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)

Abstract

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, interferonalpha, 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 oncogenetargeted cancer therapy. (Blood. 2009; 113:6528-6532)

Human T-Cell Lymphotropic Virus (HTLV-1) and Adult T-Cell Leukemia

“…Viral replication (AZT) and Tax degradation (As/IFN) may eradicate the disease through this treatment. These clinical results strengthen the concept of oncogene-targeted cancer therapy (Kchour et al 2009). Key Words: HTLV-1, ATL, Leukemia, Molecular pathogenesis, Diagnosis, Novel treatements, Oncogenesis, Mutation, Arsenic, Interferon-alpha, Zidovudine…”

PML nuclear bodies: Assembly and oxidative stress-sensitive sumoylation

“…Importantly the combination of interferon and arsenic has unambiguous clinical benefit in HTLV-1 infected Adult T-Cell Leukemia (ATL) patients, where remissions can be achieved in the absence of chemotherapy. 122,123 Spinocerebellar ataxia (SCA1) is caused by accumulation of ataxin 1, a poly-glutamine stretch containing protein, which is degraded by the PML/SUMO/RNF4 system. 90 Interferon treatment can induce clearance of ataxin 7 from the brain in a PMLor SUMO-dependent manner, resulting in clinical benefit.…”

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

“…IFNs induce a transient global polyubiquitination 61 , which could result from the hypersumoylation unravelled here. These findings have important therapeutic relevance, as IFNa promotes PML-and SUMO-dependent degradation of toxic proteins in the brain 62,63 or of the HTLV-I leukemia oncoprotein Tax 64 , with unambiguous clinical benefit 62,65,66 . Thus, similar to therapies based on manipulation of ubiquitin-dependent degradation 67,68 , this could pave the way to IFN-triggered, SUMO-based therapies promoting the proteolytic clearance of undesirable proteins 68 .…”