Patient characteristics
In this study, 129 newly diagnosed paediatric t(8;21) AML patients were enrolled. Four patients were excluded due to their death before two cycles of consolidation chemotherapy (n = 2) and withdrawal (n = 2). The remaining 125 patients were divided into low-risk (n = 70) and high-risk (n = 55) groups, according to the RUNX1-RUNX1T1 transcript levels after two cycles of consolidation chemotherapy. High-risk patients with RUNX1-RUNX1T1 transcript levels > 0.05 after the completion of two cycles of consolidation chemotherapy were automatically divided into the HSCT group (n = 27) and chemotherapy group (n = 28) according to the parents’ wish, availability of donors, and economic conditions. In the high-risk HSCT group, 25 patients received haploidentical haematopoietic stem cell transplantation (haplo-HSCT) and two patients received HLA-matched sibling donor HSCT. General information, cytogenetic characteristics, and treatment responses for each group are summarised in Table 1. There were no significant differences between the high-risk chemotherapy group and high-risk HSCT group, except for age due to the choice bias caused by parents of younger patients who believed that the risk of transplantation is too high to pursue.
Patient outcomes
The median follow-up time was 46 months (10–96 months) in surviving patients. Of the 125 patients analysed, 12 died (10 of relapse and 2 of treatment-related mortality) and 113 survived, of which 17 patients relapsed. For overall patients, the cumulative incidence of relapse (CIR) was 17.8%. The RFS and OS rates were 82.2% and 86%, respectively. Patients in high-risk HSCT group achieved neutrophil engraftment at a median time of 13 days (range, 10–38 days), platelet engraftment at a median time of 16 days (range, 7–47 days). At day +100, the cumulative rates of grades II-IV aGVHD were 31.8% (95% CI, 20.1%–48.9%) and the cumulative rates of grades III-IV aGVHD were 14.6% (95% CI, 5.2%–21.4%). The 3-year cumulative rates of moderate to severe cGVHD were 19.9% (95% CI, 8.3%– 25.8%), the 3-year cumulative rates of severe cGVHD were 19.8% (95% CI, 6.7%–22.2%). One patient died of non-relapse mortality in high-risk HSCT group.
RUNX1-RUNX1T1 transcript levels > 0.05% after second consolidation chemotherapy can effectively predict relapse
ROC analysis showed that a cut-off level of 0.05% in RUNX1/RUNX1T1 transcripts level after two courses of consolidation chemotherapy significantly predicted an event (P = 0.030; the area under curve, 0.660; sensitivity, 88.9%; specificity, 56.1%). A level significantly predicting an event could not be determined by ROC analysis after inducement chemotherapy and one course of consolidation chemotherapy. The survival of patients who received chemotherapy-based consolidation between the high-risk and low-risk groups was retrospectively analysed. Patients with RUNX1-RUNX1T1 transcripts ≤ 0.05% after the second consolidation had a significantly better 5-year RFS rate than those with > 0.05% (86.5% [95% CI, 86%–99.8%]) vs. 61.9% [95% CI, 51.96%–80.41%]; P< 0.001 Fig. 2a).
RFS
- Allogeneic haematopoietic stem cell transplantation can improve RFS in the high-risk group
As shown in Figure 2b, 5-year RFS rate was significantly better in the high-risk HSCT group than in the high-risk chemotherapy group (87.4% [95% CI, 86.0%–108.7%]) vs. 61.9% [95% CI, 51.9%–80.4%]; P=0.026, Fig. 2b). Patients in the high-risk and low-risk HSCT groups had comparable 5-year RFS rates (87.4% [95% CI, 86.0%–108.7%]) vs. 87.4% [95% CI, 86.9%–99.8%]; P=0.643).
In this study, 25 (92.5%) of patients in the high-risk HSCT group received haplo-HSCT and these patients had significantly better 5-year RFS rates compared to those who received chemotherapy-based consolidation (86.3% [95% CI, 84.0%–108.7%]) vs. 61.9% [95% CI, 51.9%–80.4%]; P= 0.039, Fig. 2c).
- Outcomes of high-risk patients with c-KIT mutations
Among patients in high-risk group, 21 had c-KIT mutations detected at diagnosis. Twelve of these patients were included in the chemotherapy group and the remaining nine were in the HSCT group. For high-risk patients with c-KIT mutations, HSCT had a potential to improve 5-year RFS rate (82.9% [95% CI, 59.3%–84.8%]) vs. 75% [95% CI, 49.3%–85.6%]; P = 0.400).
- Outcomes of high-risk patients with EI
Among the high-risk chemotherapy group, seven patients had EI at diagnosis, including three orbital, one intracranial, one mandibular mass, one spine, and one with orbital and lumbar spine infiltration; six of these patients relapsed. One extramedullary case relapsed first and the bone marrow case relapsed 2 months later. In the high-risk HSCT group, five patients had EI at diagnosis, including two orbital, one scalp mass, one lumbar spine, and one with multiple vertebrae infiltration, and all of these patients were at remission after HSCT. RFS was significantly better in high-risk HSCT patients with EI (n = 7) than in high-risk chemotherapy patients with EI (n = 5, P = 0.006).
Relapse
This study analysed 125 patients; 17 of them relapsed, with 5 relapses in the low-risk group and 12 relapses in the high-risk group. Notably, of the nine patients that relapsed in high-risk chemotherapy group, six had EI at onset. Multivariate analysis of relapse-related factors in high-risk group showed that EI at onset (HR 4.750, 95% CI: 1.537-14.678; P =0.007) and non-HSCT (HR 0.238, 95% CI: 0.064-0.883; P =0.032) were the independent risk factors for poor RFS (Table 2).
The average recurrence time in the high-risk group was 16.6 ± 7.34 months, and in the low-risk group was 28.86 ± 18.8 months. The recurrence time in the low-risk group was significantly later than in the high-risk group (P = 0.011). Notably, 50% of relapses occurred after 3 years of treatment in the low-risk group, while all the relapses occurred within 3 years of treatment in the high-risk group.
OS
The 5-year OS rate of overall patients was 86%. For the high-risk group, eleven patients died, four patients were in high-risk HSCT group, three patients died of relapse and one patient died of bronchiolitis obliterans syndrome. For the high-risk chemotherapy group, a total of seven patients died of relapse. The 5-year OS rate in high-risk HSCT group showed a better trend than that in the high-risk chemotherapy group (82.8% [95% CI, 78.6%–101.7%]) vs. 71.4% [95% CI, 62.09%–87.6%]; P = 0.26, Fig. 2d). For the low-risk group, four patients died of relapse and the 5-year OS rate was 93.3%.