title: Different clinical importance of FLT3 internal tandem duplications in AML according to FAB classification: possible existence of distinct leukemogenesis involving monocyte differentiation pathway.
abstract: Impact of FLT3 receptor tyrosine kinase activation via internal tandem duplication (ITD) of the juxtamembrane region on outcome of acute myeloid leukemia (AML) is still controversial. Recent researches reveal a role of FLT3 in monocyte differentiation in hematopoiesis. We analyzed the clinical impact of FLT3 alterations in adult AML patients excluding acute promyelocytic leukemia (APL) who received induction chemotherapy according to morphologic classification. Retrospective review of medical records from three centers in Korea between 1997 and 2007 was performed. Polymerase chain reaction was performed on genomic DNA derived from blood samples of patients before induction chemotherapy for FLT3-ITD detection. We assessed overall survival (OS), first disease-free survival (1-DFS), and response to induction chemotherapy. One hundred eighty-four patients (median age 49.1 years, range 16.0-76.5) with AML excluding APL received induction chemotherapy from three centers. FLT3-ITD was detected in 22 patients. One hundred forty-one patients were below age 60. One hundred seventy-nine patients received induction chemotherapy with cytarabine and idarubicin (AId) regimen. One hundred nineteen patients achieved complete remission (CR) after first induction chemotherapy. FLT3-ITD was not related to achievement of CR. 1-DFS was longer in patients without FLT3-ITD (median 1-DFS 16.5 vs. 8.5 months, p = 0.025). 1-DFS was not different according to FLT3-ITD status in nonmonocyte lineage leukemia (p = 0.355), while 1-DFS was shorter in monocyte lineage leukemia for FLT3-ITD positive patients (20.9 vs. 2.4 months, p < 0.001). FLT3-ITD had no impact on OS except for monocyte lineage, where OS was significantly shorter in FLT3-ITD positive group (39.4 vs. 6.0 months, p = 0.026). Moreover FLT3-ITD was stronger prognostic factors in monocyte lineage AML than risk stratification based on cytogenetics. Status of FLT3-ITD should be analyzed differently in AML patients according to morphologic profile. FLT3-ITD is a predictive and prognostic marker only in monocyte lineage patients. This result suggests an existence of distinct subset of monocyte lineage AML with leukemogenesis involving FLT3 activating pathway.
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Youngil
authors.initials: Y
authors.lastname: Koh
authors.forename: Juwon
authors.initials: J
authors.lastname: Park
authors.forename: Kwang-Sung
authors.initials: KS
authors.lastname: Ahn
authors.forename: Inho
authors.initials: I
authors.lastname: Kim
authors.forename: Soo-Mee
authors.initials: SM
authors.lastname: Bang
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Lee
authors.forename: Sung-Soo
authors.initials: SS
authors.lastname: Yoon
authors.forename: Dong
authors.initials: D
authors.lastname: Soon Lee
authors.forename: Young
authors.initials: Y
authors.lastname: Yiul Lee
authors.forename: Seonyang
authors.initials: S
authors.lastname: Park
authors.forename: Byung-Kook
authors.initials: BK
authors.lastname: Kim
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018572:Disease-Free Survival; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D007438:Introns / Q000235:genetics; D053208:Kaplan-Meier Estimate; D007723:Korea / Q000453:epidemiology; D007948:Leukemia, Monocytic, Acute / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D007951:Leukemia, Myeloid / Q000145:classification*; D015479:Leukemia, Myelomonocytic, Acute / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000473:pathology*; D038042:Myelopoiesis / Q000235:genetics*; D011379:Prognosis; D017434:Protein Structure, Tertiary; D020080:Tandem Repeat Sequences; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000032:analysis / Q000737:chemistry / Q000235:genetics*
chemical_list: C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3