Paroxysmal Nocturnal Hemoglobinuria (PNH) In Pediatric Patients: Review of a Single Center Series
Authors: Curran Kevin J. , Kernan Nancy A. , Prockop Susan E. , Scaradavou Andromachi , Small Trudy N. , Castro-Malaspina Hugo , Araten David , DiMichele Donna , O'Reilly Richard J. , Boulad Farid 
Published: October 2019

Abstract
Abstract 2231

Background:
PNH arises from a genetic mutation of hematopoietic stem cells which leads to the acquired nonmalignant clonal expansion of cells lacking glycosyl phosphatidylinositol-anchored proteins (GPI-APs). Lack of GPI-APs translates into PNH's most significant clinical features: bone marrow failure, intravascular hemolysis and thrombosis. PNH rarely occurs in children and has been reported to have a distinct clinical presentation compared to the adult population.

Results:
We provide a clinical description of 11 consecutive pediatric patients (pts) aged 11–17 years (median age 13.9 years) diagnosed with PNH since 1993 at a single institution. Bone marrow failure was the presenting clinical finding in 10 pts, including aplastic anemia (AA) (N = 9), hypoplastic myelodysplastic syndrome (MDS) (N = 1), and isolated red cell anemia (N = 1). This rate of bone marrow failure at presentation is higher than the reported rate of 24–33% seen in adult pts. Immunosuppressive therapy was the initial treatment for 8 patients with aplastic anemia and this included: antithymocyte globulin (N = 8), Cyclosporine (N = 8) and prednisone (N = 6). Partial response to immunotherapy was seen in all pts. Five pts had evidence of myelodysplastic features, including one at diagnosis. These included dysplasia with monosomy 7 for 2 pts, 5q deletion for one pt, and dysplasia with normal cytogenetics for 2 pts. The monosomy 7 abnormality was transient and resolved spontaneously for the 2 pts, while the pt with 5q deletion proceeded to transplantation. None of these pts developed excessive blasts or leukemic transformation. Thrombosis occurred in six pts with four of the pts experiencing several sites and episodes of thrombosis. Diagnosis of thrombosis occurred at presentation in one patient. Thrombosis in the remaining five pts first occurred 5–88 months from diagnosis (mean 58.8 months). This rate of thrombosis (55%) is similar to the reported rate of thrombosis in adult pts (40%) but is higher than recent reports of pediatric PNH in the literature. Treatment of thrombosis included anticoagulation and thrombolysis when appropriate. Intermittent episodes of intravascular hemolysis occurred in all 11 pts. Gross hemoglobinuria occurred in only one patient at initial presentation. This rate of gross hemoglobinuria at presentation is similar to other series of pediatric PNH, but much lower than the reported rate of 33–50% in adult pts. Of the 11 pts, 4 underwent hematopoietic stem cell transplant (HSCT) of whom 2 pts are alive and disease free. Eculizumab, a monoclonal antibody directed against the complement protein C5 was initiated in 3 pts of whom 2 pts currently have stable disease; the third non-compliant patient developed progression of thrombotic disease but has since restarted eculizumab therapy. Two pts died following complications related to thrombosis and two patients are transfusion independent with stable disease.

Conclusions:
This series represents a large single center cohort of pediatric pts diagnosed with PNH. This report highlights the high rate of bone marrow failure in pediatric pts with PNH. This differs from the adult population, and emphasizes the need for PNH testing in all children with AA or MDS, as well as children with unexplained Coombs-negative hemolysis or thrombosis. Both the high prevalence of hemolysis and high risk of thrombosis should warrant early treatment with eculizumab for pediatric pts with PNH. HSCT remains the only curative option for pediatric pts with PNH but its risk must be considered relative to the patient's disease severity, compliance and response to long-term treatment with anticoagulant and/or anticomplement therapy.

Disclosures:
No relevant conflicts of interest to declare.