2. Aplastic Anemia
• An acquired stem cell disorder
• Idiopathic (unknown etiology) in 70% of the cases
• Diagnosis of exclusion
• Important to differentiate from other causes of Bone Marrow Failure
3. Pathophysiology
• Direct damage to DNA/chromosomes by a chemical or radiation
• Inappropriate immune system activation by a trigger ( infection, drugs,
autoimmune disorder) which causes immune attack on bone marrow causing
failure
6. Epidemiology
• 2 per million in Western countries and 4-6 per million in Asia
• 2 incidence peaks: young adults and elderly
• > 25% of pediatric patients and 5-15% of adults < 40 years old have an
inherited cause
• First case described in 1888, term “aplastic anemia” first used in 1904
10. Bone Marrow Biopsy findings
• Hypocellular marrow
• Absence of blasts, dysplasia or fibrosis
• Decreased number of stem cells ( CD34 + cells) – typically to < 0.3%,
normal > 1%
• Decreased white cell, red cell and platelet precursors
• Normal number of lymphocytes
• Normal chromosomes
13. Genetic Bone Marrow Failure syndromes
• Rare, early in life
• Growth failure
• Often associated with physical abnormalities
• Associated with increased risk of leukemia and other cancers
14. Fanconi Anemia
• Short stature
• Skin hypo/hyperpigmented areas
• Skeletal abnormalities particularly
affecting thumb
17. Aplastic anemia vs Hypoplastic MDS
• Dysplasia is typically in precursors
only
• Dysplasia in > 10% of cells in
multiple cells lines ( red cells,
platelets, white cells)
• Cytogenetics abnormalities –
chromosome 5, 7
20. Supportive Care: Transfusions
• Transfusions – keep platelet count > 10, hemoglobin > 7
• Try to limit transfusions particularly in transplant eligible patients
• Blood transfusion from siblings or a family donor should be avoided in order to
minimize the risk of transplant failure caused by an immune response to donor
antigens
• Antibiotics – antifungal prophylaxis ( Voriconazole or posaconazole) , antibacterial
and antiviral prophylaxis
• No benefit of G-CSF
21. Supportive Care: Iron Overload
• Occurs from multiple RBC transfusions
• Patients with a longer life expectancy who have iron overload may benefit
from iron chelation therapy
• Deferasirox is preferred as it does not cause cytopenias
• Once anemia resolves, can use phlebotomy
• Eltrombopag has iron chelating properties as well
22. Immunosuppression : Who benefits?
• Patients > 40 years of age
• Younger patients without a matched sibling donor
23. ATG
• Standard of care
• Antithymocyte globulin (ATG) +
Cyclosporine ( CsA)
• 60-70% response rate
• Horse ( 68% response rate ) versus Rabbit
( 37% response rate)
25. Administration of ATG
• Given as an inpatient
• Given with steroids to prevent side effects ( serum sickness)
• Increased mortality in patients > 60 years of age
• IV infusion over 12-18 hours x 4 days
26. Side effects of ATG
• Early reactions including fevers, rash, rigors, BP change, fluid retention
• Anaphylaxis is rare
• Serum sickness can occurs days 7-14 from the start – joint aches, muscles
aches, rash, fever
• Serum sickness is treated with IV hydrocortisone and supportive care
• May require platelet transfusions
27. Horse vs Rabbit ATG
• Randomized prospective trial with 120 patients
• Response at 6 months ( 68 vs 37% ) and overall survival at 3 years ( 96% vs
76% ) was largely in favor of horse ATG
• 4 deaths in the horse and 14 deaths in the rabbit ATG group
28. ATG/Cyclosporine
• Although 66% responses are seen promptly after therapy, only 60% of such
population will be in true remission
• Remaining patients will either relapse or blood counts are dependent on
cyclosporine administration
• Other attempts to increase response rates by intensifying
immunosuppression have failed
• Secondary diseases – 10-15% will develop MDS or PNH at 5 years
29. Factors predicting response to ATG
• Young age
• Less severe disease
• Absolute reticulocyte count > 25 and absolute lymphocyte count > 1000
• Trisomy 8 or del ( 13q) chromosomal abnormalities
• Presence of PNH clone
30. Role of Eltrombopag
• Oral TPO ( thrombopoietin) receptor agonist
• Previously approved for the treatment of ITP ( chronic idiopathic
thrombocytopenic purpura)
• Initially tested as a single agent – overall response rate after 3-4 months of
therapy 40%
33. Addition of Eltrombopag: important findings
• Response rate was 87% ( 66% historically)
• Highest response in third group that had longest exposure to eltrombopag (
94% overall response/58% complete response
• Great majority of responses already evident at 3 months
• Average time to transfusion independence 1 month
• Survival rate > 95% at a median follow up of 2 years
34.
