APLASTIC ANEMIA

Dr Babak Tamizi far MD.Assistant Professor Of Internal MedicineAl-Zahra HospitalIsfahan University Of Medical Sciences

Aplastic anemiaA bone marrow biopsy specimen shows a virtually empty marrow

hematopoietic stem cells are unable toproliferate, differentiate, or give rise to matureblood cells and their precursors.In most cases, this failure of stem cells seems toresult from an immune mechanism.absence or low numbers of CD34 and colony-forming cells in bone marrow

hematopoietic stem cells are unable toproliferate, differentiate, or give rise to matureblood cells and their precursors.In most cases, this failure of stem cells seems toresult from an immune mechanism.absence or low numbers of CD34 and colony-forming cells in bone marrow

ESSENTIALS OF DIAGNOSIS

PancytopeniaNo abnormal cells seenHypocellular bone marrow

PancytopeniaNo abnormal cells seenHypocellular bone marrow

GENERAL CONSIDERATIONS

In aplastic anemia, bone marrow failure arisesfrom injury to or abnormal expression of thestem cellBone marrow becomes hypoplastic, andpancytopenia develops

In aplastic anemia, bone marrow failure arisesfrom injury to or abnormal expression of thestem cellBone marrow becomes hypoplastic, andpancytopenia develops

Causes of aplastic anemia

"Idiopathic" (probablyautoimmune)Drugs_Chloramphenicol– Phenylbutazone– Gold salts– Sulfonamides– Phenytoin– Carbamazepine– Quinacrine– Tolbutamide

Chemotherapy,radiotherapySystemic lupuserythematosusToxins: benzene, toluene,insecticidesPosthepatitisPregnancyParoxysmal nocturnalhemoglobinuriaCongenital (rare)

"Idiopathic" (probablyautoimmune)Drugs_Chloramphenicol– Phenylbutazone– Gold salts– Sulfonamides– Phenytoin– Carbamazepine– Quinacrine– Tolbutamide

Chemotherapy,radiotherapySystemic lupuserythematosusToxins: benzene, toluene,insecticidesPosthepatitisPregnancyParoxysmal nocturnalhemoglobinuriaCongenital (rare)

Clinical FindingsSYMPTOMS AND SIGNS

Weakness and fatigue from anemiaVulnerability to bacterial infections fromneutropeniaMucosal and skin bleeding fromthrombocytopeniaPallor, purpura, and petechiaeHepatosplenomegaly, lymphadenopathy, orbone tenderness should not be present

Weakness and fatigue from anemiaVulnerability to bacterial infections fromneutropeniaMucosal and skin bleeding fromthrombocytopeniaPallor, purpura, and petechiaeHepatosplenomegaly, lymphadenopathy, orbone tenderness should not be present

DIFFERENTIAL DIAGNOSIS

Acute leukemiaHairy cell leukemia

as splenomegaly and hypercellular marrowMyelodysplastic syndrome

presence of immature granulocytes or nucleatedred cells . marrow karyotype may show a clonalabnormality

Bone marrow infiltrative process (eg, tumor,infection, granulomatous disease)HypersplenismSystemic lupus erythematosusImmune thrombocytopenia

Acute leukemiaHairy cell leukemia

as splenomegaly and hypercellular marrowMyelodysplastic syndrome

presence of immature granulocytes or nucleatedred cells . marrow karyotype may show a clonalabnormality

Bone marrow infiltrative process (eg, tumor,infection, granulomatous disease)HypersplenismSystemic lupus erythematosusImmune thrombocytopenia

DiagnosisLABORATORY TESTSPancytopenia, although in early disease only one or twocell lines may be reducedAnemia may be severeReticulocytes always decreasedRed blood cell morphology unremarkableNeutrophils and platelets reduced in number, no immatureor abnormal forms seenSevere aplastic anemia defined by neutrophils < 500/mcL,platelets < 20,000/mcL, reticulocytes < 1%, and bonemarrow cellularity < 20%

80% risk for death by 2 years after diagnosis if treatedwith supportive care alone

Pancytopenia, although in early disease only one or twocell lines may be reducedAnemia may be severeReticulocytes always decreasedRed blood cell morphology unremarkableNeutrophils and platelets reduced in number, no immatureor abnormal forms seenSevere aplastic anemia defined by neutrophils < 500/mcL,platelets < 20,000/mcL, reticulocytes < 1%, and bonemarrow cellularity < 20%

80% risk for death by 2 years after diagnosis if treatedwith supportive care alone

DIAGNOSTIC PROCEDURES

Bone marrow aspirate and bone marrow biopsyappear hypocellular, with scant amounts ofnormal hematopoietic progenitors; noabnormal cells are seen

TreatmentMEDICATIONS

Prompt and aggressive treatment is indicatedfor most patientsAntibiotics to treat infectionsImmunosuppression with antithymocyteglobulin (ATG) plus cyclosporine (or tacrolimus)for severe aplastic anemia in adults aged > 50or those without HLA-matched siblings

Prompt and aggressive treatment is indicatedfor most patientsAntibiotics to treat infectionsImmunosuppression with antithymocyteglobulin (ATG) plus cyclosporine (or tacrolimus)for severe aplastic anemia in adults aged > 50or those without HLA-matched siblings

Immunosuppression has a low early mortalityrate (<10%), but it is not curative and carries a30 to 50% risk for relapse and a 20 to 30%probability of development of a myelodysplasticsyndrome or PNH

