Bone Marrow Failure Syndromes Including Aplastic Anemia and Myelodysplasia¶
Chapter 107 | Part 4: Oncology and Hematology
KEY CLINICAL POINTS¶
- Aplastic anemia is defined as pancytopenia with hypocellular bone marrow, with etiologies including immune-mediated destruction, genetic defects, and environmental toxins.
- Myelodysplastic syndromes (MDS) are heterogeneous disorders characterized by dysplastic hematopoiesis, cytopenias, and risk of progression to AML, with classification based on blasts, cytogenetics, and molecular mutations.
- Diagnosis of aplastic anemia requires exclusion of other causes (e.g., PNH, MDS) and involves bone marrow biopsy, flow cytometry, and genetic testing for constitutional syndromes.
- Treatment of severe aplastic anemia includes immunosuppression (ATG, cyclosporine, eltrombopag) and hematopoietic stem cell transplantation (HSCT) for eligible patients.
- Prognosis for MDS varies widely, with risk stratification using IPSS-R and IPSS-M systems incorporating molecular data.
1. DEFINITION & OVERVIEW¶
Aplastic anemia is pancytopenia with hypocellular bone marrow, resulting from immune-mediated, genetic, or environmental causes. Myelodysplastic syndromes (MDS) are characterized by dysplastic hematopoiesis, cytopenias, and risk of AML. Bone marrow failure syndromes include aplastic anemia, MDS, pure red cell aplasia (PRCA), and other single-lineage cytopenias. Classification is based on marrow morphology, cytogenetics, and molecular mutations.
Table 107-1: Differential Diagnosis of Pancytopenia¶
| Category | Conditions |
|---|---|
| Pancytopenia with Hypocellular Bone Marrow | Acquired (immune) aplastic anemia, Constitutional aplastic anemia, Hypoplastic MDS, Rare aleukemic leukemia |
| Pancytopenia with Cellular Bone Marrow | Primary marrow diseases (MDS, PNH), Secondary to systemic diseases (SLE, hypersplenism, HIV, etc.) |
1.1 Aplastic Anemia¶
Defined by pancytopenia with hypocellular marrow. Acquired vs. constitutional (e.g., Fanconi anemia, telomere biology disorders). Immune-mediated destruction, drug/toxin exposure, or genetic defects (e.g., GATA2, RUNX1 mutations).
1.2 Myelodysplastic Syndromes (MDS)¶
Heterogeneous disorders with dysplastic hematopoiesis, cytopenias, and risk of AML. Classified by blasts, cytogenetics, and molecular mutations (e.g., SF3B1, TP53). Includes subtypes like MDS-5q, MDS-SF3B1, and MDS with complex karyotypes.
2. EPIDEMIOLOGY¶
Acquired aplastic anemia incidence: 2 per million in Europe/Israel, 5–7 per million in Thailand/China. Age distribution: biphasic (teens/20s and older adults). Risk factors: drugs (benzene, chemotherapy), radiation, infections, and genetic predispositions (e.g., Fanconi anemia). MDS is more common in elderly (mean age >70), with incidence 35–>100 per million in general population.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Acquired causes: immune-mediated (e.g., drug reactions, viral infections), toxins (benzene, chemotherapy), radiation. Constitutional causes: genetic syndromes (Fanconi anemia, telomere biology disorders, GATA2/RUNX1 mutations). Pathophysiology: immune destruction of hematopoietic stem cells, telomere dysfunction, or clonal hematopoiesis. MDS involves dysplastic changes, chromosomal abnormalities, and mutations in genes like SF3B1, TP53, and ASXL1.
