The thrombopoietin mimetics eltrombopag and romiplostim in the treatment of refractory aplastic anaemia

Aplastic anaemia (AA) is potentially fatal (Scheinberg & Young, 2012). Immunosuppression is the first-line approach due to its autoimmune aetiology (Killick et al, 2016). If immunosuppression fails, allogeneic haematopoietic stem cell transplantation may be considered. Otherwise, the options are limited. Recently, the thrombopoietin mimetics eltrombopag and romiplostim have become available for treating immune thrombocytopenia (Rodeghiero & Ruggeri, 2015). Eltrombopag has been shown effective in refractory AA, inducing an overall-response rate (ORR) of 40% (Olnes et al, 2012; Desmond et al, 2014). However, only <50 eltrombopag-treated patients had been reported from a single centre, and romiplostim remains untested. We reviewed AA patients treated with thrombopoietin mimetics for ≥12 weeks. The thrombopoietin mimetics dosages varied at the discretion of the attending physician. Responses were assessed at 12 and 16 weeks (erythroid: increase of haemoglobin ≥15 g/l for pre-treatment level <90 g/l, or transfusion reduction of 4 units in 8 weeks as compared with the preceding 8 weeks; neutrophil: increase of ≥0 5 9 10/l; platelet: increase of ≥20 9 10/l) (Olnes et al, 2012). Treatment was continued with responses or count improvement not yet reaching response criteria, and discontinued after 16 weeks without count improvements. All patients gave informed consent. Thirteen consecutive refractory AA patients were treated between 2012 and 2015. Three patients were excluded (treatment: 4 and 9 weeks; ultimate diagnosis of T-cell large granular lymphocyte leukaemia; Table SI). Six men and 4 women at a median age of 49 (20–68) years were analysed (Table I; Table SII). Six patients had severe AA. Karotype was normal in all but one (Patient 6, karyotyping unsuccessful) patients. No patient showed cells deficient in glycosylphosphatidylinositol-linked proteins (Kwong et al, 1994). Median duration of AA before thrombopoietin mimetics treatment was 26 (4–360) months. Six patients had received a median of 2 (1–4) courses of antithymocyte globulin (ATG). Two patients (Patients 1, 10) refused ATG. In two other patients (Patients 3, 4), ATG and corticosteroids were considered hazardous (supplemental file 2). Eltrombopag was administered to every patient (Table I). Dose started at 25 mg/day, escalating to 50–300 mg/day, and was tapered after the best response. In six patients, ciclosporin (post-ATG, N = 5; sole therapy, N = 1) was continued. Six patients (60%) responded. Four patients (Patients 1, 3, 6, 9) achieved platelet response at 12 weeks. Patient six improved to platelet+neutrophil response at 16 weeks. On continuing treatment, Patient three achieved platelet+neutrophil response and Patients six and nine achieved trilineage response. At 16 weeks, an additional patient (Patient 4) achieved platelet response. One patient (Patient 7) with count improvement not reaching response criteria at 16 weeks finally achieved trilineage response with continued treatment. One patient with very severe AA (Patient 8) received eltrombopag and romiplostim. After two failed courses of ATG, treatment with eltrombopag (reaching 300 mg/day) and romiplostim (reaching 30 lg/kg/week) was ineffective (Fig 1A). Eight months after a failed third course of ATG, eltrombopag re-treatment resulted in a brisk platelet response. Because of dyspepsia, eltrombopag was stopped and the response was rapidly lost. Eltrombopag re-treatment led to a further platelet response. Intractable dyspepsia necessitated eltrombopag discontinuation and the response was lost. Interestingly, romiplostim re-treatment resulted in another platelet response that was unsustained. Romiplostim was finally stopped. Sixty-two weeks afterwards, circulating blasts were detected. Bone marrow examination confirmed acute myeloid leukaemia (AML). Karyotyping showed monosomy 7 in all metaphases. On retrospective fluorescence in-situ hybridization, the monosomy 7 clone was not present in the presentation marrow. However, in marrow taken before the third course of ATG, monosomy 7 was found in about 20% of cells. The most common side effect of eltrombopag was hyperpigmentation, observed in 5 patients (Fig 1B). All had doses >100 mg/day. Hyperpigmentation was reversible with dose reduction to <100 mg/day. Dyspepsia occurred in four patients, resulting in drug discontinuation in one patient (Patient 8). In Patient 3, dyspepsia heralded transaminitis (peak alanine transaminase: 360 iu/ml; range: 8–45 iu/ml). Endoscopy showed gastritis, confirmed histologically. Both gastritis and transaminitis subsided with dose reduction from 150 to 50 mg/day. For milder dyspepsia, symptomatic treatment sufficed. No adverse events occurred for doses ≤100 mg/day. The only romiplostim-treated patient experienced dyspepsia with doses >10 lg/kg/week. Symptomatic treatment sufficed. At a median follow-up of 75 (16–169) weeks after initiation of eltrombopag, seven patients were still receiving treatment,