Downloaded 53 times
More Related Content
Similar to Aplastic anemia
More from ajayyadav753
Aplastic anemia
- 1. APLASTIC ANEMIA Ajay KumarYadav PGY3,Medicine IOM-TUTH, Kathmandu 2075/05/13
- 2. LAYOUT • Historical background •How to diff. acquired Vs constitutional AA • Etiology • Clinical features • Diagnosis • Management • Bone Marrow Transplantation(BMT) • Immune Suppressive Therapy(IST)
- 3. HISTORICAL BACKGROUND • Theearliest case description of aplastic anemia was by Dr. Paul Ehrlich in 1888. • The term aplastic anemia was first introduced in 1904 by Chauffard • A patient with aplastic anemia became the first recipient of successful allogeneic bone marrow transplantation in 1972
- 4. INTRODUCTION Pancytopenia with hypocellularBone Marrow.
- 5.
- 7. ACQUIRED Vs CONSTITUTIONAL FeaturesAcquired Constitutional 1. Age of presentation Any age Usually present in the first decade of life adulthood 2. Physical anomalies Absent Present(e.g. Shot stature ,upper limb anomalies ,hypogonadism , skin manifestations) 3. Family history No May be present
- 8. CONSTITUTIONAL APLASTIC ANEMIA •FANCONI ANEMIA • Most common form of inherited bone marrow failure • AR inheritance • Characterized by defects in DNA repair and a predisposition to leukemia and solid tumors. • Anomalies : short stature, café au lait spots, and involving the thumb, radius, and genitourinary tract. • At least 16 different genetic defects • Most common : type A Fanconi anemia - mutation in FANCA.
- 9. Cont.. • DYSKERATOSIS CONGENITA(DKC) • Loss of function mutations of telomerase components • Triad of abnormal skin pigmentation, nail dystrophy, and mucosal leukoplakia • Inheritance : AD , AR , XR • AR DKC : mutations of TERC or TERT • XR DKC : mutations in the gene DKC1 dyskerin
- 10. Cont.. • INHERITED AMEGAKARYOCYTICTHROMBOCYTOPENIA • characterized by severe thrombocytopenia and megakaryocyte absence at birth. • Missense or nonsense mutations in the c-mpl gene • SHWACHMAN-DIAMOND SYNDROME • AR inheritance • Characterized by pancreatic exocrine dysfunction, metaphyseal dysostosis, and bone marrow failure
- 11. EPIDEMIOLOGY • International AplasticAnemia and Agranulocytosis Study (IAAAS), conducted in Europe and Israel, in between 1980 and 1984 • Overall incidence : 2 cases per 1 million people • The incidence may be 2-3 fold higher in SEA • Age : children and young adults , 2nd small peak after age 60 • Genetic predisposition : HLA-DR2
- 12.
- 13. Cont.. • CHEMICALS: BENZENE •Aplastic anemia , MDS , Leukemia • RADIATION • Dose dependent • Direct toxicity to stem and progenitor cells. • DNA damage tissues susceptible to mitosis are highly affected. • INFECTIONS • Seronegative hepatitis ( Non-A , non-B , Non-C ) • EBV ( IMN ) • Human Parvovirus B19 • HIV
- 14.
- 15. • PREGNANCY • Canoccur during pregnancy or shortly after delivery. • In women with a history of AA who had been treated into remission with IST, there is an increased risk for relapse during pregnancy • In contrast to idiopathic aplastic anemia, pregnancy-associated AA is often associated with spontaneous remissions. • IMMUNOLOGICAL DISEASES • GVHD • Eosinophilic fasciitis • Thymoma , Hypogammaglobulinemia • SLE
- 16. PATHOPHYSIOLOGY • STEM CELLS •Cells bearing the CD34 antigen, a marker of early hematopoietic cells, are greatly diminished • In functional studies, committed and primitive progenitor cells are virtually absent. • AUTOIMMUNITY • The recovery of marrow function in pts prepared for BMT with ATG and Cycloserine suggested that AA might be immune mediated.
- 17. Cont.. • CLONALITY • Clonalhematopoietic stem cell disorders such as PNH and MDS frequently arise from AA. • Increased survival following immunosuppressive therapy allows time for these underlying clones to develop and expand. • Up to 15% of children and adults with AA will develop MDS following IST, with monosomy 7 being the most common chromosomal abnormality. • PNH results from the expansion of an abnormal hematopoietic stem cell that harbors a somatic mutation of the X-linked gene, PIGA
- 18. CLINICAL FEATURES • HISTORY Onset : Abrupt or insidious Bleeding usually the 1st presenting symptom. Infection is unusual 1st symptom ( unlike agranulocytosis where sore throat ,anorectal abscess and sepsis occurs early ) Proportional to the peripheral blood cytopenia and may include SOB, fatigue, easy bruising, petechia, epistaxis, gingival bleeding, heavy menses, headache, and fever. Pts often feel and look remarkably well despite drastically reduced blood counts. Systemic complaints and weight loss should point to other etiologies of pancytopenia. Prior drug use, chemical exposure, and preceding viral illnesses. Family history
- 19. PHYSICAL EXAMINATION • Petechiae,ecchymoses • Pallor • Lymphadenopathy and splenomegaly are highly atypical of AA. • Café au lait spots and short stature suggest Fanconi anemia • Peculiar nails and leukoplakia suggest dyskeratosis congenita • Early graying (and use of hair dyes to mask it!) suggests a telomerase defect.
