Acquired aplastic anemia (AA) is a rare disease characterized by progressive and, in the absence of treatment, generally irreversible loss of regenerative bone marrow function, resulting in life-threatening multilineage cytopenias. The incidence is in the range of one to three events per million in Western industrialized countries, and there is no predilection for gender, age, or ethnicity. Clinical observations and mounting experimental evidence suggest an underlying acquired cellular immune attack on the hematopoietic stem cell as the disease etiology in the majority of patients. Both the diagnosis and treatment of children with AA pose unique challenges, which the recently formed North American Pediatric Aplastic Anemia Consortium (NAPAAC), composed of representatives from 22 U.S. and Canadian institutions, aims to address prospectively.
Owing to the resulting high rate of overall and disease-free survival, HLA matched related donor-hematopoietic stem cell transplantation (MRD-HSCT) is the preferred treatment for children with severe AA. However, MRD-HSCT is available only to a minority of patients because most do not have a suitable donor. The majority of patients are instead treated with an intensive immunosuppressive therapy (IST) regimen. A recent NAPAAC survey of treatment practices1 showed that, although an antithymocyte globulin– (ATG-) plus cyclosporine A– (CSA-) based combination is nearly universally used, there is broad variation among institutions in the manner of implementation of the regimen. In this article, we highlight some of the most pressing issues related to the diagnosis and care of children with AA that were identified in the NAPAAC report. The results of that study underscore the need for development of evidence-based guidelines for diagnosis and management of children with acquired AA.
Areas of Controversy
Testing for inherited bone marrow failure syndromes
Diagnosis of acquired AA requires exclusion of an underlying constitutional syndrome. Screening for inherited bone marrow failure (BMF) syndromes (e.g., Fanconi anemia, telomere diseases including dyskeratosis congenita, Diamond-Blackfan anemia, or Shwachman-Diamond syndrome) is of particular importance in young patients, as these syndromes most frequently present during childhood, and AA may be the only clinical feature that is apparent at the time of presentation and in the absence of specific laboratory-based testing. Additionally, as the inherited BMF syndromes are not responsive to IST and require adherence to specific HSCT protocols (e.g., directed testing of potential pre-symptomatic sibling donors and use of disease-tailored conditioning regimens), missed diagnoses can have dire consequences. Alternatively, excessive, unnecessary diagnostic testing should be avoided. The NAPAAC survey found testing for inherited BMF syndromes in children at the time of their AA presentation to be variable. For example, whereas most centers (89%) test for Fanconi anemia, fewer (67%) test for dyskeratosis congenita. These and related findings suggest that codification of a standardized diagnostic approach would facilitate future multi-institutional prospective clinical studies.
Infection prophylaxis
Given the profound lymphodepletion that accompanies ATG administration, along with temporary use of corticosteroids, prolonged administration of CSA, and severe neutropenia, the majority of pediatric centers use antibacterial (including against Pneumocystis jirovecii) and antifungal prophylaxis in their patients with AA who undergo treatment with an ATG-CSA-based regimen. However, multi-institutional prospective trials designed to test the efficacy of supportive care regimens in this patient population are currently lacking.
Growth factor use
The NAPAAC survey found that, in most centers, the use of granulocyte colony-stimulating factor (G-CSF) is restricted to patients with severe AA during neutropenic infections. This limited used of G-CSF may have resulted from thoughtful interpretation of the results of several trials that found no significant impact of G-CSF on survival in patients treated with ATG-CSA-based IST, and that suggested that G-CSF is a risk factor for transformation of acquired AA into myelodysplastic syndrome in patients who failed to respond to IST. Some centers, however, continue to use G-CSF at the start of treatment, highlighting the need for definitive pediatric-based studies designed to address the use of growth factor support in patients with acquired AA.
Duration of IST and post-IST management
Most centers taper the CSA component of the IST once the patient becomes transfusion independent and an adequate neutrophil count is maintained. However, given the absence of prospective studies focused on the long-term use of CSA in the treatment of children with acquired AA, carefully designed studies are needed in order to establish an evidenced-based optimal nadir concentration range for CSA; a recommendation for duration of CSA treatment and for tapering CSA; and guidelines for follow-up evaluation and management, especially for partial responders. As relapses are relatively common and clonal evolution can occur in patients many years after treatment, monitoring and management of children with treated acquired AA, who have a life expectancy of many decades, need to be optimized.
Matched unrelated donor HSCT and treatment for patients in whom primary IST fails
With the availability of high-resolution HLA typing and improvements in both conditioning strategies and supportive care and treatment of graft-versus-host disease, results after matched unrelated donor (MUD-) HSCT in children with acquired AA have improved markedly. In fact, some small case series suggest outcome parity when compared to MRD-HSCT. Accordingly, some centers now favor MUD-HSCT over repeat IST for patients in whom the initial ATG-CSA–based treatment course fails. Currently however, there is no consensus on treatment of refractory or relapsed disease, and optimal management is a moving target given the development of new therapeutic modalities such as eltrombopag, which NAPACC hopes to include in future studies.
Treatment of moderate AA
Not all children present with symptomatic, severe disease. Some maintain stable, low-grade cytopenias for months before recovering or progressing to severe AA. Going forward, it will be important to address, in this group of patients, whether preemptive IST treatment confers a more favorable outcome or whether watchful waiting prevents unnecessary exposure to immunosuppressive drugs.
Conclusions
The review of practices across major centers in the U.S. suggests that to optimize the treatment of children with acquired AA, a number of critical issues must be addressed.1 And because of the rarity of the disease, cooperative group studies such as those being initiated by NAPAAC are needed to generate evidenced-based management guidelines. The group is developing a website with resources for physicians and an opportunity to connect with experts in the field. NAPAAC’s long-term goal is to establish not only a unique database and clinical standards of care for children with acquired AA, but also a biospecimen repository that will serve to maximize group-wide resources, including applying the latest genomic technologies to gain a clearer understanding of the pathobiology of this challenging disease. NAPAAC encourages and welcomes participation of groups and individuals interested in joining in the effort to optimally manage children with acquired AA.
