Aplastic Anemia: Diagnosis and Treatment

Classification

Once the diagnosis of aplastic anemia has been made, the patient should be classified according to the severity of their disease. Disease severity is determined based on peripheral blood ANC: non-severe aplastic anemia (NSAA), ANC > 500 polymorphonuclear neutrophils (PMNs)/µL; severe aplastic anemia (SAA), 200–500 PMNs/µL; and very severe aplastic anemia (VSAA), 0–200 PMNs/µL.^4,34 Disease classification is important, as VSAA is associated with a decreased OS compared to SAA.² Disease classification may affect treatment decisions, as patients with NSAA may be observed for a short period of time, while, conversely, patients with SAA have a worse prognosis with delays in therapy.^43-45

Treatment of Inherited Aplastic Anemia

First-line treatment options for patients with IMFS are androgen therapy and hematopoietic stem cell transplant (HSCT). When evaluating patients for HSCT, it is critical to identify the presence of an IMFS, as the risk and mortality associated with the conditioning regimen, stem cell source, graft-versus-host disease (GVHD), and secondary malignancies differ between patients with IMFS and those with acquired marrow failure syndromes or hematologic malignancies.

Potential sibling donors need to be screened for donor candidacy as well as for the inherited defect. Among patients with Fanconi anemia or a telomere biology disorder, the stem cell source must be considered, with multiple studies in IMFSs and SAA showing superior outcomes with a bone marrow product compared to peripheral blood stem cells.^46-48 In IMFS patients, the donor cell type may affect the choice of conditioning regimen.^5,6 Reduced-intensity conditioning in lieu of myeloablative conditioning without total body irradiation has proved feasible in patients with Fanconi anemia, and is associated with a reduced risk of secondary malignancies.^49,50 Incorporation of fludarabine in the conditioning regimen of patients without a matched sibling donor is associated with superior engraftment and survival^46,49,51 compared to cyclophosphamide conditioning, which was historically used in matched related donors.^50,52 Adding fludarabine appears to be especially beneficial in older patients, in whom its use is associated with lower rates of graft failure, likely due to increased immunosuppression at the time of engraftment.^51,53 Fludarabine has also been incorporated into conditioning regimens for patients with a telomere biology disorder, but outcomes data are limited.⁵

For patients presenting with AML or a high-risk MDS who are subsequently diagnosed with an IMFS, treatment can be more complex, as these patients are at high risk for toxicity from standard chemotherapy. Limited data suggest that induction therapy and transplantation are feasible in this group of patients, and this approach is associated with increased OS, despite lower OS rates than those of IMFS patients who present prior to the development of MDS or AML.^54,55 Further work is needed to determine the optimal induction regimen that balances the risks of treatment-related mortality and complications associated with conditioning regimens, risk of relapse, and risk of secondary malignancies, especially in the cohort of patients diagnosed at an older age.