Abstract
AbstractTo evaluate internal tandem duplication (ITD) insertion sites and length as well as their clinical impact in younger adult patients with FLT3-ITD–positive acute myeloid leukemia (AML), sequencing after DNA-based amplification was performed in diagnostic samples from 241 FLT3-ITD–mutated patients. All patients were treated on 3 German-Austrian AML Study Group protocols. Thirty-four of the 241 patients had more than 1 ITD, leading to a total of 282 ITDs; the median ITD length was 48 nucleotides (range, 15-180 nucleotides). ITD integration sites were categorized according to functional regions of the FLT3 receptor: juxtamembrane domain (JMD), n = 148; JMD hinge region, n = 48; beta1-sheet of the tyrosine kinase domain-1 (TKD1), n = 73; remaining TKD1 region, n = 13. ITD length was strongly correlated with functional regions (P < .001). In multivariable analyses, ITD integration site in the beta1-sheet was identified as an unfavorable prognostic factor for achievement of a complete remission (odds ratio, 0.22; P = .01), relapse-free survival (hazard ratio, 1.86; P < .001), and overall survival (hazard ratio, 1.59; P = .008). ITD insertion site in the beta1-sheet appears to be an important unfavorable prognostic factor in young adult patients with FLT3-ITD–positive AML. The clinical trials described herein have been registered as follows: AML HD93 (already published in 2003), AML HD98A (NCT00146120; http://www.ClinicalTrials.gov), and AMLSG 07-04 (NCT00151242; http://www.ClinicalTrials.gov).
Highlights
Within the first 2 treatment trials (AML HD93 and acute myeloid leukemia (AML) HD98A), we focused on patients with normal karyotype, whereas in the AML Study Group (AMLSG) 07-04 trial we included patients with abnormal cytogenetics
A total of 1667 patients were screened for FLT3-ITDs within 3 consecutive AMLSG treatment trials
In 385 (23.1%) patients, one or more FLT3-ITDs were identified by conventional qualitative polymerase chain reaction (PCR) or Genescan analysis; 248 of these patients exhibited a normal karyotype
Summary
). ITD integration sites were categorized according to functional regions of the FLT3 receptor: juxtamembrane domain (JMD), n ؍148; JMD hinge region, n ؍48; beta1-sheet of the tyrosine kinase domain-1 (TKD1), n ؍73; remaining TKD1 region, n ؍13. ITD integration site in the beta1-sheet was identified as an unfavorable prognostic factor for achievement of a complete remission (odds ratio, 0.22; P ؍.01), relapsefree survival (hazard ratio, 1.86; P < .001), and overall survival (hazard ratio, 1.59; P ؍.008). ITD insertion site in the beta1sheet appears to be an important unfavorable prognostic factor in young adult patients with FLT3-ITD–positive AML. The clinical trials described have been registered as follows: AML HD93 (already published in 2003), AML HD98A The clinical trials described have been registered as follows: AML HD93 (already published in 2003), AML HD98A (NCT00146120; http://www.ClinicalTrials. gov), andAMLSG 07-04 (NCT00151242; http:// www.ClinicalTrials.gov). (Blood. 2009;114: 2386-2392)
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