Presentation on theme: "Bone Marrow Failure/ Aplastic Anemia"— Presentation transcript:
1Bone Marrow Failure/ Aplastic Anemia Dr. MERVAT A.HESHAM2008
2What is Aplastic Anemia? Aplastic Anemia is a bone marrow failure disease.Bone marrow is a Factory of Blood CellsRed Blood CellPlateletsWhite Blood CellHelp to save a Life
3Aplastic Anemia patients Aplastic Anemia patients have decreased amounts of: - Red Blood Cells- White Blood Cells- PlateletsHelp to save a Life
4Functions of Blood Cells Red Blood CellsCarry oxygen to all body organsWhite Blood CellsFight infection and keep you healthyPlateletsHelp control bleedingHelp to save a Life
5Help to save a Life www.aaaoi.org SymptomsLow Red Blood CellFatigue, Headache, Inability to ConcentrateLow White Blood CellViral Infections, Bacterial InfectionsLow PlateletsEasy Bruising, Nosebleeds, PetichiaeHelp to save a Life
6DEFINITION A disorder of the hemtopoietic system characterized by: Bone marrow - marked reduction of all 3 cell linesPeripheral blood - pancytopenia
7PATHOGENESIS Stem cell failure resulting from: 1-An acquired intrinsic stem cell defect2-An environmental causeImmune mechanismsGrowth factor deficiencyDefects in the microenvironment
8Epidemiology Incidence: 5-10:106 per year Age: 15 –30 years Sex: M = FAplastic anemia
9Etiology Hereditary Acquired 1-Schwacman – Diamond 2-Fanconi’s anemia syndrome3-Dyskeratosis congenitaAcquired1-Idiopathic2- Drugs: dose relatedidiosyncratic3-Radiation4-Chemicals5-Viruses6-Pregnancy7-PNH8-Disorders of immune system
17PATHOPHYSIOLOGYDirect toxic injury to hematopoietic stem cells can be induced by exposure toionizing radiation, cytotoxic chemotherapy, or benzene. These agents can crosslinkDNA and induce DNA strand breaks leading to inhibition of DNA and RNA synthesis.
182-Immune-mediated destruction of hematopoietic stem cells -- Direct killing of the stem cells has been hypothesized to occur via interations between Fas ligand expressed on the T-cells and Fas (CD95) present on the stem cells, which triggers programmed cell death (apoptosis).-- T-lymphocytes also may suppress stem cell proliferation by elaborating soluble factors including interferon-γ.
19-T cells from aplastic anemia patients secrete IFN-ã and tumor necrosis factor (TNF). -IFN-ã and TNF are potent inhibitors of both early and late hematopoietic progenitor cells .-Both of these cytokines suppress hematopoiesis by their effects on the mitotic cycle and, more importantly, by the mechanism of cell killing.-Activation of the Fas receptor on the hematopoietic stem cell by the Fas ligand present on the lymphocytes leads to apoptosis of the targeted hematopoietic progenitor cells.
20*Cytotoxic T cells also secrete interleukin-2 (IL-2), which causes polyclonal expansion of the T cells.* IFN-ã also induces the production of the toxic gas nitric oxide, diffusion of which causes additional toxic effects on the hematopoietic progenitor cells.
21Suppress proliferation with ligand, signals apoptosisYoung NEJM 1997
23Idiopathic AA*70% or more of casesHigher in SE AsiaM = F
24AA - Clinical ** Symptoms are due to pancytopenia: pallor, mucosal bleeding, ecchymoses, or petechiae and bacterial or fungalinfections..** Hepatosplenomegaly and lymphadenopathy do not occur; their presence suggestsan underlying leukemia.** Hyperplastic gingivitis is also a symptom of aplastic anemia.
