Patent Application
20100311652
This application claims priority under 35 U.S.C. ยง119 and all applicable treaties from EP application number EP 09161881.9, which was filed on Jun. 3, 2009.
The invention relates to the use of a genetic marker in a process for analysis of leukemia patients for use in therapy, especially for use in the prediction of the suitability of chemotherapy in a group of leukemia patients on the basis of their alleles of the marker. Further, the invention relates to chemotherapeutical agents for use in the therapy of leukemia patients that have been diagnosed to be at least heterozygous for the relevant allele of the genetic marker. Further, the invention relates to a pharmaceutical composition containing at least one known chemotherapeutical agent specified for use in the treatment of leukemia, especially for the treatment of leukemia patients being diagnosed to be homozygous for the relevant allele of the marker, especially for leukemia patients who have been identified to have a genotype that is considered a high-risk leukemia genotype, including, but not restricted to CN-AML.
Hollink et al. in Blood, 113 (23), 5951-5960 (2009) describe that 24% of diagnostic samples obtained from children suffering from AML were analysed to have an A to G mutation in a mutational hotspot of exon 7 of the Wilms tumour (WTI) gene.
Milani et al. in Nuc. Acids Res. 35(5) e34 (2007) investigated the gene expression of marker allele expression in cultivated cell lines.
In leukemia patients, especially in patients diagnosed with acute myeloid leukemia (AML), or diagnosed with acute lymphoblastic leukemia (ALL), especially for these leukemia patients having a normal cytogenetic characterisation (CN-AML), to-date a classification into risk classes is made on the basis of the presence or absence of molecular markers. The classification of leukemia patients into the high risk group can e.g. be made on the basis of the presence of the FLT3-ITD marker, and/or on the presence of wild-type NPM 1 in combination with wild-type FLT3, presence of wild-type NPM1 in combination with FLT3-ITD mutation, or presence of mutated NPM1 in combination with (/) FLT3-ITD mutation, including patients having a caryotype without aberrations, i.e. a normal caryotype (cytogenetically normal acute myeloid leukemia (CN-AML)). The high risk leukemia patients are currently treated by intensive care therapy, including stem cell transplantation. Due to the high toxicity of intensive care therapy, a mortality of up to 30% as caused by intensive therapy side effects can be observed.
In addition to Hollink et al, Paschka et al. (J. Clin. Oncol. 26, 4595-4602 (2008)) and Virappane et al. (J. Clin. Oncol. 26, 5429-5435 (2008)) describe that acquired mutations of the WTI gene are associated with poor prognosis in adult and pediatric CN-AML patients. These findings were contradicted by a large study of 617 patients (17) by the finding that mutations in WTI were not related to prognosis in CN-AML patients. In addition to the contradictory findings of the relevance of mutations in the WTI gene, previous reports are contradictory in respect of the prognostic value of WTI mRNA expression on the prognosis of AML-treatment. For example, Bergmann et al. (Blood, 90: 1217-1225 (1997)), Weisser et al. (Leukemia, 19: 1416-23 (1005)), Lapillonne (J. Clin. Oncol. 24: 1507-15 (2006)), and Inoue (Blood, 84: 3071-3079 (1994)) observed expression of WTI in 75-100% of AML patients, with high levels of WTI mRNA being associated with a favourable prognosis of AML treatment. In contrast, Gaiger et al. (Leukemia, 12: 1886-94 (1998)), Schmid et al. (Leukemia 11: 639-43 (1997)), and Rodrigues et al. (Pediatr. Blood Cancer 49: 133-8 (2007)) did not find any correlation of WTI expression levels to the outcome of AML treatment, and hence no prognostic value of WTI expression levels.
In summary, the invention relates to a process for analysis and to the use of the process for analysis of the allele of the marker Ref SNP ID rs16754 in a nucleic acid sample obtained from a human suffering from leukemia in the selection of a therapy. In this use, the leukemia is selected from AML or ALL. Further, for the use of the invention, the human has preferably been identified to have a high-risk AML genotype, and more preferably, the high-risk AML genotype is selected from the group of genotypes of wild-type NPM1 in combination with wild-type FLT3, wild-type NPM1 in combination with an FLT3-ITD mutation, and a NPM1 mutation in combination with an FLT3-ITD mutation. Generally, the human is preferably identified to have cytogenetically normal AML (CN-AML). Generally preferably, the patient carries an at least heterozygous allele with G in the marker Ref SNP rs16754, and the therapy consists of chemotherapy, more preferably, the patient homozygously carries the allele with A in the marker Ref SNP rs16754, and the therapy comprises intensive chemotherapy including stem cell therapy.
