AbstractArsenic trioxide (As2O3) with or without interferon-α (IFN) was given to 4 patients with relapsed/refractory adult T-cell leukemia/lymphoma (ATLL). Treatment with As2O3 and IFN showed an encouraging response in two moderately-aggressive ATLL patients, while As2O3 alone was ineffective in two patients with very aggressive and rapidly progressing ATLL. Further studies are needed to clarify the role of As2O3 and its usefulness when combined with IFN for the treatment of ATLL.
Induction of apoptosis and growth inhibition on ATLL cell lines by As2O3 with or without interferon-α (IFN) have been reported previously.1–3 Notably a French phase II trial of As2O3 and IFN therapy in seven patients with relapsed/refractory ATLL showed complete remission (CR) in 1 patient and partial remission (PR) in 3 patients.4 We report here the results of a pilot study of As2O3 with or without IFN for patients with relapsed/refractory ATLL carried out in a highly HTLV-I endemic area in Japan.
Patients with relapsed/refractory acute, lymphoma or unfavorable chronic type of ATLL5,6 were included. According to the original protocol, patients received a daily administration of As2O3 (0.15 mg/kg/day) alone. This protocol was later modified to add intramuscular administration of 3×10 unit of IFN (Sumiferon, Sumitomo pharmaceuticals, Osaka, Japan) three times a week during As2O3 treatment. In consideration of safety issues and on the basis of in vitro experimental results,1,2 the dose of As2O3 and IFN was set as the approved dose for the treatment of acute promyelocytic leukemia and chronic myelocytic leukemia respectively. This study was reviewed and approved by the Fukuoka University Ethics Committee and Institutional Review Board of Fukuoka University Hospital. The As2O3 solution was prepared as previously described.7 All patients provided their written informed consent. Treatment response was determined by the criteria described by Yamada et al.,8 and toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC version 2.0).
Patients’ characteristics and results of As2O3 therapy are summarized in Table 1. Adverse events observed during the treatment were managed with standard approaches. Patients 1 and 2 were heavily treated with multiple conventional chemotherapeutic agents prior to As2O3 treatment and their performance status was poor. Furthermore, disease progression was extremely rapid as suggested by the evidence that, in these patients, doubling time of serum LDH levels which correlated with tumor burden was 1 to 3 days (data not shown). On the other hand, As2O3 and IFN therapy produced promising effects in patients 3 and 4, who achieved PR and improvement of thrombocytepenia caused by massive bone marrow infiltration of ATLL cells, respectively (Figure 1). Most importantly, PR was maintained for as long as 8 months in patient 3 who had previously required uninterrupted conventional chemotherapy to avoid progression of ATLL.
Cytotoxicity of As2O3 and augmentation of its effects by combining with IFN in fresh ATLL cells obtained from patient 3 revealed in vitro by trypan blue exclusion dye. Peripheral blood mononuclear cells (PBMNC) were separated by Ficoll-Hipaque density sedimentation from heparinized peripheral blood obtained from patient 3 before starting the treatment. More than 90% of separated PBMNCs were ATLL cells as determined by the expression of CD4 and CD25 by flow cytometry. These cells were cultured with As2O3 (1.0 and 2.0 μM) and/or IFN (10 U/mL) for 120 hours. The concentrations of As2O3 were set according to pharmacokinetics in humans.9,10 Treatment with As2O3 decreased the number of viable ATLL cells as compared with control in a dose and time dependently, and IFN which had been ineffective alone, significantly enhanced the effects of As2O3 (data not shown).
Patients included in our study had been much more heavily treated before As2O3 treatment than those in the French study.4 It is difficult to determine the efficacy in patients 1 and 2 since disease progression was rapid and treatment was terminated early. Their clinical course suggests that As2O3 has a modest therapeutic potential, if any, on patients with heavily-treated and rapidly progressing ATLL. In contrast, the significant therapeutic response in patients 3 and 4 suggests that moderately-aggressive ATLL could benefit from As2O3 therapy.
In conclusion, although this study involved only a limited number of patients, it does provide important information about who could benefit from As2O3 therapy. Moderately-aggressive relapsed/refractory ATLL patients are promising candidates, while those who are heavily-treated or presenting very aggressive ATLL do not appear to benefit. Further studies are needed to determine the efficacy of As2O3 treatment and its usefulness when combined with IFN for the treatment of ATLL.
- Ishitsuka K, Hanada S, Suzuki S, Utsunomiya A, Chyuman Y, Takeuchi S. Arsenic trioxide inhibits growth of human T-cell leukaemia virus type I infected T-cell lines more effectively than retinoic acids. Br J Haematol. 1998; 103:721-8. Google Scholar
- Bazarbachi A, El-Sabban ME, Nasr R, Quignon F, Awaraji C, Kersual J. Arsenic trioxide and interferon-α synergize to induce cell cycle arrest and apoptosis in human T-cell lymphotropic virus type I-transformed cells. Blood. 1999; 93:278-83. Google Scholar
- Ishitsuka K, Hanada S, Uozumi K, Utsunomiya A, Arima T. Arsenic trioxide and the growth of human T-cell leukemia virus type I infected T-cell lines. Leuk Lymphoma. 2000; 37:649-55. Google Scholar
- Hermine O, Dombret H, Poupon J, Arnulf B, Lefrere F, Rousselot P. Phase II trial of arsenic trioxide and alpha interferon in patients with relapsed/refractory adult T-cell leukemia/lymphoma. Hematol J. 2004; 5:130-4. Google Scholar
- Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984–87). Br J Haematol. 1991; 79:428-37. Google Scholar
- Adult T-Cell Leukemia. Oxford University Press: Oxford; 1994. Google Scholar
- Ishitsuka K, Ikeda R, Utsunomiya A, Uozumi K, Hanada S, Suzuki S. Arsenic trioxide induces apoptosis in HTLV-I infected T-cell lines and fresh adult T-cell leukemia cells through CD95 or tumor necrosis factor alpha receptor independent caspase activation. Leuk Lymphoma. 2002; 43:1107-14. Google Scholar
- Yamada Y, Tomonaga M, Fukuda H, Hanada S, Utsunomiya A, Tara M. A new G-CSF-supported combination chemotherapy, LSG15, for adult T-cell leukaemia-lymphoma: Japan Clinical Oncology Group Study 9303. Br J Haematol. 2001; 113:375-82. Google Scholar
- Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY. Blood. 1997; 89:3354-60. Google Scholar
- Ishitsuka K, Shirahashi A, Iwao Y, Shishime M, Takamatsu Y, Takatsuka Y. Bone marrow necrosis in a patient with acute promyelocytic leukemia during re-induction therapy with arsenic trioxide. Eur J Haematol. 2004; 72:280-4. Google Scholar