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WO2018146239A1 - Biomarqueur de pronostic chez des patients atteints de lam - Google Patents

Biomarqueur de pronostic chez des patients atteints de lam Download PDF

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Publication number
WO2018146239A1
WO2018146239A1 PCT/EP2018/053248 EP2018053248W WO2018146239A1 WO 2018146239 A1 WO2018146239 A1 WO 2018146239A1 EP 2018053248 W EP2018053248 W EP 2018053248W WO 2018146239 A1 WO2018146239 A1 WO 2018146239A1
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WIPO (PCT)
Prior art keywords
nkp30
patients
aml
expression level
classification
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PCT/EP2018/053248
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English (en)
Inventor
Daniel Olive
Norbert Vey
Cyril FAURIAT
Anne-Sophie CHRETIEN
Christine ARNOULET
Original Assignee
INSERM (Institut National de la Santé et de la Recherche Médicale)
Université D'aix Marseille
Centre National De La Recherche Scientifique (Cnrs)
Institut Jean Paoli & Irene Calmettes
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Publication of WO2018146239A1 publication Critical patent/WO2018146239A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57426—Specifically defined cancers leukemia
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/112—Disease subtyping, staging or classification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/118—Prognosis of disease development
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70596—Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the invention relates to a method for predicting the survival time of a patient suffering from acute myeloid leukemia (AML) and classified as intermediate in the cytogenetic classification and in the ELN classification comprising i) determining in a sample obtained from the patient the expression level of NKp30 ii) comparing the expression level determined at step i) with its predetermined reference value and iii) providing a good prognosis when the expression level determined at step i) is higher than its predetermined reference value, or providing a bad prognosis when the expression level determined at step i) is lower than its predetermined reference value.
  • AML acute myeloid leukemia
  • New molecular markers have been shown to impact prognosis and may be included in future revision of ELN classification [Dohner H et al, 2010; Grimwade D et al, 2010 and Patel JP et al, 2012]
  • molecular markers do not account for the entire prognostic heterogeneity of AML and new markers are warranted.
  • accurate estimation of the risk of relapse at diagnosis or after complete remission in patients with intermediate prognosis is essential for physicians in order to evaluate the potential benefits of intensive chemotherapy and allogeneic stem cell transplantation (allo-SCT).
  • NK cells are key components of the innate immunity and substantially contribute to the antitumor immune responses, in particular in the context of AML.
  • NK cells are crucial immune effectors and play a key role in tumor rejection, with direct effect on tumor cells as well as an important role in regulation of the adaptive immune response through the cross-talk with antigen presenting cells.
  • NK cells prevent emergence of transformed cells, and are involved in response to chemotherapy and radiotherapy.
  • NK cell anti-tumor activity is triggered by NK activating receptors, including Natural Cytotoxic Receptors (NCR) such as NKp30.
  • NCR Natural Cytotoxic Receptors
  • NKp30 prognostic value As well as prospective evaluation and retrospective validation of this prognostic value in the subgroup of patients with intermediate cytogenetic risk and classified as intermediate in the ELN classification. More, they show that NKp30 recovery after complete remission is a better predictor of clinical outcome than NKp30 at diagnosis.
  • the invention relates to a method for predicting the survival time of a patient suffering from acute myeloid leukemia (AML) and classified as intermediate in the cytogenetic classification and in the ELN classification comprising i) determining in a sample obtained from the patient the expression level of NKp30 ii) comparing the expression level determined at step i) with its predetermined reference value and iii) providing a good prognosis when the expression level determined at step i) is higher than its predetermined reference value, or providing a bad prognosis when the expression level determined at step i) is lower than its predetermined reference value.
  • AML acute myeloid leukemia
  • a first aspect of the invention relates to a method for predicting the survival time of a patient suffering from acute myeloid leukemia (AML) and classified as intermediate in the cytogenetic classification and in the ELN classification comprising i) determining in a sample obtained from the patient the expression level of NKp30 ii) comparing the expression level determined at step i) with its predetermined reference value and iii) providing a good prognosis when the expression level determined at step i) is higher than its predetermined reference value, or providing a bad prognosis when the expression level determined at step i) is lower than its predetermined reference value.
