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Aquired aplastic anemia
- 2. APLASTIC ANEMIA AA is characterized by peripheral blood pancytopenia and a hypocellular bone marrow. without dysplasia or fibrosis.
- 4. Idiopathic – MC Secondary Causes
- 5. Infectious • Hepatitis-associated, typically seronegative • Epstein-Barr Virus • Cytomegalovirus • Parvovirus
- 6. • Mycobacterial Infections • Human Immunodeficiency Virus • Human Herpes Virus 6 • Varicella Zoster Virus • Measles • Adenovirus
- 7. Nutritional • Copper deficiency • Vitamin B12 • Folic acid Chemicals • Benzene • Insecticides • Pesticides • Solvents
- 8. Drugs • Non-steroidal anti-inflammatory drugs • Antibiotics • Anticonvulsants • Sulfonamides • Gold Salts • Many additional agents rarely associated with aplastic anemia • Chloramphenicol
- 9. Radiation Other Associations • Pregnancy • Inflammatory and autoimmune (e.g. systemic lupus erythematosus) • Graft-versus-Host-Disease
- 10. Camitta’s Classification Mild/Mod(hypoplastic anemia) ANC 500-1500 Platelet count - 20k-1lac Severe aplastic anemia* ANC < 500 Platelet count - <20k Very severe* ANC < 200 *in addition <25% bone marrow cellularity
- 11. Pathogenesis Overproduction of cytokines Low CD4 regulatory cells Oligoclonal CD8 cytotoxic T cells Progenitor cells
- 12. Shortened telomeres Immune susceptibility loss of heterozygosity of the short arm of chromosome 6 (6pLOH
- 14. Clinical features easy bruising or petechiae Epistaxis Menorrhagia Pallor Fatigue Exercise intolerance thrombocytopenia anemia
- 15. Recurrent infection Oral thrus Recurrent fever Neutropenia
- 16. Clinical Evaluation 1. Establishing Diagnosis and Severity of AA • Clinical history and physical examination • Complete blood count and differential count • Reticulocyte count
- 17. • Peripheral blood smear • Bone marrow aspirate and biopsy • Bone marrow cytogenetics • Liver function tests, serum bilirubin, LDH
- 20. 2. Exclusion of Inherited Bone Marrow Failure Syndromes (IBMFs) • Clinical history • Family history • Physical examination • Chromosomal breakage studies in peripheral blood
- 21. • Telomere length measurement in peripheral blood • Increased fHb (several IBMFs) • Consider c-mpl testing • Consider additional diagnostic and genetic testing for IBMFS if suspected
- 22. 3. Assess for Specific Etiologies and Association • Viral Serology (hepatitis virus panel, CMV, EBV, parvovirus, VZV, HSV, HHV6, HIV, adenovirus) • Flow cytometry of peripheral blood for Paroxysmal Nocturnal Hemoglobinuria (PNH)
- 23. • Vitamin B12 and Folate • Copper, Ceruloplasmin, Zinc • Immunology: lymphocyte subsets (including CD4+, CD25+ regulatory T cells) quantitative immunoglobulins
- 24. • Autoimmune or inflammatory disease evaluation • HLA typing • Pregnancy test • T cell receptor rearrangement
- 25. MANAGEMENT SUPPORTIVE DEFINITIVE Transfusions Treatment of infections Neutropenic precaution Prophylactic antifungals Bone Marrow Transplantation Immunosupp- ressive Therapy Others 1) Alemtuzumab 2) Hematopoietic GF’s 3) Androgens 4) Corticosteroids 5) Anti IL2 – Daclizumab, Eculizumab
- 28. TRANSFUSION Platelet transfusion if- • <10000 or • Visceral bleeding Plateletpheresis(Single donor platelets) to be preferred
- 29. RBC transfusion if • Hb%- < 8mg% • Symptomatic Avoid transfusion from related donor Minimum transfusions if BMT plan Iron chelation if prolong transfusion dependent
- 32. CURRENT APPROACH
- 33. Haematopoetic stem cell transplantation <20yrs & HLA matched donors 5yr survival rate 88-97% Matched unrelated donors, unrelated cord blood survival rate <50%
- 34. Steps HLA matching Preoperative conditioning regimen ATG + cyclophosphamide + cyclosporine Transplantation
