Immunosuppressive therapy for pediatric aplastic anemia: a North American Pediatric Aplastic Anemia Consortium study

Abstract

Quality of response to immunosuppressive therapy and long-term outcomes for pediatric severe aplastic anemia remain incompletely characterized. Contemporary evidence to inform treatment of relapsed or refractory severe aplastic anemia for pediatric patients is also limited. The clinical features and outcomes for 314 children treated from 2002 to 2014 with immunosuppressive therapy for acquired severe aplastic anemia were analyzed retrospectively from 25 institutions in the North American Pediatric Aplastic Anemia Consortium. The majority of subjects (n=264) received horse anti-thymocyte globulin (hATG) plus cyclosporine (CyA) with a median 61 months follow up. Following hATG/CyA, 71.2% (95%CI: 65.3,76.6) achieved an objective response. In contrast to adult studies, the quality of response achieved in pediatric patients was high, with 59.8% (95%CI: 53.7,65.8) complete response and 68.2% (95%CI: 62.2,73.8) achieving at least a very good partial response with a platelet count ≥50×10⁹L. At five years post-hATG/CyA, overall survival was 93% (95%CI: 89,96), but event-free survival without subsequent treatment was only 64% (95%CI: 57,69) without a plateau. Twelve of 171 evaluable patients (7%) acquired clonal abnormalities after diagnosis after a median 25.2 months (range: 4.3-71 months) post treatment. Myelodysplastic syndrome or leukemia developed in 6 of 314 (1.9%). For relapsed/refractory disease, treatment with a hematopoietic stem cell transplant had a superior event-free survival compared to second immunosuppressive therapy treatment in a multivariate analysis (HR=0.19, 95%CI: 0.08,0.47; P=0.0003). This study highlights the need for improved therapies to achieve sustained high-quality remission for children with severe aplastic anemia.

Figure 1.

Correlation between absolute reticulocyte count and hemoglobin at diagnosis. Absolute reticulocyte counts <100×10⁹/L (n=231) were plotted against the hemoglobin at diagnosis. CI: Confidence Interval.

Figure 2.

Duration of response. Kaplan-Meier analysis of duration of response for (A) all subjects or (B) subjects treated with horse anti-thymocyte globulin (rATG)/cyclosporine (CyA) who achieved at least a partial response.

Figure 3.

Immunosuppressive therapy: survival. Kaplan-Meier analysis of overall survival for (A) all subjects or (B) subjects treated with horse anti-thymocyte globulin (rATG) / cyclosporine (CyA). Kaplan-Meier analysis of event-free survival for (C) all subjects or (D) subjects treated with hATG/CyA.

Figure 4.

Outcomes after second-line therapy for relapsed/refractory disease. Kaplan-Meier analysis of (A) overall survival and (B) event-free survival for all subjects or subjects treated with horse anti-thymocyte globulin (rATG)/cyclosporine (CyA). (C) Log-rank test was used to compare event-free survival after second-line treatment with hematopoietic stem cell transplantation (HSCT) versus immunosuppressive therapy (IST) for all subjects or subjects treated with hATG/CyA.