  • AML acute myeloid leukemia
  • the invention relates to a method for predicting the overall survival (OS) of a patient suffering from acute myeloid leukemia (AML) and classified as intermediate in the cytogenetic classification and in the ELN classification comprising i) determining in a sample obtained from the patient the expression level of NKp30 ii) comparing the expression level determined at step i) with its predetermined reference value and iii) providing a good prognosis when the expression level determined at step i) is higher than its predetermined reference value, or providing a bad prognosis when the expression level determined at step i) is lower than its predetermined reference value.
  • OS overall survival
  • AML acute myeloid leukemia
  • the invention in another embodiment, relates to a method for predicting the event-free survival (EFS) of a patient suffering from acute myeloid leukemia (AML) and classified as intermediate in the cytogenetic classification and in the ELN classification comprising i) determining in a sample obtained from the patient the expression level of NKp30 ii) comparing the expression level determined at step i) with its predetermined reference value and iii) providing a good prognosis when the expression level determined at step i) is higher than its predetermined reference value, or providing a bad prognosis when the expression level determined at step i) is lower than its predetermined reference value.
  • EDS event-free survival
  • a second aspect of the invention relates to a method for predicting the survival time of a patient suffering from acute myeloid leukemia (AML) after complete remission comprising i) determining in a sample obtained from the patient the expression level of NKp30 ii) comparing the expression level determined at step i) with its predetermined reference value and iii) providing a good prognosis when the expression level determined at step i) is higher than its predetermined reference value, or providing a bad prognosis when the expression level determined at step i) is lower than its predetermined reference value.
  • AML acute myeloid leukemia
  • the invention relates to a method for predicting predicting the overall survival (OS) of a patient suffering from acute myeloid leukemia (AML) after complete remission comprising i) determining in a sample obtained from the patient the expression level of NKp30 ii) comparing the expression level determined at step i) with its predetermined reference value and iii) providing a good prognosis when the expression level determined at step i) is higher than its predetermined reference value, or providing a bad prognosis when the expression level determined at step i) is lower than its predetermined reference value.
  • OS overall survival
  • AML acute myeloid leukemia
  • the invention in another embodiment, relates to a method for predicting the event-free survival (EFS) of a patient suffering from acute myeloid leukemia (AML) after complete remission comprising i) determining in a sample obtained from the patient the expression level of NKp30 ii) comparing the expression level determined at step i) with its predetermined reference value and iii) providing a good prognosis when the expression level determined at step i) is higher than its predetermined reference value, or providing a bad prognosis when the expression level determined at step i) is lower than its predetermined reference value.
  • EFS event-free survival
  • OS Overall survival
  • AML AML
  • the overall survival rate is often stated as a two-year survival rate (notably for AML), which is the percentage of people in a study or treatment group who are alive two years after their diagnosis or the start of treatment.
  • ETS event-free survival
  • survival time regroups the terms OS and EFS.
  • a patient suffering from acute myeloid leukemia (AML) and classified as intermediate in the cytogenetic classification and in the ELN classification denotes a patient with AML and classified according two international classification: the cytogenetic classification and the ELN classification (see for example the website located at leukemia-net.org). These two classifications enable to classify patients with AML into four groups: favorable, intermediate-I, intermediate-II, adverse.
  • patient will be treated with chemotherapy alone (favorable prognosis) or with allogeneic stem cell transplantation (allo-SCT) in first complete remission (adverse prognosis) (see for example Grimwade D et al, 1998; Slovak ML et al, 2000; Dohner H et al, 2010 and Stelljes M et al, 2013).
  • chemotherapy alone
  • allogeneic stem cell transplantation allogeneic stem cell transplantation
  • the hematopoietic stem cells come from a donor related or not to the recipient but of the same species.
