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APLASTIC ANEMIA Aplastic Anemia • Aplastic anemia is a bone marrow failure syndrome characterized by peripheral pancytopenia and marrow hypoplasia. • Bone marrow failure is a term with a larger meaning, referring to disorders of the hematopoietic stem cell which involves either one cell line or all of the myeloid cell lines History of Aplastic anaemia • Paul Ehrlich (1854-1915) described the first case of aplastic anaemia in a pregnant woman who died of marrow failure in1888. • The term “aplastic anaemia” first used by Anatole Chauffard in 1904. Aplastic Anemia – epidemiology • annual incidence in Europe and US - 2 cases per million population, but 4 cases in Bangkok 6 in Thailand and 14 in Japan. • no racial predisposition exists in the United States; however, prevalence is increased in the Far East. • The male-to-female ratio is approximately 1:1. • Aplastic anemia occurs in all age groups. – a small peak in incidence in childhood. – a peak incidence in people aged 20-25 years, and a peak in people older than 60 years. Aplastic Anemia - Etiology • Congenital/inherited (20%) – Patients usually have dysmorphic features or physical stigmata. Occasionally, marrow failure may be the initial presenting feature. • • • • Fanconi anemia Dyskeratosis congenita Shwachman-Diamond syndrome Familial aplastic anemia • Acquired: 1. Drugs - Cytotoxic drugs - Antibiotics - Chloramphenicol - Anti-inflammatory - Anti-convulsant - Sulphonamides - 2-3 months usually between exposure and the development of aplastic anemia. Aplastic Anemia: (Cont.) • Acquired: – Radiations – Chemicals e.g., Benzene and pesticides, chloramphenicol, phenylbutazone, and gold, – Viruses: • • • • Hepatitis A, Non-A and Non-B Herpes simplex E-B virus Parvovirus: Transient • Important clinically in patients with hemolytic anemias • 5-10% of cases of AA in the West and 10-20% in the Far East. • 2-3 months between exposure to the virus and the development of AA. – – – – Immune: SLE, RA (rheumatoid arthritis) Pregnancy Idiopathic: 75% PNH Aplastic Anemia - Pathogenesis Potential mechanisms: – – – – – Absent or defective stem cells (stem cell failure). Abnormal marrow micro-environment. Inhibition by an abnormal clone of hemopoietic cells. Abnormal regulatory cells or factors. Immune mediated suppression of hematopoiesis. It is believed that genetic factors play a role. There is a higher incidence with HLA (11) histo comp. Antigen. Immune mechanism is involved. Aplastic Anemia - Pathogenesis (Cont…) The latest theory is: • there is an intrinsic derangement of hemopoietic proliferative capacity, which is consistent with life. • the immune mechanism attempt to destroy the abnormal cells (self cure) and the clinical course and complications depend on the balance. – – If the immune mechanism is strong, there will be severe pancytopenia. If not, there will be myelodysplasia. Aplastic Anemia - Forms of disease: • Inevitable: – • dose related e.g. cytotoxic drugs, ionizing radiation. The timing, duration of aplasia and recovery depend on the dose. Recovery is usual except with whole body irradiation. Idiosyncratic: – unpredictable to drugs e.g., anti-inflammatory antibiotics, anti-epileptic, these agents usually do not produce marrow failure in the majority of persons exposed to these agents. Common Traits To All Various Causes • Aplasia due to any cause may recover after immunosuppressive therapy indicating that immune mechanisms are involved. • Transition to a clonal disorder of hemopoiesis can occur in any patient who has recovered bone marrow function, suggesting that fragility of the hemopoietic system is common to all forms of aplasia. Aplastic Anemia – Clinical Features • anemia pallor and/or signs of congestive heart failure, such as shortness of breath. • thrombocytopenia bruising (eg, ecchymoses, petechiae) on the skin, gum bleeding, or nosebleeds. • neutropenia