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Aplastic anemia in the elderly
pathophysiology to that seen in younger patients. The majority of AA cases in the elderly are idiopathic, since hardly any genetic or viral etiologies are found in this population.7,8 However, distinguishing AA from hypocel- lular myelodysplasia or acute myeloid leukemia (AML) is clearly essential at this age.9 The gender ratio is also dif- ferent: although the majority of AA patients under 40 are men, six in 10 patients over the age of 60 are women.7 From a biological perspective, more mutations are found in AA among the elderly that are potentially associated with adverse outcomes.10 Conversely, cytogenetic abnor- malities are more frequent in younger patients.11 Moreover, age over 60 years has been identified as an independent risk factor for mortality in AA.4,10
Various therapeutic options for AA can be proposed. Immunosuppressive regimens – with anti-thymocyte globulin (ATG) associated with cyclosporine-A (CsA), or CsA alone – have been used to treat AA in the elderly, but have been little studied in this population.7,12,13 ATG-CsA regimen is recommended as first line in patients over the age of 60 with severe or very severe AA.14,15 Other options may include androgens, eltrombopag, alemtuzumab, sup- portive care alone, monitoring with no active treatment, and palliative care; however, none of these has been stud- ied specifically in the elderly. Likewise, data on combined treatments with CsA remains scarce. Eltrombopag has been added to the most recent recommendations for treating AA in the elderly, and may be used as a stand- alone second-line treatment.15 Androgens, with or with- out CsA, are recommended as a first-line treatment for non-severe AA.14 Allogeneic hematopoietic stem-cell transplantation (AHSCT) with a matched sibling donor is recommended as front-line treatment for patients under the age of 40.16 Recent study suggests that matched sib- ling donor AHSCT with reduced intensity conditioning may be safely performed after the age of 40 with encour- aging outcome.17 However, in older patients, AHSCT is associated with higher risks, as well as treatment-related mortality and toxicity, even when sibling donors are used.16,18,19 Consequently, AHSCT in patients over the age of 50 is usually only undertaken in very rare and specific cases.16,18
Our study therefore aimed to describe the epidemiolo- gy and treatments administered to elderly AA patients in France, as well as to address the factors associated with treatment response and outcome in this population.
Methods
Study Design and Case Detection
We conducted a retrospective study in 19 centers in France on behalf of the French Reference Center for Aplastic Anemia. Cases that fitted the inclusion criteria were identified within a 10-year period (1/1/2007 to 12/31/2016). We started by including all patients whose symptoms and treatments were reviewed month- ly in the French Reference Center for Aplastic Anemia. We then asked the pathologist of each center to send us reports concerning patients with aplasia or hypoplasia in their bone marrow biopsy analysis, among whom we identified patients with AA. Before inclusion, all cases were reviewed (AC, FSF, RPL) and data were anonymously collected in a case report form. In accordance with French law, written consent was not required for this retrospective non-interventional study. Patients provided a non-opposition statement.
Population
Patients who were diagnosed with AA by a bone marrow biop- sy at the age of 60 or over were included in the study. All histolog- ic diagnoses were made or confirmed in the French lymphopath network, on an expert basis analysis. Patients with toxic or chemotherapy-related aplasia, hypocellular myelodysplasia or AML according to previously published criteria,9 or paroxysmal nocturnal hemoglobinuria (PNH) without AA, were all excluded.
Definitions
Severe AA (SAA) was defined according to the Camitta criteria20 as a bone marrow hypoplasia (<30%) shown by a biopsy with two of the three following criteria: polymorphonuclear neu- trophils (PMN) <0.5x109/L, platelets <20x109/L, or reticulocytes <20x109/L. Very severe AA (vSAA) was defined using the same three criteria, but with PMN <0.2x109/L.21 Mild AA was defined by medullar hypoplasia and two associated cytopenias, but no cri- terion for SAA.
Complete remission (CR) was declared if the patient had the following blood counts without any transfusion: PMN >1x109/L, hemoglobin >10g/dL, and platelets >100x109/L. Partial response (PR) was defined by the absence of any criterion for either SAA or CR. For patients with mild AA, PR was defined by a significant and stable improvement in the blood counts and no more transfu- sion requirements, along with no criterion for CR. All other situa- tions corresponded to treatment failure. Responses were consid- ered to be assessable if the treatment line had been initiated more than three months previously, or if a response had occurred before this time.
Treatment lines corresponded to the period between the date of diagnosis for the first line or date of treatment initiation for the fol- lowing lines and either the date of the next treatment line or the date of patient death. Erythropoietin (EPO) and granulocyte- colony stimulating factor (G-CSF) were considered to be support- ive care treatments rather than treatment lines.
PNH clones were assessed using flow cytometry analysis on PMNs and monocytes. PNH clone size detection was considered to be positive if above 5%. At inclusion, the Charlson comorbidity index was assessed.22,23 Performance status was evaluated at the beginning of each treatment line. Adverse events were assessed using the CTCAEV4.0 scoring system.
Statistical analysis
Statistical analysis is described in the Online Supplementary Material.
Results
We identified 88 patients from the 19 participating cen- ters who fulfilled the inclusion criteria during the study period. Median follow up was 32.1 months (979 days). Our population had a median age of 68.5 years (range 60- 89), with 43 women (49%). At diagnosis, the severity of aplastic anemia was mild for 38 patients (43%), severe for 32 (36%), and very severe for 18 (21%); the median Charlson comorbidity index was 2 (range 0-6), with a median performance status of 1 (range 0-3). Population characteristics and main baseline biological results are shown in Table 1. Median blood count values were as fol- lows: PMN 0.705x109/L (range 0-7.4); lymphocytes 1.3x109/L (0.031-3.94); hemoglobin 8.25g/dL (3-13.6); mean corpuscular volume (MCV) 94fL (80-115); reticulo- cytes 23.5x109/L (0-90); and platelets 10.5x109/L (1-82). Bone marrow aspirates were taken from all patients at
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