Bone Marrow Failure Syndromes Including Aplastic Anemia and Myelodysplasia¶
Chapter 107 | Part 4: Oncology and Hematology · Part 4 – Oncology: Hematologic Malignancies · Chapter 107
Key Clinical Points¶
- Aplastic anemia is defined as pancytopenia with bone marrow hypocellularity, distinguished from peripheral destruction (hemolysis, ITP) or marrow infiltration.
- The diagnosis of acquired aplastic anemia is usually straightforward based on pancytenis with a fatty bone marrow biopsy; immune-mediated destruction is the primary mechanism.
- Constitutional aplastic anemias (IBMFS) include Fanconi anemia, dyskeratosis congenita, and telomere biology disorders, often presenting with physical anomalies (short stature, leukoplasia, nail dystrophy).
- Flow cytometry is a sensitive diagnostic test for Paroxysmal Nocturnal Hemoglobinuria (PNH); a PNH clone is strongly suggestive of immune-mediated disease.
- The standard first-line therapy for severe acquired aplastic anemia is immunosuppression with antithymocyte globulin (ATG), cyclosporine, and eltrombopag ('triple therapy').
- Hematopoietic stem cell transplantation (HSCT) is the first choice for younger patients with a fully matched sibling donor; transplant cures marrow failure, whereas immunosuppression leaves patients at risk of relapse.
- Benzene is a notorious cause of bone marrow failure; incidence correlates with cumulative exposure, but susceptibility varies among workers.
- In aplastic anemia, infection is an unusual first symptom (unlike agranulocytosis), and bleeding is the most common early symptom due to thrombocytopenia.
- Patients with aplastic anemia should avoid transfusion of blood from family members to prevent sensitization to histocompatibility antigens in transplant candidates.
- Chromosome breakage studies using diepoxybutane or mitomycin C are required to diagnose Fanconi anemia in children and younger adults.
DEFINITION & CLASSIFICATION¶
• Core Definition: Bone marrow failure diseases include aplastic anemia, myelodysplastic syndrome (MDS), pure red cell aplasia (PRCA), and other single-lineage cytopenias. • Mechanism of Pancytopenia: Result from deficient hematopoiesis → distinguished from peripheral destruction (hemolytic anemias, ITP/splenomegaly) or granulocyte loss in immune leukopenias. • Etiology Factors: Marrow damage may be secondary to infection, inflammation, poisoning, or cancer. • Diagnostic Distinction: Separation between aplastic anemia and hypoplastic MDS can be complex due to similar marrow pathology.
1.1 Classification of Aplastic Anemia¶
Definition (Harrison's 22e): Aplastic anemia is pancytopenia with bone marrow hypocellularity.
• Acquired Aplastic Anemia: Immune-mediated destruction of hematopoietic cells. • Constitutional Aplastic Anemia: Inherited syndromes (e.g., Fanconi anemia, dyskeratosis congenita) typically presenting in early childhood with physical anomalies; telomere biology disorders/germline predispositions can present in adults without physical signs.
• Table 107-1 (Differential Diagnosis of Pancytopenia): ◦ Hypocellular Bone Marrow: Acquired (immune) aplastic anemia, Constitutional (Fanconi, telomere), Hypoplastic MDS, Rare aleukemic leukemia, some acute lymphoid leukemia, rare lymphomas, and Copper deficiency. ◦ Cellular Bone Marrow: Primary bone marrow diseases (MDS, PNH, Myelofibrosis, etc.), Secondary to systemic disease (SLE, hypersplenism, infections like Q fever/Leishmaniasis). ◦ Hypocellular Bone Marrow ± Pancytopenia: Q fever, Legionnaires' disease, Anorexia nervosa/starvation.
• Table 107-2 (Classification of Aplastic Anemia and Single Cytopenias): ◦ Acquired: Aplastic Anemia, Secondary (Radiation, Drugs/chemicals, Viruses like EBV, HCV, HIV-1, Immune diseases like Eosinophilic fasciitis, PNH, Pregnancy). ◦ Inherited/Constitutional: Fanconi anemia, Dyskeratosis congenita/telomere disease, Shwachman-Diamond syndrome, Familial aplastic anemia/leukemia predisposition (GATA2, RUNX1, CTLA4), Nonhematologic syndromes (Down, Dubowitz, Seckel).
