APLASTIC ANEMIA,

MYELODYSPLASIA AND
RELATED BONE
MARROW FAILURE
SYNDROMES
 INTRODUCTION

• HYPOPROLIFERATIVE ANEMIAS ASSOCIATED with

MARROW DAMAGE:
• Aplastic anemia
• Myelodysplasia (MDS)
• Pure red cell aplasia (PRCA)
• Myelophthisis

• BONE MARROW FAILURE:

• Pancytopenia- anemia, leukopenia, thrombocytopenia
• Results from deficient hematopoiesis
 DIFFERENTIAL DIAGNOSES OF
PANCYTOPENIAS
• I. PANCYTOPENIA with HYPOCELLULAR BONE MARROW:
• Acquired aplastic anemia
• Constitutional aplastic anemia (Fanconi’s anemia, dyskeratosis
congenita)
• Myelodysplastic syndromes
• Aleukemic leukemia (AML)
• Acute lymphoid leukemia
• Lymphoma of the bone marrow

• II. HYPOCELLULAR MARROW with or without CYTOPENIAS

• Q fever
• Legionnaire’s disease
• Anorexia nervosa, starvation
• Mycobacteria
 DIFFERENTIAL DIAGNOSES OF
PANCYTOPENIAS
• III. PANCYTOPENIA with CELLULAR BONE MARROW
• A. PRIMARY BONE MARROW DISEASES
• Myelodysplasia syndromes
• Paroxysmal nocturnal hemoglobinuria (PNH)
• Myelofibrosis
• Aleukemic leukemia
• Myelophthisis
• Bone marrow lymphoma
• Hairy cell leukemia

• B. SECONDARY to SYSTEMIC DISEASES

• Systemic lupus erythematosus (SLE)
• Hypersplenism
• Vitamin B12 & folate deficiencies
• Overwhelming infections
• Alcohol
• Brucellosis
• Sarcoidosis
 APLASTIC ANEMIA

• DEFINITION:
• Pancytopenia with bone marrow hypocellularity

• TYPES:
• IATROGENIC- bone marrow hypocellularity after intense
cytotoxic chemotherapy for cancer
• CONSTITUTIONAL- aplastic anemia with typical physical
anomalies
• Fanconi’s anemia
• Dyskeratosis congenita
• ACQUIRED- abrupt onset of low blood counts in a previously
well adult
• Seronegative hepatitis
• Following a course of a medical drug
CLASSIFICATION OF APLASTIC ANEMIA

• I. ACQUIRED APLASTIC ANEMIA:

• A. SECONDARY
• 1. RADIATION
• 2. DRUGS and CHEMICALS
• Regular effects
• Idiosyncratic reactions
• 3. VIRUSES
• Epstein Barr virus (Infectious mononucleosis)
• Hepatitis (non-A, non-B, non-C hepatitis)
• Parvovirus B19 (transient aplastic crisis, PRCA)
• HIV-1 (AIDS)
• 4. IMMUNE DISEASES
• Eosinophilic fasciitis
• Hypoimmunoglobulinemia
• Thymoma, thymic carcinoma
• Graft-vs-host disease in immunodeficiency
• 5. PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)
• 6. PREGNANCY
• B. IDIOPATHIC
CLASSIFICATION OF APLASTIC ANEMIA

• II. INHERITED APLASTIC ANEMIA

• A. Fanconi’s anemia
• B. Dyskeratosis congenita
• C. Schwachman-Diamond syndrome
• D. Reticular dysgenesis
• E. Amegakaryocytic thrombocytopenai
• F. Familial aplastic anemias
• Preleukemia (monosomy 7)
• Nonhematologic syndrome (Down’s, Dubowitz, Seckel)
 CLASSIFICATION OF SINGLE
CYTOPENIAS
• I. ACQUIRED SINGLE CYTOPENIAS
• A. Pure red cell aplasia (PRCA)
• B. Neutropenia/ Agranulocytosis
• 1. Idiopathic
• 2. Drugs, toxins
• C. Pure white cell aplasia
• D. Thrombocytopenia
• 1. Drugs, toxins
• 2. Idiopathic amegakaryocytic