Further, the invention relates to a process or use of the analysis of the genotype of a patient in the selection of a therapy for a leukemia patient, wherein the analysis comprises the determination of the allele of the marker ref SNP rs16754 in a nucleic acid sample obtained from the patient.
In a further embodiment, the invention relates to a kit of parts and to the use of a kit of parts containing oligonucleotides which are complementary to at least a section of the human WTI gene corresponding to SEQ ID No. 1 for the analysis of the allele of the marker Ref SNP ID rs16754 in a nucleic acid sample obtained from a human suffering from leukemia, for selecting a therapy. Preferably, therein the allele of the marker Ref SNP ID rs16754 is G and the therapy consists of chemotherapy.
In a further embodiment, the invention relates to a chemotherapeutical agent as a pharmaceutical composition for the treatment of a human leukemia patient who has been identified to carry an at least heterozygous allele with G in the marker Ref SNP rs16754, and to the use of a chemotherapeutical agent for the production of a pharmaceutical composition for the treatment of a human leukemia patient who carries an at least heterozygous allele with G in the marker Ref SNP rs16754. Preferably, the leukemia patient is identified to have a high-risk AML genotype. More preferably, the high-risk AML genotype is selected from the group of genotypes of wild-type NPM1 in combination with wild-type FLT3, wild-type NPM1 in combination with an FLT3-ITD mutation, and a NPM1 mutation in combination with an FLT3-ITD mutation, and the high risk leukemia patient is identified to have cytogenetically normal AML (CN-AML).
In a further embodiment, the invention relates to a pharmaceutical compound containing at least one chemotherapeutical active compound for use in the therapy of leukemia, which pharmaceutical compound is accompanied by instructions for use in the treatment of AML patients only who carry the allele G of marker Ref SNP ID rs16754. Preferably, the instructions define the AML patients as high-risk AML genotype.
Embodiments of the present invention to provide an analytical method which is useful for the identification of patients, especially patients classified as high risk leukemia patients, who can be treated successfully by standard chemotherapy, especially by chemotherapy only, e.g. without stem cell transplantation, instead of intensive treatment generally used for high risk leukemia patients, which intensive treatment can involve stem cell therapy. Classification into the high-risk class can e.g. be done as described above.
Embodiments provide a pharmaceutical composition for use in the treatment of leukemia, especially for leukemia in patients who are classified as high risk patients, the composition comprising chemotherapeutical agents, as well as the use of chemotherapeutical agents for the production of pharmaceutical compositions for use in treatment of leukemia in high risk leukemia patients.
Preferred embodiments of the invention provide such analytical methods and pharmaceutical compositions by providing a sub-group of leukemia patients, especially of high risk leukemia patients, especially high risk leukemia patients diagnosed for AML or ALL, preferably CN-AML, and by providing an analytical method for use in the identification of a sub-group of high risk leukemia patients, which sub-group of high risk leukemia patients can be treated successfully by chemotherapy, especially using chemotherapeutical agents which are today used for the treatment of low risk or intermediate risk leukemia patients. Further, the invention provides for a process for analysis of the sub-group of patients, and for the use of chemotherapeutical agents for the production of pharmaceutical compositions for the treatment of leukemia, wherein the patients are identified, e.g. by the analytical method of the invention, as the sub-group of high-risk leukemia patients who at least heterozygously carry the minor allele of the marker.
It has been found that in high risk leukemia patients, who are defined in accordance with the classification as used to-date, especially leukemia patients who have been diagnosed positive for wild-type NPM1 in combination with wild-type FLT3 (FLT3-ITDnegative), or wild-type NPM1 in combination with the FLT3-ITD mutation, or mutated NPM1 in combination with the FLT3-ITD mutation, or MLL partial tandem duplication (PTD) mutation, or mutations of NPM1 and FLT3-ITD as well as CEBPA, including in each case cytogenetically normal AML (CN-AML), one allele of the marker SNP ID: rs16754 is a suitable prognostic indicator of the outcome of a chemotherapy in the treatment of this sub-group of patients, i.e. without stem cell transplantation therapy of this sub-group of high-risk leukemia patients.
