Haematologica, Vol 92, Issue 5, 719-720 doi:10.3324/haematol.10703
Copyright © 2007 by Ferrata Storti Foundation

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Acute Leukemia

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

Kenji Ishitsuka^*,, Junji Suzumiya^*, Mikiko Aoki^*, Kentaro Ogata^°, Shuuji Hara^°, Kazuo Tamura^*

^* 1st Department of Internal Medicine, Fukuoka University
^° Department of Pharmacy, Fukuoka University Hospital

Correspondence: Kenji Ishitsuka, 1^st Department of Internal Medicine, Fukuoka University, 7-45-1 Jonan-ku, Fukuoka, 814-0180, Japan. Phone: international +81.92.801.1011. Fax: international +81.92.865.5656. E-mail: kenjiishitsuka{at}fukuoka-u.ac.jp

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Arsenic trioxide (As₂O₃) with or without interferon- (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- (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 ATLL^5,6 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 3x10⁶ unit of IFN (Sumiferon^TM, 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.

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

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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).

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.

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1. Ishitsuka K, Hanada S, Suzuki S, Utsunomiya A, Chyuman Y, Takeuchi S, et al. 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.[CrossRef][Web of Science][Medline]
2. Bazarbachi A, El-Sabban ME, Nasr R, Quignon F, Awaraji C, Kersual J, et al. Arsenic trioxide and interferon- synergize to induce cell cycle arrest and apoptosis in human T-cell lymphotropic virus type I-transformed cells. Blood 1999;93:278-83.[Abstract/Free Full Text]
3. 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.[Web of Science][Medline]
4. Hermine O, Dombret H, Poupon J, Arnulf B, Lefrere F, Rousselot P, et al. 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.[CrossRef][Web of Science][Medline]
5. 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.[Web of Science][Medline]
6. Shimoyama M. Chemotherapy of ATL. In: Takatsuki K, ed. Adult T-Cell Leukemia, Oxford: Oxford University Press. 1994. p. 221-37.
7. Ishitsuka K, Ikeda R, Utsunomiya A, Uozumi K, Hanada S, Suzuki S, et al. 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.[Web of Science][Medline]
8. Yamada Y, Tomonaga M, Fukuda H, Hanada S, Utsunomiya A, Tara M, et al. 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.[CrossRef][Web of Science][Medline]
9. Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, et al. Use of arsenic trioxide (As₂O₃) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 1997;89:3354-60.[Abstract/Free Full Text]
10. Ishitsuka K, Shirahashi A, Iwao Y, Shishime M, Takamatsu Y, Takatsuka Y, et al. Bone marrow necrosis in a patient with acute promyelocytic leukemia during re-induction therapy with arsenic trioxide. Eur J Haematol 2004;72:280-4.[CrossRef][Web of Science][Medline]

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