Romiplostim safety and efficacy for immune thrombocytopenia in clinical practice: 2-year results of 72 adults in a romiplostim compassionate-use program.

Romiplostim, a thrombopoietic agent with demonstrated efficacy against immune thrombocytopenia (ITP) in prospective controlled studies, was recently licensed for adults with chronic ITP. Only France has allowed romiplostim compassionate use since January 2008. ITP patients could receive romiplostim when they failed to respond to successive corticosteroids, intravenous immunoglobulins, rituximab, and splenectomy, or when splenectomy was not indicated. We included the first 80 patients enrolled in this program with at least 2 years of follow-up. Primary platelet response (platelet count ≥ 50 × 10(9)/L and double baseline) was observed in 74% of all patients. Long-term responses (2 years) were observed in 47 (65%) patients, 37 (79%) had sustained platelet responses with a median platelet count of 106 × 10(9)/L (interquartile range, 75-167 × 10(9)/L), and 10 (21%) were still taking romiplostim, despite a median platelet count of 38 × 10(9)/L (interquartile range, 35-44 × 10(9)/L), but with clinical benefit (lower dose and/or fewer concomitant treatment(s) and/or diminished bleeding signs). A high bleeding score and use of concomitant ITP therapy were baseline factors predicting romiplostim failure. The most frequently reported adverse events were: arthralgias (26%), fatigue (13%), and nausea (7%). Our results confirmed that romiplostim use in clinical practice is effective and safe for severe chronic ITP. This trial was registered at www.clinicaltrials.gov as #NCT01013181.

HTLV-1 evades type I interferon antiviral signaling by inducing the suppressor of cytokine signaling 1 (SOCS1).

Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of Adult T cell Leukemia (ATL) and the neurological disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the majority of HTLV-1-infected individuals remain asymptomatic carriers (AC) during their lifetime, 2-5% will develop either ATL or HAM/TSP, but never both. To better understand the gene expression changes in HTLV-1-associated diseases, we examined the mRNA profiles of CD4+ T cells isolated from 7 ATL, 12 HAM/TSP, 11 AC and 8 non-infected controls. Using genomic approaches followed by bioinformatic analysis, we identified gene expression pattern characteristic of HTLV-1 infected individuals and particular disease states. Of particular interest, the suppressor of cytokine signaling 1--SOCS1--was upregulated in HAM/TSP and AC patients but not in ATL. Moreover, SOCS1 was positively correlated with the expression of HTLV-1 mRNA in HAM/TSP patient samples. In primary PBMCs transfected with a HTLV-1 proviral clone and in HTLV-1-transformed MT-2 cells, HTLV-1 replication correlated with induction of SOCS1 and inhibition of IFN-α/ß and IFN-stimulated gene expression. Targeting SOCS1 with siRNA restored type I IFN production and reduced HTLV-1 replication in MT-2 cells. Conversely, exogenous expression of SOCS1 resulted in enhanced HTLV-1 mRNA synthesis. In addition to inhibiting signaling downstream of the IFN receptor, SOCS1 inhibited IFN-ß production by targeting IRF3 for ubiquitination and proteasomal degradation. These observations identify a novel SOCS1 driven mechanism of evasion of the type I IFN antiviral response against HTLV-1.

Meta-analysis on the use of zidovudine and interferon-alfa in adult T-cell leukemia/lymphoma showing improved survival in the leukemic subtypes.

PURPOSE: Human T-cell lymphotropic virus type-I-associated adult T-cell leukemia/lymphoma (ATL) is an aggressive, chemotherapy-resistant malignancy. Multiple small studies using zidovudine (AZT) and interferon-alfa (IFN-α) have shown response in patients with ATL. However, the impact of this innovative antiviral treatment strategy on long-term survival remains undetermined. PATIENTS AND METHODS: We report a meta-analysis of antiviral therapy of ATL. Medical records of 254 patients with ATL who were treated in the United States, the United Kingdom, Martinique, and continental France were individually reviewed. RESULTS: According to Shimoyama classification, there were 116 patients with acute ATL, 18 patients with chronic ATL, 11 patients with smoldering ATL, and 100 patients with ATL lymphoma. In 231 patients with available survival data, first-line therapy was recorded in 207 patients. Five-year overall survival rates were 46% for 75 patients who received first-line antiviral therapy (P = .004), 20% for 77 patients who received first-line chemotherapy, and 12% for 55 patients who received first-line chemotherapy followed by antiviral therapy. Patients with acute, chronic, and smoldering ATL significantly benefited from first-line antiviral therapy, whereas patients with ATL lymphoma experienced a better outcome with chemotherapy. In acute ATL, achievement of complete remission with antiviral therapy resulted in 82% 5-year survival. Antiviral therapy in chronic and smoldering ATL resulted in 100% 5-year survival. Multivariate analysis confirmed that first-line antiviral therapy significantly improves overall survival of patients with ATL (hazard ratio, 0.47; 95% CI, 0.27 to 0.83; P = .021). CONCLUSION: These results confirm the high efficacy of AZT and IFN, which should now be considered the gold standard first-line therapy in leukemic subtypes of ATL.