It has been found that the allele containing a G in marker SNP ID: rs16754, also termed minor allele for the purposes of the present invention, is coupled to a positive prognosis of treatment by chemotherapy also for high risk leukemia patients. Accordingly, high risk leukemia patients as defined above, including CN-AML patients, who e.g. carry a FLT3-ITD mutation, with or without an NPM1 mutation, or who have wild-type FLT3/wild-type NPM1 (no FLT3-ITD mutation), if analysed to carry the minor (G) allele of the marker SNP ID: rs16754 heterozygously or homozygously, can be identified by the analytical process according to the invention, and can be treated with a positive prognosis by chemotherapy as e.g. used currently for low risk and intermediate risk leukemia patients, preferably excluding stem cell transplantation. Therefore, the present invention provides for a selection process of a sub-group of high-risk leukemia patients, which sub-group can be treated with a positive prognosis by chemotherapy, while avoiding the severe side effects of the treatment currently applied to high risk patients, which sub-group is characterized by the minor allele of the marker SNP ID: rs16754. The marker including the reference number of a single nucleotide polymorphism (Ref SNP ID) rs16754 is e.g. available at NCBI data bank (build 129), and is also termed C1107 A>G at GenBank entry NM/024426.3 (NM-024426.3: c.1107 A>G). The enclosed nucleotide sequence SEQ ID No. 1 is the WTI gene according to Refseq. NM024426, containing at nucleotides 197 to 1750 the coding sequence, exon 7 at nucleotides 1295 to 1445, and marker SNP ID: rs16754 at position 1303, which corresponds to nucleotide 1107 of the coding sequence section (nt 197 to 1750).
Consequently, the use of the analytical method of the present invention, by identifying from the group of high risk leukemia patients a sub-group on the basis of the minor allele of the marker allows to use chemotherapeutical treatment to this sub-group of high risk leukemia patients with a positive prognosis, instead of subjecting the sub-group of patients to high risk intensive treatments generally used for the treatment of the group of high risk patients. Accordingly, the invention allows to reduce the overall mortality of high risk leukemia patients which is caused by side-effects of intensive treatment, in combination with a better prospect of healing for this sub-group of high risk leukemia patients by selecting the patients which are at least heterozygous for the minor allele of marker SNP: ID rs16754. In accordance with the positive prognosis of chemotherapy for this sub-group of patients, the invention also provides for the use of chemotherapeutical agents for the production of pharmaceutical compositions for use in the treatment of leukemia, especially in high risk patients, wherein the patients are characterized in having the minor allele of the marker SNP ID: rs16754 at least heterozygously.
Accordingly, the invention provides a pharmaceutical composition comprising at least one chemotherapeutical agent suitable for treatment of leukemia, which pharmaceutical composition is accompanied by instructions for use indicating that the composition is suitable for leukemia patients of the sub-group, i.e. suitable for use in the treatment of leukemia patients, especially high-risk leukemia patients, preferably CN-AML, which patients are diagnosed to have the minor allele of the marker SNP ID: rs16754, i.e. heterozygously (A/G) or homozygously (G/G).
Further, the invention provides a process for the treatment of leukemia in, human patients by a pharmaceutical composition comprising at least one chemotherapeutical agent, which process is for patients who at least heterozygously carry the allele 0 of the marker SNP ID: rs16754. In accordance with the selection of the sub-group of high-risk leukemia patients for a treatment consisting of chemotherapy, i.e. excluding stem cell therapy, the invention also provides for a process for the treatment of leukemia patients, comprising the steps of analysing the alleles of the marker SNP ID: rs16754, and applying a treatment consisting of chemotherapy to patients who are diagnosed to carry the minor allele of the marker SNP ID: rs16754 at least heterozygously. Alternatively or additionally, the process comprises the step of applying an intensive chemotherapeutical treatment comprising stem cell therapy to patients who are diagnosed to carry the major allele of marker SNP ID: rs16754 homozygously.
The preferred pharmaceutical agent for use in the present invention for the treatment of high risk leukemia patients having the minor allele of the marker at least in a heterozygous state comprises idarubicin, etoposide, cytarabine, fludarabine, G-CSF, daunorubicin, e.g. in chemotherapeutical regimens comprising FLAG-Ida (chemotherapy with fludarabine, cytarabine, G-CSF, and idarubicin), and high-dose cytarabine (HD-AraC).
