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Blood, 25 June 2009, Vol. 113, No. 26, pp. 6528-6532. Prepublished online as a Blood First Edition Paper on May 1, 2009; DOI 10.1182/blood-2009-03-211821. This Article Abstract Full Text (PDF) All Versions of this Article: blood-2009-03-211821v1 113/26/6528    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Kchour, G. Articles by Bazarbachi, A. PubMed PubMed Citation Articles by Kchour, G. Articles by Bazarbachi, A. Related Collections Free Research Articles Lymphoid Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS Phase 2 study of the efficacy and safety of the combination of arsenic trioxide, interferon alpha, and zidovudine in newly diagnosed chronic adult T-cell leukemia/lymphoma (ATL) Ghada Kchour1, Mahdi Tarhini2, Mohamad-Mehdi Kooshyar3, Hiba El Hajj4, Eric Wattel5, Mahmoud Mahmoudi1, Hassan Hatoum4, Hossein Rahimi3, Masoud Maleki6, Houshang Rafatpanah1, S. A. Rahim Rezaee7, Mojtaba Tabatabaei Yazdi8, Abbas Shirdel3, Hugues de Thé9, Olivier Hermine10, Reza Farid1, and Ali Bazarbachi4 1 Immunology Research Centre Bu-Ali Research Institute, 2 Department of Pathology and Laboratory Medicine, and 3 Department of Internal Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; 4 Department of Internal Medicine, American University of Beirut, Beirut, Lebanon; 5 Oncovirologie et Biothérapies, Centre National de la Recherche Scientifique (CNRS) FRE 3011, Université Claude Bernard, Centre Léon Bérard, Hopital Edouard Herriot, Lyon, France; 6 Department of Dermatology, and 7 Microbiology and Virology Research Center, Bu-Ali Research institute, Mashhad University of Medical Sciences, Mashhad, Iran; 8 Department of Pharmaceutical Biotechnology, College of Pharmacy, Tehran University of Medical Science, Tehran, Iran; 9 CNRS Unité Mixte de Recherche (UMR) 7151, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Paris, France; and 10 CNRS UMR 8603 and Department of Hematology, Necker Hospital, Paris, France    Abstract Top Abstract Introduction Methods Results Discussion Authorship References   Adult T-cell leukemia/lymphoma (ATL) is resistant to chemotherapy and carries a dismal prognosis particularly for the acute and lymphoma subtypes. Promising results were obtained with the combination of zidovudine and interferon-alpha. Chronic ATL has a relatively better outcome, but poor long-term survival is noted when patients are managed with a watchful-waiting policy or with chemotherapy. In ATL cell lines, arsenic trioxide shuts off constitutive NF-B activation and potentiates interferon-alpha apoptotic effects through proteasomal degradation of Tax. Clinically, arsenic/interferon therapy exhibits some efficacy in refractory aggressive ATL patients. These results prompted us to investigate the efficacy and safety of the combination of arsenic, interferon-alpha, and zidovudine in 10 newly diagnosed chronic ATL patients. An impressive 100% response rate was observed including 7 complete remissions, 2 complete remissions but with more than 5% circulating atypical lymphocytes, and 1 partial response. Responses were rapid and no relapse was noted. Side effects were moderate and mostly hematologic. In conclusion, treatment of chronic ATL with arsenic, interferon-alpha, and zidovudine is feasible and exhibits an impressive response rate with moderate toxicity. Long-term follow up will clarify whether this will translate to disease cure. Overall, these clinical results strengthen the concept of oncogene-targeted cancer therapy.    Introduction Top Abstract Introduction Methods Results Discussion Authorship References   Adult T-cell leukemia/lymphoma (ATL) is an aggressive proliferation of mature activated CD4+ T cells associated with the human T-cell lymphotropic virus type I (HTLV-I).1 Leukemia develops after a very long latency period and is preceded by oligoclonal expansions of HTLV-I–infected activated T cells.2 These clonal expansions result from the expression of the viral transactivator protein Tax, which activates various cellular genes3 and creates an autocrine loop involving interleukin-2, interleukin-15, and their cognate receptors.4 The diversity in clinical features and prognosis of ATL patients has led to its subclassification into smoldering, chronic, lymphoma, and acute subtypes.5 Patients with aggressive ATL (acute and lymphoma subtypes) generally have a very poor prognosis because of