Discussion
We describe an interesting case of idiopathic very severe aplastic anemia (VSAA) in an 80-year old male who did not have any obvious secondary risk factors. VSAA is defined as bone marrow hypoplasia <30% on a bone marrow trephine biopsy AND two of the three following criteria: polymorphonuclear neutrophils <0.2 x 109/L, platelets <20 x 109/L or absolute reticulocyte count< 20 x 109/L5. Over the age of 60 AA, 6 in 10 patients are women as opposed to a higher male incidence in the younger age group6.
AA in the elderly may demonstrate a variety of molecular mutations. Next generation sequencing (NGS) by Yoshizato, et al on 439 patients with AA demonstrated no significant relationship between the presence of molecular mutations and response to IST7. However, on individual gene assessment, molecular mutations in BCOR, BCORL1 and PIGA were associated with a better response to IST while mutations in DNMT3A and AXL1 were linked to an adverse outcome7.
Cytogenetic abnormalities are seen in 4-5% of aplastic anemia patients over the age of 608. A French nationwide survey study of 88 aplastic anemia patients over the age of 60 demonstrated 8% of these patients had cytogenetic abnormalities. The common cytogenetic abnormalities encountered were Y deletions, trisomy 8, 13p deletion, 4q deletion, chromosome 14 aberrations and one split of IgH locus9. Our patient in this case revealed -Y and trisomy 8 cytogenetic abnormalities which were consistent with findings found in the literature.
High frequency of HLA-DR2 and its serologic spilt HLA-DR15 are overexpressed in AA and hypoplastic MDS. Saunthararajah, et al studied two cohorts at the National Institute of Health (NIH) which consisted of 148 patients with severe AA in cohort 1 and 2609 patients with severe AA who received allogenic SCT in cohort 2. Thirty-two of forty-seven HLA-DR15 positive AA and thirty-one of fifty-two HLA-DR15 negative AA patients responded to the combination ATG-CsA therapy10. Hence, the presence of HLA-DR15 overexpression does not predict a response to IST in AA10.
Several other biomarkers may contribute to responsiveness of immunosuppressive therapy (IST) in elderly AA. Shorter duration of AA, younger age at diagnosis, a higher absolute neutrophil count, a higher absolute lymphocyte count, a higher baseline platelet count, higher CsA levels during the first 2 weeks of commencement of IST, longer telomere length, positive minor PNH clone, lower thrombopoietin (TPO) levels and increased IFN-gamma expression in the bone marrow indicate better response to IST11.
Telomeres shorten with age and is a marker of an aging process. Significant abnormal shortening of telomeres of bone marrow nucleated cells have been seen in elderly AA12. Telomeres are structures with tandem DNA repeats of 5’-TTAGGG-3’12. Increased oxidative and haematopoietic stress contribute to the abnormal shortening of telomeres which in turn lead to genomic instability in AA12.
The Dutch Society of Hematology national guidelines recommends a combination of equine- ATG 40mg/kg daily for 4 days, oral CsA therapy and subcutaneous G-CSF as first line therapy in patients with severe AA not suitable for allogenic haematopoietic stem cell transplantation13,14. This combination incorporating G-CSF is efficacious as it allows quick neutrophil recovery and identifies early non-responders. The use of G-CSF was not associated with any increase in clonal transformation13. The overall survival (OS) at 6 and 12 months in elderly patients (aged 60 years and above) treated with ATG-CsA combination therapy was 96% and 88% respectively as compared to only 35% with CsA alone, 22% with eltrombopag alone and 21% with androgen alone14,15. The overall response rates (ORR) in patients over 70 years receiving ATG-CsA was 81%15. Patients aged more than 70 receiving ATG-CsA did not appear to suffer from any additional complications than the younger age group and tolerated the treatment well15. Among the common complications seen this subgroup of elderly AA patients (>70 years old) who received ATG-CsA combination therapy were infections (88%), followed by acute kidney injury (50%), cardiovascular complications (31%), haemorrhagic manifestations (19%) and neurological complications (13%)15. Reducing the dose of ATG without administering CsA in elderly AA was associated with a lower risk of treatment toxicity but the response was dismal as only 1 out of the 14 elderly patients achieved a partial haematological response in a British multicentre study16. It is interesting to note that the addition of oral eltrombopag at a median maximum dose of 150mg daily (50-300mg) to standard ATG-CsA combination therapy in newly diagnosed severe AA with a median age of 47 (19-66), produced an ORR of 90% (trilineage response: 60%, neutrophil response: 20%, platelet response: 30%) at 12 weeks of therapy17. Eltrombopag is well tolerated in the elderly. Besides, sex hormones such as oral testosterone 40mg/day for 5 days per week demonstrated a 59% ORR in patients with persistent cytopenia after ATG-CsA therapy18. Combination of CsA and androgens would be the treatment of choice for frail patients above the age of 70 who are not suitable for the more intensive ATG-CsA therapy18.