Translocation t(6;9) is a rare recurring cytogenetic aberration resulting in the formation of a chimeric fusion gene, DEK-NUP214 (previously known as DEK-CAN) that occurs in <2% of adult or pediatric AML. This translocation has been reported in AML and less frequently in myelodysplastic syndrome and Ph-negative chronic myeloid leukemia. Those with this translocation have been reported to have poor response to induction chemotherapy and high rate of post remission relapse. AML with t(6;9) is associated with multilineage dysplasia, marrow basophilia, and more recently associated with high prevalence of FLT3/ITD, where FLT3/ITD is reported in significant majority of those with t(6;9). Recent clinical trials have allocated high-risk patients including with those FLT3/ITD to the high-risk arm of the treatment protocols. However, given such a high overlap between t(6;9) and FLT3/ITD, an established prognostic factor, contribution of this translocation in absence of FLT3/ITD has come into question, thus patients with t(6;9) without FLT3/ITD have remained as standard risk in current pediatric clinical protocols. This study defines the contribution of FLT3/ITD to clinical outcome in patients with t(6;9) by comparing the outcome in this patient population with and without FLT3/ITD.
Of the 3791 children, adolescents and young adults treated on six consecutive pediatric AML trials, 48 cases (1.3%) of AML with the t(6;9)(p23;q34) were identified [CCG 2861/2891 (n=7), POG 9421 (n=6), CCG-2961 (n=10), AAML03P1 (n=8), and AAML0531 (n=17)]. Of these 48 patients with t(6;9), diagnostic specimens were available on 38 (79%) patients for FLT3 mutation analysis. FLT3/ITD was identified in 24 out of 38 evaluable patients (63.2%), and mutations of the activation loop domain of FLT3 (FLT3/ALM) were identified in 2 patients (5%). Patient demographics and disease characteristics were compared in the study cohort with and without FLT3/ITD. There was a significant ethnic variation where 79% of those with FLT3/ITD were Caucasian compared to 31% of FLT3/ITD-negative patients (p=0.006). Patients with FLT3/ITD had a significantly higher median diagnostic WBC (51.6 × 103/μL vs. 19.9 × 103/μL; p=0.016) as well as a higher median marrow blasts percentage (70% vs. 47%; p=0.004). With regards to FAB subtype distribution, all patients with t(6;9) had M1, M2 or M4 FAB, with no difference in distribution based on FLT3/ITD status. Overall complete remission (CR) after induction chemotherapy was achieved in 26 of the 36 evaluable patients (72%). t(6;9) patients with FLT3/ITD had a CR rate at the end of course 1 of 46% vs. 79% in those without FLT3/ITD (p=0.049). Clinical outcome for the t(6;9) patients was determined based on the presence or absence of FLT3/ITD. Actuarial overall survival (OS) at 5 years from study entry for the entire study cohort was 32% ± 17%. Patients with and without FLT3/ITD had an OS of 39% vs. 20% respectively (p=0.916). For patients who achieved a remission after induction chemotherapy, relapse risk (RR) for those with and without FLT3/ITD was 55% vs. 100% (p=0.150) with a corresponding OS from remission of 41% vs. 26% (p=0.96). This study confirms that patients with t(6;9) are at high-risk of relapse and poor outcome regardless of the presence or absence of FLT3-ITD, and should be considered for allocation to the high risk arm of protocol therapies.
No relevant conflicts of interest to declare.
This icon denotes a clinically relevant abstract
Asterisk with author names denotes non-ASH members.