High-Dose Cyclophosphamide in the Treatment of Children with Acquired Severe Aplastic Anemia Refractory to Conventional Immunosuppression.
Authors: Hord Jeffrey D. , Whitlock James A. , Carcamo Benjamin , Pais Ray C. , Blatt Julie , Dinndorf Patricia A. , Wang Winfred C. 
Published: October 2019

Severe aplastic anemia (SAA), an illness characterized by the depletion of hematopoietic precursors within bone marrow leading to pancytopenia, has an overall mortality rate of >75% if left untreated. For children with human leukocyte antigen (HLA)-identical sibling donors, the treatment of choice for acquired SAA is allogeneic bone marrow transplant (BMT) with long-term survival of 70%–85%. For the 80% of children who lack suitable bone marrow donors, the standard treatment is immunosuppression with anti-thymocyte globulin (ATG), cyclosporine A (CSA), and often hematopoietic growth factors. Large series utilizing this immunosuppressive therapy have demonstrated a complete response rate of 60%–80%.

When a patient does not have an HLA-identical sibling and fails to respond to conventional immunosuppression, options for further treatment are limited. One option is to pursue a matched unrelated donor (MUD) BMT, but matched donors are not available for all patients and long-term survival ranges between 20%– 60%. Treatment with high-dose cyclophosphamide is another option for refractory SAA patients that appears promising but has not been extensively studied in children.

In 1999, a group of pediatric hematology centers joined together to study the use of high-dose cyclophosphamide for the treatment of children with acquired SAA not eligible for BMT and refractory to immunosuppression (Pediatric Aplastic Anemia Cooperative Trial #2). The goals of this study were to determine the response rate and toxicity associated with high-dose cyclophosphamide in children with refractory SAA. Between 10/1/99 and 6/3/02, 6 patients from 6 different centers were enrolled and received 4 days of intravenous cyclophosphamide (45 mg/kg/day), MESNA, and GM-CSF (250 mcg/m2/day SC) post-cyclophosphamide. The patient population consisted of 4 males and 2 females ranging in age from 2 to 18 years. The interval between diagnosis of SAA and cyclophosphamide treatment ranged from 8 to 88 months. All had failed to respond to earlier treatment with ATG and CSA.

Twelve months following cyclophosphamide, there was 1 complete response (transfusion independent and normal blood counts), 1 partial response (transfusion independent but with moderate pancytopenia), 2 infectious deaths without recovery of blood counts, and 1 failure to respond. One patient was removed from the study before response could be assessed. High-dose cyclophosphamide in this population was associated with significant toxicity as 2 patients developed disseminated fungal infections within 30 days of starting therapy leading to death at day 18 in one. Another patient experienced grade 3 gingivitis/stomatitis lasting about 30 days.

In summary, high-dose cyclophosphamide can lead to marrow recovery in some children with refractory SAA but is associated with the potential for life-threatening infectious complications, especially with fungus.