EPIDEMIOLOGY¶
• Incidence: ◦ Europe and Israel: 2 cases per million persons annually. ◦ Thailand and China: 5 to 7 per million. • Demographics: ◦ Gender: Men and women affected equally. ◦ Age Distribution: Bimodal peak (teens/twenties and older adults).
ETIOLOGY & PATHOPHYSIOLOGY¶
• Immune-mediated: T-cell activation, IFN-γ signaling, and Fas-mediated apoptosis. • Physical/Chemical Damage: ◦ Radiation: Damages DNA and tissues dependent on active mitosis. ◦ Benzene: Notorious cause; linked to aplastic anemia and leukemia via hydroquinone/quinone intermediates. • Constitutional Genetic Syndromes: ◦ Fanconi anemia: Autosomal recessive, defect in DNA repair (cross-linking agents). ◦ Ribosomopathies: Diamond-Blackfan anemia, Shwachman-Diamond syndrome. ◦ Telomere biology disorders: Mutations in TERC, TERT, or shelterin proteins (TINF2). ◦ Germline predispositions: GATA1, RUNX1 mutations.
3.1 Chemical and Drug Injury¶
• Mechanism: Extrinsic damage from radiation/chemicals; idiosyncratic reactions to drugs via toxic intermediates.
• Table 107-3 (Drugs and Chemicals Associated with Aplastic Anemia): ◦ High Risk: Cytotoxic drugs (alkylating agents, antimetabolites), Benzene. ◦ Moderate Probability: Chloramphenicol, Insecticides, Antiprotozoals (quinacrine, chloroquine, mepacrine), NSAIDs (phenylbutazone, indomethacin, ibuprofen, sulindac, aspirin), Anticonvulsants (hydantoins, carbamazepine, phenacemide, felbamate), Heavy metals (gold, arsenic, bismuth, mercury), Sulfonamides, Antihistamines, Estrogens. ◦ Lower/Tenuous Probability: Other antibiotics (streptomycin, tetracycline, methicillin, mebendazole, trimethoprim/sulfamethoxazole), Sedatives/tranquilizers, Allopurinol, Methyldopa, Quinidine, Lithium, Guanidine, Potassium perchlorate, Thiocyanate, Carbimazole.
3.2 Infections¶
• Viral: EBV (infectious mononucleosis), non-A, non-B, non-C hepatitis, Parvovirus B19 (causes pure red cell aplasia), HIV-1.
3.3 Constitutional Genetic Syndromes¶
• Fanconi anemia: Autosomal recessive; progression to pancytopenia and malignancy. ◦ Telomere biology disorders: Mutations in TERC, TERT, or shelterin proteins. ◦ Dyskeratosis congenita: Mucous membrane leukoplasia, dystrophic nails, reticular hyperpigmentation.
CLINICAL FEATURES¶
• Presentation: Abrupt or insidious. • Symptoms: ◦ Bleeding: Most common early symptom (bruising, gum oozing, nosebleeds). ◦ Anemia: Lassitude and dyspnea. ◦ Infection: Unusual as a first symptom. • Physical Appearance: Patients may look well despite severe pancytopenia.
• Laboratory Studies: ◦ Blood Smear: Large erythrocytes, paucity of platelets/granulocytes. ◦ Indices: MCV commonly increased; Reticulocytes absent or few. ◦ Morphology: Lymphocyte nuclei may be abnormal.
4.2 Diagnosis¶
• Bone Marrow Biopsy: Must show hypocellularity and absence of dysplasia. ◦ Flow Cytometry: Detects PNH clones. ◦ Genetic Testing: Identifies IBMFS mutations (FANCA, TERC, TERT).
DIFFERENTIAL DIAGNOSIS¶
• Aplastic Anemia vs. MDS: ◦ Aplastic Anemia: Hypocellular marrow, NO dysplasia. ◦ MDS: Presence of dysplasia and blasts. • Aplastic Anemia vs. PNH: ◦ PNH: Presents with hemolysis and flow cytometry-positive clones.
