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Aplastic Anemia
Delva Deauna-Limayo, MD
Types of Blood Cells
Normal Range Decrease
3.93-5.69 million
cells/µL
HemoglobinMales: 13-17.5 g/dL
Females: 12-15.5 g/dL
Anemia
3500 - 10,500 cells/µL Leukopenia
150,000-450,000
cells/µLThrombocytopenia
PANCYTOPENIA
Occurs in 2-4 individuals per million population per year
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Immune destruction of hematopoiesis.
Neal S. Young et al. Blood 2006;108:2509-2519
©2006 by American Society of Hematology
Presentation - Anemia
Presentation Causes
• PRIMARY• Congenital – Fanconi anemia
• Idiopathic (67%)
• SECONDARY• Chemicals – benzene, toluene
• Drugs – chloramphenicol, phenytoin, carbamazapine
• Insecticides
• Ionizing Radiation
• Infections – HIV, EBV, hepatitis
• Autoimmune Disease - Eosinophilic fascitis
• Paroxysmal Nocturnal Hemoglobinuria
• Pregnancy
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Work Up
• Physical Examination
• Complete Blood Count (CBC)
• Bone Marrow Examination
• Specialized Testing
Work Up
• Physical Examination
• Complete Blood Count (CBC)
• Bone Marrow Examination
• Specialized Testing
Complete Blood Count (CBC) with differential
TYPE NORMAL RANGE
Absolute (Percent)
White Blood Cell (WBC) 3500 - 10,500/µL
Differential
Neutrophils 2000-7000/µL (40-80%)
Lymphocytes 1000-3000/µL (20-40%)
Monocytes 200-1000/µL (2-10%)
Eosinophils 20-500/µL (1-6%)
Basophils 20-100/µL (<1-2%)
Absolute Neutrophil Count (ANC ) = WBC x (seg +bands %) ̷ 100
Neutropenia - decreased neutrophil counts
Complete Blood Count (CBC) with differential
TYPE NORMAL RANGE
Absolute (Percent)
Red Blood Cell (RBC) 3.93 - 5.69 million cells/µL
Reticulocyte Count 40,000 - 95,000/µL (0.5-1.5%)
Platelets 150,000 - 450,000/µL
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Work Up
• Physical Examination
• Complete Blood Count (CBC)
• Bone Marrow Examination
• Specialized Testing
Bone Marrow Biopsy
Normal Aplastic Anemia
Work Up
• Physical Examination
• Complete Blood Count (CBC)
• Bone Marrow Examination
• Specialized Testing
• Flow Cytometry - CD59 for PNH
• Cytogenetic Analysis - MDS
• Chromosomal breakage - Fanconi Anemia
Diagnostic Criteria
• MODERATE AA• BM cellularity < 30%
• Absence of severe pancytopenia
• Depression of at least 2 of 3 blood elements
• SEVERE AA• BM cellularity < 25%
• ANC < 500
• Absolute reticulocyte count < 40,000
• Platelet count < 20,000
• VERY SEVERE AA• ANC < 200
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Treatment
• Allogeneic hematopoietic stem cell transplant (HSCT)
• Immunosuppressive Therapy (IST)
• Thrombopoietin (TPO) receptor agonists
• Supportive
• Blood Transfusions
• Granulocyte colony stimulating factor (GCSF)
• Infection treatment/prevention
Treatment - Frontline
Hematopoietic Stem Cell Transplant (HSCT)
• Balance likely benefit, feasibility and toxicity
• Severe or very severe AA who have available donor• Allogeneic HSCT
• Age < 50 y/o
• Comobities
• HLA matched related (sibling) preferred• 30% will match
1 D'Souza A, Zhu X. Current Uses and Outcomes of Hematopoietic Cell
Transplantation (HCT): CIBMTR Summary Slides, 2016. Available at: http://www.cibmtr.org
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D'Souza A, Zhu X. Current Uses and Outcomes of Hematopoietic Cell
Transplantation (HCT): CIBMTR Summary Slides, 2016. Available at: http://www.cibmtr.org
Cross Race Probability for HLA Matching (Unrelated)
Donor Race
Pat
ient
Race
WHITE AA ASIAN HISP NATIVE
WHITE .77 .52 .43 .68 .70
AA .18 .61 .08 .26 .20
ASIAN .29 .15 .78 .30 .32
HISP .54 .42 .35 .69 .57
NATIVE .61 .49 .53 .71 .76
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Complications post HSCT
Adapted from: Woo et al www.emedicine.com 2/05
Oral mucositis may occur in up to 70% of patients.
Results in pain, infections, inadequate nutrition and prolonged hospitalization
Complications post HSCT
Infections: Cytomegalovirus Pneumonia
Adapted from: www.kjronline.orgAdapted from: med.nagoya-cu.ac.jp
Infections: Aspergillus (Mold) Pneumonia
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Infections: Herpes Infections
Adapted from: www.bioport.orgAdapted from: www/emedicine.com
Graft vs Host Disease
• Pathogenesis:
• Donor T cells recognize recipient’s Ag as foreign
• Cytokine release: T-cell activation; tissue injury
• Risk Factors:
• Mismatched grafts
• Older age
• Gender differences; parity
• Chemotherapy/radiation
• Prior transfusions
• Type and stage of disease
• Infections: herpes, CMV
Adapted from: www.med.sc.edu
Adapted from [email protected]
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Infections
Disability
Quality of life
Endocrine
Metabolism
Nutrition
Pain
Ocular sicca
Oral ulcers
Nail dystrophy
Skin sclerosis
Deep sclerosis
Bronchiolitis obliterans
Loss of bile ducts
Fasciitis
Skin ulcers
Spectrum of
manifestations
in chronic GVHD
Adapted: Pavletic S, Chronic GVHD
Treatment - Frontline: IST
• IST – Immunosuppressive Therapy
• Older patients, no suitable donor
• Horse Anti-thymocyte Globulin (ATG)• 40 mg/kg IV over 4-6 hrs daily x 4
• Cyclosporine • 10-12 mg/kg orally in two divided doses
• Monitored to keep trough levels between 200-400 ng/mL
• Continued for ~ 6 months
• Glucocorticoids• administered with ATG to reduce serum sickness
• Prednisone or Methylprednisolone 1 mg/kg daily x 2 weeks then taper by day 30.