intrinsic chemoresistance of malignant cells, a large tumor burden with multiorgan failure, hypercalcemia, and/or frequent infectious complications due to a profound T-cell immune deficiency.6,7 Patients with indolent ATL (ie, the chronic or smoldering subtypes) have a better prognosis.6 However, data from Japan showed poor long-term survival results when these patients are managed with a watchful-waiting policy until disease progression or with chemotherapy.8 Indeed, 4-year survival in chronic ATL is less than 30%.6 We and others showed that high response rates are achieved in ATL patients with the combination of the antiretroviral nucleotide analog zidovudine (AZT) and interferon alpha (IFN).9–14 However, most patients eventually relapse, which underlines the need for new therapeutic approaches. Arsenic trioxide (As) is a very effective treatment of acute promyelocytic leukemia (APL),15 a distinct subtype of acute myeloid leukemia that is characterized by unique clinical characteristics and a specific cytogenetic abnormality, t(15;17), which results in a reciprocal translocation between the PML gene on chromosome 15 and the retinoic acid receptor (RAR-) gene on chromosome 17.16,17 Clinically, As directly targets and degrades PML/RARA fusion protein, inducing clinical remission of APL patients. In ATL cells, we have previously shown that As synergizes with IFN to induce cell cycle arrest and apoptosis.18 At the molecular level, the combination of As/IFN specifically induces proteosomal degradation of the HTLV-1 oncoprotein Tax and reversal of NF-B activation.19,20 Such specific targeting of the viral oncoprotein by IFN/As treatment, reminiscent of As targeting of PML/RAR in APL, provides strong rational for combined IFN/As therapy in ATL patients. In that sense, we previously reported the results of a phase 2 trial of As/IFN combination in 7 patients with relapsed/refractory aggressive ATL after AZT, IFN, and chemotherapy.21 One patient achieved complete remission, 3 achieved partial remission, and 3 progressed. The patient in complete remission (CR) is still alive after more than 5 years of follow up. These results indicate that treatment with As and IFN is feasible and exhibits an antileukemic effect in vivo in these selected aggressive ATL patients with poor prognosis. However, the slow pharmacokinetics of As (duration to obtain maximum levels, low maximum levels) that we observed in our previous study, and the refractory status of these patients to many drugs including IFN, argue for the use of As and IFN earlier in the course of the disease, either as maintenance therapy or in association with AZT/IFN as first-line therapy of ATL. Similarly, a transient response to As/IFN combination was reported in Japan in 2 patients with refractory acute ATL.22 In this prospective phase 2 study, in line with our previous findings, we investigated the efficacy and safety of the treatment with the combination of As, IFN, and AZT in 10 newly diagnosed chronic ATL patients from the region of Mashhad in northeast Iran. We show that this combination treatment is feasible and exhibits a remarkably high response rate with moderate side effects.    Methods Top Abstract Introduction Methods Results Discussion Authorship References   Patients' characteristics Ten newly diagnosed, previously untreated, chronic ATL patients were included in this prospective phase 2 study after giving informed consent. Patient enrollment started in 2007. These patients were referred to the hematology-oncology department of Ghaem and Imam Reza hospitals, Mashhad University of Medical Sciences. All ATL patients had serologic evidence of HTLV-I infection by enzyme-linked immunosorbent assay (ELISA) and confirmation of HTLV-I positivity by standard polymerase chain reaction (PCR; data not shown). Flow cytometric analysis of peripheral blood at diagnosis showed that tumor cells were CD4+, CD8–, and CD25+ (Table 1). All patients had chronic ATL according to the Shimoyama classification criteria for ATL.5 The patient's characteristics are shown in Table 1. This study was approved by the ethical committee of Mashhad University of Medical Sciences and patient informed consent was obtained in accordance with the Declaration of Helsinki. View this table: [in this window] [in a new window]   Table 1. Patient characteristics at initiation of treatment   Study design and treatment schedule Treatment