How should severe aplastic anemia be treated in a patient under 50 years old with a human leukocyte antigen‑matched sibling donor, and what are the options if a donor is not available?

Treatment of Severe Aplastic Anemia in Patients Under 50 Years

For patients under 50 years old with severe aplastic anemia and an HLA-matched sibling donor, allogeneic hematopoietic stem cell transplantation (allo-HSCT) should be performed as first-line therapy, as it offers the highest cure rates and long-term disease-free survival compared to immunosuppressive therapy. 1, 2, 3

First-Line Treatment Algorithm

For Patients WITH HLA-Matched Sibling Donor

Proceed directly to allogeneic bone marrow transplantation as the treatment of choice for patients under 50 years old. 1, 4, 3

• Conditioning regimen: Use cyclophosphamide plus antithymocyte globulin (ATG) as the standard myeloablative conditioning approach. 4
• Stem cell source: Bone marrow is preferred over peripheral blood stem cells for matched sibling transplants in aplastic anemia. 4
• GVHD prophylaxis: Administer cyclosporine A combined with methotrexate. 4
• Expected outcomes: Actuarial 10-year survival reaches 73% with matched sibling donor transplantation, with significantly better results in younger patients (79% in those <16 years versus 68% in adults). 5

Critical advantage over immunosuppression: Transplantation eliminates the persistent long-term risks of disease relapse and secondary myelodysplastic syndrome or acute myeloid leukemia that plague patients treated with immunosuppressive therapy alone. 2

For Patients WITHOUT HLA-Matched Sibling Donor

The priority order for alternative donor sources is: 1, 2

1. HLA-matched unrelated donor (MUD) from international registries
2. HLA-haploidentical donor if a matched unrelated donor is not rapidly available

Key consideration: Recent data suggest that both matched unrelated donor and haploidentical transplantation may be preferable to immunosuppressive therapy as first-line treatment, given the superior long-term disease-free survival and lower risk of clonal evolution. 2

If transplantation is not immediately feasible, initiate immunosuppressive therapy (IST) as a bridge:

• Triple therapy regimen: Equine antithymocyte globulin (ATG) + cyclosporine A + eltrombopag. 3
• Actuarial 10-year survival with IST: Approximately 68-70% in adults, though without the curative potential of transplantation. 5
• Age-related outcomes: IST results are significantly better in children compared to adults (81% versus 70%), especially in very severe aplasia (83% versus 62%). 5

Critical Timing Considerations

HLA typing must be performed immediately at diagnosis, before initiating any treatment, to identify potential donors among family members and in unrelated donor registries. 2, 3

Avoid delays: Longer intervals between diagnosis and transplantation (>3 months) are associated with higher mortality risks. 6 Early referral to a transplant center is essential when this treatment option is being considered. 6

Age-Specific Outcomes

Mortality risks increase progressively with age even within the under-50 population: 6

• Patients <20 years: baseline mortality risk
• Patients 20-40 years: 1.69-fold higher mortality risk (P<0.0001)
• Patients >40 years: 2.70-fold higher mortality risk compared to <20 years (P<0.0001)

Platelet recovery is slower in older patients: Those over 40 years have significantly lower likelihood of platelet recovery compared to patients under 20 years (OR 0.45, P=0.01). 6

Common Pitfalls to Avoid

Do not delay transplant referral for a trial of immunosuppression in patients under 50 with identified donors—this increases the diagnosis-to-transplant interval and worsens outcomes. 6

Do not assume IST is equivalent to transplantation: While IST can achieve remission, it carries persistent risks of relapse (no improvement in IST outcomes since 1996) and secondary malignancies that transplantation eliminates. 2, 5

Performance status matters: Patients with poor performance scores have higher mortality risks, emphasizing the need for early intervention before clinical deterioration. 6

Pediatric patients (<16 years) have superior outcomes with both transplantation (79% 10-year survival) and IST (81% survival), making aggressive curative approaches even more justified in this age group. 5