Prolonged Hypogammaglobulinemia in a Child With Down Syndrome After Treatment of Acute Lymphoblastic Leukemia With Immunochemotherapy Including Blinatumomab

Children with Down syndrome (DS) have a 20- to 40-fold higher risk of developing B precursor acute lymphoblastic leukemia (ALL) [1] and are three times more likely to develop fatal infections during chemotherapy, despite modification of protocols and intensified supportive care [2, 3]. Immunochemotherapy offers the potential for increased efficacy and lower toxicity and, therefore, is of particular interest to this group of patients. We report prolonged hypogammaglobulinemia in a patient with DS following treatment for ALL with immunochemotherapy, including blinatumomab, suggesting a possible predisposition to this adverse event in children with DS. A 2-year and 9-month-old male child with DS, hypothyroidism, and repaired atrioventricular septal defect presented to the emergency room with progressive fatigue, irritability, left elbow pain, and abnormal gait. A blood count and smear showed pancytopenia and blasts (hemoglobin 92 g/L; white blood cell count 6.7, platelets 86, blasts 3.38/µL). A bone marrow aspirate confirmed the diagnosis of NCI-standard risk B precursor ALL (infiltration with 84% lymphoblasts expressing CD10, CD19, cTdT; cytogenetics showed a hyperdiploid karyotype without trisomy 4 and 10; cerebrospinal fluid was negative for blasts). He was enrolled in the clinical trial COG AALL1731 and received immunochemotherapy, including three infusions of blinatumomab. Due to a positive measurable residual disease (MRD) result (0.26%) at the end of the induction phase, treatment was intensified to high-risk ALL chemotherapy. A repeat MRD result at the end of the intensive consolidation phase was negative (< 0.01%) (treatment phases: induction, consolidation, blina #1, interim maintenance, blina #2, delayed intensification [Days 1–29], blina #3, maintenance) [4]. The patient's course was complicated by grade 3–4 stomatitis, two episodes of pneumatosis intestinalis (each within 2 weeks of a vincristine/glucocorticoid pulse during maintenance, both treated with bowel rest and antibiotics, and one associated with Escherichia coli bacteremia), chronic diarrhea (for 1 year; including four episodes of Norovirus, of which one was treated with nitazoxanide). Due to inability to tolerate vincristine/glucocorticoid pulses, he was taken off the clinical trial during the third course of maintenance therapy. Gastroenterological evaluation showed villous blunting in a duodenal biopsy and no evidence of celiac disease. Poor oral intake and chronic diarrhea led to severe failure to thrive. His weight (12.2 kg, 43rd percentile, at diagnosis; 10.7 kg, 2.9th, at the start of maintenance) reached a nadir (9.8 kg, 0.1th) during the third course of maintenance then stagnated during the remainder of maintenance therapy despite intensive interventions with parental nutrition and nasogastric feeds. Following the completion of immunochemotherapy, his chronic diarrhea gradually resolved, his weight increased, and 9 months later, he approached the pre-diagnosis weight percentile (18.2 kg, 36th). He remains in remission 16 months after completing ALL therapy (44 months after diagnosis). The patient's serum immunoglobulin G (IgG) level was slightly decreased at diagnosis of ALL (4.3 g/L; normal range 5.4–13.6 g/L), markedly decreased by the start of maintenance (1.1 g/L, after completion of three courses of blinatumomab; 11 months from diagnosis) and remained at this low level until 3 months following completion of therapy (20 months from completion of blinatumomab course #3; 30.5 months from diagnosis) (see Figure 1). He received a first dose of intravenous immunoglobulin supplementation (intravenous immunoglobulin [IVIG], 0.4 g/kg for a level below 4.0 g/L) at the start of consolidation therapy. Monthly supplementation was administered from the end of blinatumomab course #2/start of the delayed intensification phase (8 months from diagnosis) until 3 months after completion of maintenance therapy (30.5 months from diagnosis; total of 29 doses). At that point, his serum IgG levels remained > 4.0 g/L without IVIG infusions and his port-a-cath was removed. The number of CD19-positive B cells in his blood had been markedly decreased at the start of blinatumomab course #1 (3/µL; 4 months from diagnosis) as well as at the end of the course #3 (0/µL; 11 months from diagnosis), and increased to normal levels 3 months after completing maintenance chemotherapy (525/µL, normal range, 434–1274; 30.5 months from diagnosis). Blinatumomab, the bispecific T-cell engager linking CD19-expressing ALL blasts with CD3 on the surface of cytotoxic T cells, is a significant recent advancement of pediatric ALL therapy [4-6]. It has a particular anticipated benefit in children with DS, who even in the contemporary treatment period continue to face an increased risk of infection-related mortality during chemotherapy for ALL [3]. Secondary hypogammaglobulinemia was observed in 26% of children without DS 6 months after conventional chemotherapy for ALL [7] and is also an on-target/off-tumor effect of blinatumomab on non-malignant, CD19-positive B-cell precursors [8]. Children with DS have lower numbers of B (and T) lymphocytes [9-11], due to the absence of their physiologic expansion during the first year of life, as well as deficiencies in IgG subsets [12]. Prolonged hypogammaglobulinemia was previously also observed in patients with a genetic predisposition to more pronounced inhibition of IgG production after anti-CD20 therapy with rituximab [13, 14]. Until prospective data determine the incidence, severity, and duration of hypogammaglobulinemia induced by chemotherapy or immunochemotherapy for ALL in children with DS, practitioners are advised to inform patients/families about the potential for prolonged immunoglobulin replacement and to monitor for this complication. In our view, this potential adverse event is manageable and outweighed by the expected benefit of immunochemotherapy in patients with DS and ALL. The authors declare no conflicts of interest.

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