• II. INHERITED SINGLE CYTOPENIAS

• A. Congenital PRCA (Diamond-Blackfan anemia)
• B. Neutropenia/ Agranulocytosis
• 1. Kostmann’s syndrome
• 2. Schwachman-Diamond syndrome
• 3. Reticular dysgenesis
• C. Thrombocytopenia
• 1. Amegakaryocytic thrombocytopenia
• 2. Thrombocytopenia with absent radii
 EPIDEMIOLOGY

• Equal frequency between men and women

• Biphasic age distribution

• Major peak in the teens and twenties
• Second rise in the elderly
 ETIOLOGY

• 1. RADIATION:
• Damages DNA
• Tissues dependent on active mitosis are particularly
susceptible
• Sources:
• Nuclear accidents- power plants, hospitals, laboratories, industry
(food sterilization, metal radiography)
• Exposure to stolen, misplaced or misused sources
• MDS and leukemia are late effects of irradiation

• 2. CHEMICALS
• BENZENE- linked to aplastic anemia, acute leukemia, and
blood and marrow abnormalities
 ETIOLOGY

• 3. INFECTIONS
• Hepatitis
• Patients are usually young men who have recovered from a bout of
liver inflammation 1-2 months earlier
• Usually seronegative
• Infectious mononucleosis (EBV)
• Parvovirus B19

• 4. DRUGS
• A. Agents that regularly produce marrow depression as major
toxicity in commonly employed doses or normal exposures:
• Cytotoxic drugs used in chemotherapy: alkylating agents,
antimetabolites, antimitotics, some antibiotics
 ETIOLOGY
• B. Agent/s that frequently but not inevitably produce bone
marrow aplasia: BENZENE

• C. Agents associated with aplastic anemia but with a relatively

low probability:
• Chloramphenicol
• Insecticides
• Antiprotozoals: quinacrine, chloroquine, mepacrine
• NSAIDs: phenylbutazone, indomethacin, ibuprofen, sulindac, ASA
• Anticonvulsants: hydantoins, carbamazepine, phencemide, felbamate
• Heavy metals: gold, arsenic, bismuth, mercury
• Sulfonamides
• Some antibiotics
• Atithyroid drugs (methimazole, methyuracil, PTU)
• Antidiabetes drugs (tolbutamide, chlopropramide)
• Carbonic anhydrase inhibitors (acetazolamide, metazolamide)
• Antihistamines (cimetidine, chlorpheniramine)
• D-penicillamine
• Estrogens (in pregnancy and in high doses in animals)
 ETIOLOGY

• D. Agents whose association with aplastic anemia is more

tenuous:

• Antibiotics (streptomycin, tetracycline, methicillin, mebendazole, TMP-

SMX, flucytosine)
• Sedatives and tranquilizers (chlorpromazine, prochlorperazine,
piperacetazine, chlordiazepoxide, meprobamate, methyprylon)
• Allopurinol
• Methyldopa
• Quinidine
• Lithium
• Guanidine
• Potassium perchlorate
• Thiocyanate
• Carbimazole
 ETIOLOGY

• 5. IMMUNOLOGIC DISEASES
• Transfusion-associated GVHD- aplastic anemia occurs after
transfusion of unirradiated blood products to an
immunodeficient recipient
• Eosinophilic fasciitis- a rare collagen vascular syndrome
characterized by painful induration of subcutaneous tissues
and aplastic anemia
• SLE

• 6. PREGNANCY
• Aplastic anemia may very rarely occur and recur during
pregnancy and resolve with delivery or with spontaneous or
induced abortion
 ETIOLOGY

• 7.PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)

• An acquired mutation in the PIG-A gene in a hemotopoietic stem cell

• 8. CONGENITAL DISORDERS
• FANCONI’S ANEMIA
• An autosomal recessive disorder manifesting as:
• Congenital developmental anomalies: short stature, café-au-lait spots,
anomalies involving the thumb, radius and GUT
• Progressive pancytopenia
• Increased risk of malignancy
• DYSKERATOSIS CONGENITA
• Characterized by mucous membrane leukoplasia, dystrophic nails, reticular
hyperpigmentation and the development of aplastic anemia during
childhood
• SCHWACHMAN-DIAMOND SYNDROME
• Marrow failure with pancreatic insufficiency and malabsorption
 PATHOPHYSIOLOGY

• Bone marrow failure results from severe damage to

the hematopoietic stem cell compartment

• Replacement of bone marrow by fat (biopsy, MRI of

the spine)

• Cells bearing the CD34 antigen, a marker of early

hematopoietic cells, are greatly diminished

• Committed and primitive progenitor cells are

virtually absent
 PATHOPHYSIOLOGY

• DRUG INJURY:
• Altered drug metabolism has been invoked as a likely
mechanism
• Polar drugs and chemicals with limited water solubility are
more likely to produce injury
• Enzymatic degradation to highly reactive electrophilic
intermediates are toxic because of their propensity to bind to
cellular macromolecules

• IMMUNE-MEDIATED INJURY:
• Increased numbers of activated cytotoxic T cells
• Cytokine measurements show a Th1 immune response
• Interleukin-2
• Interferon-γ and TNF induce Fas expression on CD34 cells leading to
apoptotic cell death
 CLINICAL FEATURES

• HISTORY:
• BLEEDING- most common early symptom
• Easy bruising, bleeding from the gums, epistaxis, heavy menstrual
flow, petechiae
• ANEMIA:
• Symptoms: lassitude, weakness, shortness of breath, pounding
sensation in the ears
• INFECTION

• PHYSICAL EXAMINATION:
• Petechiae, ecchymoses
• Retinal hemorrhages
• Pallor of the skin and mucous membranes
• Fanconi’s anemia: café-au-lait spots and short stature
• Dyskeratosis congenita: peculiar nails and leukoplakia
 LABORATORY STUDIES
• BLOOD:
• Peripheral blood smear (PBS): large erythrocytes and a paucity of platelets and
granulocytes
• Increased mean corpuscular volume (MCV)
• Absent or few reticulocytes
• Normal or reduced lymphocyte numbers

• BONE MARROW:
• Aspirate appears dilute on smear
• Fatty biopsy specimen may be grossly pale on withdrawal
• Hematopoietic cells occupy < 25% of the marrow space
• “Dry tap”: suggests fibrosis or myelophthisis

• ANCILLARY STUDIES:
• Fanconi’s anemia: chromosome breaking studies of peripheral blood using
diepoxybutane (DEB) and mitomycin C
• Myelodysplasia: chromosome studies of bone marrow cells
• PNH: flow cytometric studies
• EBV and HIV: serologic studies
 DIAGNOSIS

• Pancytopenia with a fatty, empty bone marrow

• Aplastic anemia is a disease of the young and should be a
leading diagnosis in the pancytopenic adolescent or young
adult

• DIFFERENTIAL DIAGNOSES:
• SECONDARY PANCYTOPENIA- the primary diagnosis is usually obvious
from either history or PE
• Alcoholic cirrhosis- massive spleen
• History of metastatic cancer
• History of SLE
• Obvious miliary TB on CXR
• CONSTITUTIONAL APLASTIC ANEMIA- diagnosis is suggested by family
history, abnormal blood counts since childhood, presence of
associated physical abnormalities
• MDS- favored by finding megakaryocytes and myeloid precursor cells
and typical cytogenetic abnormalities
NORMAL BONE MARROW ASPIRATE
SMEAR
APLASTIC ANEMIA BONE MARROW
ASPIRATE SMEAR
 PROGNOSIS

• The natural history of aplastic anemia is rapid

deterioration and death

• The major prognostic determinant is the blood count

• SEVERE DISEASE:
• Defined by the presence of 3 parameters
• 1) Absolute neutrophil count (ANC) < 500/µL
• 2) Platelet count < 20,000/ µL
• 3) Corrected reticulocyte count < 1% or absolute reticulocyte count
< 60,000/µL
• Survival of patients who fulfill the above criteria is about 20% at
1 year of diagnosis with only supportive care
 TREATMENT

• A. BONE MARROW TRANSPLANTATION

• The best therapy for the young patient with a fully histocompatible
sibling donor
• Long-term survival rates for children are 80% or better
• Transplant morbidity and mortality are increased among adults due to:
• Higher risk of graft-vs-host disease (GVHD)
• Serious infections

• B. IMMUNOSUPPRESSION
• 1. ANTILYMPHOCYTE GLOBULIN (ALG) or ANTITHYMOCYTE GLOBULIN
(ATG)
• Horse ATG: 40 mg/kg/day for 4 days
• Rabbit ALG: 3.5 mg/kg/day for 5 days
• Side Effect: SERUM SICKNESS
• A flu-like illness with a characteristic cutaneous eruption and arthralgia which
develop 10 days after initiating treatment
• Treatment: Methylprenisolone 1mg/kg/day for 2 weeks
 TREATMENT
• 2. CYCLOSPORINE
• Administered orally at an initial dose of 12 mg/kg/day in adults (15 mg/kg/day in
children)
• Subsequent adjustment is done according to blood levels obtained every 2 weeks
• Side Effects:
• Nephrotoxicity
• Hypertension
• Seizures
• Opportunistic infections- Pneumocystis jirovecii

• IMMUNOSUPPRESSION vs. TRANSPLANTATION:

• Increasing age and the severity of the neutropenia are the most important
factors in adults who have a matched family donor
• Older patients do better with ATG and cyclosporine
• Transplant is preferred if granulocytopenia is profound
• Reluctant patients may be treated by immunosuppression
• Transplant is used for failure to recover blood counts or occurrence of late
complications
 TREATMENT
• C. OTHER THERAPIES
• Androgens
• Hematopoietic growth factors
• Granulocyte colony-stimulating factor (G-CSF)
• Granulocyte-macrophage CSF (GM-CSF)
• Interleukin-3
• Splenectomy

• D. SUPPORTIVE CARE
• Infection in the presence of severe neutropenia
• Prompt administration of parenteral, broad-spectrum antibiotics: Ceftazidime or a
combination of an aminoglycoside, cephalosporin and semi-synthetic penicillin as
empiric therapy
• Hand washing
• Persistent or recrudescent fever implies fungal disease (Candida or Aspergillus) and may
be averted by timely administration of anti-fungal therapy
• Platelet transfusion once or 2x weekly in order to maintain platelet count > 20,000 / µL
• RBC transfusion to maintain a hemoglobin value of 70 g/L (90 g/L if there is an
underlying cardiac or pulmonary disease)
• 2 units every 2 weeks
• Deferoxamine should be added at the 50th transfusion to avoid 2⁰ hemochromatosis
 PURE RED CELL APLASIA (PRCA)

• Characterized by:
• Anemia
• Reticulocytopenia
• Absent or rare erythroid precursor cells in the bone marrow
• PRCA is usually acquired

• DIFFERENTIAL DIAGNOSES:
• DIAMOND-BLACKFAN ANEMIA (Congenital PRCA)
• Diagnosed at birth or in early childhood
• Responds to glucocorticoid treatment
• TEMPORARY RED CELL FAILURE
• Occurs in transient aplastic crisis of hemolytic anemias due to:
• Acute Parvovirus infection
• Transient erythroblastopenia of childhood which may affect normal
children
 CLASSIFICATION OF PRCA
• A. SELF-LIMITED
• Transient erythroblastopenia of childhood
• Transient aplastic crisis of hemolysis (acute B19 parvovirus infection)

• B. FETAL RED BLOOD CELL APLASIA

• Nonimmune hydrops fetalis (in utero B19 parvovirus infection)

• C. HEREDITARY PRCA
• Congenital PRCA (Diamond-Blackfan syndrome)

• D. ACQUIRED PRCA
• 1. Thymoma and malignancy
• Thymoma
• Lymphoid malignancies (and more rarely other hematologic diseases)
• Paraneoplastic to solid tumors
• 2. CTDs
• SLE, juvenile RA, RA, multiple endocrine gland insufficiency
• 3. Viruses (Persistent B19 parvovirus, hepatitis, adult T cell leukemia virus, EBV)
• 4. Pregnancy
• 5. Drugs (especially phenytoin, azathioprine, chloramphenicol, procainamide,
isoniazid)
• 6. Antibodies to erythropoietin 7. Idiopathic
 CLINICAL ASSOCIATIONS

• 1. PRCA has important associations with IMMUNE SYSTEM

DISEASES:
• A. Thymoma
• B. Large granular lymphocytosis
• C. Chronic lymphocytic leukemia
• D. Hypogammaglobulinemia

• 2. IDIOSYNCRATIC DRUG REACTIONS

• 3. PERSISTENT PARVOVIRUS B19 INFECTION

• Causes a benign exanthem of childhood (Fifth disease) and a
polyarthralgia syndrome in adults
• Cause a tansient aplastic crisis and an abrupt but temporary worsening of
anemia in patients with underlying hemolysis
• The bone marrow shows:
• Red cell aplasia
• Giant pronormoblasts – the cytopathic sign of B19 parvovirus infection
ETIOLOGIC IMMUNOMECHANISMS

• 1. Autoantibodies to RBC precursors

• 2. T cell inhibition

• 3. Cytotoxic lymphocyte activity

• 4. Natural killer cell activity inhibitory of erythropoiesis

• 5. Parvovirus B19 infection

• Viral tropism for human erythroid progenitor cells by its use of
erythrocyte B antigen as a cellular receptor
• Direct cytotoxicity of virus causes anemia if demands on
erythrocyte production are high
 TREATMENT

• Red cell aplasia is compatible with long survival with

supportive care:
• Erythrocyte transfusions
• Iron chelation

• In the presence of an underlying disease:

• Thymoma: tumor excision
• Parvovirus B19 infection: IV immunoglobulin therapy(0.4g/kg
daily for 5 days)
• Idiopathic PRCA: immunosuppressive therapy with
glucocorticoids, cyclosporine, ATG, azathioprine or
cyclophosphamide
• History of drug exposure: avoidance of the implicated drug
 MYELODYSPLASIAS (MDS)

• A heterogenous group of hematologic disorders broadly

characterized by:
• 1. Cytopenias associated with a dysmorphic (or abnormal
appearing) and usually cellular bone marrow
• 2. Ineffective blood cell production

• 5 ENTITIES:
• 1) Refractory anemia (RA)
• 2) Refractory anemia with ringed sideroblasts (RARS)
• 3) Refractory anemia with excess blasts (RAEB)
• 4) Refractory anemia with excess blasts in transformation
(RAEB-t)
• 5) Chronic myelomonocytic leukemia (CMML)
 EPIDEMIOLOGY

• MDS is a disease of the elderly

• Mean age of onset: 68 years

• Slight male preponderance

• MDS is a relatively common form of bone marrow failure

with incidence rates of:
• 35 to > 100 million persons in the general population
• 120 to > 500 million in the elderly

• Therapy-related MDS is not age-related and may occur

in as many as 15% of patients within a decade following
intensive combined modality treatment for cancer
 ETIOLOGY

• MDS is caused by environmental exposures to:

• RADIATION
• BENZENE

• SECONDARY MDS:
• Occurs as a late toxicity of CANCER TREATMENT
• Radiation and radiomimetic alkylating agents (busulfan,
nitrosourea, procarbazine)- latent period of 5-7 years
• Radiation and DNA topoisomerase inhibitors- latent period of 2
years
 PATHOPHYSIOLOGY

• MDS is a clonal hematopoietic stem cell disorder leading to

impaired cell proliferation and differentiation

• CYTOGENETIC ABNORMALITIES are found in about half of

patients
• Aneuploidy > translocation
• The type and number of cytogenetic abnormalities strongly correlate
with the probability of leukemic transformation and survival

• Both presenting and evolving hematologic manifestations

result from:
• 1. Accumulation of multiple genetic lesions
• Sideroblastic anemia, ineffective erythropoiesis, disordered iron metabolism
• 2. Loss of tumor suppressor genes (p53, IRF-1)
• 3. Activating oncogene mutations (N-ras)
• 4. Antiapoptotic gene (Bcl-2)- increase apoptosis of marrow cells
 CLINICAL FEATURES

• Anemia presenting as:

• Gradual onset of fatigue and weakness
• Dyspnea
• Pallor

• Fever and weight loss should point to a

myeloproliferative rather than myelodysplastic process

• PHYSICAL EXAMINATION:
• Signs of anemia
• Splenomegaly
• Unusual skin leisons: Sweet syndrome (febrile neutrophilic
dermatosis)
• Autoimmune syndromes
 LABORATORY STUDIES

• BLOOD:
• Anemia
• Blood smear
• RBCs: macrocytic and dimorphic
• Platelets: large with no granules
• Neutrophils
• Hypogranulated
• Hypersegmented, ringed or abnormally segmented nuclei
• Contain Dohle bodies
• Functionally deficient