Immunosuppression has a low early mortalityrate (<10%), but it is not curative and carries a30 to 50% risk for relapse and a 20 to 30%probability of development of a myelodysplasticsyndrome or PNH

TreatmentMEDICATIONS

Useful regimen is equine ATG, 40 mg/kg/dayintravenously for 4 days, in combination withcyclosporine, 6 mg/kg orally twice daily, givenin hospital in conjunction with corticosteroids,and transfusion and antibiotic supportCorticosteroids are given with ATG (prednisone1–2 mg/kg/day initially followed by taper) toavoid complications of serum sickness

Useful regimen is equine ATG, 40 mg/kg/dayintravenously for 4 days, in combination withcyclosporine, 6 mg/kg orally twice daily, givenin hospital in conjunction with corticosteroids,and transfusion and antibiotic supportCorticosteroids are given with ATG (prednisone1–2 mg/kg/day initially followed by taper) toavoid complications of serum sickness

TreatmentMEDICATIONS

Rabbit ATG is more immunosuppressive thanequine ATG and may also be used; the dose is3.5 mg/kg for 4 daysHigh-dose immunosuppression withcyclophosphamide, 200 mg/kg, has producedremissions in refractory cases and should beconsidered for patients without suitable bonemarrow donors

Rabbit ATG is more immunosuppressive thanequine ATG and may also be used; the dose is3.5 mg/kg for 4 daysHigh-dose immunosuppression withcyclophosphamide, 200 mg/kg, has producedremissions in refractory cases and should beconsidered for patients without suitable bonemarrow donors

TreatmentMEDICATIONS

Androgens (eg, oxymetholone, 2–3 mg/kgorally once daily) used commonly in pastDespite low response rate, some patients canbe maintained successfully with androgens

Androgens (eg, oxymetholone, 2–3 mg/kgorally once daily) used commonly in pastDespite low response rate, some patients canbe maintained successfully with androgens

THERAPEUTIC PROCEDURES

Supportive measures only for mild casesAllogeneic bone marrow transplantation istreatment of choice for severe aplastic anemiain adults aged < 50 with HLA-matched siblingsAllogeneic transplantation using unrelateddonor if immunosuppression is not effectiveRed blood cell and platelet transfusions asnecessary

Supportive measures only for mild casesAllogeneic bone marrow transplantation istreatment of choice for severe aplastic anemiain adults aged < 50 with HLA-matched siblingsAllogeneic transplantation using unrelateddonor if immunosuppression is not effectiveRed blood cell and platelet transfusions asnecessary

Transplantationstem cell transplantation from a histocompatible sibling

Transplantation is a curative treatmentonly 25 to 30% of patients have a histocompatiblesiblingmortality risk ranging from 10% in children andyoung adults to more than 20% in older patientsTransfusions of blood products from family members should be avoided intransplant candidates (graft rejection after transplantation)

Transplantation is a curative treatmentonly 25 to 30% of patients have a histocompatiblesiblingmortality risk ranging from 10% in children andyoung adults to more than 20% in older patientsTransfusions of blood products from family members should be avoided intransplant candidates (graft rejection after transplantation)

OutcomeComplications

Bacterial infectionsBleedingBacterial infectionsBleeding

PROGNOSIS

Median survival in severe aplastic anemiawithout treatment is ~3 months, and 1-yearsurvival is only 20%Allogeneic bone marrow transplantation ishighly successful in children and young adultswith HLA-matched siblings, with durablecomplete response rate > 80%

Median survival in severe aplastic anemiawithout treatment is ~3 months, and 1-yearsurvival is only 20%Allogeneic bone marrow transplantation ishighly successful in children and young adultswith HLA-matched siblings, with durablecomplete response rate > 80%

PROGNOSIS

ATG treatment produces partial response in~60% of adults, usually in 4–12 weeks; long-term prognosis of responders is goodParoxysmal nocturnal hemoglobinuria ormyelodysplasia or other clonal hematologicdisorders develop in as many as 25% ofnontransplanted patients after many years offollow-up

ATG treatment produces partial response in~60% of adults, usually in 4–12 weeks; long-term prognosis of responders is goodParoxysmal nocturnal hemoglobinuria ormyelodysplasia or other clonal hematologicdisorders develop in as many as 25% ofnontransplanted patients after many years offollow-up

WHEN TO REFERAll patients should be referred tohematologist

WHEN TO ADMITTreatment of neutropenic infection

WHEN TO REFERAll patients should be referred tohematologist

WHEN TO ADMITTreatment of neutropenic infection

Management of aplastic anemia.HLA = human leukocyteantigen; KPS = Karnofskyperformance status score.*Alternative therapy includes asecond course ofimmunosuppressive therapyand allogeneic stem celltransplantation from an HLA-matched sibling for olderpatients and stem celltransplantation from anunrelated donor or a partiallymatched related donor foryounger and older patients whoare refractory toimmunosuppressive therapiesand are also severelythrombocytopenic andrefractory to platelettransfusions.

Management of aplastic anemia.HLA = human leukocyteantigen; KPS = Karnofskyperformance status score.*Alternative therapy includes asecond course ofimmunosuppressive therapyand allogeneic stem celltransplantation from an HLA-matched sibling for olderpatients and stem celltransplantation from anunrelated donor or a partiallymatched related donor foryounger and older patients whoare refractory toimmunosuppressive therapiesand are also severelythrombocytopenic andrefractory to platelettransfusions.

The end