Different clinical importance of FLT3 internal tandem duplications in AML according to FAB classification: possible existence of distinct leukemogenesis involving monocyte differentiation pathway
Different clinical importance of FLT3 internal tandem duplications in AML according to FAB classification: possible existence of distinct leukemogenesis involving monocyte differentiation pathway
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DOI：
10.1007/s00277-009-0733-7
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发表时间：
2009-11-01
影响因子：
3.5
通讯作者：
Kim, Byung-Kook
中科院分区：
文献类型：
--
作者：
Koh, Youngil;Park, Juwon;Kim, Byung-Kook
FLT 3受体酪氨酸激酶通过内膜区内部串联重复（ITD）激活对急性髓系白血病（AML）预后的影响仍有争议。最近的研究揭示了FLT 3在造血中单核细胞分化中的作用。我们分析了FLT 3改变在成人AML患者中的临床影响，不包括根据形态学分类接受诱导化疗的急性早幼粒细胞白血病（APL）。对1997年至2007年期间韩国三家中心的病历进行了回顾性审查。对诱导化疗前患者血液样本的基因组DNA进行聚合酶链反应，用于FLT 3-ITD检测。我们评估了总生存期（OS）、首次无病生存期（1-DFS）和对诱导化疗的反应。184例AML（不包括APL）患者（中位年龄49.1岁，范围16.0-76.5岁）接受了来自三个中心的诱导化疗。22例患者检测到FLT 3-ITD。141例患者年龄在60岁以下。179例患者接受阿糖胞苷和依达罗肽（AId）方案诱导化疗。119例患者在首次诱导化疗后达到完全缓解（CR）。FLT 3-ITD与CR的实现无关。1-无FLT 3-ITD患者的DFS较长（中位1-DFS 16.5 vs 8.5个月，p = 0.025）。1-在非单核细胞系白血病中，DFS根据FLT 3-ITD状态没有差异（p = 0.355），而对于FLT 3-ITD阳性患者，单核细胞系白血病中的1-DFS较短（20.9个月对2.4个月，p < 0.001）。FLT 3-ITD对OS没有影响，但单核细胞谱系除外，FLT 3-ITD阳性组的OS显着更短（39.4 vs 6.0个月，p = 0.026）。此外，FLT 3-ITD是单核细胞系AML中比基于细胞遗传学的危险分层更强的预后因素。AML患者FLT 3-ITD状态应根据形态学特征进行不同分析。FLT 3-ITD仅在单核细胞谱系患者中是预测和预后标志物。这一结果表明存在不同的单核细胞谱系AML亚群，其白血病发生涉及FLT 3激活途径。
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.