Single-Center Experience of Immunosuppressive Therapy with or without Eltrombopag in Patients with Aplastic Anemia

Background Immune-mediated destruction of hematopoietic stem (HSC) and progenitor cells, leading to their depletion, has been implicated as the pathophysiology behind bone marrow (BM) failure in aplastic anemia (AA). Immunosuppressive therapy (IST) using antithymocyte globulin (ATG) and cyclosporine has been successfully used in the treatment of cytopenias in patients (pts) with severe aplastic anemia (AA). Recently, the thrombomimetic eltrombopag (E-PAG) has been shown to have activity in refractory AA, presumably by increasing the numbers of BM HSCs. To simultaneously target both immune destruction and HSC depletion, we studied the combination of E-PAG with IST in pts with newly diagnosed severe AA. Methods This is a single-arm phase II study evaluating the following combination in pts with AA: hATG 40 mg/kg/day (or 35 mg/kg/day for age ≥ 55 yrs) intravenously (IV) for 4 days, methylprednisone 1mg/kg/day IV daily for 5 days (prior to each dose of ATG), followed by PO prednisone tapered off over 1 month, G-CSF (filgrastim or pegfilgrastim) SQ for up to 3 months, and cyclosporine (5 mg/kg) daily for up to 6 months. After the results of E-PAG in refractory AA, the protocol was amended to study the addition of E-PAG to IST. It was started at a dose of 50mg PO daily with increase by 25mg Q2 weeks to a max of 150mg PO daily in the absence of platelet response. Responses were assessed at 3 and 6 months after initiating therapy per the standard criteria. Results A total of 31 pts with untreated AA were enrolled; the first 17 (55%) were treated with IST alone and the next 14 (45%) with IST + E-PAG. The characteristics of pts in the 2 cohorts are listed in Table 1. Pts receiving E-PAG were older, had significantly lower blood counts, and were less likely to have T-cell receptor clonality (27% vs. 60%, P=0.06). Twenty-one of the 31 evaluable pts responded (ORR=68%), including 7 CR (23%). Pts receiving IST + E-PAG had a higher ORR rate vs. IST alone (79% vs. 59%, P=0.28) and a longer median time to response (TTR, 46 vs. 37 days, P=0.14). Table 2 outlines the pretreatment pt characteristics of responders vs. non-responders. Overall, responding pts had significantly higher pretreatment WBC (P=0.04) and ANC (P=0.05); were more likely to have a detectable PNH clone (P=0.07); and less likely to have oligoclonal T-cells. Figure 1 shows OS by therapy and response. The 12-month OS for pts receiving IST vs. IST+ E-PAG was 86% vs 94% (P=0.90), respectively. The 12-month OS for responders vs. non-responders was 100% vs. 58% (P=0.01), respectively. The treatment was tolerable, with no additional toxicities noted after the addition of E-PAG. The most common grade 3/4 non hematologic toxicities were infection (3), musculoskeletal pain (3), transaminase elevation (1), fatigue (1), intracranial bleed (1), chest pain (1), headache (1), and serum sickness (1). One pt had an allergic reaction (grade 3) and was taken off protocol. Despite including older pts and those with significantly lower blood counts, the cohort receiving E-PAG had a higher ORR than IST alone, albeit with a longer TTR. A higher WBC count and ANC as well as the presence of a PNH clone were associated with response and response was associated with an improved OS. The combination of hATG, cyclosporine, steroids, G-CSF and E-PAG is a well-tolerated and effective regimen in the treatment of aplastic anemia and should be studied further. Disclosures Off Label Use: Use of eltrombopag in the frontline treatment of aplastic anemia is off-label. Daver:ImmunoGen: Other: clinical trial, Research Funding. Cortes:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Teva: Research Funding; BerGenBio AS: Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. DiNardo:Novartis: Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria.