Acquired Aplastic Anemia in Children

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Key points

  • Acquired aplastic anemia (AA) is an acquired condition of bone marrow failure characterized by peripheral pancytopenia and a hypoplastic bone marrow.

  • There is increasing evidence that acquired AA is immune mediated.

  • Bone marrow transplantation (BMT) is the recommended first-line therapy for patients with a human leukocyte antigen (HLA)-matched sibling donor, with 5-year survival rates exceeding 90%.

  • Immunosuppressive therapy (IST) with horse antithymocyte globulin and cyclosporine is the

Definitions

AA is characterized by peripheral blood pancytopenia and a hypocellular bone marrow without dysplasia or fibrosis (Fig. 1). The degree or severity of AA is defined by peripheral blood cell counts in the presence of a hypocellular bone marrow (Box 1).1, 2 AA in children is distinct from that in adults; inherited AA is more frequently found in children and the human leukocyte antigen (HLA) association differs, suggesting an age-specific immune pathogenesis. Moreover, there are age-specific

Epidemiology

Acquired AA is a rare disorder with an incidence of about 2 in 1 million children per year in North America and Europe and a 2- to 3-fold higher incidence in Asia.6 The peak incidence is in adolescents and young adults as well as in the elderly, with a roughly equal male to female ratio.6 A classification of AA based on etiology is summarized in Table 1.

Pathogenesis

For many years, an immune-mediated pathogenesis has been postulated for AA because immunosuppressive therapy (IST) is often successful in the treatment of AA, and bone marrow lymphocytes from AA patients can suppress normal bone marrow in vitro.7 Results from numerous laboratories have demonstrated increased cytokine expression, low CD4 T regulatory cells, oligoclonal CD8 cytotoxic T cells, and, to a lesser extent, expansion of specific CD4 cell populations in the bone marrow of AA patients.8, 9

Clinical presentation

Most children with AA present with signs and symptoms resulting from advanced pancytopenia, with others being diagnosed by incidental laboratory findings. Thrombocytopenia may manifest as easy bruising or petechiae. Epistaxis and menorrhagia in postmenarchal girls are other common complaints at presentation. Anemia may manifest as pallor, fatigue, or exercise intolerance. Neutropenia may predispose to infections and, thus, fever or focal signs of infection can occur as initial complaints.

Establishing the diagnosis

A comprehensive history should include exposure to medications, recreational drugs, and chemicals as well as preceding infectious symptoms. The family history needs to be detailed, and assessed for diseases and signs suggestive of IBMFS (Table 2). A comprehensive laboratory panel is requested to establish the diagnosis of AA, classify its severity, and screen for potential causative factors (Table 3). A bone marrow aspirate and biopsy are needed to establish the diagnosis (see Fig. 1). A

Supportive care

Gains in survival for patients with acquired AA are due in part to the improvement in supportive therapy.18 However, infections and bleeding still remain a major cause of morbidity and mortality in this patient population.19, 20 In an afebrile patient with a good performance status (Eastern Cooperative Oncology Group/WHO/Zubrod 0–2), the evaluation of AA may be performed in the outpatient setting in a center and by a care team experienced in treating AA patients.

Although there is a lack of

Definitive treatment

Once a diagnosis is firmly established, BMT and IST are currently the primary treatment options for AA patients, both children and adults. Numerous studies have established that BMT is highly successful when an HLA-matched sibling is available (matched related donor [MRD]), with 5-year survival rates of 90% and higher, making BMT the recommended first-line therapy in this setting (Fig. 5). In North America, the current practice is to reserve matched unrelated donor (URD) BMT for patients with

Bone marrow transplant

The current standard approach to BMT for pediatric patients with acquired AA is summarized in Table 5.

Immunosuppressive therapy

IST is currently the first-line therapy for patients with SAA or vSAA who lack an MRD (see Fig. 5). Most centers treating patients with AA use ATG and CSA as their first-line IST. In the United States, horse ATG (hATG, ATGAM; Upjohn, Kalamazoo, MI) is most commonly used. Table 7 summarizes the IST treatment algorithm using hATG/ATGAM. A short course of corticosteroids is used to reduce the risk of serum sickness. There is no other role for corticosteroids in AA, thus dosing should be adjusted

Moderate or nonsevere AA

The approach to patients with moderate AA is less defined. Studies on the natural history of nonsevere AA (NSAA) are inconsistent, most likely because of the heterogeneity of this patient population, differences in the study populations (pediatric vs adult NSAA), and the difficulty in excluding IBMFS and low-grade MDS. Often patients with NSAA require only supportive therapy and no specific treatment for their cytopenia. NSAA may resolve spontaneously or progress to SAA. In children,

Response

A complete response (CR) is defined as a normalization of peripheral blood values in at least 2 separate blood cell counts at least 4 weeks apart (Box 3). Response is usually assessed 3, 6, and 12 months after ATG initiation. Response to treatment usually occurs within 3 to 6 months of treatment initiation, but in some patients the response may be delayed. The 6-month response rate for hATG+CSA varies among studies from 60% to 77%, with these recent studies estimating a current 10-year OS of

Summary

Acquired AA is a rare, life-threatening disorder, which is thought to be due to immune-mediated destruction of hematopoietic cells in the BM. Great advances have been made in the last decade in the understanding of its pathogenesis, as well as in the care and treatment of children with AA, which is now associated with excellent OS surpassing 90%. Allogeneic BMT offers the opportunity for cure in children if a suitable histocompatible donor is available. Comparable long-term survival in SAA is

Acknowledgments

The authors thank all patients with AA for participating in their BMF studies at CHOP/UPENN; Beverly J. Paul, RN, for her contributions in the care of BMF patients; Michele E. Paessler, DO, Pathology, CHOP, for providing the images used in Fig. 1; Talene Metjian, PharmD, Brian T. Fisher, DO, MSCE, Infectious Diseases, and Shefali Parikh, MD, Hematology, The Children’s Hospital of Philadelphia, for sharing the algorithm for anti-infective prophylaxis in patients with SAA shown in Fig. 5; Neil

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  • Cited by (0)

    Funding Sources: NCI NIH R01 CA105312 and Buck Family Endowed Chair in Hematology (M. Bessler); NHLBI K12 HL087064, The Canuso Foundation Innovation Grant, and The Children’s Hospital of Philadelphia CTRC Junior Investigator Pilot Grant Program (Funded by NCATS NIH UL1TR000003) (T.S. Olson).

    Conflict of Interest: None.

    1

    H.D. Hartung and T.S. Olson contributed equally to this work.

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