consisted of intravenous As (10 mg/day, 5 days/wk), subcutaneous IFN (Pooyesh Darou Pharmaceutical, Tehran, Iran; 5 million units/day), and oral AZT (900 mg/day). Arsenic was initially planned for a duration of 60 days. However, after poor tolerance in the first patient who received 60 days of As together with AZT and IFN, the protocol was amended to 30 days of As. In case of toxicity, AZT and IFN were either transiently interrupted or their dose was reduced to 600 mg/day and 3 million units per day, respectively. Arsenic dose was not reduced in case of toxicity, but As treatment was transiently interrupted. Details about treatment dose, treatment duration, and treatment interruption are listed in Table 2. Treatment of nonresponders was at the discretion of the investigator. View this table: [in this window] [in a new window]   Table 2. Treatment schedule   Response criteria Complete remission (CR) was defined as a normalization of the complete blood count (CBC) associated with a disappearance of all measurable tumors lasting at least 1 month. Patients with persistence of less than 5% atypical lymphocytes were, however, considered in CR because this situation may be seen in healthy carriers of HTLV-I. Very good partial response (VGPR) was defined as a normalization of the CBC associated with a disappearance of all measurable tumors lasting at least 1 month, but with persistence of more than 5% atypical lymphocytes on peripheral blood smear. Partial response (PR) was defined as a decrease of more than 50% in the number of leukemia cells and in the size of all measurable tumors. No response (NR) was defined as less than 50% decrease in the number of leukemia cells or in the size of any measurable tumor, or as disease progression. Progression-free survival (PFS) was defined as the period between initiation of treatment and the date of disease progression, death, or last follow-up. Overall survival (OS) was defined as the period between initiation of treatment and the date of death or last follow-up. Proviral load The HTLV-I viral copy number per microliter of blood was calculated from the cell count and the average viral copy number per cell as assessed by quantitative PCR. Real-time quantitative PCR was performed on DNA extracted from peripheral blood mononuclear cells as previously described, using primers and Taqman probe positioned on tax gene and albumin gene for normalization.23 TaqMan amplification was carried out in reaction volumes of 25 µL, with the use of the qPCR MasterMix (Eurogentec, Leuven, Belgium). Each sample was analyzed in triplicate with the use of 250 ng DNA in each reaction. Thermal cycling was initiated with a 2-minute incubation at 50°C, followed by a first denaturation step of 10 minutes at 95°C and then by 45 cycles at 95°C for 15 seconds and 58°C for 1 minute for tax (or 60°C for 1 minute for albumin).    Results Top Abstract Introduction Methods Results Discussion Authorship References   Toxicity and dose adjustment Toxicity (WHO > 3) occurred in 4 patients (Table 3). Most patients experienced hematologic toxicity, especially at the end of the first month of treatment (grade > 1 [6 patients], grade > 3 [3 patients]). Extrahematologic toxicities (grade > 1 [7 patients], grade > 2 [1 patient]) included gastrointestinal (nausea and vomiting) and hepatic (cytolysis and cholestasis) signs. Overall, toxicity resulted in dose reduction or transient discontinuation of treatment in 7 patients. In addition to these objective toxicities, we noted that most patients experienced severe fatigue during the last week of arsenic therapy. This was rapidly reversible after arsenic discontinuation. View this table: [in this window] [in a new window]   Table 3. Toxicity (WHO grade)   Most patients could achieve the initially planned duration of arsenic treatment (30 days) and are still receiving maintenance therapy with AZT and IFN, albeit at reduced dose as shown in Table 2. Overall, AZT was transiently interrupted in 2 patients or given at a reduced dose in 6 patients. Similarly, IFN was transiently interrupted in 2 patients or given at a reduced dose in 5 patients. Finally, As was transiently interrupted in one patient. Response and survival All patients initially presented with symptomatic chronic ATL. The most frequent symptoms were cutaneous manifestations with maculopapular rash, severe itching, and skin ulcerations (Figure 