PARP-14 combines with tristetraprolin in the selective posttranscriptional control of macrophage tissue factor expression
2014
Background: Adult patients undergoing remission-induction (RI) chemotherapy for newly diagnosed acute lymphoblastic leukaemia (ALL) are at high risk of invasive fungal disease (IFD), particularly invasive aspergillosis. The prevalence of IFD in this population has not been widely studied. There is currently no approved standard for antifungal prophylaxis and it is recommended by the European Working Group for Adult ALL that azole antifungal agents be avoided because of drug interactions with vincristine, a standard component of induction chemotherapy regimens. Methods: This was a double-blind, multicentre, placebo-controlled study in patients aged ≥18 years receiving RI chemotherapy for newly diagnosed ALL. Study subjects received either liposomal amphotericin B (L-AMB) 5mg/kg or placebo by IV infusion twice weekly in a 2:1 random allocation. The primary endpoint of the study was the proportion of subjects with proven or probable invasive fungal infection (IFI) assigned in a blinded review by an independent data review board (IDRB) using EORTC/MSG (European Organization for Research and Treatment of Cancer/Mycoses Study Group) definitions (1). Subjects were closely monitored for signs and symptoms of IFI, including biweekly galactomannan and β-D-glucan assessments. Clinical, laboratory or radiographic findings suggestive of IFI prompted further investigation according to a specified protocol. Subjects with defined clinical and mycological criteria or a halo sign on chest CT had prophylaxis interrupted and pre-emptive antifungal therapy initiated while further diagnostic procedures were undertaken. Prophylaxis was stopped when subjects met protocol-specified criteria for proven or probable IFI and appropriate antifungal therapy started. Secondary objectives included safety and tolerability of prophylactic L-AMB and the impact of IFI prevention on the efficacy of RI chemotherapy. Results: A total of 355 subjects from 83 centres in 13 countries in Europe (including Turkey and Israel) and South America were randomised and received at least 1 dose of either L-AMB (n=237) or placebo (n=118). Sixteen subjects were excluded from the efficacy analysis, 1 due to misdiagnosis (AML) and 15 due to protocol-prohibited antifungal treatment. 7.9% (18/228) subjects in the L-AMB group and 11.7% (13/111) subjects in the placebo group were considered by the IDRB to have experienced a proven or probable IFI (p=0.24, RR 0.33 [CI -0.32 to 0.66]). Of these, 1 case (0.4%) in the L-AMB group and 3 cases (2.7%) in the placebo group were considered proven. In subjects who were neutropenic (absolute neutrophil count 9 /L) ≥10 days, the incidence was 6.9% (12/174) in the L-AMB group versus 13.1% (11/84) in the placebo group (p=0.10). Overall mortality was similar: 7.2% (17/237) in the L-AMB group vs 6.8% (8/118) in the placebo group (p=1.00) as was the incidence of serious adverse events (SAEs; 33.3% (79/237) vs 32.2% (38/118), [p=0.90]). SAEs of any grade related to the study drug were reported for 8.4% subjects (20/237) in the L-AMB group compared with 1.7% subjects (2/118) (p=0.02) in the placebo group. The most common (>5%) study drug-related adverse events (AEs) were hypokalaemia (10.5% [25/237] vs 3.4% [4/118] p=0.02) and increased creatinine (6.3% [15/237] vs. 0% [p=0.003]). Complete remission at the end of RI chemotherapy was achieved by 72.6% (172/237) subjects in the L-AMB group versus 78.8% (93/118) subjects in the placebo group (p=0.24). Conclusions: In this study, the largest of its kind to date, the rate of IFI among adult patients undergoing RI chemotherapy for newly diagnosed ALL was 11.7% in the placebo group. Study subjects who received L-AMB at 5mg/kg twice weekly for prophylaxis showed a reduction in IFIs relative to placebo (RR 0.33 [CI -0.32 to 0.66]), although this did not reach statistical significance (p=0.24). L-AMB prophylaxis was generally well tolerated. The incidence of IFI in patients with ALL receiving RI therapy indicates that antifungal prophylaxis is merited in this patient population. Further analysis is needed to determine which patients might benefit the most. clinicaltrials.gov number: NCT01259713 (1) De Pauw et al 2008 Clin Infect Dis 46: 1813–1821 Disclosures Cornely: Gilead Sciences: Consultancy, Research Funding, Speakers Bureau. Off Label Use: Liposomal Amphotericin B (AmBisome®) is a broad spectrum antifungal agent indicated for the treatment of severe systemic and/or deep mycoses, empiric treatment of presumed fungal infections in febrile neutropenic patients and treatment of visceral leishmaniasis. In this study the efficacy, safety and tolerability of prophylactic liposomal amphotericin B (AmBisome®) was explored for the prevention of invasive fungal infections in subjects receiving remission-induction chemotherapy for Acute Lymphoblastic Leukaemia (the AmBiGuard trial).. Leguay: Gilead Sciences: Research Funding. Maertens: Gilead Sciences: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Castagnola: Gilead Sciences: Research Funding. Anagnostopoulos: Gilead Sciences: Research Funding. Allione: Gilead Sciences: Research Funding. Heussel: Gilead Sciences: Consultancy, Speakers Bureau. Donnelly: Astellas, Gilead, Merck, Pfizer: Consultancy, Honoraria, Research Funding. Agrawal: Gilead, Pfizer, Astellas, MSD, Bio-Rad: Honoraria, Research Funding. Garner: Gilead Sciences: Employment, Equity Ownership. Simcock: Gilead Sciences: Employment, Equity Ownership. Hawkins: Gilead Sciences: Employment, Equity Ownership. Goekbuget: Gilead Sciences: Consultancy, Honoraria.
Keywords:
- Clinical endpoint
- Placebo
- Off-label use
- Absolute neutrophil count
- Population
- Molecular biology
- Immunology
- Induction chemotherapy
- Tolerability
- Adverse effect
- Medicine
- Untranslated region
- RNA
- Three prime untranslated region
- Tissue factor
- Messenger RNA
- Tristetraprolin
- Regulation of gene expression
- Biology
- Tumor necrosis factor alpha
- Correction
- Source
- Cite
- Save
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