Currently, about one-third of patients with aplastic anaemia are refractory to anti-thymocyte globulin (ATG). This, combined with the immediate cost of ATG, causes a considerable fraction of Chinese patients refuse to receive ATG/ciclosporin-based immunosuppressive regimens. For such patients, an alternative approach is urgently needed.
This study investigated the suitability of treatment with arsenic trioxide (ATO) plus ciclosporin as a novel therapeutic approach for patients with aplastic anaemia. A total of 10 consecutive adults with a diagnosis of severe aplastic anaemia (SAA), defined according to standard criteria (Rosenfeld et al, 2003), were enrolled between April 2007 and May 2009. The study was approved by the Institutional Review Board at Henan Tumour Hospital and all patients signed an informed consent.
All patients with SAA were administered ATO plus ciclosporin. ATO was administered at a dose of 0·15 mg/kg intravenously daily for 5 d every week for 8 weeks. If necessary, a second course was performed after an interval of 1 week. Ciclosporin (5 mg/kg orally daily) was started from day one for 6 months. The dose was adjusted to achieve a whole blood trough level of 100–200 ng/ml.
The primary end points were significant haematological responses or transfusion independence. Response was defined as the absence of recent transfusion. Complete response (CR) was defined as satisfaction of all three peripheral blood count criteria: (i) absolute neutrophil count (ANC) >1 × 109/l; (ii) haemoglobin >100 g/l; (iii) platelet count >100 × 109/l. Partial response (PR) was defined as transfusion independence combined with ANC >0·5 × 109/l, haemoglobin >80 g/l, and platelet count >30 × 109/l. Transfusion dependence was taken as evidence of no response. Relapse was indicated by the requirement for blood transfusion after having been independent from transfusions for at least 3 months.
The clinical characteristics of patients entered into the study are summarized in Table 1. The overall response rate at 8 weeks was 100% (10/10); 30% (3/10) CR and 70% (7/10) PR. The median time to initial response was 41 d (range, 38–46 d). Seven patients with a PR continued to receive a second course of ATO and continued to have clinically significant improvements in blood counts. Five of them eventually met response criteria for CR at 17 weeks after the initiation of treatment, to give 17-week overall CR and overall response rates of 80% (8/10) and 100% (10/10), respectively (Table 1). Serial bone marrow biopsies showed haematopoietic recovery accompanied by a decrease in adipocyte number in patients after achieving a response (Fig 1). To date, no patient has relapsed and shown evidence of clonal evolution or cytogenetic abnormalities.
|Patient||Age (years)/gender||Platelet count (×109/l)||Haemoglobin (g/l)||ANC (×109/l)||Time to initial Response (days)||Time to maximum response (days)||Final response||Present status|
|Before therapy||After maximum response||Before therapy||After maximum response||Before therapy||After maximum response|
|1||21/M||9||124||50||109||0·1||2·1||38||51||CR||CR and well 62 months|
|2||36/F||12||151||51||116||0·2||1·8||46||69||CR||CR and well 53 months|
|3||43/M||15||59||47||84||0·1||0·7||40||61||PR||PR and well 50 months|
|4||39/F||11||127||59||126||0·2||1·9||43||101||CR||CR and well 46 months|
|5||27/M||6||118||57||122||0·3||1·8||43||94||CR||CR and well 41 months|
|6||23/M||9||140||61||110||0·2||1·7||44||86||CR||CR and well 40·6 months|
|7||35/F||13||76||60||87||0·2||0·8||41||73||PR||PR and well 40·1 months|
|8||41/M||13||109||61||134||0·4||1·9||41||83||CR||CR and well 39 months|
|9||39/F||16||128||59||125||0·3||1·8||39||53||CR||CR and well 37·3 months|
|10||19/M||10||119||58||123||0·1||2·0||41||91||CR||CR and well 36 months|
ATO-related toxicities in the 10 patients were: skin reactions (rash, n = 1), gastrointestinal reactions (nausea, n = 1), liver dysfunction (n = 1) and facial oedema (n = 2). All the side effects were modest and responded to symptomatic treatment. No patient discontinued therapy because of ATO-related toxicities.
The fact that immunotherapy proves effective in the majority of SAA patients supports the assumption that patients with SAA must have residual haematopoietic progenitors in their bone marrow. SAA is characterized by a reduced number of haematopoietic cells and adipocyte replacement in the bone marrow. Studies suggest that bone marrow adipocytes are predominantly negative regulators of the bone marrow microenvironment (Naveiras et al, 2009). Bone marrow adipocytes are less supportive of haematopoiesis than those of other cell types derived from mesenchymal progenitors, such as bone marrow myofibroblasts or osteoblasts (Nishikawa et al, 1993; Corre et al, 2006). Moreover, adipocytes secrete tumour necrosis factor alpha and neuropillin-1, which can inhibit progenitor activity or impair haematopoietic proliferation (Zhang et al, 1995; Belaid-Choucair et al, 2008). In addition, data show that ablation of the bone marrow adipocyte compartment can induce osteogenesis (Naveiras et al, 2009), which promotes a more supportive environment for haematopoietic reconstitution (Calvi et al, 2003; Naveiras et al, 2009). This is in accordance with the data indicating that surgical removal of the adipocyte-rich marrow induces haematopoietic infiltration and new osteoid and trabecular bone formation in rabbit tibias (Tavassoli et al, 1974). Considering that adipocytes and osteoblasts originate from the common precursors known as mesenchymal stem cells (MSCs) within the bone marrow, where both display an inverse or reciprocal relationship (Nuttall & Gimble, 2004), and that ATO could regulate the adipogenic and osteogenic differentiation of MSCs by significantly inhibiting adipogenic differentiation and enhancing MSC osteogenic differentiation (Cheng et al, 2011), ATO might serve as an adjuvant to haematopoietic recovery for patients with SAA in immunosuppressive therapy. In our study, all patients achieved clinically significant responses to ATO plus ciclosporin. Therefore, treatment with ATO plus ciclosporin may be a novel therapeutic approach in patients with aplastic anaemia. Further studies should be done to accumulate more patients and evaluate the therapeutic efficacy of this combination.