  • NKp30 denotes a receptor of the natural cytotoxicity receptors (NCRs) family. NKp30 is a triggering receptor expressed on the plasmatic membrane of NK cells, also known as CD337 or NCR3.
  • sample denotes, blood, peripheral-blood, serum, plasma or purified NK cells.
  • the sample is fresh or frozen.
  • patient refers to an individual with symptoms of AML.
  • Measuring the expression level of NKp30 can be done by measuring the gene expression level of NKp30 or by measuring the level of the protein NKp30 and can be performed by a variety of techniques well known in the art.
  • the expression level of a gene may be determined by determining the quantity of mRNA.
  • Methods for determining the quantity of mRNA are well known in the art.
  • the nucleic acid contained in the samples e.g., cell or tissue prepared from the patient
  • the extracted mRNA is then detected by hybridization (e. g., Northern blot analysis, in situ hybridization) and/or amplification (e.g., RT-PCR).
  • LCR ligase chain reaction
  • TMA transcription- mediated amplification
  • SDA strand displacement amplification
  • NASBA nucleic acid sequence based amplification
  • Nucleic acids having at least 10 nucleotides and exhibiting sequence complementarity or homology to the mRNA of interest herein find utility as hybridization probes or amplification primers. It is understood that such nucleic acids need not be identical, but are typically at least about 80% identical to the homologous region of comparable size, more preferably 85% identical and even more preferably 90-95% identical. In certain embodiments, it will be advantageous to use nucleic acids in combination with appropriate means, such as a detectable label, for detecting hybridization.
  • the nucleic acid probes include one or more labels, for example to permit detection of a target nucleic acid molecule using the disclosed probes.
  • a nucleic acid probe includes a label (e.g., a detectable label).
  • a "detectable label” is a molecule or material that can be used to produce a detectable signal that indicates the presence or concentration of the probe (particularly the bound or hybridized probe) in a sample.
  • a labeled nucleic acid molecule provides an indicator of the presence or concentration of a target nucleic acid sequence (e.g., genomic target nucleic acid sequence) (to which the labeled uniquely specific nucleic acid molecule is bound or hybridized) in a sample.
  • a label associated with one or more nucleic acid molecules can be detected either directly or indirectly.
  • a label can be detected by any known or yet to be discovered mechanism including absorption, emission and/ or scattering of a photon (including radio frequency, microwave frequency, infrared frequency, visible frequency and ultra-violet frequency photons).
  • Detectable labels include colored, fluorescent, phosphorescent and luminescent molecules and materials, catalysts (such as enzymes) that convert one substance into another substance to provide a detectable difference (such as by converting a colorless substance into a colored substance or vice versa, or by producing a precipitate or increasing sample turbidity), haptens that can be detected by antibody binding interactions, and paramagnetic and magnetic molecules or materials.
  • detectable labels include fluorescent molecules (or fluorochromes).
  • fluorescent molecules or fluorochromes
  • Numerous fluorochromes are known to those of skill in the art, and can be selected, for example from Life Technologies (formerly Invitrogen), e.g., see, The Handbook— A Guide to Fluorescent Probes and Labeling Technologies).
  • fluorophores that can be attached (for example, chemically conjugated) to a nucleic acid molecule (such as a uniquely specific binding region) are provided in U.S. Pat. No.
  • fluorophores include thiol-reactive europium chelates which emit at approximately 617 mn (Heyduk and Heyduk, Analyt. Biochem. 248:216-27, 1997; J. Biol. Chem. 274:3315-22, 1999), as well as GFP, LissamineTM, diethylaminocoumarin, fluorescein chlorotriazinyl, naphtho fluorescein, 4,7-dichlororhodamine and xanthene (as described in U.S. Pat. No. 5,800,996 to Lee et al.) and derivatives thereof.
  • fluorophores known to those skilled in the art can also be used, for example those available from Life Technologies (Invitrogen; Molecular Probes (Eugene, Oreg.)) and including the ALEXA FLUOR® series of dyes (for example, as described in U.S. Pat. Nos. 5,696,157, 6, 130, 101 and 6,716,979), the BODIPY series of dyes (dipyrrometheneboron dif uoride dyes, for example as described in U.S. Pat. Nos.
