Decreased Incidence of Clonal Evolution to Myelodysplastic Syndrome/Acute Myeloid Leukemia with Monosomy 7 in Children with Aplastic Anemia Following Reduced Use of G-CSF.
Authors: Takahashi Yoshiyuki , Ohara Akira , Kobayashi Ryoji , Yabe Hiromasa , Tsuchida Masahiro , Mugishima Hideo , Morimoto Akira , Ohga Shoichi , Bessho Fumio , Tsukimoto Ichiro , Nakahata Tatsutoshi , Kojima Seiji 
Published: April 2020

Abstract
A serious complication of aplastic anemia (AA) is evolution to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In a previous nationwide study conducted between 1988 and 1992 in Japan, 11 of 67 patients treated with immunosuppressive therapy (IST) and G-CSF developed MDS/AML with monosomy 7, giving a cumulative incidence of 47±17% over 6 years. In the study, all but one of the patients who developed MDS/AML had received G-CSF for more than 12 months. Recently, a European survey confirmed our finding that a significantly higher hazard of MDS/AML is associated with the use of G-CSF in patients with AA after IST. Another recent study also showed that a high concentration of G-CSF favors expansion of preexisting monosomy 7 clones in vitro. Since 1993, we prospectively examined the relationship between the development of MDS/AML with monosomy 7 and the use of G-CSF in newly diagnosed AA patients. Here, we report a marked decrease in the incidence of secondary MDS/AML with monosomy 7 in our prospective study for AA. From 1993 to 2006, 387 newly diagnosed AA children who received antithymocyte globulin (ATG) and cyclosporine with or without G-CSF entered the two consecutive prospective studies. Cytogenetic data were available in 377 patients. Eleven of these 377 patients were then excluded from the study because of cytogenetic abnormalities at diagnosis, consisting of 5 somatic chromosomal defects and 6 clonal abnormalities including one monosomy 7 and three trisomy 8. The median age of the 366 evaluable patients was 9 years, ranging from 1 to 18 years. The median follow up period of the surviving patients was 60 months (range: 1 to 167 months). The cumulative durations of G-CSF therapy were as follows: 0 days (n=111), 1–30 days (n=66), 31–60 days (n=70), 61–90 days (n=43), 91–180 days (n=52), 181–365 days (n=17), over 366 days (n=4), and unknown (n=3). Twenty-one of the 369 analyzed patients developed clonal cytogenetic abnormalities between 6 and 62 months (median: 18 months) after the time of diagnosis, giving a cumulative incidence of 7.1 ± 1.5% at 6 years. Cytogenetic analysis revealed monosomy 7 (10 patients), trisomy 8 (6 patients), others (5 patients) at the time of clonal evolution. The cumulative incidence of MDS/AML with monosomy 7 was 3.0 ± 1.0% in patients who received IST and G-CSF. Chromosomal abnormalities strongly predicted the outcome. Five of the 10 patients with monosomy 7 died without SCT. The remaining 5 patients who received SCT are currently alive. All of the 11 patients with other chromosomal abnormalities are also alive either with SCT (n=3) and without SCT (n=8). Three of the 10 patients with monosomy 7 received G-CSF for longer than 12 months and all of them died but none of the 11 patients with other chromosomal abnormalities received G-CSF over 12 months. Notably, although only 4 of the 366 patients received G-CSF over 12 months, three of them developed MDS/AML with monosomy 7. We observed a drastic decrease in the cumulative incidence of MDS/AML with monosomy7 in AA patients treated with IST and G-CSF. The current study confirms the finding of our previous report, which suggested a close relationship between long-term use of G-CSF and secondary MDS/AML with monosomy 7 in AA patients.