Unsuccessful Association of Zidovudine and Interferon Alpha for Acute Adult T-Cell Leukemia Lymphoma

Dermatology ◽  
1999 ◽  
Vol 198 (1) ◽  
pp. 103-105 ◽  
Author(s):  
H. Dega ◽  
O. Chosidow ◽  
F. Charlotte ◽  
C. Francès ◽  
S. Herson ◽  
...  
Keyword(s):  
T Cell ◽  
Interferon Alpha ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia

scholarly journals The Combination Of Arsenic, Interferon-Alpha, and Zidovudine Restores An “Immunocompetent-like” Micro-Environment In Patients With Adult T-Cell Leukemia/Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5100-5100
Author(s):  
Ghada Kchour ◽  
S. A. Rahim Rezaee ◽  
Reza Farid ◽  
Akram Ghantous ◽  
Houshang Rafatpana ◽  
...  
Keyword(s):  
T Cell ◽  
Arsenic Trioxide ◽  
Interferon Alpha ◽  
T Cell Leukemia ◽  
Off Label Use ◽  
Cell Leukemia ◽  
Transcript Levels ◽  
Off Label ◽  
Adult T Cell Leukemia ◽  
Ifn Γ

Abstract Background HTLV-I associated adult T-cell leukemia/lymphoma (ATL) carries a dismal prognosis due to chemo-resistance and immuno-compromised micro-environment. The combination of zidovudine and interferon-alpha (IFN) significantly improved survival in ATL. Promising results were reported by adding arsenic trioxide to zidovudine and IFN. Methods Here we assessed Th1/Th2/Treg cytokine gene expression profiles in 16 ATL patients before and 30 days after treatment with arsenic/IFN/zidovudine, in comparison with HTLV-I healthy carriers and sero-negative blood donors. Results ATL patients at diagnosis displayed a Treg/Th2 cytokine profile with significantly elevated transcript levels of Foxp3, interleukin-10 (IL-10), and IL-4 and had a reduced Th1 profile evidenced by decreased transcript levels of interferon-γ (IFN-γ) and IL-2. Most patients (15/16) responded, with CD4+CD25+ cells significantly decreasing after therapy, paralleled by decreases in Foxp3 transcript. Importantly, arsenic/IFN/zidovudine therapy sharply diminished IL-10 transcript and serum levels concomittant with decrease in IL-4 and increases in IFN-γ  and IL-2 mRNA, whether or not values were adjusted to the percentage of CD4+CD25+ cells. Conclusions The observed shift from a Treg/Th2 phenotype before treatment toward a Th1 phenotype after treatment with arsenic/IFN/zidovudine may play an important role in restoring an immuno-competent micro-environment, which enhances the eradication of ATL cells and the prevention of opportunistic infections. Disclosures: Off Label Use: Off label use of arsenic trioxide, zidovudine and interferon-alpha for the treatment of adult T cell leukemia/lymphoma.

Zidovudine Blocks NF-κB activity in Vivo in Adult T-Cell Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2524-2524 ◽  
Author(s):  
Juan Carlos Ramos ◽  
Luis M. Diaz ◽  
Michele Manrique ◽  
Rosangela Lima ◽  
Ngoc L Toomey ◽  
...  
Keyword(s):  
T Cell ◽  
Interferon Alpha ◽  
Phase Ii ◽  
Target Genes ◽  
Recent Analysis ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Resistant Disease

