Characteristics and outcome of patients with core-binding factor acute myeloid leukemia and FLT3-ITD: results from an international collaborative study

Abstract

To evaluate the prognostic impact of FLT3-ITD in core-binding factor acute myeloid leukemia in an international, multicenter survey on 97 patients (52%, t(8;21)(q22;q22); 48% inv(16)(p13q22)/t(16;16)(p13;q22)). Median age was 53 (range, 19-81) years. Complete remission (CR) after anthracycline-based induction (n=86) and non-intensive therapy (n=11) was achieved in 97% and 36% of the patients. Median follow-up was 4.43 years (95%-CI, 3.35-7.39 years). Median survival after intensive and non-intensive treatment was not reached and 0.96 years, respectively. In intensively treated patients, inv(16) with trisomy 22 (n=11) was associated with a favorable 4-year relapse-free survival rate of 80% (95%-CI, 59-100%) as compared to 38% (95%-CI, 27-54%; P=0.02) in all other CBF-AML/FLT3- ITD positive patients (n=75). Overall, 24 patients underwent allogeneic hematopoietic cell transplantation (allo-HCT), 12 in first CR and 12 after relapse. Allo-HCT in first CR was not beneficial (P=0.60); however, allo-HCT seems to improve median survival in relapsed patients compared to chemotherapy (not reached versus 0.6 years; P=0.002). Excluding inv(16) with trisomy 22, our data indicate that the outcome of CBF-AML patients with FLT3-ITD seems to be inferior compared to published data on those without FLT3-ITD, suggesting that prognostically these patients should not be classified as favorable-risk. FLT3-inhibitors may improve outcome in those patients.

Prognostic significance of FLT3-ITD length in AML patients treated with intensive regimens

“…There were two patients with core binding factor (CBF) translocations (one RUNX-RUNX1T1 and one CBFB-MYH11) and FLT3-ITD mutations. CBF translocations have been associated with FLT3-ITD mutations in very few patients, and there is no clear information regarding their ELN prognostication [18][19][20] . Therefore, these patients were not included in the analysis stratified by 2010 ELN genetic risk 21 .…”

Combination of KIT and FLT3‐ITD mutation status with minimal residual disease levels guides treatment strategy for adult patients with inv(16) acute myeloid leukemia in first complete remission

“…Moreover, in a large prospective study, FLT3 ‐ITD did not affect relapse free survival (RFS) and OS of 176 patients with inv (16) AML 24 . However, a recent CBF‐AML study that only included patients with FLT3 ‐ITD + revealed that their outcomes appear inferior to published data on those without FLT3 ‐ITD 25,26 . Furthermore, in a murine transplantation model, the interaction of FLT3 ‐ITD with CBFB–MYH11 could promote progression to AML 27 .…”

“…FLT3-ITD. 25,26 Furthermore, in a murine transplantation model, the interaction of FLT3-ITD with CBFB-MYH11 could promote progression to AML. 27 In the present study, we found that FLT3-ITD + was an independent poor prognostic factor for CIR, suggesting that it should be considered when classifying inv ( 16) AML.…”

<i>FLT3-ITD</i> signals bad news for core binding factor acute myeloid leukemia unless trisomy 22 comes to the rescue

“…In summary, as the genomic age continues to reveal further prognostic heterogeneity within conventional AML subgroups, we will increasingly be challenged with when to pull the trigger on the use of allogeneic HCT and when to use a growing number of newly approved AML drugs, such as FLT3 inhibitors and so forth, for uncommon clinical scenarios for which definitive randomized evidence may never become available. The current work by Kayser et al 9 adds to the growing list of AML scenarios in which the presence of FLT3 -ITD represents bad news, including among patients with CBF AML. Physicians are likely to formulate a logic circuit that suggests that: (i) it makes sense to use an FLT3 inhibitor to target FLT3- ITD when detected in CBF AML; (ii) patients with concurrent trisomy 22 should not be candidates for allogeneic HCT in first complete remission; (iii) close monitoring of MRD, potentially with RT-qPCR performed monthly on blood for at least the first 12 months, is warranted; and (iv) allogeneic HCT should be ready to action early if MRD progression is confirmed.…”

“…The paper published by Kayser and colleagues 9 in this issue of Haematologica is a multi-institutional retrospective cohort analysis addressing the role of FLT3 -internal tandem duplication (ITD) co-mutation in CBF AML. The study included 97 patients with similar proportions of t(8;21)(q22;q22) and inv(16)(p13q22)/t(16;16)(p13.1;q22).…”