Patients with t (8;21) (q22; q22) or RUNX1-RUNX1T1 rearrangement were classified as low-risk and accounted for 10% of pediatric AML[1]. However, relapse is currently the main factor affecting the survival of pediatric patients with t (8;21) AML, which is a problem that urgently needs addressing. The aim of this study was to investigate the effect of allo-HSCT on reducing the recurrence of high-risk pediatric t (8;21) AML based on MRD-guided treatment and to further explore the prognostic factors affecting pediatric t (8;21) AML to guide risk factor stratification treatment.
In this study, RUNX1/RUNX1T1 transcripts were used after two cycles of consolidation chemotherapy as a dividing line between the low- and high-risk group; ≥0.05 identified a member of the high-risk group. For the patients who received chemotherapy as post-remission therapy, the high-risk patients had a high CIR (38.1%) compared to low-risk patients who had a low CIR (12.6%, P = 0.001). Therefore, we believe that RUNX1/RUNX1T1 transcripts after two cycles of consolidation chemotherapy are particularly important MRD monitoring points, which may reflect the sensitivity of leukemia cells to cytarabine. This is consistent with the findings of previous studies[9, 10]
We next assessed how to reduce the likelihood of relapse for the high-risk group with chemotherapy resistance. The antileukemic effect of HSCT has been established in multiple studies[11, 12]. We evaluated the prognostic impact of allo-HSCT for high-risk patients, and found that the transplant group had significantly better 5-year EFS% than the chemotherapy group. Therefore, allo-HSCT could significantly reduce the relapse rates of high-risk t (8;21) patients. In this study, the average recurrence time of the high-risk-chemo group was 16.6 ± 7.34 months, and 50% of low-risk patients relapsed after 3 years of treatment. We believe that the recurrence of rate of the high-risk group is related to the fact that chemotherapy resistance and MRD uncleared completely. This is also the main reason for HSCT, which thoroughly cleared the residual leukemia and effectively reduced the recurrence rate of high-risk children compared to chemotherapy. For the low-risk group, relapse is more closely related to mechanisms such as clonal evolution[13], and among patients with t(8;21), some trials have confirmed that those who had different cytogenetics at relapse had significantly improved survival after transplantation[14]. In this study, two patients of the low-risk group relapsed after 3 years of treatment and t (8; 21) disappeared after relapse. They received allo-HSCT as their salvage treatment after relapse and are currently experiencing event-free long-term survival.
Due to the high rates of HSCT-related mortality and morbidity, HSCT is recommended for pediatric patients with high-risk AML. Therefore, this study is the first to explore the effect of HSCT for pediatric t (8; 21) patients. Based on MRD-guided risk stratification treatment, we demonstrated that allo-HSCT could significantly improve EFS. For OS, although allo-HSCT improved the survival rate of the high-risk group, this difference was not statistically significant because two patients of the chemo group were successfully treated with salvage-HSCT after relapse and one transplant-related death in the transplant group. This is consistent with the results of a previous study[15]. Whether the positive effect of HSCT on CR1 high-risk t (8;21) can be replaced by salvage-transplant after relapse was considered. This has not yet been determined due to a lack of large randomized controlled trials. However, this is the focus and goal of our future studies. Moreover, many clinical trials have confirmed that although some patients who have relapsed can survive through salvage therapy, the OS% is unsatisfactory and significantly lower than that of CR1 patients[16, 17]. Meanwhile, MRD levels before transplantation can predict the recurrence rate after transplantation[18, 19]. Therefore, HSCT is still necessary for some high-risk patients in CR1 to improve prognosis. As a result, although transplant-related mortality is high, finding a balance between the risk of relapse and reducing transplant-related mortality to improve OS t (8;21) relies on precise risk stratification to guide treatment.
The prognostic significance of the KIT mutation in pediatric t (8;21) AML is controversial. Some researchers believe that the KIT mutation has no significance for the prognosis of AML[20, 21]. Others have reported poor outcomes for KIT-positive t(8;21)-patients, and KIT mutations as indicators for transplantation[22, 23]. In this study, the prognosis of the C-KIT + high-risk-HSCT group was better than that of the C-KIT + high-risk-chemo group, but the difference was not statistically significant. This could be attributed to the limited sample size with KIT mutations in this study, and because some pediatric patients were receiving TKI drugs during chemotherapy intermission, which may have affected the results. Therefore, a large sample size for clinical trials is required to determine the significance.
Among the high-risk-chemotherapy group, six patients had EI at diagnosis. Five of these patients relapsed, one with an extramedullary relapse first and a bone marrow relapse 2 months later. In the high-risk-HSCT group, five patients with EI at diagnosis experienced no recurrence after allo-HSCT. In addition, a multivariate prognostic analysis of relapse-related factors in the high-risk group was performed that showed that for the patients with EI if MRD was not cleared well, the recurrence rate increased significantly. Meanwhile, allo-HSCT improved the prognosis of the patients. Studies regarding the significance of EMI on pediatric AML are few and conflicting, even for t (8;21) AML which is the most closely related to EMI. The Catholic University of Korea analyzed the characteristics and outcomes of 40 patients who were diagnosed with and treated for RUNX1-RUNX1T1 (+) AML. They demonstrated that the presence of myeloid sarcoma type EMI at diagnosis may predict the risk of relapse in pediatric RUNX1-RUNX1T1 (+) AML[24], which is consistent with our results. However, studies regarding allo-HSCT improving the prognosis of pediatric t (8; 21) with EI are not available.
However, there are some limitations to this study. First, this was a nonrandomization controlled trial which was a source of bias. However, recruiting large-scale numbers of patients for randomized trials to explore indicators for transplantation in high-risk pediatric patients is difficult and unrealistic for pediatric t (8;21) AML with 10% incidence, and there are no such studies currently in progress. Second, some patients were receiving with TKI drugs during chemotherapy intermission which may affect the results of this study to some extent.