Refractory Anemia With Excess Blasts Type II (RAEB-2) Associated With Depakote Use in a Pediatric Patient

Abstract

Refractory anemia with excess blasts (RAEB) is a high-grade myelodysplastic syndrome (MDS). Per 2008 WHO adult criteria, presence of Auer rods in blasts qualifies a case as RAEB-2, irrespective of blast percentage. Direct bone marrow (BM) suppression, including cytopenias and dysmyelopoiesis, has been associated with valproic acid, a commonly used agent in management of bipolar disorder and refractory childhood epilepsy. However, in most cases, dyspoiesis is transient; pediatric high-grade MDS has not been previously reported. We report a 14-year-old boy with attention-deficit/hyperactivity disorder, bipolar disorder, and autism treated with Depakote, a valproic acid derivative, for 8 years. He presented with pallor, fatigue, weight loss, and bruising. CBC demonstrated pancytopenia (WBC 3.8 [4.0-10.5 k/muL], RBC 2.94 [4.2-5.6 M/muL], MCV 97 [78-95 fL], platelet 25 [150-450 k/muL]) and 4% blasts. Peripheral blood (PB) featured increased nucleated red blood cells (20 nrbcs/100 WBC) with nuclear irregularities/binucleation, dysplastic neutrophils, and myeloblasts with occasional Auer rods. BM revealed trilineage dyspoiesis, increased myeloblasts lacking Auer rods(4%), and rare ring sideroblasts. Immunophenotypic analysis using four-color flow cytometry demonstrated an abnormal 3.9% population of CD45 (dim+), CD34(-), CD117(+), CD38(+), CD33(+), CD13(+), HLA-DR(+), large cells with low side-scatter. Karyotype/FISH for abnormalities in 5q, 7q, 20q, 8+, MLL, CBFB, RARA, t(8;21), and t(9;22) were normal. A diagnosis of RAEB-2 was established (2008 WHO). Depakote was discontinued, and the patient underwent an allogeneic cord blood hematopoietic cell transplant 29 days after diagnosis. His post-transplant course was complicated by dermatologic stage 2 graft vs host disease, renal insufficiency leading to gabapentin toxicity, and seizures; currently, he is doing well. RAEB is very rare in the pediatric population. To our knowledge, this is the first reported case of Depakote-associated RAEB-2. With the increasing use of valproic acid, this case illustrates the importance of careful PB and BM examination to rule out high-grade dysplasia in pediatric patients.