1). Treatment with As, IFN, and AZT resulted in an impressive 100% response rate (Table 4). At day 30, 5 patients achieved PR and 5 patients achieved VGPR defined as a normalization of the CBC associated with a disappearance of all measurable tumors lasting at least 1 month, but with persistence of more than 5% of atypical lymphocytes on peripheral blood smear. Impressively, within 2 to 4 weeks, skin lesions almost disappeared (Figure 1). Interestingly, in the 7 patients for whom initial and day-30 DNA was available, HTLV-I proviral load significantly decreased from an average of 1415 copies/µL blood to 226 copies/µL (P < .05; Table 5). All patients continued to improve their response (Table 4; Figure 1). Indeed, disease evaluation at last follow up showed that 7 patients were in CR, 2 patients were in VGPR (solely because of the presence of 6% and 8% of atypical lymphocytes on peripheral blood smear, respectively), and 1 patient was in PR (after a short follow up of 2 months, his lymphocytosis decreased from 185 000 x 109/L to 6400 x 109/L). After a median follow-up of 8 months (range, 2-15 months), all patients are still alive; none of them relapsed or progressed. View larger version (63K): [in this window] [in a new window]   Figure 1. Treatment with arsenic, interferon, and zidovudine results in rapid resolution of ATL skin manifestations. (Top panels) Representative skin manifestations in patient 1 at diagnosis (left) and after 1 month of therapy (right). (Bottom panels) Representative skin manifestations in patient 3 at diagnosis (left), after 2 weeks of therapy (middle), and after 8 months of therapy (right).   View this table: [in this window] [in a new window]   Table 4. Response and follow-up   View this table: [in this window] [in a new window]   Table 5. Variation of HTLV-I proviral load between initiation of treatment and day 30      Discussion Top Abstract Introduction Methods Results Discussion Authorship References   In this prospective phase 2 study, we show promising clinical results of an As/IFN/AZT combination in 10 newly diagnosed chronic ATL patients from northeast Iran. An impressive 100% response rate was observed, including 7 patients who achieved CR, 2 patients who achieved VGPR (clinical and biologic CR except for the presence of more than 5% atypical lymphocytes on peripheral blood smear), and 1 achieved PR (after a short follow-up of 2 months, lymphocytosis decreased by more than 95%). Although this impressive response rate could be partly explained by the presence of AZT and IFN in the As/IFN/AZT triple combination, it is noteworthy that the response rate and particularly the CR rate with AZT/IFN alone in published studies9–14 is less than what is observed in this study. Moreover, the highest rates of response were previously reported with the use of high doses of AZT and high doses of IFN (6 million units/m2), whereas most of our patients received a much lower dose of IFN (total dose of 5 to 3 million units). Finally, although the follow-up of our study is relatively short (median follow-up of 8 months), none of the patients relapsed or progressed. Altogether, these results strongly suggest that As significantly improved the response rate of AZT/IFN. The triple combination of As/IFN/AZT was feasible with moderate and manageable side effects. Hematologic toxicity necessitated transient treatment interruption or dose reduction in some patients. Extrahematologic toxicity consisted mainly of gastrointestinal discomfort. However, it is noteworthy that severe fatigue was noted during the last week of arsenic therapy in most patients. This was rapidly reversible after arsenic discontinuation. Hence, a shorter duration of arsenic (3 weeks) may be associated with increased tolerance and should be explored in future trials. Overall, based on this study, in patients with chronic ATL, the recommended starting dose of the 3 agents during the first month of treatment would be AZT (900 mg/day), IFN (5 million IU/day), and As (10 mg/day). Dose reduction of AZT (to 600 mg/day) and IFN (to 3 million IU/day) should be done in case of severe toxicity. This should be followed by maintenance AZT/IFN at the same dose. However, a phase 1 study is now recommended to establish the maximal tolerated dose for each drug in this highly effective combination regimen. As for the mechanism of action, we have previously shown that, ex vivo, the combination