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Aplastic Anemia.pptx

  1. 1. Aplastic Anemia Prepared by Kelvin Samike Mmed II Facilitator: Prof. Antony Oyekunle
  2. 2. Introduction • Refers to pancytopenia in association with bone marrow hypoplasia/aplasia • A life-threatening form of bone marrow failure • If untreated, is associated with very high mortality • Most often due to immune injury to multipotent hematopoietic stem cells. • Term "aplastic anemia" is a misnomer because the disorder is characterized by pancytopenia
  3. 3. PATHOPHYSIOLOGY • AA is associated with loss of HSCs and the resultant decrease in mature blood cells • Conflicting demands of self-renewal and differentiation can lead to pancytopenia. • Pathophysiologic processes that lead to loss of HSCs and cause AA include:  Autoimmune mechanisms  Direct injury to HSCs (eg, by drugs, chemicals, irradiation)  Viral infection  Clonal and genetic disorders
  4. 4. PATHOPHYSIOLOGY • It is hypothesized that drugs, chemicals, viruses, or mutations alter the immunologic appearance of HSCs and lead to autoimmune destruction • Cytotoxic lymphocytes and type I cytokines appear to be proximate effectors of autoimmune aplasia in AA • IFN gamma initiates a cytokine cascade implicated in increased apoptotic death of HSCs in AA
  5. 5. Clonal Evolution • Development of clonal abnormalities in blood cells during the course of an individual's life • AA may coexist with or evolve into other disorders, such as  Paroxysmal nocturnal hemoglobinuria (PNH)  Myelodysplastic syndromes (MDS)  Acute myeloid leukemia (AML) • In some cases, immune destruction of the aberrant HSCs contributes to the cytopenias.
  6. 6. CLINICAL MANIFESTATIONS • Recurrent infections due to neutropenia • Infections are typically bacterial, including sepsis, pneumonia, and urinary tract infection • Invasive fungal infection is a common cause of death • Mucosal hemorrhage or menorrhagia due to thrombocytopenia • Fatigue and cardiopulmonary findings associated with progressive anemia
  7. 7. CLINICAL MANIFESTATIONS • Some patients present with hemolytic anemia or thrombosis that may suggest co-existent paroxysmal nocturnal hemoglobinuria (PNH) • Liver, spleen, and lymph nodes are not typically enlarged and no jaundice in AA • Other patients are asymptomatic and present with abnormal blood counts
  8. 8. EVALUATION • Complete blood count suggestive of AA, should establish the diagnosis of AA • Seek to identify an underlying cause • Distinguish it from other categories of pancytopenia • Bone marrow biopsy is required to establish the diagnosis of AA
  9. 9. Bone Marrow Examination • Required to establish the diagnosis of AA and exclude other causes of pancytopenia • The biopsy should be performed at a site that has not suffered prior direct damage (eg, radiation, trauma, infection) • Diagnostic criteria, Pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrate or marrow fibrosis.
  10. 10. Specialized Testing • In all adults with AA, Exclude coexistent disorders, such as  Paroxysmal nocturnal hemoglobinuria,  Myelodysplastic syndrome  Acute leukemia • Flow cytometry for assessment of cell surface CD59 on peripheral blood red blood cells or neutrophils • Cytogenetic and molecular testing of bone marrow
  11. 11. Specialized Testing • In all children with AA we suggest genetic testing • To identify inherited genetic abnormalities • Genetic abnormalities should also be considered in adults with AA • Who fail to respond to treatment with anti- thymocyte globulin (ATG)
  12. 12. DIFFERENTIAL DIAGNOSIS • Megaloblastic anemia  Hypersegmented neutrophils  Macro-ovalocytes on the peripheral blood smear  Megaloblastic changes in the bone marrow examination  Low serum levels of vitamin B12 and/or folate
  13. 13. DIFFERENTIAL DIAGNOSIS Infiltrative disorders • Bone marrow by fibrosis (eg, myeloproliferative neoplasms such as primary myelofibrosis) • Malignancies (eg, MDS, AML, lymphoma, multiple myeloma, carcinoma) • Present with myelophthisic changes on the peripheral blood smear (eg, schistocytes, nucleated red blood cells) • And morphologic, cytogenetic, and/or molecular abnormalities of the bone marrow
  14. 14. DIFFERENTIAL DIAGNOSIS Reversible bone marrow suppression • Predictable, dose-dependent effects of cytotoxic chemotherapy or radiation therapy, • Overwhelming sepsis, or acute viral infection can cause transient, reversible pancytopenia with hypoplastic bone marrow
  15. 15. DIFFERENTIAL DIAGNOSIS Hypoplastic MDS • The hypocellular variant of MDS can be very difficult to distinguish from AA • Dysplastic changes in bone marrow and/or cytogenetic or molecular abnormalities that are characteristic of MDS
  16. 16. Classification of AA Based on Severity Severe AA • Bone marrow cellularity <25 percent (or 25 to 50 percent if <30 percent of residual cells are hematopoietic) • At least two of the following  Peripheral blood absolute neutrophil count (ANC) <500/microL (<0.5 X 109/L)  Peripheral blood platelet count <20,000/microL  Peripheral blood reticulocyte count <20,000/microL
  17. 17. Classification of AA Based on Severity Very severe AA • Diagnosis of very severe aplastic anemia (vSAA) include the criteria for SAA (above) and ANC is <200/microL Non-severe AA — Criteria for non-severe AA :  Hypocellular bone marrow (as described for SAA)  Peripheral blood cytopenias not fulfilling criteria for SAA or vSAA (see above)
  18. 18. Treatment of aplastic anemia in adults • Medical fitness • Performance status (PS) and comorbid illnesses to determine medical fitness for intensive therapies
  19. 19. ECOG • In general, patients with ECOG PS >2 are medically-unfit for  Hematopoietic cell transplantation (HCT)  May not tolerate intensive immunosuppressive therapy (IST).
