Therapeutic potential of arsenic trioxide with or without interferon-α for relapsed/refractory adult T-cell leukemia/lymphoma

Abstract

Arsenic 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.

Figure 1.Clinical course in patient 3 (A) and patient 4 (B). A. Treatment, the number of white blood cells (bold line) and ATLL cells (thin line) are shown. The patient died in November 2004. B. Treatment and platelet count are shown. VP-16; etoposide, PSL; prednisolone, THP-COP; pirarubicin. cyclophosphamide, vincristine and prednisolone, DOP; dexamethason, vincristine, peplomysin, *; etoposide 100 mg (3 days) and PSL 60 mg (5 days), **; etoposide 50 mg (5 days).

Table 1.Patients’ characteristics and results of As₂O₃ therapy.

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.