fever, cellulitis, pneumonia, or sepsis • jaundice and evidence of clinical hepatitis in subset of patients Aplastic Anemia – Clinical Features • adenopathy or organomegaly should suggest an alternative diagnosis. • In any case of aplastic anemia, look for physical stigmata of inherited marrow failure syndromes such as – – – – – – skin pigmentation, short stature, microcephaly, hypogonadism, mental retardation, skeletal anomalies. Aplastic Anemia – investigations • • • • • • • • FBC Reticulocyte count Blood film. B12/folate. Liver function tests Virology Bone marrow aspirate & trephine PNH screen. Aplastic Anemia – FBC • Anemia is common, and red cells appear morphologically normal. The reticulocyte count usually is less than 1%. • Thrombocytopenia, with a paucity of platelets in the blood smear. • Agranulocytosis (ie, decrease in all granular white blood cells, including neutrophils, eosinophils, and basophils) and a decrease in monocytes are observed. A relative lymphocytosis occurs. • The degree of cytopenia is useful in assessing the severity of aplastic anemia. Bone marrow exam • A bone marrow biopsy is performed in addition to the aspiration. In aplastic anemia, these specimens are hypocellular. • Aspirations alone may appear hypocellular because of technical reasons (eg, dilution with peripheral blood), or they may appear hypercellular because of areas of focal residual hematopoiesis. • A core biopsy provides a better idea of cellularity; the specimen is considered hypocellular if it is less than 30% cellular in individuals younger than 60 years or less than 20% in those older than 60 years. BM Aspiration BM Biopsy BM biopsy hypocellular ,increased fat spaces APLASTIC ANEMIA – other investigations • Hemoglobin electrophoresis may show elevated fetal hemoglobin. • Biochemical profile, including evaluation of transaminases, bilirubin, lactic dehydrogenase, Coombs test, and kidney function, is useful in evaluating etiology and differential diagnosis. • Serologic testing for hepatitis EBV, CMV, and HIV • Autoimmune disease evaluation for evidence of collagenvascular disease • The Ham test or sucrose hemolysis test frequently is performed for excluding PNH. • Histocompatibility testing should be conducted early to establish potential related donors, especially in younger patients. Aplastic Anemia - Criteria for diagnosis (1) 1. Cytopenia Hb <10g/dL ANC <1,5 G/L PL <100 G/L 2. Bone marrow histology and cytology - decreased marrow cellularity (< 25%) - increased fat cells component - no extensive fibrosis - no malignancy or storage disease Aplastic Anemia - Criteria for diagnosis (2) 3. No preceding treatment with X-ray or antyproliferative drugs 4. No lymphadenopathy or hepatosplenomegaly 5. No deficiencies or metabolic diseases 6. No evidence of extramedullary hematopoiesis APLASTIC ANEMIA – differential • • • • • • • Pancytopenia Acute Myelogenous Leukemia Anemia Aplastic Anemia Hairy Cell Leukemia Paroxysmal Nocturnal Hemoglobinuria Immune pancytopenias in connective tissue disorders (eg, systemic lupus erythematosus, refractory anemia) Causes of pancytopenia 1.Failure of production of blood cells a) bone marrow infiltration - acute leukemias - hairy cell leukemia - multiple myeloma - lymphoma - myelofibrosis - metastatic carcinoma b) aplastic anemia 2. Ineffective hematopoesis - myelodysplastic syndrome - vit.B12 and folate deficiency 3. Increased destruction of blood cells - hipersplenism - autoimmune disorders - paroxysmal nocturnal hemoglobinuria 4. Myelosuppression after irradiation or antiproliferative drugs Classification of aplastic anemia 1. Severe aplastic anemia is defined if at last two of the following criteria are present: - ANC < 0.5 G/l - PLT < 20 G/l - RTC < 1% (20 G/l) Hypoplastic bone marrow (less than 25%) on biopsy 2. Very severe aplastic anemia - criteria as above but ANC < 0.2 G/l 3. Non-severe aplastic anemia. Evolution