• Table 107-4 (Classification of Pure Red Cell Aplasia): ◦ Self-limited: Transient erythroblastopenia of childhood, B19 infection, Fetal/Nonimmune hydrops fetalis, Constitutional (Diamond-Blackfan). ◦ Acquired: MDS (5q-), Cancer, Thymoma, Lymphoid malignancies, Connective tissue disorders (SLE, RA), Viruses (B19, HCV, EBV), Pregnancy, Drugs (phenytoin, azathioprine, chloramphenicol, procainamide, isoniazid).
DIAGNOSTIC APPROACH¶
- Initial Screening: ◦ Perform CBC and peripheral blood smear to identify pancytopenia (large RBCs, low platelets/granulocytes).
- Bone Marrow Biopsy: ◦ Confirm hypocellularity and absence of dysplasia.
- Flow Cytometry: ◦ Detect PNH clones (sensitive indicator for immune-mediated disease).
- Genetic Testing & Specialized Assays: ◦ Identify IBMFS mutations (FANCA, TERC, TERT) → use chromosome breakage studies (diepoxybutane/mitomycin C) for Fanconi anemia; use telomere length assays for telomere biology disorders.
6.2 Ancillary Studies¶
• Chromosome Breakage: Diepoxybutane or mitomycin C (required for Fanconi anemia in children/young adults). • Telomere Length Assays: For telomere biology disorders.
MANAGEMENT & TREATMENT¶
- First-line Therapy (Severe Acquired AA): ◦ Immunosuppression: ATG (equine or rabbit) + cyclosporine ± eltrombopag ('triple therapy').
- Hematopoietic Stem Cell Transplantation (HSCT): ◦ First choice for younger patients with a fully matched sibling donor. ◦ Benefit: Cures marrow failure; avoids risk of relapse seen in immunosuppression.
- Transfusion Management: ◦ Avoid blood from family members → prevent sensitization to histocompatibility antigens (crucial for transplant candidates). ◦ Use leukoreduced, irradiated blood products.
- Refractory Cases: ◦ Eltrombopag: 50–75 mg/day (improves platelet counts). ◦ G-CSF: Used for neutropenia. ◦ Androgens: Stanozolol (5–10 mg/day) or danazol (400–800 mg/day) → monitor for virilization and liver function.
7.1 Immunosuppressive Therapy¶
• Regimen: ATG + cyclosporine ± eltrombopag. • Monitoring: Monitor for infections and graft-versus-host disease.
PROGNOSIS & COMPLICATIONS¶
• Prognosis Factors: Severity, age, and response to therapy. • Complications: ◦ Infection. ◦ Bleeding. ◦ Transformation to MDS or AML. ◦ IBMFS patients have higher malignancy risk.
SPECIAL POPULATIONS¶
• Pregnancy: Pregnancy-related aplastic anemia resolves with delivery. • PNH Development: PNH clones may develop in aplastic anemia patients years after recovery. • IBMFS: Requires genetic counseling.
KEY PEARLS & HIGH-YIELD POINTS¶
• Pearl: Bleeding is the most common early symptom in aplastic anemia (due to thrombocytopenia). • Trap: Confusing aplastic anemia with MDS (Aplastic anemia has NO dysplasia). • Pearl: Flow cytometry is a sensitive test for PNH clones. • Trap: IBMFS may present without physical anomalies.
