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Background Adult T-cell leukemia-lymphoma (ATL) is an aggressive mature lymphoid proliferation associated with poor prognosis. Standard of care includes chemotherapy and/or the combination of zidovudine and interferon-alpha. However, most patients experience relapse less than 6 months after diagnosis. Allogeneic stem cell transplantation is the only curative treatment, but is only feasible in a minority of cases. We previously showed in a mouse model that Arsenic trioxide (As2O3) targets ATL leukemia initiating cells. Results As2O3 consolidation was given in 9 patients with ATL (lymphoma n = 4; acute n = 2; and indolent n = 3), who were in complete (n = 4) and partial (n = 3) remission, in stable (n = 1) and in progressive (n = 1) disease. Patients received up to 8 weeks of As2O3 at the dose of 0.15 mg/kg/day intravenously in combination with zidovudine and interferon-alpha. One patient in progression died rapidly. Of the remaining eight patients, three with indolent ATL subtype showed overall survivals of 48, 53 and 97 months, and duration of response to As2O3 of 22, 25 and 73 months. The other 5 patients with aggressive ATL subtype had median OS of 36 months and a median duration of response of 10 months. Side effects were mostly hematological and cutaneous (one grade 3) and reversible with dose reduction of AZT/IFN and/or As2O3 discontinuation. The virus integration analysis revealed the regression of the predominant malignant clone in one patient with a chronic subtype. Conclusion These results suggest that consolidation with As2O3 could be an option for patients with ATL in response after induction therapy and who are not eligible for allogeneic stem cell transplantation.

ATL carries a very bad prognosis because of intrinsic chemoresistance and severe immuno-suppression. In acute ATL, chemotherapy combinations improved response rate but failed to achieve a significant impact on survival. Patients with chronic and smoldering ATL have a better prognosis but long-term survival is poor when patients are managed with a watchful-waiting policy or with chemotherapy. The antiviral combination of zidovudine (AZT) and interferon-alpha (IFN) improves survival in leukemic subtypes of ATL (smoldering and chronic ATL and acute ATL with wild type p53) and should be considered as standard first line therapy. However, it is mandatory to 1) use it in leukemic forms as first line therapy and not after one or more cycles of chemotherapy; 2) start with high doses of both agents since reduced doses are often not effective. ATL lymphoma may benefit from initial chemotherapy combined to or followed by AZT/IFN and this approach should be tested in prospective clinical trials. Prophylaxis of opportunistic infections and intrathecal chemotherapy are mandatory. Yet, most patients relapse and alternative therapies are mandatory. IFN and arsenic trioxide induce Tax proteolysis, synergize to induce apoptosis in ATL cells and cure Tax-driven ATL in mice through specific targeting of leukemia initiating cell activity. Therefore, to prevent relapse, clinical trials assessing consolidative targeted therapies such as arsenic/IFN combination, histone deacetylase inhibitors or novel monoclonal antibodies particularly brentuximab in CD30 positive cases or the promising anti CCR4 antibodies, are mandatory after achieving CR with AZT/IFN. Finally, allogeneic BMT should be considered in suitable patients.

Background The prognosis of Adult T-cell leukemia/lymphoma (ATLL) associated with HTLV1 is dismal. The response to conventional chemotherapy ranges between 20 and 70% and relaspe is constant. Median survival is 8 to 13 months. Chronic and smouldering ATLL have a longer survival, ranging from 18 to 72 months at 5 years. Interferon alpha (IFNa) and AZT combination therapy is effective in acute, chronic and smouldering ATLL, sometimes leading to complete response and has a better prognosis than conventional chemotherapy (5 year survival of 82% in acute and 100% in chronic and smouldering forms reaching a complete response). Patients with ATLL/lymphoma do not benefit from IFNa+AZT combination and despite initial response to chemotherapy, all patients eventually relapse. Arsenic trioxyde (AsO3) in combination with IFNa has in vitro activity with a negative regulation of the Tax oncoprotein and leads to apoptosis of HTLV1 transformed lymphocytes. A recent study has showed a benefit in chronic forms of ATLL.

Bovine Leukemia Virus (BLV) and the closely related Human T-cell leukemia virus-1 (HTLV-1) are deltaretrovirus that induce leukemia/lymphoma in about ~5% of infected individuals. The mechanisms responsible for cellular transformation have remained largely enigmatic as both viruses are largely transcriptionally silent in tumors and show multiple integration sites in the host genome. The recent application of high throughput sequencing to track proviral insertion sites in the host genome has provided a number of insights into the evolution of deltaretrovirus infections and the progression of tumor clones in deltaretrovirus induced leukemia/lymphoma. However the protocols currently utilised have a number of limitations, including relatively high sequencing costs, the use of custom sequencing primers, no examination of the region upstream of the provirus and limited dynamic range for determining clone abundance. We have developed an alternative high throughput sequencing protocol for identifying proviral integration sites in BLV and HTLV-1 infected individuals that uses off-the-shelf Illumina primers for the addition of adapters and indexes. This greatly simplifies the process of multiplexing libraries and does away with the need for custom sequencing primers. Additionally our approach assays the region upstream of the provirus in addition to the downstream region, giving additional information on the frequency of 5’ deletions in proviruses and increasing the dynamic range of the assay. We have tested the approach on over 1 BLV and HTLV-1 samples, representing both tumors and preleukemic stages. Our approach allowed for a more accurate determination of clone abundance in tumors and by assaying the 5’ end of the provirus identified clones overlooked with previously published methods. Finally, by facilitating greater multiplexing of libraries we have reduced the cost to a level where the technique may be attractive in a clinical setting.

Human T Lymphotropic Virus type 1 infection is associated with a malignant lymphoproliferation named Adult T cell Leukemia/Lymphoma (ATLL). STLV-1, the simian counterpart of HTLV-1 also causes an ATLL-like disease. During the surveillance of our STLV-1 naturally infected Papio anubis cohort (n=45), we identified a 9 years-old female baboon exhibiting dyspnea, marked emaciation, and a lymphocyte count over 1010/L, pulmonary metastases and skin lesions similar to that observed in human ATLL patients. These symptoms suggested a hematologic malignancy induced by STLV1. This diagnosis was confirmed by the evidence of massive lymphoproliferation in an inguinal lymph node biopsy and the presence of lymphocytes with characteristic abnormal nuclei (i.e. flower cells) in blood smears. As is the case for humans, the animal received a combination of AZT (Combivir) and alpha interferon (viraferon, 50 μg/week) for 4 months. During this period, blood proviral load (PVL) was measured every week. Due to the absence of health improvement and only a slight decrease in the PVL, the animal was euthanased. Histological analysis of the secondary lymphoid organs was performed, and PVL was measured in 25 different organs. All lymphoid organs contained CD3+, CD25+ lymphocytic infiltrates. Furthermore, lymphoma cells were found in lungs and liver. Tax-positive cells were detected by immunohistochemistry in spleen, lung, mesenteric, axillary, inguinal, tracheo-bronchial, lymph nodes. While all organs were PCR positive, the highest PVL was found in lymph nodes, spleen and lungs. Finally, the oligoclonality and the clonal diversity was analyzed in PBMCs throughout the treatment but also in the different organs. In conclusion, non-human primates naturally infected with STLV-1 represent a useful model to study viral pathogenesis and to evaluate new treatments.