Clinical and morphologic predictors of outcome in aplastic anemia patients treated with eltrombopag

Background Aplastic anemia (AA) is a rare autoimmune disease with high morbidity and mortality mainly due to bleeding and infections. Although immunosuppressive therapy (IST) is a highly effective first line treatment, up to 30-40% of cases would be refractory to or relapse after IST. TPO mimetic eltrombopag (EPAG) has demonstrated 40% response in refractory AA, however little is known about predictors of response. Aims To evaluate clinical/morphologic predictors of response and outcome in a cohort of EPAG treated patients. Methods 49 AA patients treated with EPAG in a compassionate use program from January 2012 to July 2017 were evaluated. Clinical and hematologic parameters including treatment response (PR=transfusion independence, CR=hematologic normalization) and marrow characteristics were collected. Results Table 1 shows baseline clinical and morphologic characteristics: all cases were transfusion dependent and 4 showed cytogenetic aberrations (+8, delY, and del13q in 2 cases). 43 cases had received a previous treatment (IST or androgen). Patients received EPAG for a median of 4 months (range 3.5-30), and 11 cases (22%) responded, of whom 4 PR and 7 CR. Median time to best response was 3 months. Compared to baseline, 21% of cases became RBC and 14% PLT transfusion independent. Hematologic improvement was observed in all three lineages (mean Hb, PLT and ANC increase was 34+12.4 g/L p<0.001, 80+53x103/mcL p<0.001, and 1.25+0.95x103/mcL, p=0.02, respectively). The presence of moderate disease was associated with a better response (73% in responders vs 24 in non-responders, p=0.004), together with a lower lymphoid marrow percentage (9.1 vs 18.1%, p=0.04), and with a smaller PNH clone (0.69+1.1% versus 11.22+24%, p=0.01). Patients who relapsed after IST showed a better response to EPAG (p=0.05). Marrow cellularity significantly improved after EPAG therapy in responders (p=0.004), whereas PNH clone dynamic changes did not show any relationship with response. 29 % of cases experienced an adverse event including nausea (N=2, grade I and II), diarrhea (2, grade II and III), liver enzyme elevation (3, grade II), rash (grade II), muscle cramps (grade I), pneumonia (grade III), sepsis (grade III), and bone marrow fibrosis (2). Eleven patients (9 responders and 2 non-responders) are still on treatment, whereas 38 discontinued because of death (11), lack of response (21), loss of response (2), evolution to MDS (1), treatment intolerance (1), no response with increase in marrow fibrosis (1), and longstanding CR with bone marrow fibrosis (1). Three cases relapsed after 7, 15 and 34 months, respectively. One received danazol, another cyclosporin and tacrolimus, and the latter was re-challenged with EPAG with a new CR. Among non-responders, 10 cases received supportive care, 6 androgens, 1 ATG, 3 cyclosporin, and 7 underwent HSCT. One patient with large PNH clone was treated with eculizumab. Median overall survival (OS) calculated from the beginning of eltrombopag was 9 months (range 4-54 months), and was significantly longer in patients responding to eltrombopag therapy (34 versus 7 months, p=0.003), with 100% OS in responders versus 50% in non-responders at 12 months. Conclusion EPAG is effective and safe in the real world setting, although with a lower response rate (22%). Non-severe AA, relapsed disease rather than refractory AA, smaller PNH clone, and lower marrow lymphoid percentage seem to correlate with better response to treatment. Finally, response to treatment significantly predicts better survival.