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

Abstract

Treatment of aplastic anemia (AA) in the elderly is particularly challenging due to higher toxicity and lower efficacy of the available therapies. In fact, 30-40% of patients eligible for intensive immunosuppressive treatment (IST) with horse anti-thymocyte globulin (ATG) plus cyclosporine (CyA) will relapse and only a few cases would be candidates for hematopoietic stem cell transplant (HSCT). Moreover, ATG might be contraindicated in frail patients or in those with infectious comorbidities, and CyA alone is of limited benefit. Recently, prospective trials show the clinical efficacy of eltrombopag in refractory/relapsed AA, with up to 40% hematologic improvement, and, intriguingly, persistent remission upon discontinuation in robust responders. Moreover, eltrombopag was added to frontline IST, with an overall response rate exceeding 80%. Clinical and laboratory characteristics predicting eltrombopag response in AA are still largely unknown, and data about real-life use of this drug are scarce. Here we analyzed the baseline hematologic and morphological (bone marrow aspirate and trephine) variables and clinical course of 49 AA cases treated with eltrombopag at two tertiary hematologic institutions in the UK, from January 2012 to January 2018. We focused on efficacy, safety, impact on disease outcome, and on potential clinical and laboratory predictors of treatment response (Online Supplementary Methods). Median age was 67 years [interquartile range (IQR): 50.571.5, 82% >60 years], 56% of cases had severe or very severe AA, and the majority were either red cell or platelet transfusion dependent (Table 1). Endogenous erythropoietin (EPO) and thrombopoietin (TPO) levels were markedly elevated in all cases, and telomere length (TL) reduced (<10 percentile) in 11. Regarding bone marrow (BM) features, all cases displayed reduced cellularity; the relative percentage of lymphoid cells was >10% in 20 cases, with no clonal lymphoid infiltrate or cases of T-cell large granular lymphocytic (TLGL) leukemia by immunohistochemistry or immunophenotyping. Cytogenetics were abnormal in four patients (2 with del13q, one each with trisomy 8 and loss of Y), and failed in eight cases (16%) of whom one showed presence of the +8 by fluorescence in situ hybridization (FISH). Paroxysmal nocturnal hemoglobinuria (PNH) clone was detected in 32 patients (65%), and clone size was <1% in 11 cases, 1-10% in 12, 10-50% in 5, >50% in 3 cases (one requiring eculizumab). Seven patients were treatment naïve and 42 had received prior therapy (median: 1; range: 1-3), of whom eight patients had relapsed and 34 were refractory AA (Online Supplementary Figure S1). The median time from diagnosis to eltrombopag was 330 days (IQR: 108-695), shorter for the treatment naïve group. Patients received eltrombopag for a median of four months (range: 3.5-30 months) at median dose of 150 mg/day, and CyA was continued in three patients. Overall 11 patients (22%) responded to eltrombopag, nine partial response (PR) and two complete response (CR) according to the criteria of the European Group for Blood and Marrow Transplantation (EBMT) (first response) at 12 weeks. Six patients converted their PR into CR (best response) on continuing treatment. Mean time to first response was 4.4+2 months and to best response was 12.3+10.5 months. Interestingly, all responders attained trilineage hematologic improvement and robust response, as by National Institutes of Health criteria. Mean Hb level increase from baseline was 34+12.4 g/L, platelet count increase was 80+53x10/L, and ANC increase 1.25+0.95x10/L (P<0.001, P<0.001, and P=0.02, respectively). Moreover, 21% and 14% cases became red cell and platelet transfusion independent, respectively. BM re-evaluation after eltrombopag (n=25) showed significantly increased cellularity (30+26% vs. 16+13%; P=0.004), more prominent in responders, and one responding patient displayed increased fibrosis (from MF0 to MF2). Considering PNH clone size dynamic after eltrombopag treatment, median granulocyte size increased in ten cases (mean