  • a fluorescent label can be a fluorescent nanoparticle, such as a semiconductor nanocrystal, e.g., a QUANTUM DOTTM (obtained, for example, from Life Technologies (QuantumDot Corp, Invitrogen Nanocrystal Technologies, Eugene, Oreg.); see also, U.S. Pat. Nos. 6,815,064; 6,682,596; and 6,649, 138).
  • Semiconductor nanocrystals are microscopic particles having size-dependent optical and/or electrical properties.
  • a secondary emission of energy occurs of a frequency that corresponds to the handgap of the semiconductor material used in the semiconductor nanocrystal. This emission can he detected as colored light of a specific wavelength or fluorescence.
  • Semiconductor nanocrystals with different spectral characteristics are described in e.g., U.S. Pat. No. 6,602,671.
  • semiconductor nanocrystals can he produced that are identifiable based on their different spectral characteristics.
  • semiconductor nanocrystals can he produced that emit light of different colors hased on their composition, size or size and composition.
  • quantum dots that emit light at different wavelengths based on size (565 mn, 655 mn, 705 mn, or 800 mn emission wavelengths), which are suitable as fluorescent labels in the probes disclosed herein are available from Life Technologies (Carlshad, Calif).
  • Additional labels include, for example, radioisotopes (such as 3 H), metal chelates such as DOTA and DPTA chelates of radioactive or paramagnetic metal ions like Gd3+, and liposomes.
  • radioisotopes such as 3 H
  • metal chelates such as DOTA and DPTA chelates of radioactive or paramagnetic metal ions like Gd3+
  • liposomes include, for example, radioisotopes (such as 3 H), metal chelates such as DOTA and DPTA chelates of radioactive or paramagnetic metal ions like Gd3+, and liposomes.
  • Detectable labels that can he used with nucleic acid molecules also include enzymes, for example horseradish peroxidase, alkaline phosphatase, acid phosphatase, glucose oxidase, beta-galactosidase, beta-glucuronidase, or beta-lactamase.
  • enzymes for example horseradish peroxidase, alkaline phosphatase, acid phosphatase, glucose oxidase, beta-galactosidase, beta-glucuronidase, or beta-lactamase.
  • an enzyme can he used in a metallographic detection scheme.
  • SISH silver in situ hyhridization
  • Metallographic detection methods include using an enzyme, such as alkaline phosphatase, in combination with a water-soluble metal ion and a redox-inactive substrate of the enzyme. The substrate is converted to a redox-active agent by the enzyme, and the redoxactive agent reduces the metal ion, causing it to form a detectable precipitate.
  • Metallographic detection methods also include using an oxido-reductase enzyme (such as horseradish peroxidase) along with a water soluble metal ion, an oxidizing agent and a reducing agent, again to form a detectable precipitate.
  • an oxido-reductase enzyme such as horseradish peroxidase
  • Probes made using the disclosed methods can be used for nucleic acid detection, such as ISH procedures (for example, fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH) and silver in situ hybridization (SISH)) or comparative genomic hybridization (CGH).
  • ISH procedures for example, fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH) and silver in situ hybridization (SISH)
  • CGH comparative genomic hybridization
  • ISH In situ hybridization
  • a sample containing target nucleic acid sequence e.g., genomic target nucleic acid sequence
  • a metaphase or interphase chromosome preparation such as a cell or tissue sample mounted on a slide
  • a labeled probe specifically hybridizable or specific for the target nucleic acid sequence (e.g., genomic target nucleic acid sequence).
  • the slides are optionally pretreated, e.g., to remove paraffin or other materials that can interfere with uniform hybridization.
  • the sample and the probe are both treated, for example by heating to denature the double stranded nucleic acids.
  • the probe (formulated in a suitable hybridization buffer) and the sample are combined, under conditions and for sufficient time to permit hybridization to occur (typically to reach equilibrium).
