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.