4/17/2017

1

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

4/17/2017

2

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

4/17/2017

3

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

4/17/2017

4

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

4/17/2017

5

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

4/17/2017

6

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

4/17/2017

7

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

4/17/2017

8

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 www@vh.com

4/17/2017

9

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

4/17/2017

10

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

4/17/2017

11

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

4/17/2017

12

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

4/17/2017

13

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

4/17/2017

14

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