  • the chromosome preparation is washed to remove excess probe, and detection of specific labeling of the chromosome target is performed using standard techniques.
  • a biotinylated probe can be detected using fluorescein-labeled avidin or avidin-alkaline phosphatase.
  • fluorescein-labeled avidin or avidin-alkaline phosphatase For fluorochrome detection, the fluorochrome can be detected directly, or the samples can be incubated, for example, with fluorescein isothiocyanate (FITC)- conjugated avidin. Amplification of the FITC signal can be effected, if necessary, by incubation with biotin-conjugated goat antiavidin antibodies, washing and a second incubation with FITC- conjugated avidin.
  • FITC fluorescein isothiocyanate
  • samples can be incubated, for example, with streptavidin, washed, incubated with biotin-conjugated alkaline phosphatase, washed again and pre-equilibrated (e.g., in alkaline phosphatase (AP) buffer).
  • AP alkaline phosphatase
  • probes labeled with fluorophores can be directly optically detected when performing FISH.
  • the probe can be labeled with a nonfluorescent molecule, such as a hapten (such as the following non- limiting examples: biotin, digoxigenin, DNP, and various oxazoles, pyrrazoles, thiazoles, nitroaryls, benzofurazans, triterpenes, ureas, thioureas, rotenones, coumarin, courmarin-based compounds, Podophyllotoxin, Podophyllotoxin-based compounds, and combinations thereof), ligand or other indirectly detectable moiety.
  • a hapten such as the following non- limiting examples: biotin, digoxigenin, DNP, and various oxazoles, pyrrazoles, thiazoles, nitroaryls, benzofurazans, triterpenes, ureas, thioureas, roten
  • Probes labeled with such non-fluorescent molecules (and the target nucleic acid sequences to which they bind) can then be detected by contacting the sample (e.g., the cell or tissue sample to which the probe is bound) with a labeled detection reagent, such as an antibody (or receptor, or other specific binding partner) specific for the chosen hapten or ligand.
  • a labeled detection reagent such as an antibody (or receptor, or other specific binding partner) specific for the chosen hapten or ligand.
  • the detection reagent can be labeled with a fluorophore (e.g., QUANTUM DOT®) or with another indirectly detectable moiety, or can be contacted with one or more additional specific binding agents (e.g., secondary or specific antibodies), which can be labeled with a fluorophore.
  • the probe, or specific binding agent (such as an antibody, e.g., a primary antibody, receptor or other binding agent) is labeled with an enzyme that is capable of converting a fluorogenic or chromogenic composition into a detectable fluorescent, colored or otherwise detectable signal (e.g., as in deposition of detectable metal particles in SISH).
  • the enzyme can be attached directly or indirectly via a linker to the relevant probe or detection reagent. Examples of suitable reagents (e.g., binding reagents) and chemistries (e.g., linker and attachment chemistries) are described in U.S. Patent Application Publication Nos. 2006/0246524; 2006/0246523, and 2007/ 01 17153.
  • multiplex detection schemes can he produced to facilitate detection of multiple target nucleic acid sequences (e.g., genomic target nucleic acid sequences) in a single assay (e.g., on a single cell or tissue sample or on more than one cell or tissue sample).
  • a first probe that corresponds to a first target sequence can he labelled with a first hapten, such as biotin, while a second probe that corresponds to a second target sequence can be labelled with a second hapten, such as DNP.
  • the bound probes can he detected by contacting the sample with a first specific binding agent (in this case avidin labelled with a first fluorophore, for example, a first spectrally distinct QUANTUM DOT®, e.g., that emits at 585 mn) and a second specific binding agent (in this case an anti-DNP antibody, or antibody fragment, labelled with a second fluorophore (for example, a second spectrally distinct QUANTUM DOT®, e.g., that emits at 705 mn).
