Clinical implications of FLT3 mutations in pediatric AML

Meshinchi, Soheil; Alonzo, Todd A.; Stirewalt, Derek L.; Zwaan, Michel; Zimmerman, Martin; Reinhardt, Dirk; Kaspers, Gertjan J. L.; Heerema, Nyla A.; Gerbing, Robert B.; Lange, Beverly J.; Radich, Jerald P.

doi:10.1182/blood-2006-03-009233

Cited by 355 publications

(372 citation statements)

References 33 publications

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“…CD33 expression was also correlated with molecular prognostic factors. [16][17][18][19] FLT3/ITD, NPM1, and CEBPA mutations were detected in 15%, 6%, and 6% of evaluable samples, respectively. There was a statistically significant increase in FLT3/ITD prevalence with increasing CD33 expression when analyzed by quartiles (8% for Q1, 10% for Q2, 20% for Q3, and 22% for Q4; P Ͻ .001, Figure 1B) and for NPM1 mutations (1% for Q1, 5% for Q2, 7% for Q3, and 10% for Q4; P ϭ .001), but there was no definitive trend in CEBPA prevalence among quartiles (Table 1).…”

Section: Cd33 Expression Levels and Correlation With Disease Charactementioning

confidence: 99%

Correlation of CD33 expression level with disease characteristics and response to gemtuzumab ozogamicin containing chemotherapy in childhood AML

Pollard

Alonzo

Loken³

et al. 2012

Blood

100

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CD33 is expressed on the majority of acute myeloid leukemia (AML) leukemic blasts and is the target for gemtuzumab ozogamicin (GO), a toxin-conjugated anti-CD33 mAb. In the present study, we quantified the CD33 mean fluorescent intensity of leukemic blasts prospectively in 619 de novo pediatric AML patients enrolled in Children's Oncology Group GOcontaining clinical trials and determined its correlation with disease characteristics and clinical outcome. CD33 expression varied more than 2-log fold; a median mean fluorescent intensity of 129 (range, 3-1550.07) was observed. Patients were divided into 4 quartiles, quartiles 1-4 (Q1-4) based on expression and disease characteristics and clinical response defined across quartiles. High CD33 expression was associated with high-risk FLT3/ITD mutations (P < .001) and was inversely associated with lowrisk disease (P < .001). Complete remission (CR) rates were similar, but patients in Q4 had significantly lower overall survival (57% ؎ 16% vs 77% ؎ 7%, P ‫؍‬ .002) and disease-free survival from CR (44% ؎ 16% vs 62% ؎ 8%, P ‫؍‬ .022). In a multivariate model, high CD33 expression remained a significant predictor of overall survival (P ‫؍‬ .011) and diseasefree survival (P ‫؍‬ .038) from CR. Our findings suggest that CD33 expression is heterogeneous within de novo pediatric AML. High expression is associated with adverse disease features and is an independent predictor of inferior outcome. IntroductionCD33 is a myeloid antigen (Ag) expressed on malignant blasts of most patients with acute myeloid leukemia (AML) and is a target of the toxin-conjugated humanized IgG4 anti-CD33 mAb gemtuzumab ozogamicin (GO; Mylotarg). The clinical efficacy of GO was initially demonstrated in relapsed AML patients with CD33 ϩ AML. [1][2][3][4] Although in vitro studies revealed a direct relationship between CD33 expression and GO-induced cytotoxicity, 5 conflicting data were obtained from correlative studies conducted within the context of GO clinical trials for adult relapsed AML, suggesting that CD33 expression may be associated with other AML prognostic factors. 2,[6][7][8] With recent data from the Medical Research Council AML 15 clinical trial suggesting that GO may have preferential efficacy in select AML populations, 9 there is increased interest in determining which subset of patients may most benefit from this targeted agent. Because GO targets surface CD33, our aim in the present study was to determine the variability of CD33 expression and disease characteristics within pediatric AML. We quantified CD33 expression on the surface of leukemic blasts prospectively and determined the correlation of expression levels of this Ag with disease characteristics and clinical outcome within the context of 2 consecutive Children's Oncology Group (COG) trials of GO. Methods Patients and treatmentPediatric patients with de novo AML who were enrolled in COG trials AAML03P1 and AAML0531 were eligible for the present study. COG AAML03P1 was a pilot study in which patients with de novo AML received GO...

