications and graft‐versus‐host disease. However, allogeneic stem cell transplantation is only applicable to the small cohort of ATLL patients who are young. Allotransplantation with reduced‐conditioning intensity is an attractive alternative that could be used in older patients. A phase I clinical trial on 16 ATLL patients with a median age of 57 years (range 51–67) showed this to be a feasible treatment in this population of patients and suggested the presence of a possible graft‐versus‐leukaemia effect.42
- Adult T‐cell leukaemia/lymphoma is a unique T‐cell neoplasm aetiologically linked to the human T‐cell lymphotropic virus HTLV‐1.
- The disease has distinct clinical and laboratory features; it is classified into four clinical forms, the acute form being the most common.
- The prognosis is poor, with refractoriness to treatment and a median survival of <1 year for the acute and lymphoma forms.
- The best responses are achieved with a combination of zidovudine, interferon and chemotherapy. Consolidation with stem cell transplant should be considered in young patients.
Patients with ATLL are severely immunocompromised and should receive prophylaxis to prevent opportunistic infections due to Pneumocystis jiroveci, herpes and fungi with co‐trimoxazole, acyclovir and itraconazole or fluconazole. In addition, a screen for Strongyloides stercoralis is recommended; if the parasite is found, treatment with thiobendazole or albendazole is indicated.
In conclusion, despite the advances in the knowledge of the molecular and oncogenic mechanisms involved in the development of ATLL in HTLV‐I infected individuals, the outlook of this disease remains dismal and the choice of treatment controversial. It seems that the best results are achieved with a combination of antiretroviral drugs (zidovudine), interferon and chemotherapy. This combination should be considered the first line treatment in these patients. In young patients, responses should be consolidated with conventional or reduced conditioning intensity regimes and stem‐cell transplantation.