  • a first specific binding agent in this case avidin labelled with a first fluorophore, for example, a first spectrally distinct QUANTUM DOT®, e.g., that emits at 585 mn
  • a second specific binding agent in this case an anti-DNP antibody, or antibody fragment, labelled with a second fluorophore (for example, a second spectrally distinct QUANTUM DOT®,
  • Probes typically comprise single-stranded nucleic acids of between 10 to 1000 nucleotides in length, for instance of between 10 and 800, more preferably of between 15 and 700, typically of between 20 and 500.
  • Primers typically are shorter single- stranded nucleic acids, of between 10 to 25 nucleotides in length, designed to perfectly or almost perfectly match a nucleic acid of interest, to be amplified.
  • the probes and primers are "specific" to the nucleic acids they hybridize to, i.e. they preferably hybridize under high stringency hybridization conditions (corresponding to the highest melting temperature Tm, e.g., 50 % formamide, 5x or 6x SCC.
  • SCC is a 0.15 M NaCl, 0.015 M Na-citrate).
  • the nucleic acid primers or probes used in the above amplification and detection method may be assembled as a kit.
  • a kit includes consensus primers and molecular probes.
  • a preferred kit also includes the components necessary to determine if amplification has occurred.
  • the kit may also include, for example, PCR buffers and enzymes; positive control sequences, reaction control primers; and instructions for amplifying and detecting the specific sequences.
  • the methods of the invention comprise the steps of providing total RNAs extracted from cumulus cells and subjecting the RNAs to amplification and hybridization to specific probes, more particularly by means of a quantitative or semiquantitative RT-PCR.
  • the expression level is determined by DNA chip analysis.
  • DNA chip or nucleic acid microarray consists of different nucleic acid probes that are chemically attached to a substrate, which can be a microchip, a glass slide or a microsphere-sized bead.
  • a microchip may be constituted of polymers, plastics, resins, polysaccharides, silica or silica-based materials, carbon, metals, inorganic glasses, or nitrocellulose.
  • Probes comprise nucleic acids such as cDNAs or oligonucleotides that may be about 10 to about 60 base pairs.
  • a sample from a test subject optionally first subjected to a reverse transcription, is labelled and contacted with the microarray in hybridization conditions, leading to the formation of complexes between target nucleic acids that are complementary to probe sequences attached to the microarray surface.
  • the labelled hybridized complexes are then detected and can be quantified or semi-quantified. Labelling may be achieved by various methods, e.g. by using radioactive or fluorescent labelling.
  • Many variants of the microarray hybridization technology are available to the man skilled in the art (see e.g. the review by Hoheisel, Nature Reviews, Genetics, 2006, 7:200-210).
  • Expression level of a gene may be expressed as absolute expression level or normalized expression level.
  • expression levels are normalized by correcting the absolute expression level of a gene by comparing its expression to the expression of a gene that is not a relevant for determining the cancer stage of the patient, e.g., a housekeeping gene that is constitutively expressed.
  • Suitable genes for normalization include housekeeping genes such as the actin gene ACTB, ribosomal 18S gene, GUSB, PGKl, TFRC, GAPDH, GUSB, TBP and ABL1. This normalization allows the comparison of the expression level in one sample, e.g., a patient sample, to another sample, or between samples from different sources.
  • Predetermined reference values used for comparison may comprise "cut-off or "threshold" values that may be determined as described herein.
  • Each reference (“cut-off) value for NKp30 expression may be predetermined by carrying out a method comprising the steps of a) providing a collection of samples from patients suffering of AML (after diagnosis of
  • step e providing, for each sample provided at step a), information relating to the actual clinical outcome for the corresponding cancer patient (i.e. the duration of the event free survival (EFS) or the overall survival (OS) or both);
  • information relating to the actual clinical outcome for the corresponding cancer patient i.e. the duration of the event free survival (EFS) or the overall survival (OS) or both;
  • NKp30 has been assessed for 100 AML samples of 100 patients.
  • the 100 samples are ranked according to their expression level.
  • Sample 1 has the best expression level and sample 100 has the worst expression level.
  • a first grouping provides two subsets: on one side sample Nr 1 and on the other side the 99 other samples.