of AA - Clinical course 1 • Stable AA • Pancytopenia remains stable over months to years. • Greater the degree of pancytopenia the worse the prognosis. (see severe aplastic anaemia) Evolution of AA - Clinical course 2 • Progressive or fluctuating aplasia. • Initially small degrees of pancytopenia or single lineage cytopenia. • Progressive sometimes following viral infections. • Occasionally single cytopenia e.g. thrombocytopenia becomes true aplastic anaemia. Evolution of AA - Clinical course 3. • Unstable Aplasia. • Improvement in counts may be associated with abnormal clones. • PNH clone in up to 20% of long term aplastic anaemia. • Often only detected by lab tests and not clinically significant. Aplastic Anemia - Treatment • Withdrawal of etiological agents. • Supportive. • Restoration of marrow activity: – Bone marrow transplant – Immunosuppressive treatment - Prednisolone - Cyclosporin - Splenectomy – Androgens – Growth factors - Antilymphocyte glob. - Anti T cells abs. APLASTIC ANEMIA – treatment • Supportiv care – Transfusion – Treatment of anemia – Treatment of bleeding – Prevention and treatment of infection HLA identical sibling BMT • Age <40 years. • Conditioning with Cyclophosphamide & antithymocyte globulin, with cyclosporin and methotrexate. • Long term overall survival = 80-90% • Chronic graft versus host disease (GVHD) remains a problem for 25-40% of patients. Hematopoietic stem cell transplatation in severe aplastic anemia 1. Advantages - correction of hematopoietic defect - long-term survival: 80% - 90% (HLA-matched sibling donor) - majority of the patients appear to be cured 2. Restrictions - age below 40 - suitable donor available in less than 30% (sibling) - 25-40% risk of GVHD - 5-15% risk of graft failure in multitransfused patients - high mortality after MUD-HSCT - solid tumors (12%) Immunosuppressive therapy • Indicated for patients > 40 years • Patients with no HLA matched sibling donors. • Anti-Thymocyte Globulin(ATG) or antilymphocyte globulin (ALG), cyclosporin, methylprednisolone. • Best results are for combination therapy. • Response is slow, 4-12 weeks to see early improvement. Immunosuppressive therapy • Immunosuppressive therapy – Antithymocyte globulin, equine (Atgam) - 10-20 mg/kg/day for 8-14 days. – Antithymocyte globulin, rabbit (Thymoglobulin) - 0,75 mg/kg/day for 8 days. – Cyclosporine (Sandimmune, Neoral) - 1.5-2 mg/kg IV q12h, – Methylprednisolone (Medrol, Solu-Medrol) - :5 mg/kg IV on days 1-8; then tapered using PO 1 mg/kg on days 9-14; further tapering over days 15-29. Stop after 1 mo except in evidence of serum sickness. – Cyclophosphamide (Cytoxan) : 45 mg/kg/d IV for 4 d. Immunosuppressive therapy 2 • Response rates 60-70% • Relapses are common and continued supportive care needed. • Up to 50% of relapsed patients will respond to 2nd course of immunosuppressive therapy. APLASTIC ANEMIA – treatment • Other treatments : – Androgens : • these agents push the resting hematopoietic stem cells into cycle, making them more responsive to differentiation by hematopoietic growth factors and stimulate endogenous secretion of erythropoietin. • most are masculinizing and poorly tolerated by females and children. • The response rate is limited to approximately 45%, and results may require 6-10 months of therapy. – Hematopoietic growth factors - G-CSF and GM-CSF, may be useful in patients with neutropenia who have infections, without requiring a WBC transfusion. Therapy of non-severe aplastic anemia 1. „Watch and wait” 2. Androgens (?) 3. Supportive care: blood and platelet transfusion, antibiotics, growth factors 4. Immunosuppressive treatment in selected patients APLASTIC ANEMIA – complications • • • • Infections Bleeding Iron overload Complications of BMT – Graft versus host disease – Graft failure Treatment for adults with acquired severe aplastic anaemia. Treatment for adults with acquired non severe aplastic anaemia .