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Section: Cd33 Expression Levels and Correlation With Disease Charactementioning

confidence: 99%

Correlation of CD33 expression level with disease characteristics and response to gemtuzumab ozogamicin containing chemotherapy in childhood AML

Pollard

Alonzo

Loken³

et al. 2012

Blood

100

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“…The size of the ITD is negatively correlated with 5-year overall survival of acute myeloid leukemia (AML) patients (4). Furthermore, the allelic ratio ITD/WT Flt3 is a significant and independent prognostic factor for relapse in pediatric AML (5). Apart from the ITD mutations, point mutations in the kinase domain of Flt3 that can induce constitutive kinase activity have been described in both pediatric and adult AML (6).…”

mentioning

confidence: 99%

Suppressor of Cytokine Signaling 6 (SOCS6) Negatively Regulates Flt3 Signal Transduction through Direct Binding to Phosphorylated Tyrosines 591 and 919 of Flt3

Kazi

Sun

Phung

et al. 2012

Journal of Biological Chemistry

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Background:Flt3 is an important regulator of hematopoiesis and is often found mutated and constitutively active in patients with acute myeloid leukemia. Results: SOCS6 is up-regulated by Flt3 activation and binds to phosphorylated Flt3. Conclusion: SOCS6 is a negative regulator of Flt3 signaling. Significance: Our results provide a role for SOCS6 in Flt3 signaling. The absence of SOCS6 promotes transformation of cells by Flt3 ITD.

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“…In a large pediatric study involving 630 children with de novo AML, FLT3-ITD mutations were found in 12% of the patients, and FLT3 activation loop domain mutations were observed in B7% of patients, with poorer progression-free survival associated with FLT3-ITD (Meshinchi et al, 2006). In a study involving 234 pediatric AML patients, FLT3-ITD mutations were found in 11.5% of patients who were classified as significantly older with lower remission induction rates and lower 5-year probability rates of event-free survival (Zwaan et al, 2003).…”

Section: Drug Resistance In Mutant Flt3-positive Pediatric Amlmentioning

confidence: 99%

Drug resistance in mutant FLT3-positive AML

et al. 2010

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Mutant Fms-Like Tyrosine kinase-3 (FLT3), which is expressed in the leukemic cells of a subpopulation of acute myeloid leukemia (AML) patients, represents an attractive target for the therapy of AML. There are several FLT3 inhibitors presently in clinical trials with sufficient efficacy and toxicity features to warrant further testing in combination with standard therapies. However, the transient and partial responses observed in AML patients treated with FLT3 inhibitors, coupled with the discovery of drug-resistant leukemic blast cells in AML patients, have made resistance to FLT3 inhibitors a growing concern. In this study, we provide an overview of the role of mutant FLT3 in AML, FLT3 inhibitors under clinical and preclinical investigation, mechanisms of resistance to FLT3 inhibitors, and possible therapeutic approaches to overcoming this resistance.

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Clinical implications of FLT3 mutations in pediatric AML

Cited by 355 publications

References 33 publications

Correlation of CD33 expression level with disease characteristics and response to gemtuzumab ozogamicin containing chemotherapy in childhood AML

Correlation of CD33 expression level with disease characteristics and response to gemtuzumab ozogamicin containing chemotherapy in childhood AML

Suppressor of Cytokine Signaling 6 (SOCS6) Negatively Regulates Flt3 Signal Transduction through Direct Binding to Phosphorylated Tyrosines 591 and 919 of Flt3

Drug resistance in mutant FLT3-positive AML

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