Table 107-2: Classification of Aplastic Anemia and Single Cytopenias¶
| Category | Conditions |
|---|---|
| Acquired | Aplastic Anemia (Radiation, Drugs, Viruses) |
| Inherited/Constitutional | Fanconi Anemia, Dyskeratosis Congenita, GATA2/RUNX1 Mutations |
4. CLINICAL FEATURES¶
Symptoms: fatigue, pallor, bleeding (petechiae, ecchymoses), infections. Physical findings: splenomegaly, signs of telomere biology disorders (short stature, nail dystrophy). In MDS: dysplastic morphology in blood and marrow, anemia, thrombocytopenia, and neutropenia. Constitutional syndromes: physical anomalies (Fanconi anemia, Diamond-Blackfan anemia).
5. DIFFERENTIAL DIAGNOSIS¶
PNH, MDS, leukemia, drug-induced aplasia, infections (e.g., parvovirus), autoimmune disorders (e.g., SLE), and systemic diseases (e.g., HIV, sarcoidosis). Distinguishing features: marrow morphology, cytogenetics, flow cytometry for PNH clones, and genetic testing for constitutional syndromes.
6. INVESTIGATIONS & DIAGNOSIS¶
Laboratory tests: CBC, reticulocyte count, peripheral blood smear, iron studies, PNH flow cytometry. Bone marrow biopsy: hypocellular or dysplastic marrow. Chromosome breakage studies, flow cytometry for PNH, and genetic testing (e.g., FANCA, TERC, TERT). Diagnostic criteria: pancytopenia with hypocellular marrow, exclusion of other causes.
Table 107-3: Drugs and Chemicals Associated with Aplastic Anemia¶
| Category | Examples |
|---|---|
| Cytotoxic Drugs | Alkylating agents, Antimetabolites, Antimitotics, Some Antibiotics |
| Toxins | Benzene, Chloramphenicol, Insecticides, Heavy Metals |
| Immune Mediators | Antibiotics (e.g., Trimethoprim/Sulfamethoxazole), NSAIDs, Anticonvulsants |
7. MANAGEMENT & TREATMENT¶
Immunosuppression: ATG, cyclosporine, eltrombopag (triple therapy). Supportive care: transfusions, antifungals, and infection prophylaxis. HSCT: first-line for young patients with matched donors. Lenalidomide for 5q- syndrome. For MDS: hypomethylating agents (azacitidine, decitabine), lenalidomide, and HSCT for high-risk cases.
Table 107-7: Revised International Prognostic Scoring System (IPSS-R)¶
| Parameter | Risk Categories |
|---|---|
| Marrow Blast Categories | £2%, >2%–<5%, 5–10%, >10–30% |
| Cytogenetic Abnormalities | Good, Intermediate, Poor |
| Cytopenias | Hemoglobin <80 g/L, Platelets <50,000/mL, Neutrophils <800/mL |
| Age and Performance Status | Included in risk stratification |
| Prognostic Model | 5 Risk Categories (Improved Predictive Power) |
8. PROGNOSIS & COMPLICATIONS¶
Severe aplastic anemia: rapid progression to death without treatment. MDS prognosis varies: 5q- syndrome has better outcomes, while complex karyotypes and TP53 mutations correlate with poor survival. Complications: infections, hemorrhage, progression to AML, and comorbidities in elderly patients.
9. SPECIAL CONSIDERATIONS¶
Pregnancy: rare complications, management with immunosuppression. Pediatric cases: constitutional syndromes (e.g., Diamond-Blackfan anemia, Fanconi anemia). Elderly patients: higher risk of transplant-related mortality, use of reduced-intensity conditioning. Genetic counseling for inherited syndromes.
10. KEY POINTS & CLINICAL PEARLS¶
- Aplastic anemia requires rapid diagnosis and treatment to prevent mortality. 2. Immunosuppressive therapy (ATG, cyclosporine, eltrombopag) is first-line for acquired cases. 3. HSCT is curative for eligible patients with matched donors. 4. MDS risk stratification using IPSS-R and molecular data guides therapy. 5. Constitutional syndromes (e.g., Fanconi anemia) require genetic testing and early intervention.