Reference Tables¶
TABLE 107-1 Differential Diagnosis of Pancytopenia Pancytopenia with Hypocellular Bone Marrow Acquired (immune)…¶
Harrison's 22e, p.808
| Pancytopenia with Hypocellular Bone Marrow | |
|---|---|
| Acquired (immune) aplastic anemia | |
| Constitutional aplastic anemia (Fanconi anemia, telomere biology disorders, and others) |
|
| Hypoplastic myelodysplastic syndrome | |
| Rare aleukemic leukemia | |
| Some acute lymphoid leukemia | |
| Rare lymphomas of bone marrow | |
| Copper deficiency | |
| Pancytopenia with Cellular Bone Marrow | |
| Primary bone marrow diseases Myelodysplastic syndromes Paroxysmal nocturnal hemoglobinuria (PNH) Myelofibrosis Aleukemic leukemia Myelophthisis Bone marrow lymphoma Hairy cell leukemia |
Secondary to systemic diseases Systemic lupus erythematosus Hypersplenism B , folate deficiency 12 Copper deficiency Alcohol HIV infection Brucellosis Sarcoidosis Tuberculosis Leishmaniasis Sepsis |
| Hypocellular Bone Marrow ± Pancytopenia | |
| Q fever | |
| Legionnaires’ disease | |
| Anorexia nervosa, starvation | |
| Mycobacterium | |
| 107 | Bone Marrow Failure Syndromes Including Aplastic Anemia and Myelodysplasia Neal S. Young, Emma M. Groarke |
TABLE 107-2 Classification of Aplastic Anemia and Single Cytopenias ACQUIRED Aplastic Anemia Secondary¶
Harrison's 22e, p.809
| ACQUIRED | INHERITED/CONSTITUTIONAL |
|---|---|
| Aplastic Anemia | |
| Secondary | Fanconi anemia |
| Radiation | Dyskeratosis congenita/telomere disease |
| Drugs and chemicals | Shwachman-Diamond syndrome |
| Regular effects Idiosyncratic reactions Viruses |
Familial aplastic anemia/leukemia predisposition syndromes: GATA2, RUNX1, CTLA4, and others |
| Epstein-Barr virus (infectious mononucleosis) |
Nonhematologic syndromes (Down, Dubowitz, Seckel) |
| Hepatitis (non-A, non-B, non-C hepatitis) |
|
| Parvovirus B19 (transient aplastic crisis, pure red cell aplasia [PRCA]) |
|
| HIV-1 (AIDS) | |
| Immune diseases | |
| Eosinophilic fasciitis | |
| Hypoimmunoglobulinemia | |
| Large granular lymphocytosis (LGL) | |
| Thymoma/thymic carcinoma | |
| Graft-versus-host disease in immunodeficiency |
|
| Paroxysmal nocturnal hemoglobinuria (PNH) |
|
| Pregnancy | |
| Idiopathic (immune) | |
| Cytopenias |
TABLE 107-3 Some Drugs and Chemicals Associated with Aplastic Anemia Agents that regularly produce marrow depression as…¶
Harrison's 22e, p.810
- Agents that regularly produce marrow depression as major toxicity in commonly
used doses or normal exposures:
Cytotoxic drugs used in cancer chemotherapy: alkylating agents,
antimetabolites, antimitotics, some antibiotics
Agents that frequently but not inevitably produce marrow aplasia:
Benzene
Agents associated with aplastic anemia but with a relatively low probability:
Chloramphenicol
Insecticides
Antiprotozoals: quinacrine and chloroquine, mepacrine
Nonsteroidal anti-inflammatory drugs (including phenylbutazone,
indomethacin, ibuprofen, sulindac, aspirin)
Anticonvulsants (hydantoins, carbamazepine, phenacemide, felbamate)
Heavy metals (gold, arsenic, bismuth, mercury)
Sulfonamides: some antibiotics, antithyroid drugs (methimazole,
methylthiouracil, propylthiouracil), antidiabetes drugs (tolbutamide,
chlorpropamide), carbonic anhydrase inhibitors (acetazolamide and
methazolamide)
Antihistamines (cimetidine, chlorpheniramine)
d-Penicillamine
Estrogens (in pregnancy and in high doses in animals)
Agents whose association with aplastic anemia is more tenuous:
Other antibiotics (streptomycin, tetracycline, methicillin, mebendazole,