- 20. LAB DIAGNOSIS • PBS Large RBCs , Paucity of platelets and granulocytes. MCV : commonly increased. Reticulocytes : absent or few The presence of immature myeloid forms suggests leukemia or MDS Nucleated RBCs suggest marrow fibrosis or tumor invasion Abnormal platelets suggest either peripheral destruction or MDS.
- 21. BONE MARROW • Ahypocellular bone marrow is required for the diagnosis of AA . • 1-2 cm core biopsy is essential for assessing cellularity • The presence of a small percentage of myeloid blasts or dysplastic features in the myeloid or megakaryocyte lineages favors a diagnosis of hMDS. • The % of CD34+ cells in the BM is often helpful : the % of CD34+ cells is usually ≤0.3% in AA, whereas the CD34 % is either normal (0.5% to 1.0 %) or elevated in hMDS. • Dry tap : Myelofibrosis , Myelopthisis
- 22. D/D OF HYPOCELLURMARROW 1. Acquired AA 2. Inherited AA esp. Fanconi anemia 3. Hypoplastic MDS (hMDS) : 15% of MDS 4. Hypoplastic PNH
- 23. MDS Vs AA Wintrobe’sclinical hematology 13th edidtion
- 25. Ancillary tests • Chromosomebreakage studies of peripheral blood using diepoxybutane or mitomycin C : To R/O Fanconi anemia. • Flow cytometry / FLAER of peripheral blood : To R/O PNH
- 26. CLASSIFICATION OF AABASED ON SEVERITY OF PANCYTOPENIA • Severe aplastic anemia (SAA) • Bone marrow cellularity <25% + 2/3 peripheral blood criteria: • Absolute neutrophil count <500/mm3 • Platelet count <20,000/mm3 • Reticulocyte count <60,000/mm3 or <1% corrected reticulocyte count • Very severe aplastic anemia (vSAA) • Same as SAA with absolute neutrophil count <200/mm3 • Non severe (moderate aplastic anemia) • Bone marrow cellularity <25% • Peripheral blood cytopenia do not fulfill criteria for SAA
- 27.
- 28.
- 29. Treatment cont.. • Therisk of morbidity and mortality from AA correlates best with the severity of the cytopenia rather than bone marrow cellularity. • The 2-year mortality rate with supportive care alone for patients with SAA or VSAA approaches 80%, with invasive fungal infections and overwhelming bacterial sepsis being the most frequent causes of death. • NSAA is seldom life-threatening and in many instances requires no therapy
- 30. SUPPORTIVE CARE • TRANSFUSIONS Pts with symptomatic anemia and/or thrombocytopenia a/w wet purpura or bleeding require immediate BT. All transfusions in pts with suspected AA s/b irradiated to prevent transfusion- associated GVHD. If the patient is a potential BMT candidate and is CMV negative or the CMV status is unknown, CMV transmission should be avoided by either leukoreduction or the use of CMV-negative products. Blood donation from family members should be avoided to prevent alloimmunization that could also complicate future BMT
- 31. What is thetarget Hb and platelet ? • Platelet : 10,000/cu mm • Hb :7 g/dl ( 9 g/dl if there is ass. Cardiac or pulmonary disease)
- 32. Cont.. • ANTIBIOTICS Ptswith ANC that are consistently <200μL, prophylaxis with oral antibiotics, such as a quinolone and a triazole antifungal, is reasonable. Pts with febrile neutropenia s/b treated promptly with broad-spectrum antibiotics; in patients with persistent fever after the initiation of antibacterial antibiotics, aspergillus coverage should be added. Prophylaxis for PCP s/b given to all pts for at least 6 months after IST, BMT, or high-dose cyclophosphamide therapy.
- 33. Cont.. • GROWTH FACTORS •Should not be used in lieu of definitive therapy. • They are often used after IST or high-dose cyclophosphamide therapy to accelerate hematopoietic recovery. • Their use has not been shown to improve survival. • ATG+CSA+G-CSF identifies early non responders, and perhaps may indicate an urgent transplant approach.
- 34. Definitive Therapy forSevere Aplastic Anemia • BONE MARROW TRANSPLANTATION Allogeneic BMT from an HLA-matched sibling donor is the treatment of choice at most centers for young patients <40 yrs. The age effect : Very strong age effect with survival of 82%, 72%, 53% for patients aged 1-20, 21- 40 and over 40 years , due to a higher incidence of graft failure and GvHD A major advantage of BMT over standard IST Marked reduction in the risk of relapse and Reduction in the outgrowth of late clonal disorders such as MDS and PNH.
