10-Year-Outcome of Acquired Aplastic Anemia Children Treated with Antithymocyte Globulin, Cyclosporine with or without G-CSF.
Authors: Ohara Akira , Kojima Seiji , Kobayashi Ryoji , Kosaka Yoshiyuki , Ohga Shoichi , Sugita Kanji , Yabe Hiromasa , Tsuchida Masahiro , Bessho Fumio , Mugishima Hideo , Tsukimoto Ichiro , Nakahata Tatsutoshi 
Published: April 2020

Abstract
BACGROUND: Acquired aplastic anemia (AA) is thought to be an immune-mediated disease. Immunosuppressive therapy (IST) has been the treatment of choice for patients who did not have suitable donors. Previously, we had published promising results of IST for children with acquired AA. In the study, overall survival rate (OS) at 4 years was 83% in patients with vSAA and 92% in those with SAA/nonSAA.
OBJECTIVES: Here we report follow-up results focusing on pediatric patients with relapse and clonal diseases, MDS/AML and PNH.
PATIENTS and TREATMENT: From 1992 to 1997, 119 newly diagnosed children with acquired AA (median age; 9) entered AA-92 study. 50 vSAA patients were treated with ATG+CyA+mPSL+danazole +G-CSF, 36 SAA and 28 nonSAA patients were treated with ATG+CyA+mPSL+danazole +/−G-CSF. Complete remission (CR) was defined as a neutrophil count &gt;1.5x10^9/L, a platelet count &gt;100xx10^9/L, and a hemoblobin level of &gt;11 g/dl. Partial response (PR) was defined as a neutrophil count &gt;0.5x10^9/L, a platelet count &gt;20x10^9/L, and a hemoglobin level of &gt;8.0 g/dl. Relapse was indicated by the return of the PB counts to levels meeting the definition of SAA and/or the requirement for blood transfusion. Response rate was 71% at 6 months in vSAA patients, 65% in SAA/nonSAA patients, respectively. There was no statistical difference in 6-month response rate between G-CSF +/− treatments. No patient responded after 6 months. Therefore, 75 responders and 29 non-responders at 6 months were analyzed their OS, relapse rate (RR), and treatment-failure-free survival (TFFS). The median observation time of surviving patients is 118 months, ranging from 75 to 168 months.
RESULTS: Among 119 patients, 38 patients received BMT and 17 patients died during an observation period. The OS was 81.9+−3.8% at 10 years, but has not reached plateau. Of the 75 6mo-responders, 23 patients relapsed and the RR was 33.6+−6.0% at 10 years. TFFS of the 75 was 67.4+−5.5%. Fourteen patients received 2nd ATG therapy and 5 of them responded. Eleven of the 23 patients with relapse received alternative donor BMT and 8 are alive. 10y-OS of these relapsed patients was 73.4+−9.4%. Nineteen of the 29 6mo-non-responders received alternative donor BMT and 15 are alive. There is no statistically significant difference in 10y-OS between the responders and the non-responders (89.1+−3.7% vs. 75.0+−8.2%, p=0.09). New clonal abnormalities appeared in 9 of 119 patients (10.0+−3.2%KM probability): monosomy 7(3 patients), trisomy 8(3 patients), trisomy 9, trisomy11, del (13)(1 patient each). There is no statistically difference in 10y-OS, RR, and incidence of clonal abnormality between randomized G-CSF+/− treatments. Clinical PNH with symptomatic hemolysis developed in 3 of the responder patients, 96, 105 and 138 months after the AA diagnosis, respectively. Among 65 surviving responders, 33(51%) have CR and 26(40%) PR at last follow-up time.
CONCLUSIONS: Our data demonstrate that IST is effective for children with acquired AA, but relapse are common. Effective 2nd line treatment should be developed. PNH developed even in pediatric AA patients during long-term observation.