25AA - Labs No RBC = pale, tachycardic No plt = bruising, bleeding No WBC = infectionRetic < 1%Plt < 20,000ANC < 500
28AA - Evaluation *CBC w/ diff and retic *Send DEB (Fanconi’s test) *Bone marrow*Send DEB (Fanconi’s test)*Send Hep A, B, C, D titers HIV*Test for PNH (CD55, CD59)*HLA typing*Fetal hemoglobin*Liver and renal function chemistries
29*Quantitative immunoglobulins, C3, C4, and complement. * Autoimmune disease evaluation: Antinuclear antibody (ANA), total hemolytic complement (CH50), Coombs’ test.* HLA typing: Patient and family done at the time of diagnosis of severe aplastic anemia to ensure a timely transplant.
30CLASSIFICATION Designation Criteria Peripheral blood BM biopsy Severe aplastic anemia-2 / 3 values-Neutrophils < 500/mL-Platelets < 20,000/ ul--Reticulocyte index < 1%-Marked hypocellular < 25% cellularity-Moderate hypocellular <25-50%-normal cellularity with <30% of remaining cell hematopoieticVery severe aplastic anemiaAs above but neutrophils < 200/mLInfection present
31Help to save a Life www.aaaoi.org Treatment OptionsBone MarrowTransplantGrowth HormonesImmune SuppressiveTherapySupportive CareHelp to save a Life
32TREATMENT 1-Withdrawal of the etiologic agent 2-Supportive treatment Blood and platelet transfusion used with caution- sensitization (filtered)3-Allogeneic BMT-Preferably from sibling-Curative in 60-90% of patients-Applicable only for a third of patients*ImmunosuppressionCyclosporin + ATGCorticosteroidsHigh dose cyclophosphamide*G-CSF/ GM-CSF/ EPO - maybe**Response rate 50-70% Occurs 2-3 months post Rx.
33AA Newer *Mycophenolate mofetil (MMF) - cytotoxic to T cells *Monoclonal Ab against IL-2 receptor which is present on activated lymphocytes
34AA - Outcomes Age, Younger is better BMT Immunosuppression - 60 - 80% < 20 yr with a sib… 75%yr with a sib…60%< 20 yr unrelated BMT… 40%yr unrelated BMT…35%Immunosuppression %But for how long and consequences…
42Clinical Features Progressive bone marrow failure Most common etiology of inherited bone marrow failureOthers include dykeratosis congenita, amegakaryocytic thrombocytopenia, Schwachman-Diamond syndromeIncreased risk of MDS and AML (15,000x)Many have monosomy 7, or duplication of 1q (Auerbach et al., Cancer Genet Cytogenet 1991)
43Clinical FeaturesIncreased risk of solid tumor formation (hepatic, esophageal, oropharyngeal, vulvar)Average age at diagnosis is 23*Cumulative incidence ~30% by age 45***Shimamura et al., Gene Reviews 2002 (genetests.org)**Alter et al. Blood 2003
44FA - genetics Identification of subtypes (compliment groups) A, B, C, D1, D2, E, F, GIdentical clinicallySub-units of a common protein/ common pathwayProtein modifies FANCD2FANCD2 interacts with BRCA1 and 2BRCA1 and 2 needed for DNA repair
47PATHOPHYSIOLOGYDNA damage activates a complex consisting of Fanconi proteins A, C, G, and F. This in turn leads to the modification of the FANCD2 protein. This protein interacts, for example, with the breast cancer susceptibility gene BRCA1.
48*Fanconi anemia cells are characterized by hypersensitivity to chromosomal breakage as well as hypersensitivity to G2/M cell cycle arrest induced by DNA cross-linking agents.*In addition there is sensitivity to oxygen-free radicals and to ionizingradiation.