35. Side effects
• Two patients discontinued Eltrombopag early due to severe rash
• Liver test abnormalities did not limit administration and were transient
• Health-related quality-of-life surveys showed an improvement in physical
health and overall health-related quality of life after treatment that correlated
with hematologic response.
36. Patients who are not eligible for ATG
• Eltrombopag + cyclosporine A produced a high level of response and
transfusion independence in treatment naïve patients with severe aplastic
anemia
• SOAR trial
39. Cyclosporine maintenance and taper
• Early discontinuation leads to high rate of relapse
• Maintenance delays relapse
• Full dose Cyclosporine targeting therapeutic trough of 200-300 mcg/L for
approximately 12 months
• Slow taper with no more than 10% dose reduction at a time over the course
of one year
40. Problems with IST
• Delayed blood count recovery – 2-6 months
• Relapse – 25-40% at 5 years
• Primary refractory to immunosuppression – 10-20%
• Clonal evolution to PNH 25% have clone at diagnosis
• Clonal evolution into MDS/AML – 20-25% at 10 years
• NOT curative
41. Clonal Evolution
• Progression to MDS/AML in 15%, PNH 10%
• Most common clonal abnormality in AA is the development of PNH clones-
check at the time of the diagnosis and monitor throughout the treatment
• The presence of even a subclinical PNH clone has been found to correlate
with an improved response to immunosuppressive therapy
42. Relapsed/Refractory Aplastic Anemia
• 35% of patient who initially respond will relapse during or after cyclosporine
taper
• Another 35% are refractory to frontline treatment
• Most can be salvaged with either full dose cyclosporine or second course of
ATG ( rabbit if got horse initially)
• Transplant therapies are usually reserved for relapsed patients who failed an
attempt of salvage with a second course of immunosuppression
43. Role of Transplant in Aplastic Anemia
• Initially donors were limited to matched related donors ( sibling)
• Now expanded to MUD ( matched unrelated donor) and haploidentical
donors ( children, parents, nieces/nephews) with post transplant
cyclophosphamide use
• Children and young adults with matched sibling should undergo transplant as
a first line therapy
45. Aplastic anemia and COVID
• Consequences of infection in patients with aplastic anemia are not clear
• Patients receiving IST are considered at higher risk of infection
• COVID can be an initiating event or drop blood counts in patients with
ongoing disease or those in remission
46. Should patients with AA get COVID
vaccination?
• Current known risk – versus-benefit considerations favor vaccine
administration particularly in patients with other risk factors ( age, obesity,
other medical problems)
• Patient who received ATG/Cyclosporine may not mount response within 6
months of treatment
• Patient post transplant should follow post transplantation guidelines on
vaccination
47. Aplastic Anemia and Pregnancy
• Supportive care is the mainstay of the treatment
• Platelet count should be kept > 20
• Cyclosporine is safe in pregnancy if needed
• Pregnancy and a good obstetrical outcome are possible for women
previously treated with IST
48. PNH and Aplastic Anemia
• All patients should be screened for PNH using flow cytometry testing on the
blood
• If positive test every 3 months for the first 2 years, then can reduce
frequency if stable
• Small clones detected in 50% of the patients does not change
management
• Large clones can cause hemolysis as well as increased risk of blood clots
49. Treatment in the elderly
• Older age is not a reason to withhold treatment
• IST is the treatment of choice
• If unable to tolerate ATG can consider CSA alone, alemtuzumab
50. Romiplostim
• 84 % hematologic response at 27 weeks and 39 % trilineage response at 53
weeks
• Three patients had grade ≥3 hepatic toxicity, but all other adverse effects (eg,
headache, muscle spasms) were mild or moderate.
• Effective and well tolerated
• Not associated with clonal evolution
51. Prognosis of Aplastic Anemia
• Current 5- or 10-year survival rates are as high as 80 to 90 %, compared with
10 to 20 % in the 196
• Untreated, SAA has a one-year mortality of over 70 %