- 35. Transplant Material Maternal related donor bone marrow Unrelated donor bone marrow Autologous cord blood Unrelated cord blood transplantation (CBT) Haploidentical stem cell transplantation
- 36. Approach to BMT for Pediatric AA
- 37. Complications GVHD Secondary solid tumors Effect on growth n development Effect on endocrine function Effect on gonadal function Preexisting anti HLA antibodies affect outcome
- 38. Follow-up For at least one year post-transplant Fever Pneumocystis prophylaxis- one year Antivaral prophylaxis-one year
- 39. After one year- • Assessments of growth • Endocrine function • Pulmonary function • Bone health • Cancer screening
- 40. Keys To A Successful Transplant Level of HLA matching Good conditioning regimen Use of leukocyte free products Fludarabine conditioning Use of BM stem cell plants rather than peripheral blood .
- 42. ATG- Anti Thymocyte Globulin 2 types – horse and rabbit ATG Mechanism – Act against T- lymphocytes, down regulating production of IFN gamma, IL2
- 43. Horse vs Rabbit ATG Rabbit ATG more lymphocytotoxic Hematologic response to rabbit ATG (37%) about half that observed with standard horse ATG (68%), Inferior survival noted in the rabbit ATG arm .
- 44. Prerequisites Skin testing to be done for hypersensitivity Double lumen central catheter Platelet count to be maintained above 20k Drugs like ß-blockers to be avoided Avoid starting on weekends or late during day
- 45. How To Administer? DOSE –40mg/kg over 4hrs daily for 4days Prednisone 1 mg/kg started on day1, continued for 2 weeks (prophylaxis for serum sickness) Premedications – Diphenhydramine, Acetaminophen Hydration n supplemental oxygen
- 46. Side Effects & Management Serum sickness- Steroids Rash, fever- Diphenhydramine, acetaminophen Rigors- Mepiridine Inc transaminases – regular monitoring
- 47. Monitoring response Response – within first 3 months Earliest response – appearance of granulocytes and nucleated RBC’s Order of rise – 1. RBC’s ( inc HbF) 2. WBC’s 3. Platelets
- 48. Cyclosporine Fungal cyclic undecapeptide Inhibits T-cell - IL-2, IFN-gamma Cyclosporine alone lower response rates & higher risk of disease progression Best results seen as combined IST(with ATG) 5yr survival rate- 70%
- 49. How to administer? Twice daily to maintain trough levels 100- 250ng/ml Starting dose 15mg/kg/day Response takes weeks to months Minimum trial period should be 3-6mths Ideally ATG×4days & cyclosporine×6-12mths Cyclosporine should be gradually tapered
- 50. Adverse Effects & Management Hypertension – Amlodipine Hirsutism Gingival hyperplasia – Azithromycin Increase creatinine levels – monitoring and adjusting dose
- 51. if creat > 2mg/ml – temporary cessation n reintroduction at lower doses P.carinii pneumonia- monthly aerosolized pentamidine Dev of Clonal hematopoeitic disorders
- 53. 20-40% fail to respond to combined IST Give second course – 77% respond Patients failing to respond to 2 courses- unlikely to respond to third course Give trial of androgens, eltromopag, g-csf
- 54. Role of steroids High dose steroids not recommended as 1st line Methylprednisolone in the dose 2mg/kg/day as 0.5mg/kg/dose 6hrly Prednisone taper following 8 day course of IV methylprednisolone over total of 15 days
- 55. Role of G-CSF Used in addition to ATG &CSA Increases neutrophil recovery No increase in trilineage response Flu like symptoms Inc risk of clonal evolution
- 56. Role of Eltromopag Thrombopoeitin mimetic Ideally should be ineffective- already high levels In contrast – 40% responded (bilineage/trilineage) Inc Hb n BM cellularity SE – risk of progression to MDS