- 36. • CONDITIONING REGIMEN •Cyclophosphamide (50 mg/kg/day × 4 days) with or without ATG, is commonly used for conditioning before SCT. • Current guidelines from EBMT and the British Society for Standards in Haematolgy , call for a combination of FLU-CY, combined with ATG (FCA) or alemtuzumab (CAMPATH) (FCC), for SAA pts over the age of 30, receiving a matched sibling donor transplant.
- 37. Bone Marrow (BM)or Peripheral Blood (PB)?? • British guidelines, call for BM as a stem cell source, in ATG based conditioning and • BM should be the only acceptable stem cell source for transplants from HLA identical siblings in SAA.
- 38. Alternative Donor BoneMarrow Transplantation • Unrelated donors and mismatched transplants have almost twice the transplant-related mortality and risk of GVHD as matched sibling donor transplant. • The ideal UD, is a male, HLA matched at the A,B,C,DRB1 loci, less than 30 years of age, CMV matched with the recipient. • The conditioning regimen would include FLU-CY-ATG (FCA) and low dose TBI, or FLU-CY-CAMPATH (FCC) .
- 40. Unrelated Cord Blood(UCB)Transplant • Indication : Pts who do not have a suitable UD. • The conditioning regimen for CB transplants, is identical to the regimen which is proposed for UD transplants, although MTX is omitted from GVHD prophylaxis of CB grafts; one dose of rituximab 150 mg is recommended on day+5, to prevent EBV lymphoproliferative disorders
- 41. Haploidentical(HAPLO) Transplant • Youngpts who do not have a matched UD or a suitable CB unit, and have failed at least one course of IST, or have rejected a previous UD or CB graft, are eligible for a transplant from HLA haploidentical family donors (HAPLO). • Still in the experimental stage.
- 42. IMMUNOSUPPRESSIVE THERAPY(IST) • ANTI-THYMOCYTEGLOBULIN(ATG)/CYCLOSPORIN(CSA ) BASED THERAPY Indication : Not a candidate for BMT because of older age or lack of a matched sibling donor. ATG is produced by immunizing animals (horse or rabbit) against human thymocytes. The largest experience is with horse ATG, although rabbit ATG has recently been approved for use in the US. A RCT demonstrated that horse ATG/CSA is superior to rabbit ATG/CSA in terms of response at 6 months (68% vs 37%), and 3 year survival (96% vs 76%) .
- 44. IST cont.. Theresponse rates to ATG/CSA range between 60% and 80% , with 5-year survival rates comparable to BMT. In contrast to BMT, most pts are not cured of their disease. Most pts respond within 6 to 12 wks after receiving ATG/CSA. ATG is usually given over 4 days but CSA must be continued for at least 6 to 12 months before tapering the drug. Persistent cytopenia is common and many patients relapse, become dependent on cyclosporine, or develop secondary clonal disease such as PNH or MDS.
- 45. IST cont.. • HIGH-DOSECYCLOPHOSPHAMIDE • High-dose cyclophosphamide remains (often in conjunction with ATG) is the most commonly used BMT conditioning regimen for AA. • Complete reconstitution of autologous hematopoiesis occurs in 10% to 15% of pts undergoing allogeneic BMT for AA. • 10-year survival (84%) in patients with autologous recovery was equivalent or better than in patients who engrafted (74%) • High-dose cyclophosphamide without BMT has been used to treat aplastic anemia patients who lack a suitable donor
- 46. RELAPSED AND REFRACTORYSEVERE AA • No standard algorithm • As much as 30% to 40% of pts do not respond to initial therapy and another 20% to 40% of responding patients relapse. • Therapeutic options include • Allogeneic BMT (usually from an unrelated or mismatched donor), • Re-treatment with ATG/CSA, • Alemtuzumab, or • High-dose cyclophosphamide
- 47. ELTROMBOPAG (EPAG) • Initialencouraging results in refractory pts • EPAG has been used together with ATG +CSA , as initial treatment in 88 patients . • The overall response at 6 months was 85%, with survival in the order of 90%. • Cytogenetic abnormalities and clonal evolution to MDS occurred at a similar frequency compared to standard IST.
- 48. TREATMENT OF PATIENTABOVE THE AGE OF 60. • BMT is rarely offered to pts > 60 years, due to high transplant related mortality. • Pts between 60 and 70 years of age, s/b treated with conventional ATG+CSA along with G-CSF, because of faster neutrophil recovery. • Above the age of 70 or 80, pts are rather frail use CSA plus androgens, and reserve CSA+ATG for fit patients.
- 49.
- 50. REFERENCE • Wintrobe’s clinicalhematology 13th edition • Harrison 19th edition • Blood journal 2017,How I treat aplastic anemia
- 51.
Editor's Notes
- #10 Telomerase reverse transcriptase (TERT) RNA component of telomerase (TERC)