  • the next grouping provides on one side samples 1 and 2 and on the other side the 98 remaining samples etc., until the last grouping: on one side samples 1 to 99 and on the other side sample Nr 100.
  • Kaplan Meier curves are prepared for each of the 99 groups of two subsets. Also for each of the 99 groups, the p value between both subsets was calculated.
  • the reference value is selected such as the discrimination based on the criterion of the minimum p value is the strongest.
  • the expression level corresponding to the boundary between both subsets for which the p value is minimum is considered as the reference value. It should be noted that the reference value is not necessarily the median value of expression levels.
  • the reference value (cut-off value) may be used in the present method to discriminate AML samples and therefore the corresponding patients.
  • Kaplan-Meier curves of percentage of survival as a function of time are commonly used to measure the fraction of patients living for a certain amount of time after treatment and are well known by the man skilled in the art.
  • Such predetermined reference values of expression level may be determined for any gene defined above.
  • the level of the protein NKp30 may also be measured and can be performed by a variety of techniques well known in the art.
  • protein concentration may be measured for example by capillary electrophoresis-mass spectroscopy technique (CE-MS) or ELISA performed on the sample. Detection of protein concentration in the sample may also be performed by measuring the level of the protein NKp30.
  • the "level of protein” or the “protein level expression” means the quantity or concentration of said protein.
  • the "level of protein” means the level of NKp30 protein fragments.
  • the "level of protein” means the quantitative measurement of the protein NKp30 expression relative to a negative control.
  • Such methods comprise contacting a sample with a binding partner capable of selectively interacting with proteins present in the sample.
  • the binding partner is generally an antibody that may be polyclonal or monoclonal, preferably monoclonal.
  • the presence of the protein can be detected using standard electrophoretic and immunodiagnostic techniques, including immunoassays such as competition, direct reaction, or sandwich type assays.
  • immunoassays such as competition, direct reaction, or sandwich type assays.
  • assays include, but are not limited to, Western blots; agglutination tests; enzyme-labeled and mediated immunoassays, such as ELISAs; biotin/avidin type assays; radioimmunoassays; Immunoelectrophoresis; immunoprecipitation, capillary electrophoresis- mass spectroscopy technique (CE-MS).etc.
  • the reactions generally include revealing labels such as fluorescent, chemio luminescent, radioactive, enzymatic labels or dye molecules, or other methods for detecting the formation of a complex between the antigen and the antibody or antibodies reacted therewith.
  • the aforementioned assays generally involve separation of unbound protein in a liquid phase from a solid phase support to which antigen-antibody complexes are bound.
  • Solid supports which can be used in the practice of the invention include substrates such as nitrocellulose (e. g., in membrane or microtiter well form); polyvinylchloride (e. g., sheets or microtiter wells); polystyrene latex (e.g., beads or microtiter plates); polyvinylidine fluoride; diazotized paper; nylon membranes; activated beads, magnetically responsive beads, and the like.
  • an ELISA method can be used, wherein the wells of a microtiter plate are coated with a set of antibodies against the proteins to be tested. A sample containing or suspected of containing the marker protein is then added to the coated wells. After a period of incubation sufficient to allow the formation of antibody-antigen complexes, the plate(s) can be washed to remove unbound moieties and a detectably labeled secondary binding molecule is added. The secondary binding molecule is allowed to react with any captured sample marker protein, the plate is washed and the presence of the secondary binding molecule is detected using methods well known in the art. Methods of the invention may comprise a step consisting of comparing the proteins and fragments concentration in circulating cells with a control value.
  • concentration of protein refers to an amount or a concentration of a transcription product, for instance the protein NKp30.
  • a level of a protein can be expressed as nanograms per microgram of tissue or nanograms per milliliter of a culture medium, for example. Alternatively, relative units can be employed to describe a concentration.
  • concentration of proteins may refer to fragments of the protein NKp30.
  • fragment of NKp30 protein may also be measured.
  • the detection of the level of NKp30 can be performed by flow cytometry.
