Case Studies for Fellows

Case Study: Three-year-old Boy With Pancytopenia

A three-year-old boy with no significant medical history presents to his pediatrician with a two-month history of petechial rash and intermittent epistaxis. He has had a cough, has experienced rhinorrhea, and has been fussier than normal. No fevers, weight loss, or unusual fatigue were reported. He is tracking along his growth curves and is meeting his developmental milestones appropriately.

He is an only child, born full term at 38 weeks with no significant complications. There is no significant family medical history. His only recent medications include acetaminophen and diphenhydramine.

Physical examination shows that he is afebrile and has no dysmorphic features. Scattered petechiae noted on the patient's trunk and extremities, as well as a few ecchymoses on his bilateral lower extremities. There has been no hepatosplenomegaly or significant lymphadenopathy, and extremities are normal.

Laboratory Results

  Value Reference Range
Hemoglobin (g/dL) 9.2 11.5-13.5
Hematocrit (%) 26.6 34.0-40.0
Mean corpuscular volume (fL) 88.7 75.0-87.0
Leukocytes 1.1 x 109/L 6.0-15.5 x 109/L
Absolute neutrophil count 207 x 106/L 1,500-7,770 x 106/L
Platelets 12 x 109/L 250-550 x 109/L
Reticulocyte count 29 x 109/L 18-100 x 109/L

The patient underwent a bone marrow biopsy and aspirate, which demonstrates marrow cellularity ranging from 5 to 20 percent cellularity (average 10%). No blasts or dysplastic features were identified. Karyotype analysis was unsuccessful. A diepoxybutane test was negative and whole-genome next-generation sequencing did not reveal any mutations.

Which of the following is the most appropriate management at this time?

  1. Monitor complete blood count every three months for worsening cytopenias with annual marrow evaluation
  2. Horse antithymocyte globulin and cyclosporine
  3. Intravenous immunoglobulin
  4. Eltrombopag
  5. Matched unrelated donor hematopoietic stem cell transplantation

Answer: B. Horse antithymocyte globulin and cyclosporine

This patient has severe aplastic anemia (SAA). SAA is most commonly immune-mediated and is defined as having bone marrow cellularity lower than 25 percent and two or more of the following1: peripheral blood neutrophil count lower than 0.5 × 109/L; peripheral blood platelet count lower than 20 × 109/L, and peripheral blood reticulocyte count lower than 20 × 109/L.

There is no required duration of cytopenias to establish a diagnosis of aplastic anemia (AA).

AA is a diagnosis of exclusion. Diagnostic workup in pediatric patients often includes consideration of hematologic malignancies, viral etiologies such as parvovirus, and inherited bone marrow failure (BMF) syndromes. Inherited BMF syndromes encompass a wide range of disorders, and a thorough family history and patient physical examination may help target diagnostic evaluation. However, even in the absence of any notable features, diagnostic workup in patients with BMF should include chromosome breakage studies (diepoxybutane test) to rule out Fanconi anemia, telomere length studies to rule out dyskeratosis congenita, paroxysmal nocturnal hemoglobinuria test (fluorescently labeled inactive toxin aerolysin test), and pancreatic enzymes to evaluate for Shwachman-Diamond syndrome.

The treatment of choice for SAA is human leukocyte antigen (HLA)–matched sibling donor hematopoietic stem cell transplantation (HSCT), which is curative. If no sibling donor is available, immunosuppressive therapy with horse antithymocyte globulin (hATG) and cyclosporine (CSA) is recommended. Eltrombopag (choice C), a thrombopoietin-receptor agonist, has previously been shown to improve response rates when added to hATG and CSA in treatment-naïve patients.2 However, more recent results presented at the 2019 ASH Annual Meeting did not show a similar benefit when eltrombopag was added to immunosuppressive therapy in pediatric patients.3 A watch-and-wait approach (choice A) is typically not appropriate for patients with SAA given the ongoing risk for infection.

Although immunosuppressive therapy with hATG and CSA has led to good response rates in the pediatric population,4 there remains an ongoing risk of relapse and later clonal evolution. Matched unrelated donor (MUD) HSCT (choice B) was historically reserved for patients with SAA who had failure to respond to immunosuppressive therapy; however, as outcomes in MUD HSCTs have improved, clinical trials are currently underway to investigate whether MUD HSCTs may be offered as a first-line therapy for patients with SAA without HLA-matched sibling donors.

References:

  1. Davies JK, Guinan EC. An update on the management of severe idiopathic aplastic anaemia in children. Br J Haematol. 2007;136:549-564.
  2. Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag added to standard immunosuppression for aplastic anemia. N Engl J Med. 2017;376:1540-1550.
  3. Groarke EM, Patel BA, Diamond C, et al. Outcomes in pediatric patients with severe aplastic anemia treated with standard immunosuppression and eltrombopag. Blood. 2019;134(Suppl 1):454.
  4. Scheinberg P, Wu CO, Nunez O, et al. Long-term outcome of pediatric patients with severe aplastic anemia treated with antithymocyte globulin and cyclosporine. J Pediatr. 2008;153:814-819.

Case study submitted by Anu Gollapudi, MD, of Seattle Children’s Hospital, Seattle, WA.