In the following analysis, cytogenetically normal acute myeloid (CN-AML) leukemia patients were investigated by analysing mutations in the Wilm's tumor 1 (WTI) gene, and analysing WTI gene expression. It has been found that the marker SNP ID: rs16754 (databank SNP build 129) of WTI can be used as a prognostic marker for the outcome of chemotherapy in CN-AML patients, namely that patients carrying the minor allele at least heterozygously, including high risk leukemia patients, have a positive prognosis for chemotherapy. This positive prognosis also of high-risk leukemia patients for chemotherapy, preferably for chemotherapy without stem cell therapy, on the basis of the allele of SNP ID: rs16754 is unknown in the field, and allows a more specific treatment of leukemia patients. Accordingly, patients having the major allele of the marker SNP ID: rs16754 homozygously cannot be treated by chemotherapy alone with a positive prognosis, and it is therefore preferred to assign these patients to high intensity treatment including stem cell therapy.
In the study providing the basis for the present invention, diagnostic bone marrow or peripheral blood samples obtained from 249 adult patients with de novo or secondary AML (classified as MO-M2, M4-M7 in the French-American-British classification) at normal cytogenetics were analysed. All patients received intensive, response-adapted double induction and consolidation chemotherapy after written informed consent prior to therapy, with approval by the institutional review board of the Medizinische Hochschule Hannover.
Generally, mononuclear cells from samples were enriched by Ficoll density gradient centrifugation. Preferably, samples were analysed by G- and R-banding analysis and by fluorescence in situ hybridisation (FISH) using a comprehensive DNA probe set, as e.g. described in Metzke-Heidemann et al. (Genes Chromosomes Cancer 31: 10-14 (2001)).
Genomic DNA was extracted for analysis using ion exchange purification using the AllPrep DNA/RNA kit (Qiagen, Germany) according to the manufacturer's instructions. For amplification of sections of the WTI gene, the polymerase chain reaction (PCR) was used, followed by purification of amplification products and their direct sequencing using dideoxy nucleotide termination cycle sequencing and analysis on an automated detection device, a 3130 GeneticAnalyser (AppliedBiosystems, Germany) with automatic fragment detection. For confirmation of point mutations, including insertions, deletions or duplications, fragments were confirmed by sub-cloning in vector pGEM-T (obtainable from Promega, Germany). For RNA analysis, cDNA was generated by M-MLV reverse transcriptase (obtainable from Invitrogen) with random hexamer priming, coupled with PCR, using the WTI ProlileQuant kit (Ipsogen, France) according to the manufacturer's instructions. The analysis of mutation FLT3-ITD was according to Frohling et al. (Blood 100: 4372-4380 (2002)), of MLL-PTD according to Whitman et al. (Blood 106, 345-52 (2005)) or Caligiuri et al. (Cancer Res. 58:55-9 (1998)), of NPM1 according to Doehner et al. (Blood 106: 3740-3746 (2005)), and of CEBPA according to Frohling et al. (J. Clin. Oncol. 22: 624-633 (2004)).
For PCR analysis, a fragment of exon 7 containing the marker SNP ID: rs16754 was amplified from genomic patient DNA using forward primer CTCCAGTGCTCACTCTCCCTC (Seq ID No. 2), and reverse primer CCTTAGCAGTGTGAGAGCCTG (Seq ID No. 3). The amplification product was purified and sequenced, e.g. using a 3130 Genetic Analyzer (ABI).
Statistical analysis was in accordance with Heuser et al. (Blood 108: 3898-3905 (2006), or Blood 110: 1639-47 (2007)), defining complete remission (CR), relapse-free survival (RFS), and overall survival (OS) in accordance with recommended criteria (Cheson et al., J. Clin. Oncol. 21: 4642-4649 (2003)), using the statistical programme SPSS16.0 (obtained from SPSS Science, Chicago, USA).
For WTI expression analysis, samples were classified into 2 groups with respect to the median value of WTI expression (median normalized copy number, transcript number of WTI per ABL-transcript: 1.171, 0.0011-44.84).
For pairwise comparison, the Kolmogorov-Smirnov test for continuous variables and the Chi-squared test for categorical variables was made. Estimation of distribution of RFS and OS was made by the Kaplan-Meier method, and comparison of differences of survival curves by the log-rank test. For multivariate analysis, a Cox proportional hazards model was constructed for RFS and OS, adjusting for potential confounding covariates using the forward-selection method of Cox, J. R. Stat. Soc. B 34: 187-202 (1972). As variables for model inclusion were considered age, hemoglobin, platelet count, blast percentage in peripheral blood or bone marrow (above or below median), sex, ECOG performance status (0, 1, or 2, respectively), presence of a mutation in NPM 1 and wild-type FLT3 as one group, presence of mutations in CEBPA, MLL-PTD, and in WTI, high or low WTI expression, and presence of mutation in SNP ID: rs16754 (homozygous for major allele vs. heterozygous or homozygous for minor allele). Variables with P of 0.1 or less in univariate analysis for RFS or OS were included in the statistical model. The two-sided level of significance was set at P below 0.05.