- 57. Role of cyclophosphamide Used in past Efficacy similar to horse ATG Fewer relapse rate But excessively toxic and inc risk of fungal infections Not recommended anymore
- 58. Prognosis The estimated 10-year survival rate--- patient receiving immunosuppression- 68% Hematopoietic cell transplantation (HCT)- 73%
- 59. References NIH Public Access,Pediatr Clin North Am. Author manuscript; available in PMC 2014 December 01.Published in final edited form as:Pediatr Clin North Am. 2013 December ; 60(6): 1311–1336. doi:10.1016/j.pcl.2013.08.011. Aplastic Anemia Treatment & ManagementUpdated: Apr 04, 2017 Author: Sameer Bakhshi, MD; Chief Editor: Emmanuel C Besa, MD PracticalPediatric Hematology(Anupam Sachdeva) Nelson Textbook of Pediatrics
Editor's Notes
- Schematic representation of a relationship between genetic mutations, disease penetrance, and gene-environment interaction in the pathogenesis of bone marrow failure. Mutations with a high disease penetrance almost always cause disease, i.e. mutations in the Fanconi Anemia genes (FANC), in the SBDS gene causing Shwachman Diamond Syndrome, or in DKC1 causing X-linked Dyskeratosis Congenita. In contrast, mutations in genes with low disease penetrance may not manifest as clinically apparent bone marrow failure, examples include mutations in the TERT gene responsible for autosomal dominant Dyskeratosis Congenita or in certain DBA genes responsible for Diamond Blackfan Anemia.3 Genetic polymorphisms associated with AA don’t cause disease in the majority of carriers but, in combination with other modifier genes and the appropriate environmental insult, may contribute to the development of AA. Examples are HLA-DR2 in adult AA and HLA-B14 in pediatric AA or GSTT1 gene deletions
- acquired AA results from the aberrant activation of one or more auto-reactive T cell clones due to alteration of antigens presented by the Major Histocompatibility Complex (MHC) on the surface of Antigen Presenting Cells (APC). This antigen alteration is triggered by viral infection, chemical exposure, or genetic mutation, and leads to the inappropriate activation of antigen-specific effector T cells and decreased activity of regulatory T cells, which normally serve to prevent auto-immunity. T cell activation leads to IL-2-driven expansion and differentiation of T cells into effector and memory T cells. These pro-inflammatory T cells produce a variety of cytokines, including FAS Ligand (FASL), interferon-γ (IFN-γ), and Tumor Necrosis Factor α (TNFα), which 1) induce HSC apoptosis and 2) alter gene regulation and decrease protein synthesis to prevent HSC cell cycling, ultimately leading to bone marrow failure. Immune suppression therapy disrupts T cell-driven HSC destruction by inhibiting T cell responses at several points along this pathway.
- Bone marrow aspirate and biopsy from a patient with acquired AA. Hematopoietic elements are greatly reduced, and there is replacement of marrow space with adipose tissue. Focal islands of left-shifted erythropoiesis.
- Chromosomal breakage- fanconi anemia Telomerase length- DC
- Telomerease – DC C-mpl familial aplastic anemia
- ATG- anti thymocyte globulin Pjp prophylaxis- aerosolised pentamidine monthly dosing Galactomannan; aspergillus assay
- Tbi total body irriadiation Mmf- mycophenolate mofetil
- first-line therapy [73] for patients with severe or very severe aplastic anemia (SAA or VSAA, respectively) who are older than 40 years and as second-line therapy in younger patients with SAA or VSAA if a human leukocyte antigen (HLA)–matched sibling donor is not available.
- Horse atg is preferred
- At present only use for prophylaxis of serum sickness following IST