TY - JOUR
T1 - RNA-based FLT3-ITD allelic ratio is associated with outcome and ex vivo response to FLT3 inhibitors in pediatric AML
AU - Cucchi, David G.J.
AU - Denys, Barbara
AU - Kaspers, Gertjan J.L.
AU - Janssen, Jeroen J.W.M.
AU - Ossenkoppele, Gert J.
AU - Haas, Valérie de
AU - Zwaan, C. Michel
AU - van den Heuvel-Eibrink, Marry M.
AU - Philippe, Jan
AU - Csikós, Tamás
AU - Kwidama, Zinia
AU - Moerloose, Barbara de
AU - De Bont, E. S.J.M.
AU - Lissenberg-Witte, Birgit I.
AU - Zweegman, Sonja
AU - Verwer, Femke
AU - Vandepoele, Karl
AU - Schuurhuis, Gerrit Jan
AU - Sonneveld, Edwin
AU - Cloos, Jacqueline
N1 - Publisher Copyright:
© 2018 by The American Society of Hematology.
PY - 2018/5/31
Y1 - 2018/5/31
N2 - Controversy exists whether internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-internal tandem duplication [ITD]) allelic ratio (AR) and/or length of the ITD should be taken into account for risk stratification of pediatric acute myeloid leukemia (AML) and whether it should be measured on RNA or DNA. Moreover, the ITD status may be of relevance for selecting patients eligible for FLT3 inhibitors. Here, we included 172 pediatric AML patients, of whom 36 (21%) harbored FLT3-ITD as determined on both RNA and DNA. Although there was a good correlation between both parameters ARspearman 5 0.62 (95% confidence interval, 0.22-0.87) and ITDlengthspearman 5 0.98 (95% confidence interval, 0.90-1.00), only AR ‡ 0.5 and length ‡48 base pairs (bps) based on RNA measurements were significantly associated with overall survival (AR: Plogrank 5 .008; ITDlength: Plogrank 5 .011). In large ITDs (>156 bp on DNA) a remarkable 90-bp difference exists between DNA and RNA, including intron 14, which is spliced out in RNA. Ex vivo exposure (n 5 30) to FLT3 inhibitors, in particular to the FLT3-specific inhibitor gilteritinib, showed that colony-forming capacity was significantly more reduced in FLT3-ITD-AR ‡ 0.5 compared with ITD-AR-low and ITD2 patient samples (P < .001). RNA-based FLT3-ITD measurements are recommended for risk stratification, and the relevance of AR regarding eligibility for FLT3-targeted therapy warrants further study.
AB - Controversy exists whether internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-internal tandem duplication [ITD]) allelic ratio (AR) and/or length of the ITD should be taken into account for risk stratification of pediatric acute myeloid leukemia (AML) and whether it should be measured on RNA or DNA. Moreover, the ITD status may be of relevance for selecting patients eligible for FLT3 inhibitors. Here, we included 172 pediatric AML patients, of whom 36 (21%) harbored FLT3-ITD as determined on both RNA and DNA. Although there was a good correlation between both parameters ARspearman 5 0.62 (95% confidence interval, 0.22-0.87) and ITDlengthspearman 5 0.98 (95% confidence interval, 0.90-1.00), only AR ‡ 0.5 and length ‡48 base pairs (bps) based on RNA measurements were significantly associated with overall survival (AR: Plogrank 5 .008; ITDlength: Plogrank 5 .011). In large ITDs (>156 bp on DNA) a remarkable 90-bp difference exists between DNA and RNA, including intron 14, which is spliced out in RNA. Ex vivo exposure (n 5 30) to FLT3 inhibitors, in particular to the FLT3-specific inhibitor gilteritinib, showed that colony-forming capacity was significantly more reduced in FLT3-ITD-AR ‡ 0.5 compared with ITD-AR-low and ITD2 patient samples (P < .001). RNA-based FLT3-ITD measurements are recommended for risk stratification, and the relevance of AR regarding eligibility for FLT3-targeted therapy warrants further study.
UR - http://www.scopus.com/inward/record.url?scp=85048150537&partnerID=8YFLogxK
U2 - 10.1182/blood-2017-12-819508
DO - 10.1182/blood-2017-12-819508
M3 - Article
C2 - 29669779
AN - SCOPUS:85048150537
SN - 0006-4971
VL - 131
SP - 2485
EP - 2489
JO - Blood
JF - Blood
IS - 22
ER -