It has been found that patients having the minor allele of SNP ID: rs16754 at least heterozygously in comparison to patients who are homozygous for the major allele of SNP ID: rs16754 show no significant difference in baseline characteristics, treatment regimens, or in the frequencies of mutations in FLT3-ITD (P=0.4, 28% vs. 34%), NPM1 (P=0.96, 59% vs. 58%), CEBPA (P=0.36, 19% vs. 14%), MLL-PTD (P=0.35, 2% vs. 4%), WTI (P=0.25, 16% vs. 10%), or the low risk mutation status of mutation in NPM1 in combination with no FLT3-ITD (P=0.87, 36% vs. 35%). Comparison of patients having a mutation in WTI to patients with wild-type WTI also showed no significant difference in baseline characteristics (except for a lower hemoglobin level in patients with a WTI mutation), treatment modalities, and frequencies of further mutations. The expression levels of WTI were similar in patients with minor allele of SNP ID: rs16754 and patients homozygous for the major allele of SNP ID: rs16754, as well as for patients with or without WTI mutations (e.g. mutations in the WTI gene except for marker SNP ID: rs16754, e.g. further acquired mutations).
The significance of the allele of the marker SNP ID: rs16754 is shown in
The results shown in
The positive prognosis of the presence of the minor allele of marker SNP ID: rs16754 on RFS and OS was also found when restricting the analysis to NPMUFLT3-IDTD high-risk patients with wild-type CEBPA (RFS, n=91, HR=0.43, 95% CI 0.22 to 0.83; P=0.01; OS, n=126, HR=0.39, 95% CI 0.22 to 0.71, P=0.002), which patients also form a preferred group of high-risk AML patients in the invention.
The correlation of the presence of the at least heterozygous minor allele of marker SNP ID: rs16754 with a positive prognosis of chemotherapy, in the present study approx. 13% (33 from 243) of AML patients could not be identified by any other marker or mutation. Presence of the minor allele of SNP rs16754 is an independent predictor of relapse-free survival (RFS) (HR 0.49, 95% CI 0.3 to 0.81, P=0.005) and overall survival (OS) (HR 0.44, 95% CI 0.27 to 0.74, P=0.002), as e.g. determined in multivariate analysis.
Therefore, according to the present knowledge, the prognostic value of the presence of the minor allele of the marker SNP ID: rs16754 for chemotherapy of high-risk leukemia patients is unique. Accordingly, the use of the analysis of the marker SNP ID: rs16754 for the selection of the therapeutic treatment of high-risk leukemia patients, and the use of chemotherapeutical agents for use in the production of a pharmaceutical composition in the treatment of leukemia in high-risk patients who at least heterozygously carry the minor allele of the marker SNP ID: rs16754 could not be expected from the analysis of other genetic markers known to be analysed for identifying a suitable therapy against leukemia.
An intent-to-treat analysis of the patients having the minor allele of marker SNP ID: rs16754 for whom information on a related donor for stem cell transplantation showed that allogeneic stem cell transplantation had no significant impact on OS in these patients. For the purposes of this invention, reference to WTI mutations denotes mutations in the WTI gene, except for the marker SNP ID: rs16754. Accordingly, WTI mutations include aberrations in the nucleotide sequence which result in a modified gene product. In order to take account of natural variation in WTI gene sequence, WTI mutations preferably are gene aberrations that occur in AML patients but are not found in healthy humans. Generally, aberrations occurring in the WTI gene of healthy humans as well as in AML patients are considered polymorphisms, and in the case of the amino acid sequence encoded being without changes considered silent polymorphisms, which are not necessarily linked to AML.
The results of
Further, it was found that the expression level of WTI does not correlate with the prognostic value of the alleles of marker SNP ID: rs16754.