Abstract Adult T-cell leukemia (ATL) is a lymphoid malignancy caused by the human T-cell leukemia virus type I (HTLV-I), which carries a poor prognosis. A hallmark of ATL is the high constitutive expression of NF-κB, which predominantly exerts an anti-apoptotic effect contributing to chemotherapy resistance. Many of the elegant studies about the pathogenesis of ATL have focused on Tax, a viral transactivator of NF-κB, using HTLV-I expressing cell lines and mouse models, however in primary tumors the virus remains latent and Tax is not detected. We and other investigators have demonstrated the clinical efficacy of Zidovudine (AZT) and interferon-alpha (IFNα) combination therapy in both chronic and acute ATL subtypes with some patients achieving clinical remission or stable disease for many years while on maintenance therapy. The exact mechanisms of these antiviral drugs in ATL remain unclear. In a recent analysis of primary ATL tumors, we implicated the expression of both c-Rel and the NF-κB target gene product IRF-4/MUM-1 in AZT/IFN resistant disease. We have recently opened to accrual a Phase II clinical trial titled Prospective Study of the Molecular Characteristics of Sensitive and Resistant Disease in Patients with HTLV-I Associated Adult T Cell Leukemia Treated with Zidovudine Plus Interferon alpha-2b, which includes the novel use of pegylated interferon-alpha and valproic acid (as HDAC inhibitor) in the maintenance phase as an attempt to eradicate residual ATL clones, which usually occurs after AZT and IFNα therapy even after longterm remission. Our goals are also to study the anti-tumor mechanisms of these drugs in ATL, and define molecular criteria for response. As part of the correlative studies in our Phase II trial, we have analyzed leukemic ATL cells collected from patients during the first 48 hours of treatment (AZT given alone prior to IFN) and found in vivo stabilization of IκB (the repressor protein of NF-κB) by Western Blot in patients responding to the treatment, suggesting a role for this antiviral drug in blocking NF-κB activity as previously hypothesized in our laboratory. We also examined the expression of NF-κB related genes using a custom designed gene expression array by a novel technology (NanoString Inc.) of selected NF-κB target genes and found downregulation of most these genes in vivo by AZT alone. So far, all ATL tumors analyzed exhibited high expression of many NF-κB target genes, and over forty of these are differentially overexpressed in ATL specimens as compared to normal CD4+ T-cells. Some the differentially expressed genes include those encoding NF-κB/Rel, interferon regulatory factor (IRF), and bcl-2 related proteins. A comprehensive analysis of over forty ATL tumors, including specimens collected in both Miami and Brazil, is ongoing and expected to be completed soon. Baseline tumor characteristics and prognostic variables of previously collected tumors, as well interim results of our clinical and molecular studies will be reported.

A Worldwide Meta-Analysis on the Use of Zidovudine and Interferon-alpha for the Treatment of Adult T–Cell Leukemia/Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2049-2049 ◽  
Author(s):  
Ali Bazarbachi ◽  
Gerard Panelatti ◽  
Juan Carlos Ramos ◽  
Patricia Tortevoye ◽  
Zaher Otrock ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Interferon Alpha ◽  
Meta Analysis ◽  
Prolonged Survival ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
First Line ◽  
Adult T Cell Leukemia ◽  
Ifn Therapy

Abstract HTLV-I associated adult T cell leukemia/lymphoma (ATL) is an aggressive T cells malignancy, with poor prognosis due to chemotherapy resistance. Multiple small phase II studies using zidovudine (ZDV) and interferon-alpha (IFN) showed response in ATL patients. However, the impact of this therapy on ATL prognosis remains to be determined. Here, we report a worldwide meta-analysis on the use of ZDV/IFN treatment for ATL in 209 patients treated from 1994 to 2006. Patients were recruited in the USA (27 patients), the UK (13 patients), Martinique (102 patients) and France metropolitaine (67 patients). Collected data included geographic origin, age, sex, type of the disease, clinical presentation, LDH levels, calcemia, and lymphocytes number. Median age was 49 years (range 16 to 95). According to Shimoyama classification, there were 98 acute ATL, 20 chronic ATL, 9 smouldering ATL, 75 ATL lymphoma, and 7 patients with an unknown subtype. Hypercalcemia was present in 60% of patients. The data concerning the course of the disease were also collected, particularly the response status, the length of the response, the duration of ZDV+IFN therapy, as well as previous and post chemotherapy treatments. One hundred patients received first line ZDV+IFN therapy. In these patients, response rate was 66%, including 43% of patients achieving complete remission (CR). Median overall survival and 5 year overall survival rate were 24 months and 50% for patients who received first line ZDV+IFN therapy, versus 7 months and 20% for patients who received first line chemotherapy. When analysis was performed by ATL subtype, patients with acute, chronic, and smouldering ATL significantly benefited from first line ZDV+IFN therapy, whereas no additional benefit was achieved in patients with ATL lymphoma. Achievement of CR with first line ZDV+IFN therapy resulted in prolonged survival of more than 10 years in 70% of the study population, and 75% of the acute ATL subgroup. Finally, first line ZDV+IFN therapy in chronic and smouldering ATL resulted in 100% overall survival at 10 years. In conclusion, these results confirm that treatment of ATL using ZDV and IFN results in a high response and CR rates particularly in acute, chronic and smouldering ATL, resulting in impressive prolonged survival and hence should be considered as gold standard first line therapy.

scholarly journals Deciphering the molecular basis of arsenic/interferon-alpha induced eradication of leukemia initiating cells in adult T cell leukemia