Analysis of the ten-eleven translocation 2 (TET2) gene in familial myeloproliferative neoplasms.

The JAK2(V617F) mutation does not elucidate the phenotypic variability observed in myeloproliferative neoplasm (MPN) families. A putative tumor suppressor gene, TET2, was recently implicated in MPN and myelodysplastic syndromes through the identification of acquired mutations affecting hematopoietic stem cells. The present study analyzed the TET2 gene in 61 MPN cases from 42 families. Fifteen distinct mutations were identified in 12 (20%) JAK2(V617F)-positive or -negative patients. In a patient with 2 TET2 mutations, the analysis of 5 blood samples at different phases of her disease showed the sequential occurrence of JAK2(V617F) and TET2 mutations concomitantly to the disease evolution. Analysis of familial segregation confirmed that TET2 mutations were not inherited but somatically acquired. TET2 mutations were mainly observed (10 of 12) in patients with primary myelofibrosis or patients with polycythemia vera or essential thrombocythemia who secondarily evolved toward myelofibrosis or acute myeloid leukemia.

Retinal vasculitis caused by adult T-cell leukemia/lymphoma.

BACKGROUND: To report a case of lymphomatous infiltration and bilateral retinal vasculitis observed among 83 cases of adult T-cell leukemia (ATL) treated in the University Hospital Center in Fort-de-France (Martinique, French West Indies) between 1984 and 2003. CASE: A complete clinical ophthalmologic examination was performed in this patient along with fluorescein angiography. OBSERVATIONS: After being checked for diffuse adenopathies, myodesopsias, and phosphenes, the 35-year-old patient was diagnosed with ATL. The ocular impairment, present since the onset of ATL as peripheral subretinal infiltrates, spread progressively and afferently to the rest of the retina in the form of an essentially venous vasculitis. Impairment of the vitreous was noted only in the end stages of disease progression. As ocular lesions progressed, the general state of the patient degraded at the same time despite chemotherapeutic measures. CONCLUSION: Among the more than 300 seropositive for human T-cell lymphotropic virus type 1 (HTLV-1) or patients with HTLV-1-associated myelopathy/tropical spastic paraparesis treated at our hospital in the last 20 years, and among the 83 cases of ATL, only this single case of retinal vasculitis associated with HTLV-1 was observed (1/83, 1.2%) in Martinique, confirming the geographic variability of the clinical phenotype of HTLV-1 infection. The incidence of retinal vasculitis in ATL patients may signify an even worse prognosis than initially indicated.

Treatment of adult T-cell leukemia-lymphoma by CHOP followed by therapy with antinucleosides, alpha interferon and oral etoposide.

UNLABELLED: Adult T-cell leukemia-lymphoma (ATLL) has a very bad prognosis and remains resistant to conventional therapy. Promising results have been reported with the combination of zidovudine (AZT) and alpha-interferon (IFN). METHOD: A combination with IFN and antinucleoside [AZT or zalcitabine (ddC)] was applied since 1995 in Martinique (French West Indies). An initial treatment with two cycles of CHOP was added to reduce initial tumoral burden, followed by antiretroviral (ARV) therapy associated with etoposide. We report the characteristics and outcomes of 29 patients diagnosed with an ATLL between 1990 and 1999. The overall median survival was 8 months. A striking improvement of survival was observed when comparing the periods between 1990-1994 and 1995-1999 (17 months versus 3 months, p = 0.004). During the second period, seven patients received a therapy with oral etoposide, antinucleoside and IFN, among which, six patients received an initial induction CHOP chemotherapy. No major toxicity was observed with this strategy. In conclusion, the progression of survival since 1995 suggests that a therapeutic approach combining initial polychemotherapy with CHOP followed by ARV drugs, IFN and oral etoposide is an interesting option in treating patients with ATLL.