Relapse of Children with Aplastic Anemia after Immunosuppressive Therapy

Although the therapeutic outcome for acquired aplastic anemia (AA) has improved markedly with the introduction of immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine A (CyA), a significant portion of patients treated with IST subsequently relapse and require second-line therapy. However, detailed analysis of the relapse cases has not been reported. In this study, we assessed the relapse rate, response to second-line treatment after relapse and prognosis. From November 1992 to July 2007, 473 newly diagnosed AA children (213 female, 260 male) entered two consecutive prospective studies (AA-92 and AA-97). The median age was 8 years, ranging from 1 to 18 years. Patients with very severe (n = 210), severe (n = 149) and non-severe disease (n = 114) received initial IST consisting of ATG and/or CyA. At six months after the initial IST, 280 patients (59.2%) achieved CR (n = 94) or PR (n=186). Relapse is defined by conversion to no response (NR) from partial or complete response (PR/CR). Among the 280 patients who responded to IST, 49 (17.5%) relapsed. The cumulative incidence of relapse was 19.6% at 10 years and the median time to relapse was 18 months, ranging 7 to 138 months. Among the 49 patients who relapsed, 22 received a second round of IST with ATG and CyA. Fourteen patients (63.6%) responded to the second round. However, three relapsed, and two developed paroxysmal nocturnal hemoglobinuria. Eight patients received CyA after relapse. Four patients responded to CyA, but two relapsed subsequently. Hematopoietic stem cell transplantation (HSCT) was attempted in 26 patients who relapsed after initial responses. Before HSCT, nine received a second course of IST with ATG and CyA and two received CyA. Fifteen patients progressed directly to HSCT. Bone marrow transplantation (BMT) from an HLA-matched sibling (n =7), HLA-matched family member (n = 1), or HLA-mismatched family member (n = 2) was performed in 10 patients, and all are presently alive. BMT from an unrelated donor was attempted in 13 patients, and four died of complications related to BMT. Cord blood transplantation from an unrelated donor was attempted in two patients and two patients are alive. Of the 26 patients who received HSCT, 21 are alive and well, 22 to 137 months (median 72 months) following transplantation. There were seven deaths out of total 49 who initially relapsed. The causes of death were HSCT-related complications (n = 5), MDS/acute myelogenous leukemia (n = 1), bacteremia (n = 1). Eight of 9 patients who received HSCT following a second round of IST are alive and well. The present study suggests that a second round of IST should be offered to the patients who relapse, and HSCT should be considered for the patients who fail to respond to the second round of IST.