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Abstract

Abstract: S148

Type: Oral Presentation

Session title: AML epidemiology and genetics

Background
Internal tandem duplications of the FLT3 gene (FLT3-ITD), present in approximately 25% of newly diagnosed adult AML, are associated with poor prognosis, in particular in cases of high mutant to wild-type allelic ratio (AR) and/or insertion site (IS) in the beta1-sheet.

Aims

To investigate the relationship between ITD IS and patient (pt) outcome.

Methods
Roche 454 next generation sequencing (NGS) was performed in 452/555 (81.4%) FLT3-ITD positive pts enrolled into the RATIFY trial (NCT00651261).

Results

NGS identified 908 ITDs with up to 9 ITDs/pt; 242 (53.5%) pts exhibited ≥2 ITD clones (2 ITDs, 29%; 3 ITDs, 12.8%; 4 ITDs, 5.3%; 5 ITDs, 4%; 6 ITDs, 0.7%; 7 ITDs, 1.5%; 9 ITDs, 0.2%). Median ITD-size was 45 nucleotides (range, 6-246); all ITDs were in-frame with direct head-to-tail orientation. According to the 4 functional domains, 488 ITDs (53.7%) were located within the juxtamembrane domain (JMD), 155 (17.1%) within the hinge region of JMD, 250 (27.5%) within the beta1-sheet, and 15 (1.7%) 3´of beta1-sheet. In the 242 pts featuring multiple ITD clones, 698 concurrent IS were delineated with coexistent integrations within JMD (41.5%) being the most frequent, followed by JMD and beta1-sheet (20.2%), and within beta1-sheet (12.2%). ITD size strongly correlated with IS, in that the more C-terminal the IS, the longer the inserted fragment (P<0.001).

NPM1 mutations (NPM1mut), present in 203/358 pts (56.7%), were positively correlated with IS in JMD (P=0.03) and inversely with IS in the hinge region (P=0.02) and the beta1-sheet (P=0.007).

Complete remission (CR) was achieved in 274/452 (60.6%) pts. The impact of ITD IS on response to induction was assessed in a logistic regression model. ITD IS were categorized in (i) JMD sole (n=251), (ii) JMD and beta1-sheet (n=111), and (iii) beta1-sheet sole (n=75). Co-variables were midostaurin treatment, log2 of NGS-based AR, number of ITDs, log2 of WBC counts, age, and NPM1mut. In this model, number of ITDs (OR, 0.79; P=0.04) and WBC counts (OR, 0.82; P=0.008) predicted lower CR rate, while NPM1mut was favorable for CR achievement (OR, 2.07; P=0.003).

Survival analysis according to categorized IS groups showed that pts exhibiting insertion exclusively in the beta1-sheet had significantly inferior OS (P=0.04) compared to the other 2 groups. In multivariate models for OS and CIR, including allogeneic hematopoietic stem-cell transplantation in first CR (HCT) as time-dependent covariate, consistently unfavorable variables were FLT3-ITD IS in beta1-sheet sole (compared to JMD sole: OS: HR, 1.59; P=0.02; CIR: HR, 2.48; P=0.002; and compared to JMD/beta1-sheet: OS: HR, 2.39; P=0.002; CIR: HR, 1.92; P=0.09) and WBC counts (OS: HR, 1.12; P=0.01; CIR: HR, 1.14; P=0.04), while favorable variables were midostaurin (OS: HR, 0.72; P=0.03; CIR: HR, 0.64; P=0.03) and HCT (OS: HR, 0.50; P<0.001; CIR: HR, 0.45; P=0.002). Cox regression models according to IS revealed HCT as only consistent variable of favorable impact for OS across all 3 IS subgroups. Other variables impacted prognosis only in individual models. Notably, midostaurin was significant only for pts with FLT3-ITD IS in JMD sole (HR, 0.54; P=0.003).

Conclusion

In this cohort of 452 FLT3-ITD mutated AML pts treated within the RATIFY trial the negative prognostic impact of beta1-sheet IS was confirmed. Furthermore, the beneficial effect of additional midostaurin could be validated, in particular for pts with IS in JMD sole. In addition these data further stress the favorable impact of allogeneic HCT.

