Both the Subtypes of Kit Mutation and Minimal Residual Disease Are Associated with Prognosis in Core Banding Factor Acute Myeloid Leukemia

Background: No consensus has been reached on the relationship between kit mutation and prognosis in core banding factor acute myeloid leukemia(CBF-AML). Our preverious analysis of kit mutation subtypes in patients with RUNX1-RUNX1T1 suggested poor prognosis associated with D816/D820 mutation.

Objective:

To investigate further risk stratification according to different subtypes of kit mutations and minimal residual disease（MRD）in CBF-AML.

Methods:

A total of 205 patients aged 16-70 years old with CBF-AML, who were diagnosed in our hospital, were analyzed retrospectively from January 2014 to April 2019. The effects of kit mutation subtypes and MRD on the overall survival (OS) and relapse free survival(RFS) were analyzed.

Results: Of all, 118 males and 87 females were included. The median age were 38（15-70）years old. Patients with RUNX1-RUNX1T1 and patients with CBFB-MYH11 accounted for 71.1% (147/205) and 28.3% (58/205) respectively. The ratio of kit mutation was 33.2% (68/205), of which, 52/147(35.4%) patients were RUNX1-RUNX1T1 positive, and 16/58 (27.6%) patients were CBFB-MYH11 positive. Of 68 patients with kit mutation, patients with D816/D820 mutation accounted for 50.0%(34/68) and the rest 34 cases were non D816/D820 mutation. The rate of D816/D820 mutation was 50% (26/52) and 50% (8/16) respectively in Patients with RUNX1-RUNX1T1 and patients with CBFB-MYH11. During the median follow-up time 28（7-72) months，10 patients were lost and a total of 195 patients were available. 42.6%（83/195）patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT). 112 patients who did not received allo-HSCT were divided into three group: 85 patients without kit mutation(group A) , 15 patients with D816/D820 nutation(group B), 12 patients with non-D816/D820 nutation(group C). The 3-year overall survival(OS) and 3-year relapse free survival(RFS) between group A and B did not have significance(P=0.603, 0.601). Both the 3-year OS and 3-year RFS of group B were superior to group C(65.5% VS 8.3%; 73.3% VS 14.4%, P=0.002, 0.003), and the 3-year OS and 3-year RFS of group A were superior to group C(68.1% VS 8.3%; 75.2% VS 14.4%, P=0.000; 0.000). So group A and B were defined as low risk group (97 patients), group C defined as high risk group(15 patients). The 3-year OS and 3-year RFS of high risk group were significantly lower than those of low risk group(14.4% VS 75.4%、8.3% VS 68.4%, P=0.000、0.000). After 2 cycles of consolidation, MRD (the transcript of RUNX1-RUNX1T1 or CBFB-MYH11) ＞0.1% could predicted disease recurrence(P=0.000). Patients who got MRD＜0.1%(49 patients) after two cycles of consolidation chemotherapy could have higher 3-year OS and 3-year RFS than those who did not (63 patients) (94.1%VS 49.9%; 96.3% VS 36.4%, P=0.000; 0.000). During the follow-up time, patients who achieved MRD＜0.1%(81patients) also had higher 3-year OS and 3-year RFS than those did not(31 patients)(81.8% VS 6.7%; 75.7% VS 12.9%, P=0.000，0.000). Multivariate analysis showed D816/D820mutation, MRD＞0.1% after two cycles of consolidation chemotherapy, MRD＞0.1% during the follow-up time were poor prognosis on OS and RFS, and kit mutation had not effect on OS and RFS. A total of 91 patients out of 195 patients had D816/D820 mutation (30 patients) or MRD＞0.1% after two cycles of consolidation chemotherapy and MRD＞0.1% (61 patients) during the follow-up time, the 3-year OS and 3-year RFS significantly increased in the group of 57 patients who received allo-HSCT than the group of 34 patients who did not(91.0% VS 22.1%; 91.2% VS 15.9%，P=0.000, 0.000).

Conclusion: The real high risk patients must be recognized during the treatment of CBF-AML: D816/D820mutation, MRD＞0.1% after two cycles of consolidation chemotherapy and MRD＞0.1% during the follow-up time. Allo-HSCT can improve the survival of patients who were distinguished under the accurate stratification.