Anna Koget DO 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 ID: 1035856
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1. Understanding Aplastic Anemia Anna Koget, D.O.
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. PathophysiologyDirect 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
4. Aplastic Anemia: clinical presentation Low blood counts Anemia fatigue, shortness of breath, pallor Thrombocytopenia bleeding, bruisingNeutropenia infections , fever
5. Aplastic Anemia: Laboratory Studies Pancytopenia ( all cell lines are low) Low reticulocyte count
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
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8. Bone Marrow Biopsy
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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
11. Causes of Aplastic Anemia Idiopathic ( unknown etiology) 75% Chemicals ( benzene, insecticides, pesticides) Radiation Medications ( chloramphenicol, antibiotics, NSAIDs, quinines) Infections – HIV, hepatitis, COVID , rarely other viruses- CMV, EBVPregnancy Eating disorders PNH
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13. Genetic Bone Marrow Failure syndromesRare, early in life Growth failureOften 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
15. Dyskeratosis Congenita Nail dystrophy Lacy skin pigmentation Oral leukoplakia
16. Emberger Syndrome Peripheral lymphedema GATA2 mutation
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
18. Treatment of Aplastic Anemia: Overview Supportive care –transfusions, growth factors Immunosuppression – ATG, cyclosporine, steroidsEltrombopag Allogeneic stem cell transplantation
19. N Engl J Med 2018; 379:1643-1656
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 antigensAntibiotics – 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)
24. Horse and Rabbit ATG
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/CyclosporineAlthough 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 > 1000Trisomy 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%
31. Addition of Eltrombopag to Standard treatment
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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 monthSurvival rate > 95% at a median follow up of 2 years
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35. Side effects Two patients discontinued Eltrombopag early due to severe rash Liver test abnormalities did not limit administration and were transientHealth-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
37. SOAR trial Phase 2 trial Cyclosporine +/- Eltrombopag
38. Response Rate
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 monthsSlow 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 AnemiaInitially 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
44. Complications of Transplant Failure to engraft GVHD
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 infectionCOVID 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 treatmentPatient post transplant should follow post transplantation guidelines on vaccination
47. Aplastic Anemia and PregnancySupportive 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 weeksThree 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 196Untreated, SAA has a one-year mortality of over 70 %
52. Thank you! Contact Informationanna.koget@ahn.org412-578-4484