trimethoprim/sulfamethoxazole, flucytosine)
Sedatives and tranquilizers (chlorpromazine, prochlorperazine,
piperacetazine, chlordiazepoxide, meprobamate, methyprylon)
Allopurinol
Methyldopa
Quinidine
Lithium
Guanidine
Potassium perchlorate
Thiocyanate
Carbimazole
TABLE 107-4 Classification of Pure Red Cell Aplasia Self-limited¶
Harrison's 22e, p.814
- Self-limited
Transient erythroblastopenia of childhood
Transient aplastic crisis of hemolysis (acute B19 parvovirus infection)
Fetal red blood cell aplasia
Nonimmune hydrops fetalis (in utero B19 parvovirus infection)
Constitutional pure red cell aplasia
Congenital pure red cell aplasia (Diamond-Blackfan anemia)
Acquired pure red cell aplasia
Primary immune
MDS (5q- syndrome)
Cancer
Thymoma
Lymphoid malignancies (and more rarely other hematologic diseases)
Paraneoplastic to solid tumors
Connective tissue disorders with immunologic abnormalities
Systemic lupus erythematosus, juvenile rheumatoid arthritis, rheumatoid arthritis
Multiple endocrine gland insufficiency
Viruses
Persistent B19 parvovirus, hepatitis, adult T-cell leukemia virus, Epstein-Barr
virus
Pregnancy
Drugs
Especially phenytoin, azathioprine, chloramphenicol, procainamide, isoniazid
Antibodies to erythropoietin
Idiopathic (immune)
TABLE 107-5 World Health Organization (WHO) 2022 Classification of Myelodysplastic Syndromes (MDS)/Neoplasms¶
Harrison's 22e, p.815
| NAME | BLASTS | CYTOGENETICS | MUTATIONS |
|---|---|---|---|
| MDS with Defining Genetic Abnormalities | |||
| <5% BM and <2% PB | 5q deletion alone, or with 1 other abnormality other than –7/7q del |
||
| MDS with low blasts and SF3B1 mutation (MDS-SF3B1)a |
<5% BM and <2% PB | Absence of 5q–, –7, or complex karyotype |
SF3B1 |
| <20% BM and PB | Usually complex | ||
| <5% BM and <2% PB | |||
| MDS, hypoplasticb | <5% BM and <2% PB | ||
| 5–9% BM or 2–4% PB | |||
| MDS with increased blasts-2 | 10–19% BM or 5–19% PB or Auer rods | ||
| 5–19% BM; 2–19% PB |
TABLE 107-6 International Consensus Classification (ICC) 2022 Classification of Myelodysplastic Syndromes…¶
Harrison's 22e, p.815
| NAME | BLASTS | CYTOGENETICS | MUTATIONS |
|---|---|---|---|
| MDS with 5q deletion (MDS-5q) | <5% BM and <2% PB | 5q deletion alone, or with 1 other abnormality other than –7/7q del |
Any, except multi-hit TP53 |
| <5% BM and <2% PB | Absence of 5q–, –7, abn3q26.2, or complex karyotype |
||
| MDS, NOS without dysplasia (no dysplastic lineages) | <5% BM and <2% PB | –7/7q del or complex | Any except multi-hit TP53 or SF3B1 (VAF ≥10%) |
| <5% BM and <2% PB | Any except 5q– | ||
| MDS, NOS with multi-lineage dysplasia (≥2 dysplastic lineages) |
<5% BM and <2% PB | Any except 5q– | Any except multi-hit TP53 or SF3B1 (VAF ≥10%) |
| 5–9% BM or 2–9% PB | Any | ||
| MDS with increased blasts-2 | 10–19% BM or PB | Any, except AML defining | Any except TP53, NPM1, bZIP, CEBPA |
TABLE 107-7 Revised International Prognostic Scoring System (IPSS-R) 1. Marrow blast categories 2. Refined cytogenetic…¶
Harrison's 22e, p.817
-
- Marrow blast categories
≤2%, >2%–<5%, 5–10%, >10–30%
2. Refined cytogenetic abnormalities and risk groups
16 (vs 6) specific abnormalities, 5 (vs 3) subgroupsa
3. Evaluation of depth of cytopeniasb
Clinically and statistically relevant cut points used
4. Inclusion of differentiating features
Age, performance status, serum ferritin, LDH, β-microglobulin
2
5. Prognostic model with 5 (vs 4) risk categories
Improved predictive power
- Marrow blast categories