  20. 20. SUPPORTIVE CARE • Transfusions • Iron management • Infection treatment/prevention
  21. 21. All patients with SAA/vSAA • Require prompt treatment decisions and ongoing supportive care until treatment is effective. • Patients with SAA and vSAA are treated similarly • Though severity of neutropenia in vSAA further increases the urgency for initiation of treatment
  22. 22. All patients with MAA • Follow the patient closely for several weeks to months to better define the trajectory and pace of the illness • When and whom to treat  Red blood cell (RBC) transfusion- dependence  Persistent, severe neutropenia or thrombocytopenia
  23. 23. Pretreatment Management • Premedication with Acetaminophen and Diphenylhydramine before each hATG dose to reduce infusion reactions • Prednisone(or methylprednisolone) 1 to 2 mg/kg daily to prevent serum sickness should begin with the first dose of hATG • No beta blockers prior to hATG administration to allow more effective use of beta adrenergic agents to support blood pressure, in the event of a severe anaphylactic reaction to hATG
  24. 24. INTENSIVE IMMUNOSUPPRESSIVE THERAPY • Lessens the immune injury to multipotent hematopoietic stem cells in AA by reducing cytotoxic lymphocytes and associated cytokines • Triple therapy • Immunosuppressive agents (horse anti- thymocyte globulin [hATG] and cyclosporine [CsA]) together with a bone marrow stimulating agent (eltrombopag [EPAG]).
  25. 25. Administration – hATG • Given daily for four consecutive days (beginning on day 1 of triple IST) at a dose of 40 mg/kg intravenously over four hours. • If infusion reactions are severe, the duration of each daily infusion can be lengthened to 8 or even 24 hours
  26. 26. Adverse effects of hATG • Infusion reactions, Immediate infusion reactions to hATG are common and may include fevers to ≥40°C, chills, hypotension or hypertension, third space sequestration of fluid, and hypersensitivity rashes • Serum sickness – Serum sickness is manifest later than acute infusion toxicities and generally presents days to weeks after initiation of hATG with fever, rash, joint pain, malaise, or other constitutional symptoms
  27. 27. Administration Cyclosporine • Initial dose of 6 mg/kg per day by mouth in two equal divided doses • With azole antifungal agents require reduction in initial dosing to avoid supratherapeutic CsA levels • Blood pressure, and serum creatinine should be monitored • We generally treat with CsA for 12 months and initiate a slow taper
  28. 28. Adverse effects • Renal insufficiency • Hypertension • Magnesium wasting
  29. 29. Administration EPAG • Begin EPAG 150 mg by mouth once daily beginning on day 1
  30. 30. Outcomes with triple IST • Triple IST (hATG, CsA, and EPAG) offers the most favorable balance of outcomes • More than 90 percent of adults with SAA have a response to triple IST • Approximately half of patients have a complete response (CR) • Resolution of severe neutropenia and transfusion-independence generally takes one to two months
  31. 31. Outcomes with Triple IST • Trials of triple IST have excluded patients with cytogenetic abnormalities • Because of concerns that EPAG might stimulate expansion of an abnormal clone • Triple IST achieved 97 percent two-year survival • The rate of relapse was 15 percent and two- year cumulative incidence of clonal evolution was 8 percent • With median follow-up of 18 months
  32. 32. HEMATOPOIETIC CELL TRANSPLANTATION • Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for AA
  33. 33. PROGNOSIS • Current 5- or 10-year survival rates are as high as 80 to 90 percent, compared with 10 to 20 percent in the 1960s • Untreated, SAA has a one-year mortality of over 70 percent
  34. 34. REFERENCES Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood 2012; 120:1185. 1. Bielory L, Gascon P, Lawley TJ, et al. Human serum sickness: a prospective analysis of 35 patients treated with equine anti-thymocyte globulin for bone marrow failure. Medicine (Baltimore) 1988; 67:40. 2.,050716s038lbl.pdf (Accessed on Apr il 10, 2020). 3.,050574s043,050625s049lbl.pdf (Acc essed on May 22, 2020). 4.,050716s028lbl.pdf (Accessed on Apr il 20, 2020) 5. Update 6. Gill H, Leung GM, Lopes D, Kwong YL. The thrombopoietin mimetics eltrombopag and romiplostim in the treatm ent of refractory aplastic anaemia. Br J Haematol 2017; 176:991. 7. Lengline E, Drenou B, Peterlin P, et al. Nationwide survey on the use of eltrombopag in patients with severe apla stic anemia: a report on behalf of the French Reference Center for Aplastic Anemia. Haematologica 2018; 103:2 12. 8. Bacigalupo A. How I treat acquired aplastic anemia. Blood 2017; 129:1428. 9. Scheinberg P. Activity of eltrombopag in severe aplastic anemia. Blood Adv 2018; 2:3054. 10. Scheinberg P, Nunez O, Weinstein B, et al. Activity of alemtuzumab monotherapy in treatment-naive, relapsed, a nd refractory severe acquired aplastic anemia. Blood 2012; 119:345. 11. Scheinberg P, Nunez O, Wu C, Young NS. Treatment of severe aplastic anaemia with combined immunosuppressi on: anti-thymocyte globulin, ciclosporin and mycophenolate mofetil. Br J Haematol 2006; 133:606.