Eighty-one percent of patients with low expression of the WTI gene achieved a CR compared to 77% of patients with high WTI expression (P=0.4). Overall survival but not RFS of patients with high WTI expression was significantly shorter compared to patients with low WTI expression (RFS, n=186, HR=1.35; 95% CI 0.91 to 1.99; OS, HR=1.47; 95% CI 1.03 to 2.11; 5-years OS 37% v 51%, respectively). For patients in whom WTI expression was measured in peripheral blood (n=66) or in bone marrow blasts (n=163) were analyzed separately, no significant difference in OS was found in either the peripheral blood or bone marrow group (data not shown).
In multivariate analysis for OS, WTI SNP rs16754, it was found that the minor allele predicted favourable prognosis (HR 0.44, 95% CI 0.27 to 0.74, P=0.002) independently from NPM1/FLT3 mutation status, CEBPA mutation status, WTI expression status, age, WBC count, and platelet count. In multivariate analysis for RFS, presence of one at least one minor allele of SNP rs16754 was a favourable prognostic factor (HR 0.49, 95% CI 0.3 to 0.81, P=0.005), which is independent form NPM1/FLT3 mutation status, CEBPA mutation status, WBC count, and platelet count. By contrast WTI expression above or below the median was not an independent prognostic marker for OS.
The positive prognostic value of the minor allele of the marker SNP rs16754 for RFS and OS for treatment by chemotherapy only, and hence the use of chemotherapeutic agents for the production of pharmaceutical compositions for treatment of the group of AML patients carrying this minor allele, was confirmed in approx. 13% (33 patients) of the entire patient group, and especially stronger in AML high risk NPM1/FLT3-ITD patients than in low risk NPM1/FLT3-ITD patients. No other favourable genetic marker was identified which has the correlation of positive prognostic value for chemotherapy in AML patients as found for the minor allele of the marker SNP rs16754.
Analysis of healthy volunteers in respect of alleles of the marker SNP rs16754 in comparison to alleles found in AML patients did not reveal any correlation between allele distribution and AML. Currently, no phenotypic effect of the minor or major allele of the marker SNP rs16754, respectively, could be found, e.g. both alleles result in the same amino acid sequence of the translation product. As a consequence of these two observations, it is currently assumed that presence of the major allele of the marker has an impact on the response to chemotherapeutical agents, but no direct effect on the development of leukemia. Accordingly, in addition to the analytical method for the determination of the allele of the marker SNP ID: rs16754 in a leukemia patient, the present invention also relates to the use of chemotherapeutical agents, especially of idarubicin, etoposide, cytarabine, high-dose AraC, fludarabine, G-CSF, and/or daunorubicin for use in the production of a pharmaceutical composition for use in leukemia therapy in high risk CN-AML patients, who are at least heterozygous for the minor allele of the marker SNP ID: rs16754.
As it has been shown in the invention that the absence of the transcript of the WTI gene of the major allele of the marker SNP ID: rs16754 is linked to the successful treatment using chemotherapeutical agents, suppression of the major allele WTI mRNA further increases the prospects of the use of chemotherapeutical agents in the treatment of AML patients. Accordingly, the invention further provides for a pharmaceutical composition containing a nucleotide sequence encoding or containing an RNA having a nucleic acid sequence which is reverse complementary to at least a section of the WTI gene containing the major allele of the marker SNP ID: rs16754, and to the use of a nucleotide sequence encoding or containing an RNA having a nucleic acid sequence reverse complementary to at least a section of the WT 1 gene containing the major allele of the marker SNP ID: rs16754 for the production of a pharmaceutical composition, respectively, especially for use in the treatment of AML. Preferably, the nucleic acid sequence encoding or containing an RNA having a nucleic acid sequence which is reverse complementary to at least a section of the WTI gene containing the major allele of the marker SNP ID: rs 16754 is combined with a chemotherapeutical agent, e.g. for use in the treatment of AML patients who carry the major allele of the marker homozygously.
On the other hand, the invention also allows to identify high risk CN-AML patients, who are homozygous for the major allele of the marker as not suitable for chemotherapy, as the presence of the major allele in a homozygous state indicates a lack of effectiveness of standard chemotherapy. Accordingly, the invention provides for the analysis of patients in respect of the marker, for assigning these patients to intensive treatment, including stem cell therapy.
While specific embodiments of the present invention have been shown and described, it should be understood that other modifications, substitutions and alternatives are apparent to one of ordinary skill in the art. Such modifications, substitutions and alternatives can be made without departing from the spirit and scope of the invention, which should be determined from the appended claims.
Various features of the invention are set forth in the appended claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 09161881.9 | Jun 2009 | EP | regional |