• BONE MARROW:
• Dyserythropoietic changes, ringed sideroblasts and megaloblastic nuclei
associated with defective hemoglobinization in the erythroid lineage
• Hypogranulation and hyposegmentation in granulocytic precursors with an
increase in myeloblasts
• Megakaryocytes show reduced numbers of disorganized nuclei
 DIFFERENTIAL DIAGNOSES

• Deficiencies of Vitamin B12 or folate

• Vitamin B6 deficiency

• Marrow dysplasia following:

• Acute viral infections
• Drug reactions
• Chemical toxicity

• Aplasia

• Early acute leukemia

• The WHO considers the presence of 20% blasts in the marrow as
criterion that separates acute myeloid leukemia from MDS
 PROGNOSIS

• Most patients die as a result of complications of

pancytopenia and not due to leukemic transformation

• 1/3 will succumb to other diseases unrelated to MDS

• POOR PROGNOSTIC INDICATORS:

• 1. Precipitous worsening of pancytopenia
• 2. Acquisition of new chromosomal abnormalities on serial
cytogenetic determination
• 3. Increase in the number of blasts

• Therapy-related MDS: poor prognosis, with most patients

progressing within a few months to refractory AML
 TREATMENT
• CYTOTOXIC DRUGS
• 5-Azacytidine- inhibits DNA methylation and may induce the expression of genes and
improve blood counts
• Amifostine- an organic thiophosphonate that blocks apoptosis and improves blood
counts

• ATG- may improve blood counts in the following selected patients:

• Young
• HLA-D2 positive
• Have a PNH clone

• HEMATOPOIETIC GROWTH FACTORS

• ERYTHROCYTE TRANSFUSION support accompanied by chelation

• Only STEM CELL TRANSPLANTATION offers cure

 MYELOPHTHISIS

• A.K.A. SECONDARY MYELOFIBROSIS

• Marrow fibrosis can be a response to:

• 1. Invading tumor cells- usually an epithelial cancer of the breast, lung
and prostate or neuroblastoma
• 2. Infection
• Mycobacteria (M. Tb, M. avium)
• Fungi
• HIV
• Sarcoidosis
• 3. Radiation therapy or treatment with radiomimetic drugs
• 4. Congenital osteopetrosis: obliteration of the marrow space related
to absence of osteoclast remodeling
• 5. Gaucher’s disease: intracellular lipid deposition
• 6. Hematologic syndromes: CML, MM, lymphomas, myeloma, hairy cell
leukemia
 PATHOPHYSIOLOGY

• 3 DISTINCT FEATURES:

• 1) Proliferation of fibroblasts in the marrow space

(MYELOFIBROSIS)

• 2) The extension of hematopoiesis into the long bones and

extramedullary sites particularly the spleen, liver and lymph
nodes (MYELOID METAPLASIA)

• 3) INEFFECTIVE ERYTHROPOIESIS
 ETIOLOGY

• Unknown

• Dysregulated production of growth factors: most likely

mechanism
• Platelet-derived growth factor (PDGF)
• Transforming growth factor-β (TGF-β)

• Abnormal regulation of other hematopoietins

• Leads to localization of blood-producing cells in non-
hematopoietic tissues and uncoupling of the usually balanced
process of stem cell proliferation and differentiation

• Pancytopenia results despite extraordinarily large

numbers of circulating hematopoietic progenitor cells
 CLINICAL FEATURES

• PRESENTATION: normocytic, normochronic anemia

• DIAGNOSIS:
• Suggested by the characteristic leukoerythroblastic smear
• 1. Abnormal erythrocyte morphology
• Circulating nucleated RBCs
• Presence of teardrop cells
• Shape distortions
• 2. WBC numbers are elevated, with circulating myelocytes,
promyelocytes and myeloblasts
• 3. Platelets may be abundant and are often giant-sized
 PROGNOSIS AND TREATMENT

• COURSE:
• Determined by the cause: usually a metastatic tumor or an
advanced hematologic malignancy

• TREATMENT:
• Treatable causes must be excluded
• TB
• Fungi
• Transfusion support can relieve symptoms