Aplastic Anemia

Immune-mediated bone marrow failure — immunosuppressive therapy, eltrombopag, and allogeneic transplantation for pancytopenia with a hypocellular marrow

Key Points

• Aplastic anemia is bone marrow failure defined by pancytopenia with a hypocellular marrow in the absence of infiltration or dysplasia — most cases are immune-mediated (T-cell attack on hematopoietic stem cells).
• Severity is graded by blood counts and marrow cellularity: severe (SAA) and very severe (VSAA) forms are life-threatening and require urgent definitive therapy.
• For young patients with a matched sibling donor, up-front allogeneic HSCT is the treatment of choice and is potentially curative.
• For patients without a donor or who are older, first-line therapy is immunosuppression with horse antithymocyte globulin (ATG) plus cyclosporine — now combined with eltrombopag, which improves response rates.
• Eltrombopag stimulates residual hematopoietic stem cells and, added to standard immunosuppression, increases the rate and speed of hematologic response (RACE trial).
• Aplastic anemia overlaps biologically with paroxysmal nocturnal hemoglobinuria (PNH) and hypoplastic MDS — clonal evolution to MDS/AML and PNH must be monitored long-term.

Definition, Etiology, and Pathophysiology

Aplastic anemia is a syndrome of bone marrow failure characterized by pancytopenia and a hypocellular bone marrow, without abnormal infiltrate, significant fibrosis, or dysplasia. The marrow is replaced by fat, and hematopoiesis is markedly reduced across all three lineages. **Pathophysiology:** Most acquired aplastic anemia is **immune-mediated** — autoreactive cytotoxic T lymphocytes and their cytokines (interferon-γ, tumor necrosis factor) attack and destroy hematopoietic stem and progenitor cells. The strong clinical response to immunosuppression is direct evidence of this mechanism. A…

Diagnosis and Severity Classification

**Diagnostic work-up:** - **CBC with differential and reticulocyte count:** pancytopenia with reticulocytopenia (inappropriately low reticulocytes for the degree of anemia). - **Peripheral smear:** true pancytopenia without blasts, dysplasia, or abnormal cells. - **Bone marrow aspirate and biopsy:** the diagnostic cornerstone — markedly hypocellular marrow (often <25% cellularity) with preserved architecture and no infiltration or significant dysplasia/fibrosis. - **Cytogenetics and molecular studies:** to exclude MDS and identify clonal markers. - **PNH flow cytometry:** to detect a PNH…

First-Line Treatment — Transplant vs. Immunosuppression

The two definitive treatment strategies are allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST). Choice depends on patient age, disease severity, and donor availability. **Allogeneic HSCT (matched sibling donor):** - The **treatment of choice for younger patients (generally ≤40–50 years) with severe/very severe AA and an HLA-matched sibling donor** — it is potentially curative and avoids the risk of later clonal evolution seen after IST. - Reduced-intensity conditioning (e.g. cyclophosphamide with ATG, without or with low-dose radiation) is used…

Relapse, Refractory Disease, and Long-Term Monitoring

**Refractory or relapsed disease after IST:** - A second course of ATG (often rabbit ATG after horse ATG), continued or reintroduced eltrombopag, or referral for allogeneic transplant (matched unrelated or alternative donor, including haploidentical) are the main options. - Eltrombopag has activity in relapsed/refractory SAA and may be used as salvage. **Clonal evolution and long-term risks:** Patients treated with immunosuppression (as opposed to cured by transplant) carry a long-term risk of clonal disorders: - **Myelodysplastic syndrome / acute myeloid leukemia:** often associated with…