Retrovirology ◽  
2015 ◽  
Vol 12 (S1) ◽  
Author(s):  
Hiba El Hajj ◽  
Nadim Tawil ◽  
Rita Hleihel ◽  
Mark Jabbour ◽  
Ghazi Zaatari ◽  
...  
Keyword(s):  
T Cell ◽  
Interferon Alpha ◽  
Molecular Basis ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia

A prospective phase II clinical trial with the use of zidovudine and interferon-alpha in the acute and lymphoma forms of adult T-cell leukemia/lymphoma

2002 ◽  
Vol 3 (6) ◽  
pp. 276-282 ◽  
Author(s):  
Olivier Hermine ◽  
Isabelle Allard ◽  
Vincent Lévy ◽  
Bertrand Arnulf ◽  
Antoine Gessain ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Interferon Alpha ◽  
Phase Ii ◽  
Phase Ii Clinical Trial ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Prospective Phase

Targeted Therapy with Arsenic Trioxide and Interferon alpha Eradicates Leukemic Cells in SCID Mice Model of Adult T-Cell Leukemia/Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1379-1379
Author(s):  
Hiba El Hajj ◽  
Hideki Hasegawa ◽  
Marwan El-Sabban ◽  
Ghazi Zaatari ◽  
Shehrazad Saab ◽  
...  
Keyword(s):  
T Cell ◽  
Arsenic Trioxide ◽  
Interferon Alpha ◽  
Optimal Schedule ◽  
Scid Mice ◽  
Leukemic Cells ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Nf Kappab

Abstract HTLV-I associated adult T-cell leukemia (ATL) is a severe, chemotherapy-resistant malignancy associated with poor prognosis. Recently, HTLV-I Tax transgenic mice, accurately reproducing human ATL disease were generated. To develop a more consistent and rapid model of disease development, direct transfer of Tax transgenic cells into SCID mice was assessed and showed that they die within 28 days, having developed both an extremely aggressive leukemia with characteristic flower cells, and extensive lymphomatous infiltration of the spleen, lymph nodes, bone marrow, liver, kidney and lung by malignant T lymphocytes highly expressing CD25. Furthermore, and as in ATL patients, we observed marked hypercalcemia and high level of LDH. We have previously identified in vitro several potential targeted therapies for ATL. To define the optimal schedule and drug combination to be evaluated in clinical trials, we tested the following drugs using the in vivo ATL SCID model: zidovudine, interferon alpha (IFN), arsenic trioxide, the proteasome inhibitor bortezomib, and the combinations of zidovudine and IFN, or of arsenic and IFN. The combination of zidovudine and IFN had no effect on the survival of ATL SCID mice confirming the hypothesis that this combination targets the viral replication since these animals have Tax-transgenic leukemic cells but no entire HTLV-I retrovirus, contrary to ATL patients. Inhibition of NF-kappaB using bortezomib or arsenic alone almost doubled the mice survival but was not sufficient to eradicate ATL malignant cells. Strikingly, the most relevant effect on the mice survival was obtained when we used the combination of arsenic trioxide and interferon alpha, which targets both the HTLV-I Tax oncoprotein and the constitutive activation of the NF-kappaB pathway. Indeed, after 6 months of follow up, this combination totally cured 40% of the treated mice, and tripled the survival of the remaining 60%. These impressive results suggest that double targeting of Tax and NF-kappaB by the combination of arsenic trioxide and interferon alpha may suffice to cure ATL. This combination is now tested in newly diagnosed ATL patients.

scholarly journals The combination of arsenic, interferon-alpha, and zidovudine restores an “immunocompetent-like” micro-environment in patients with adult T-cell leukemia lymphoma

Retrovirology ◽  
2014 ◽  
Vol 11 (Suppl 1) ◽  
pp. O4 ◽  
Author(s):  
Ghada Kchour ◽  
SA Rahim Rezaee ◽  
Reza Farid ◽  
Akram Ghantous ◽  
Houshang Rafatpana ◽  
...  
Keyword(s):  
T Cell ◽  
Interferon Alpha ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia

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)

Blood ◽  
2009 ◽  
Vol 113 (26) ◽  
pp. 6528-6532 ◽  
Author(s):  
Ghada Kchour ◽  
Mahdi Tarhini ◽  
Mohamad-Mehdi Kooshyar ◽  
Hiba El Hajj ◽  
Eric Wattel ◽  
...  
Keyword(s):  
T Cell ◽  
Arsenic Trioxide ◽  
Interferon Alpha ◽  
Response Rate ◽  
T Cell Leukemia ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia

AbstractAdult 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-κB 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.

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