What are the primary treatment options for a patient with severe aplastic anemia, considering factors such as age, overall health, and availability of a suitable donor for Hematopoietic Stem Cell Transplantation (HSCT)?

Treatment of Aplastic Anemia

For patients with severe aplastic anemia (SAA) under age 50 with an HLA-matched sibling donor, allogeneic hematopoietic stem cell transplantation (allo-HSCT) should be offered as first-line therapy; for those without a matched sibling donor, immunosuppressive therapy (IST) with horse antithymocyte globulin (ATG) plus cyclosporine is the standard initial treatment, though upfront matched unrelated donor (MUD) transplant may be considered in pediatric patients and young adults requiring urgent intervention. 1, 2

Age-Based Treatment Algorithm

Patients Under 50 Years

• Patients with HLA-matched sibling donors should proceed directly to allo-HSCT as first-line therapy, as this provides the highest cure rates (80-90% overall survival) and eliminates the long-term risks of relapse and clonal evolution associated with IST 1, 3

• Pediatric patients and young adults with ≥9/10 loci-matched unrelated donors may also choose upfront allo-HSCT, particularly when urgent transplantation is needed due to severe cytopenias or transfusion dependence 1

• Young patients without matched sibling or unrelated donors should receive haploidentical donor (HID) HSCT as first-line therapy, as Chinese Society of Hematology guidelines demonstrate equivalent outcomes to matched sibling transplants with 3-year overall survival of 86.1% and failure-free survival of 85.0% 1

• For patients who cannot proceed immediately to transplant, IST with horse ATG plus cyclosporine serves as initial therapy, with the understanding that allo-HSCT remains the definitive treatment option for non-responders or relapsed disease 1, 4, 2

Patients 50-60 Years

• Patients aged 50-60 years with matched sibling or matched unrelated donors and ECOG performance status ≤2 should be considered for allo-HSCT, particularly after IST failure or relapse 1

• IST with horse ATG plus cyclosporine is generally preferred as first-line therapy in this age group due to increased transplant-related mortality and GVHD risk with advancing age 4, 5

• Patients between 40-50 years have intermediate outcomes with allo-HSCT (5-year overall survival 62%, disease-free survival 52%), making IST a reasonable first-line option with transplant reserved for treatment failures 5

Patients Over 60 Years

• IST with horse ATG plus cyclosporine is the standard treatment, as transplant-related complications increase substantially with age 4, 2

Donor Selection Hierarchy

When allo-HSCT is indicated, donor selection should follow this priority order:

• First choice: HLA-matched sibling donor (MSD), which provides the best outcomes with lowest GVHD rates 1, 2

• Second choice: HLA-matched unrelated donor (MUD) with 8/8 or higher matching, as outcomes now approach those of matched sibling transplants with improved donor selection and protocols 1, 4

• Third choice: Haploidentical donor (HID) when MSD or rapidly available MUD is not present, particularly for younger patients requiring urgent transplantation 1

• Bone marrow is the preferred graft source over peripheral blood stem cells when using ATG-based conditioning regimens, as it reduces GVHD risk 2

Refractory and Relapsed Disease

Treatment Failure After Initial IST

• Patients under 50 years who fail to respond to IST or relapse should undergo HID, MUD, or cord blood transplantation, as salvage allo-HSCT provides superior failure-free survival (79.8%) compared to repeat IST (56.6%) 1, 6

• Children and younger patients (age ≤35 years) with refractory SAA benefit significantly more from salvage HSCT than repeat IST, with children in the HSCT cohort achieving 100% overall survival versus 50% with repeat IST 6

• For patients 50-60 years with IST failure and ECOG ≤2, MSD or MUD transplantation is recommended over additional immunosuppression 1

Conditioning Regimens

• Cyclophosphamide plus ATG is the preferred conditioning for matched related donor transplants, providing optimal balance of engraftment and toxicity 2

• Fludarabine-based conditioning should be used for older adults, patients with risk factors for graft failure, and those receiving MUD transplants, as it reduces toxicity while maintaining efficacy 2

• For haploidentical transplants, low-dose radiotherapy with post-transplant cyclophosphamide has markedly reduced graft failure and GVHD rates 2

GVHD Prophylaxis

• Cyclosporine plus methotrexate is preferable for GVHD prophylaxis with ATG-based conditioning regimens 2

• Alemtuzumab is an acceptable alternative to ATG and may be used with cyclosporine alone, allowing use of either bone marrow or peripheral blood stem cells 2

Critical Pitfalls to Avoid

• Do not delay HLA typing until after IST failure—all patients should have HLA typing of family members and registry searches initiated at diagnosis to identify potential donors before beginning treatment 3

• Do not assume IST is safer than transplant in younger patients—the cumulative long-term risks of relapse (30-40%), clonal evolution to MDS/AML (10-15%), and need for salvage therapy make upfront transplant preferable when donors are available 3

• Do not use peripheral blood stem cells with ATG-based conditioning in matched donor transplants—bone marrow grafts significantly reduce GVHD risk 2

• Do not consider patients over 40 years automatically ineligible for transplant—carefully selected patients aged 40-50 years with good performance status and matched donors can achieve acceptable outcomes, particularly as salvage therapy 5

• Do not delay transplant in children with available matched unrelated donors—pediatric patients have superior transplant outcomes and should not undergo prolonged IST trials when suitable donors exist 1, 6