“Not many comparative studies exist to clearly establish the superiority of one [strategy] over another,” wrote the authors. “Therefore, [choosing] the best treatment for these patients should rely on major driving factors like the patient’s age and comorbidities, availability of a matched unrelated donor, the donor’s characteristics, and drug availability.”

As with frontline therapy, health care providers must take into account patient age and comorbidities when selecting second-line therapy, as these are strong predictors of outcome for both IST and HSCT. Another issue to consider is the increased tendency of aplastic anemia to evolve into myelodysplastic syndrome and acute myeloid leukemia with repeated courses of IST.

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Second-Line Treatment Decision Making

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Any patient with IST-refractory severe aplastic anemia must be referred to a center with clinicians who have expertise on aplastic anemia and bone marrow failure. After that, factors known to affect outcomes can be evaluated, and a suitably matched HSCT donor (10/10, 9/10, or 8/8 human leukocyte antigen [HLA]) can be sought.

If a suitable donor is available and the patient is younger than 40 years with no comorbidities, then the health care provider should proceed with matched family donor or matched unrelated donor HSCT. Of note, some centers limit patient age for HSCT to 30 years. If no matched (family or unrelated) donor is available, then haploidentical or cord blood HSCT may also be considered.

If the patient does not meet the center’s age cutoff for HSCT or has significant comorbidities, a second course of IST with or without eltrombopag may be used. If a second course of IST is elected, the ATG that was not used for the initial IST should be used.

“The best results are obtained in patients re-treated with rabbit ATG after the failure of the initial course of [horse] ATG,” wrote the authors.

If the patient has no response or relapses, subsequent treatment options include a third course of IST, alemtuzumab with or without cyclosporine A, eltrombopag monotherapy, androgens, or cyclosporine A monotherapy. Androgens or oral cyclosporine monotherapy are encouraged for patients from areas with limited resources, patients who are older than 60 years, or patients with comorbidities.

Future Directions

The authors suggested that the clinical use of molecular markers such as telomere length and telomerase complex and those indicative of myeloid transformation/clonal evolution may enter routine diagnostic workup, as these markers have been associated with outcomes in aplastic anemia. Furthermore, these clinical markers may lead to the development of individually tailored treatment options.

The authors called for the “identification of better combinations and sequence of treatments for refractory patients” through prospective clinical trials.


1. Young NS. Aplastic anaemia. Lancet. 1995;346(8969):228-232. doi:10.1016/s0140-6736(95)91273-8

2. Montane E, Ibanez L, Vidal X, et al. Epidemiology of aplastic anemia: a prospective multicenter study. Haematologica. 2008;93(4):518-523. doi:10.3324/haematol.12020

3. Pierri F, Dufour C. Management of aplastic anemia after failure of frontline immunosuppression [published online July 24, 2019]. Expert Rev Hematol. doi:10.1080/17474086.2019.1645003