A Napaac Survey to Understand Practices in Diagnosis and Treatment of Children with Moderate Aplastic Anemia

Among patients with acquired aplastic anemia, approximately 20% do not meet current classification as severe based on established criteria that reflect blood counts and marrow cellularity. For patients with moderate aplastic anemia (MAA), there is no set of defined diagnostic criteria, or clear standard-of-care for management. Little is known about the natural history of spontaneous recovery versus progression to severe bone marrow failure (BMF), response to conventional immunosuppressive treatment (IST), or evolution to myelodysplasia (MDS). Thus, institutional and individual practice can range from observation to immunosuppression or hematopoietic stem cell transplantation (HSCT). Recent studies of this patient population have begun to identify individuals harboring pathogenic mutations in genes known to cause BMF.

To better understand population characteristics and management practices for patients with MAA, a survey was conducted through the North American Pediatric Aplastic Anemia Consortium (NAPAAC), consisting of 52 centers with expertise in BMF across North America. A total of 65 surveys were completed by pediatric hematology-oncology providers (55 attending physicians, 5 nurse practitioners and 5 fellows).

Across all groups, there was marked variability of the MAA definition. Cytopenias were the defining criteria for diagnosis, including ANC<1000 cells/ul (79%), platelets <100K cells/ul (43%), and anemia for age (47%). In contrast, bone marrow hypocellularity (<50% cellularity) was considered by less than half (48%) of the respondents to be necessary for diagnosis. The combination of hypocellular bone marrow plus two cytopenias was considered the most common diagnostic definition of MAA (60% of participants).

Although genetic testing has begun to transform diagnosis for many hematological diseases and can alter treatment decisions for pediatric BMF disorders, only 51% currently consider next generation sequencing (NGS) and 4% consider whole exome/whole genome sequencing as part of the initial work-up for MAA. Conventional cytogenetics and FISH are used more frequently in the initial work-up (86% and 73%, respectively). The two main triggers for treatment were dependence on red blood cell- (92%) or platelet (87%) transfusions, followed by persistent cytopenias (54%) and cytogenetic abnormalities (53%). Where available, acquired somatic variants triggered treatment in 30% of responses. Interestingly, infections were a less frequent trigger for treatment (35%). The most common management approaches were observation with transfusions (79%), single agent thrombopoietin receptor agonists (71%) or ATG+Cyclosporine based immune suppressive therapy (IST, 61%). Progression to severe aplastic anemia (SAA, 97%), myelodysplastic syndrome (MDS, 97%), or refractoriness to IST (61%) were the most common indications for HSCT.Availability of a matched sibling donor (MSD, 12%) was an infrequent indication for HSCT.

A growing body of work, albeit largely in adult patients, suggests that patients with MAA represent a heterogenous group of individuals, some with genetic predisposition to BMF and inherent risk of myelodysplastic evolution. We identified that half of the responding NAPAAC practitioners use NGS panels routinely, suggesting a need for increased awareness to consider this work-up at initial diagnosis. Future studies are important to determine the yield of standard NGS testing, as the diagnosis of inherited BMF syndromes alter the strategy for long term surveillance of patients and genetic counseling for the family, as well as the use of related donor HSCT.

We observed variability regarding the diagnostic criteria and management of children with MAA by providers who are members of NAPAAC. The heterogeneous responses to our survey suggest the need to establish management guidelines for uniform work-up and treatment, and to facilitate research of this understudied population.

PC, LO: contributed equally as first authors. PK, JD: contributed equally as senior authors