49Diagnosis-*Pts. with congenital abnormalities are often diagnosed as neonates/infants*Others may be diagnosed when hematological problems occur*Median age of onset of pancytopenia is 7Usually normal CBC at birth*First develop macrocytosis, then thrombocytopenia, and eventually neutropenia
50DiagnosisBased on chromosomal hypersensitivity to cross-linking agentsChromosome fragility test: Mitomycin C (MMC) or diepoxybutane (DEB) added to lymphoctyes – increases the number of chromosome breaks and radial structuresVery specific for FA, regardless of severity of diseaseCan do chromosome breakage analysis on amniotic cells, chorionic villus cells or fetal blood
52Chromosome breakage in Fanconi Anemia cells FA cells were treated with mitomycin C and harvested in metaphase. Typical abnormalities include radial formation (green circle) and chromosome breaks (red arrows).
53Initial management Refer for genetic counseling Testing of siblingsRenal ultrasound, hearing test, eye examEndocrine evaluation if evidence of growth failure (check growth hormone levels, TSH)Referral to hand surgeon for radial ray defectsBone marrow biopsy
54Management Bone marrow failure Transfusions Androgens (e.g. oral oxymethalone) – can improve blood counts in 50% of pts.Side effects: Masculinization, acne, hyperactivity, premature closure of epiphyses, liver toxicity, hepatic adenomasGrowth factors (G-CSF, CM-CSF) – should not be used in patients with clonal cytogenetic abnormalitiesBone marrow transplantationFA cells are very sensitive to radiation and alkylating agents – can use greatly reduced doses2-yr. survival 70% for allo;* % for MUD***Guardiola et al. Bone Marrow Transplant 1998;**MacMillan et al., Br J Haematol 2000
55Management - Gene therapy *Goal is to permanently correct hematological manifestations by transducing hematopoietic progenitor cells with a vector containing the deficient gene*Knockout mice with FANCC using retroviral vectors - phenotypic correction (Gush et al., Blood 2000)*Knockout mice with FANCA and FANCC using lentiviral vectors – more promising (integrates into the genome) (Galimi et al. Blood 2002)
56Other Congenital Marrow Failures Dystkeratosis CongenitaRareDifferent modes of inheritanceEctodermal dysplasia50% develop aplastic anemia in midteensSchwachman-DiamondCartilage-Hair HypoplasiaFamilial Marrow Dysfunction
67Clinical Manifestations Symptoms of anemia*The median age at presentation of anemia is 2 months and the median age at diagnosis of DBA is 3 months.*Physical anomalies, excluding short stature*No hepatosplenomegaly.*Malignant potentialIn patients with long-standing PRCA – transfusional hemosiderosis
68Laboratory Evaluation Diagnostic criteria:--Normochromic, usually macrocytic anemia, relative to patient’s age and occasionallynormocytic anemia developing in early childhood-- Reticulocytopenia-- Normal or only slightly decreased granulocyte count-- Normal or slightly increased platelet countSupportive criteria:-Typical physical abnormalities-Increased fetal hemoglobin-Increased erythrocyte adenosine deaminase (eADA) activity
69BM*Absence of erythroblasts <1% on BM(absence of normoblasts, in some cases with relative increase in proerythroblasts or normal number of proerythroblasts with a maturation arrest).*normal myeloid and megakaryocytic series.*Usually – normal karyotype, except for preleukemic cases
71Treatment Congenital Hypoplastic Anemia CorticosteroidsAlloBMTIL-3 –experimentalPatients refractory to all treatments – regular transfusions & desferioxamine
72Treatment Acquired PRCA -Discontinuation of all drugs-R/O infections-If parvovirus suspected – high dose IgG-In the presence of thymoma – thymectomy
73-In 30-40% erythropoiesis remits within 4-8 weeks -Non-responding pts. – should be treated as primary acquired PRCA-Thymectomy in the absence of thymoma is not recommended-If an underlying disease – treat the disease
74Treatment Acquired PRCA For primary or secondary PRCA not responding to treatment of underlying disease:PrednisoneCyclophosphamide / azathioprineCyclosporineATGHigh dose IgGPlasmapheresisSplenectomyRituximab