Abstract
Background: In aplastic anemia (AA), antithymocyte globulin (ATG) plus ciclosporine (CsA) is an effective alternative to hematopoietic stem cell transplantation (HSCT). Following the National Institute of Health (NIH) randomized study (Scheinberg et al, NEJM 2011) that showed that horse ATG (hATG) was more effective than rabbit ATG for first-line treatment of severe AA, the French Health Agency (ANSM) approved a patient-named Authorization for temporary use (ATU) program of hATG (ATGAM, Pfizer) in pts with AA, since hATG (Lymphoglobuline) was withdrawn from the European market in 2007. We took advantage of this program to assess the efficacy and safety of hATG (ATGAM) on a large number of pts with severe AA, but also moderate, refractory or relapse AA, who consecutively received ATGAM in France.
PATIENTS AND METHODS: All pts not eligible for transplantation could be included in the ATU program. ATGAM was administered at a dose of 40 mg/kg/day for 4 days. CsA was administered with the dose adjusted to maintain trough blood levels of 200 to 400 ng per milliliter for one year and then decrease to stop before end of year 2. An expert reviewed applications before acceptance on behalf of the French reference center for AA. All data presented here were collected at the reference date of January 31th 2015. Latest guidelines were used to define disease severity, treatment indication, and response rates (Marsh et al BJH 2014). The primary endpoint was hematologic response at 6 months. Secondary endpoints included hematologic response at 3 months, safety, relapse, clonal evolution (myelodysplasia and acute myeloid leukemia) and survival. The study was conducted according to HelsinkiÕs Declaration.
RESULTS: Between September 2011 and January 2015, 341 pts had received at least one course of hATG plus CsA in 76 French centers (288 first line treatment, 30 for relapse and 15 for refractory AA). Characteristics of the pts are shown in Table 1. The median follow-up was 333 days (range, 2 to 876) for all pts (331 days for first line treatment, 359 days for refractory pts and 350 days for relapse). Overall response rates for pts are indicated in Table 2. For patients who received hATG plus CsA first line, 6 months overall response was 85% and 57% in pts with moderate AA and severe AA, respectively (40% at 6 months for pts with very severe AA). The only factor significantly associated with better response at 6 months was the severity of the disease: severe AA versus moderate AA, hazard ratio (HR) 0.22; 95% confidence interval (95%CI) (0.1 - 0.5); p <0.001 and very severe AA versus moderate AA (HR: 0.12; 95%CI: (0.05 - 0.28; p <0.001). The most common reported adverse events (AE) (>2%) consisted mainly in pyrexia (9.3%), urticarial reactions (5.4%), infusion site reaction (3.6%), high blood pressure (2.6%), kidney failure (2.3%), and chills (2.3%). Overall survival for the entire cohort was 90% at 1 year (90% for first line treatment, 85% for refractory pts and 97% for relapse). During the study, 30 pts died. Main causes of death were Infections in 20 pts (14 bacterial sepsis and 6 fungal infections), hemorrhage in 3 pts and other causes in 7 pts.
CONCLUSION: Efficacy and safety of ATGAM plus CsA was similar to published historical data in this large real-life cohort of patient-named ATU program with mostly severe and very severe but also moderate AA pts, as well as refractory and relapse AA pts. These data confirm ATGAM as standard of care IST to treat pts with AA not eligible for HSCT.
Research support was provided in part by Pfizer.
Peffault De Latour:Amgen: Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Récher:Celgene, Sunesis, Amgen, Novartis, Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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