Session topic: 04. Acute myeloid leukemia - Clinical

Keyword(s): AML, Flt3-ITD, Prognosis

Abstract: S148

Type: Oral Presentation

Session title: AML epidemiology and genetics

Background
Internal tandem duplications of the FLT3 gene (FLT3-ITD), present in approximately 25% of newly diagnosed adult AML, are associated with poor prognosis, in particular in cases of high mutant to wild-type allelic ratio (AR) and/or insertion site (IS) in the beta1-sheet.

Aims

To investigate the relationship between ITD IS and patient (pt) outcome.

Methods
Roche 454 next generation sequencing (NGS) was performed in 452/555 (81.4%) FLT3-ITD positive pts enrolled into the RATIFY trial (NCT00651261).

Results

NGS identified 908 ITDs with up to 9 ITDs/pt; 242 (53.5%) pts exhibited ≥2 ITD clones (2 ITDs, 29%; 3 ITDs, 12.8%; 4 ITDs, 5.3%; 5 ITDs, 4%; 6 ITDs, 0.7%; 7 ITDs, 1.5%; 9 ITDs, 0.2%). Median ITD-size was 45 nucleotides (range, 6-246); all ITDs were in-frame with direct head-to-tail orientation. According to the 4 functional domains, 488 ITDs (53.7%) were located within the juxtamembrane domain (JMD), 155 (17.1%) within the hinge region of JMD, 250 (27.5%) within the beta1-sheet, and 15 (1.7%) 3´of beta1-sheet. In the 242 pts featuring multiple ITD clones, 698 concurrent IS were delineated with coexistent integrations within JMD (41.5%) being the most frequent, followed by JMD and beta1-sheet (20.2%), and within beta1-sheet (12.2%). ITD size strongly correlated with IS, in that the more C-terminal the IS, the longer the inserted fragment (P<0.001).

NPM1 mutations (NPM1mut), present in 203/358 pts (56.7%), were positively correlated with IS in JMD (P=0.03) and inversely with IS in the hinge region (P=0.02) and the beta1-sheet (P=0.007).

Complete remission (CR) was achieved in 274/452 (60.6%) pts. The impact of ITD IS on response to induction was assessed in a logistic regression model. ITD IS were categorized in (i) JMD sole (n=251), (ii) JMD and beta1-sheet (n=111), and (iii) beta1-sheet sole (n=75). Co-variables were midostaurin treatment, log2 of NGS-based AR, number of ITDs, log2 of WBC counts, age, and NPM1mut. In this model, number of ITDs (OR, 0.79; P=0.04) and WBC counts (OR, 0.82; P=0.008) predicted lower CR rate, while NPM1mut was favorable for CR achievement (OR, 2.07; P=0.003).

Survival analysis according to categorized IS groups showed that pts exhibiting insertion exclusively in the beta1-sheet had significantly inferior OS (P=0.04) compared to the other 2 groups. In multivariate models for OS and CIR, including allogeneic hematopoietic stem-cell transplantation in first CR (HCT) as time-dependent covariate, consistently unfavorable variables were FLT3-ITD IS in beta1-sheet sole (compared to JMD sole: OS: HR, 1.59; P=0.02; CIR: HR, 2.48; P=0.002; and compared to JMD/beta1-sheet: OS: HR, 2.39; P=0.002; CIR: HR, 1.92; P=0.09) and WBC counts (OS: HR, 1.12; P=0.01; CIR: HR, 1.14; P=0.04), while favorable variables were midostaurin (OS: HR, 0.72; P=0.03; CIR: HR, 0.64; P=0.03) and HCT (OS: HR, 0.50; P<0.001; CIR: HR, 0.45; P=0.002). Cox regression models according to IS revealed HCT as only consistent variable of favorable impact for OS across all 3 IS subgroups. Other variables impacted prognosis only in individual models. Notably, midostaurin was significant only for pts with FLT3-ITD IS in JMD sole (HR, 0.54; P=0.003).

Conclusion

In this cohort of 452 FLT3-ITD mutated AML pts treated within the RATIFY trial the negative prognostic impact of beta1-sheet IS was confirmed. Furthermore, the beneficial effect of additional midostaurin could be validated, in particular for pts with IS in JMD sole. In addition these data further stress the favorable impact of allogeneic HCT.

Session topic: 04. Acute myeloid leukemia - Clinical

Keyword(s): AML, Flt3-ITD, Prognosis

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