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Methods for assessing patients with acute myeloid leukemia

A technology for myeloid leukemia and patients, applied in the fields of biochemical equipment and methods, organic chemistry, microbial determination/examination, etc., can solve problems such as complex inhibitory effects

Inactive Publication Date: 2009-01-28
VERIDEX LCC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, FTIs may have complex inhibitory effects on several cellular events and pathways

Method used

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  • Methods for assessing patients with acute myeloid leukemia
  • Methods for assessing patients with acute myeloid leukemia
  • Methods for assessing patients with acute myeloid leukemia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] Definition of clinical valuation and response

[0113] The current study is part of a publicly labelled, multicenter, non-comparative Phase 2 clinical study, in which patients with relapsed or refractory AML (Harousseau et al. (2003)) are treated with tipifarnib, for For the first 21 consecutive days of each 28-day cycle, the initial oral dose is 600 mg twice a day. The patients were divided into two groups: those with relapsed AML and those with refractory AML. A total of 252 patients (135 relapsed and 117 refractory) were treated. Eighty patients were selected to provide bone marrow samples for RNA microarray analysis, and patient consent was separately obtained for this. The overall response rate in this study was relatively low.

[0114] Therefore, for the purpose of gene expression profiling, the response to tipifarnib is defined as the patient having an objective response (complete remission [CR], complete remission with incomplete platelet recovery [CRp] or partial...

Embodiment 2

[0143] Identify genes that are differentially expressed between responders and non-responders

[0144] Second, we used gene expression data to conduct a supervised analysis to identify genes that are differentially expressed between all responders and at least 40% of non-responders. These criteria can be selected to identify genes with the highest possible level of sensitivity that can predict the response to tipifarnib. From the 11,723 genes, a total of 19 genes that can classify responders and non-responders and give a significant P value in the t-test were identified (see Table 3 and Table 10 for more details). These genes include those involved in signal transduction, apoptosis, cell proliferation, tumorigenesis and possibly FTI biology (ARHH, AKAP13, IL3RA).

[0145] Table 3 19 main genes predicting response to tipifarnib and analysis results

[0146]

[0147] Real-time RT-PCR confirmation of genetic markers

[0148] To verify the microarray gene expression data, TaqMan...

Embodiment 3

[0165] Analysis of AML prognostic gene markers

[0166] The 3 gene markers can predict prognosis independently of the type of drug treatment. To confirm this, we first evaluated gene expression markers recently identified in newly diagnosed AML patients treated with conventional chemotherapy. Bullinger et al. (2004). A cDNA array was used to define this marker, so we first matched these genes with the probes present on the Affymetrix gene chip. Among the 133 predictive genes identified by Bullinger et al., 167 probe sets (corresponding to 103 unique genes) matched the Affymetrix U133A chip. The 3 genes identified in our current analysis are not in the 133 gene list of Bullinger et al. SEQID NOs: shown in Table 4. Using these 167 probe groups, two main patient groups were defined by hierarchical clustering (Figure 8A). Kaplan-Meier analysis showed that these clusters were clearly stratified into patients with good and poor prognosis (Figure 8B, p=0.000003). Therefore, our data co...

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Abstract

Methods for treating cancer, and preferably hematological malignancy, patients include analyzing gene expression profiles and / or molecular markers of a patient to determine status and / or prognosis of the patient. The invention also provides methods of analyzing whether a non-relapsed or non-refractory patient is likely to respond to treatment with farnesyl transferase inhibitors (FTIs) and, optionally, other therapeutics. The methods are also useful for monitoring patient therapy and for selecting a course of therapy. Genes modulated in response to FTI treatment are provided and are used in formulating the profiles.

Description

[0001] Accordingly, the appendix "Sequence Listing" list is incorporated herein by reference. Background of the invention [0002] The present invention relates to a method for diagnosis, prognostics and treatment of acute myeloid leukemia (AML) based on detection of molecular markers and / or gene expression analysis. [0003] Karyotyping is currently effective in providing prognostic value, although it is also used to identify biologically different subtypes of AML. In addition, the pathogenesis of the disease involves mutations in genes such as FLT3, c-KIT, AML1, GATA1, CEBPA, and N-RAS. What is clear is that screening for FLT3 and CEBPA mutations can group patients with different risks of recurrence. Effective risk classification can enable the use of correct stem cell transplantation or other adjuvant therapies. Two recently published articles describe the gene expression profiles of newly diagnosed adult AML patients and their use in predicting clinical outcomes. Bullinger et a...

Claims

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Application Information

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IPC IPC(8): C07H21/02C07H21/04C12P19/34C12Q1/68
Inventor M·拉波尼
Owner VERIDEX LCC
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