of As and IFN selectively kills HTLV-I–infected cells, through reversion of the constitutive activation of NF-B and degradation of the Tax oncoprotein by the proteasome.18–20 Proteasome-mediated degradation of Tax by As/IFN is reminiscent of the proteasome-mediated degradation of PML-RAR by As in APL. After many years of controversy, it is now established that the viral transactivator Tax plays a critical role in initiating the leukemic process, because Tax mice transgenics develop a disease with striking ATL features.24 We recently demonstrated that As and IFN cooperate to cure mouse ATL derived from these Tax transgenics (H.E.H., M. El-Sabban, H. Hasegawa, G. Zaatari, S. Saab, A. Janin, R. Mahfouz, R. Nasr, Y. Kfoury, C. Nicot, O. Hermine, W. Hall, H.d.T., and A.B., unpublished results, May 2009). Surprisingly, this combination does not trigger an immediate growth arrest or apoptosis but rather selectively eradicates leukemia-initiating cells (LICs). This strongly suggests that LICs, rather than the bulk of the leukemia, are addicted to continuous oncogene expression. Hence, addition of As to AZT/IFN, through elimination of LICs, may result in long-term disease eradication and eventual cure. The short follow-up of our study does not allow conclusive evidence regarding overall survival. Long-term follow-up of patients treated by the combination of As/IFN/AZT will demonstrate whether this high rate of complete remission will translate in terms of disease eradication and patients cure. In aggressive ATL, preliminary results from 2 acute ATL patients suggest that addition of As to AZT/IFN during the induction phase may result in severe tumor lysis syndrome. Hence, an attractive strategy in that setting would be induction therapy with AZT/IFN to decrease the tumor bulk followed by addition of arsenic at low tumor burden to achieve CR, in a clinical situation similar to chronic ATL patients. In conclusion, treatment of ATL with As, IFN, and AZT is feasible and exhibits an impressive response rate with moderate toxicity in patients with chronic ATL. Although the follow-up was relatively short (8 months), none of the patients have relapsed, raising hopes that extinction of viral replication (AZT) and Tax degradation (As/IFN) may eradicate the disease. These clinical results strengthen the concept of oncogene-targeted cancer therapy.    Authorship Top Abstract Introduction Methods Results Discussion Authorship References   Contribution: G.K. and M.T. performed diagnostic and molecular analysis and patient follow-up and participated in study design, data analysis, and writing the paper; M.-M.K., H. Rahimi, M. Maleki, M.T.Y., and A.S. treated patients; H.E.H., E.W., M. Mahmoudi, H. Rafatpanah, and S.A.R.R. performed diagnostic and molecular analysis; H.H. analyzed data; H.d.T., and O.H. participated in study design, data analysis, and writing the paper; R.F. performed diagnostic and molecular analysis and participated in study design, data analysis, and writing the paper; and A.B. designed the study and wrote the paper. Conflict-of-interest disclosure: The authors declare no competing financial interests. Correspondence: Ali Bazarbachi, Department of Internal Medicine, American University of Beirut, PO Box 113-6044, Beirut, Lebanon; e-mail: bazarbac{at}aub.edu.lb; or Reza Farid, Immunology Research Centre Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran; e-mail: rfaridh{at}yahoo.com.    Acknowledgment   This study was supported by funds from the research council of the Mashhad University of Medical Sciences.    Footnotes   Submitted March 18, 2009; accepted April 22, 2009. Prepublished online as Blood First Edition Paper, May 1, 2009 DOI: 10.1182/blood-2009-03-211821 The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734.    References Top Abstract Introduction Methods Results Discussion Authorship References   Hinuma Y, Komoda H, Chosa T, et al. 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[Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) All Versions of this Article: blood-2009-03-211821v1 113/26/6528    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Kchour, G. Articles by Bazarbachi, A. PubMed PubMed Citation Articles by Kchour, G. Articles by Bazarbachi, A. Related Collections Free Research Articles Lymphoid Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?

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