Treatment - Frontline: IST
• ATG + CSA vs CSA alone 1
• Responses: 65% vs 39%
• Median time to transfusion independence: 6 months
• Horse ATG vs Rabbit ATG 2
• HR @ 6 mos: 68% vs 37%
• 3-yr OS: 96% vs 76%
• Responders vs Non-Responders 3
• HR @ 3 mos - 5 yr OS: 86% vs 40%
1 Fricknofen N et al. NEJM 1991;324(19):1297; 2Scheinberg P N Engl J Med 2011;365(5):430; 3Rosenfeld S et al. JAMA 2003; 289(9):1130
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ATG – Drug Reactions
• Type I – Immediate Reaction
• H1 and H2 blockers
• Acetaminophen
• Type III – Serum Sickness
• Occurs 10-14 days
• Fevers, rash, polyarthralgias
• Steroids, supportive care
• Self-limiting
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Cyclosporine
Body System Adverse Reactions
Genitourinary Renal Dysfunction
Cardiovascular Hypertension
Cramps
Skin Hirsutism
Acne
Central Nervous System
Tremor
Convulsions
Headache
Gastrointestinal
Gum Hyperplasia
Diarrhea
Nausea/Vomiting
Hepatotoxicity
Autonomic Nervous SystemParesthesia
Flushing
Hematopoietic Leukopenia
Lymphoma
Respiratory Sinusitis
Miscellaneous Gynecomastia
Cyclosporine and Bradycardia
• Possible Mechanisms
• Suppression of the automaticity of the sinus node
• ?Stimuation of the parasympathetic nervous system
• Dose-dependent association
Fujisaki G et al. Bone
Marrow Transplantation
2005; 35:211
Treatment - Frontline
• Allogeneic hematopoietic stem cell transplant (HSCT)
• Immunosuppressive Therapy (IST)
• Supportive
• Blood Transfusions
• Chelation for iron overload
• Granulocyte colony stimulating factor (GCSF)
• Infection treatment/prevention
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Treatment - Relapsed/Refractory Disease
• Rabbit ATG 1,2
• Responses: 50-77%; Survival 80-90%
• Earlier onset of serum-sickness
• Eltrombopag - TPO agonist
• Alemtuzumab
• High dose cyclophosphamide
• Allogeneic HSCT
Thrombopoietin agonists - Eltrombopag
Eltrombopag
Eltrombopag in Severe AA
• Refractory after initial IST; Severe AA
• Median age – 44 yrs
• N=25
• Response Criteria
• Platelet – 20,000 or independence from transfusion over 8 weeks
• Red – 1.5 g increase from baseline 9 and below, or transfusion
independence over 8 weeks or decrease in PRBC transfusion
requirement by 4 units over 8 weeks
• White – ANC > 500 mm3
Eltrombopag in Severe AA
• Results:
• 11/25 (44%) hematologic response in at least 1 lineage @ 12
weeks
• 9/11 – platelet transfusion independence
• 3/11 – PRBC transfusion independence
• 9/11 – ANC response (median ANC 1350)
• Duration of eltrombopag administered: median 16 months
(range: 8-32 mos)
Olnes M et al. NEJM 2012; 367: 11-9
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Clonal Evolution
• Myelodysplastic syndrome (MDS); Acute Myeloid
Leukemia (AML) 1
• 15-19% in 6-10 years
• Paroxysmal Noctural Hemoglobinuria (PNH)
• 40-50% PNH clone detected at diagnosis of AA 2
• Post IST 3
• Absent PNH clone at diagnosis
• 10% developed PNH clone (median peak - 3%)
• Median time to develop: 6 months ( 3-24 months)
• Present PNH clone at diagnosis
• 25% had expansion of PNH clones
• 15% clones > 50%
• Less than 5% required therapy
1 Young NS. Ann Intern Med. 2002: 136, 534-546; 2 Young NS. Haematologica. 2009;94(1):3–7.
:3 Scheinberg P, Marte M, Nunez O, and Young NS. Haematologica 2010;95:1075-1080. d
Overlap with Bone Marrow Failure Syndromes
Young N. Ann Intern Med. 2002: 136, 534-546
Pathophysiology of acquired aplastic anemia.
Neal S. Young et al. Blood 2006;108:2509-2519
©2006 by American Society of Hematology
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Summary
• Untreated/unresponsive Severe and Very Severe AA -
fatal
• Work up should include secondary causes and possible
associated conditions
• IST and HSCT equally effective therapies
• Tailored to patient characteristics and toxicity profiles
• Long term survival in 50-80% of patients
• Monitor for clonal evolution
Questions
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