  • the method consists of determining the mean fluorescence intensity (MFI) ratio (NKp30 MFI / isotype control MFI, referred to as rMFI) expressed on NK cells.
  • MFI mean fluorescence intensity
  • rMFI isotype control MFI
  • NKp30 when the expression level of NKp30 is high the prognosis of the patient suffering from AML is good and when the expression level of NKp30 is low the prognosis of the patient suffering from AML is bad.
  • the extracellular part of the NKp30 protein is detected.
  • methods of the invention comprise measuring the expression level of at least one further biomarker or prognostic score.
  • biomarker refers generally to a cytogenetic marker, a molecule, the expression of which in a sample from a patient can be detected by standard methods in the art (as well as those disclosed herein), and is predictive or denotes a condition of the subject from which it was obtained.
  • NKp30 Various validated prognostic biomarkers or prognostic scores may be combined to NKp30 in order to improve methods of the invention and especially some parameters such as the specificity (see for example Cornelissen et al. 2012).
  • the other biomarkers may be selected from the group of AML biomarkers consisting of cytogenetics markers (like t(8;21), t(15;17), inv(16) see for example Grimwade et al, 2010or Byrd et al, 2002), lactate dehydrogenase (see for example Haferlach et al 2003), FLT3, NPM1, CEBPa (see for example Thomasger et al, 2002, Dohner et al, 2010).
  • the prognostic scores that may be combined to NKp30 may be for example the disease risk index (DRI) (Armand et al 2012).
  • DRI disease risk index
  • kits for performing the methods of the invention comprise means for measuring the expression level of NKp30 in the sample obtained from the patient.
  • kits may include probes, primers macroarrays or microarrays as above described.
  • the kit may comprise a set of probes as above defined, usually made of DNA, and that may be pre-labelled.
  • probes may be unlabelled and the ingredients for labelling may be included in the kit in separate containers.
  • the kit may further comprise hybridization reagents or other suitably packaged reagents and materials needed for the particular hybridization protocol, including solid-phase matrices, if applicable, and standards.
  • the kit of the invention may comprise amplification primers that may be pre- labelled or may contain an affinity purification or attachment moiety.
  • the kit may further comprise amplification reagents and also other suitably packaged reagents and materials needed for the particular amplification protocol.
  • the present invention also relates to NKp30 as a biomarker for outcome of AML in a patient classified as intermediate in the cytogenetic classification and in the ELN classification.
  • a third aspect of the invention relates to a chemotherapeutic compound and/or an allogeneic stem cell (allo-SCT) for allo-SCT transplantation for use in the treatment of AML in a patient with a bad prognosis as described above.
  • the invention relates to i) a chemotherapeutic compound, and ii) an allo-SCT, as a combined preparation for simultaneous, separate or sequential use in the treatment of AML in patient with a bad prognosis as described above.
  • the invention in another embodiment, relates to a method for treating AML in a patient with a bad prognosis as described above comprising administering to said subject in need thereof a chemotherapeutic compound or a allogeneic stem cell transplantation.
  • chemotherapeutic compounds may be selected in the group consisting in: fludarabine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, platinum complexes such as cisplatin, carboplatin and oxaliplatin, mitomycin, dacarbazine, procarbazine, etoposide, teniposide, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L-asparaginase, epimbicm, 5-fluorouracil, taxanes such as docetaxel and paclitaxel, leucovorin, levamisole, i
  • additional anticancer agents may be selected from, but are not limited to, one or a combination of the following class of agents: alkylating agents, plant alkaloids, DNA topoisomerase inhibitors, anti-folates, pyrimidine analogs, purine analogs, DNA antimetabolites, taxanes, podophyllotoxin, hormonal therapies, retinoids, photosensitizers or photodynamic therapies, angiogenesis inhibitors, antimitotic agents, isoprenylation inhibitors, cell cycle inhibitors, actinomycins, bleomycins, anthracyclines, MDR inhibitors and Ca2+ ATPase inhibitors.
  • further therapeutic active agent can be administred to the patient.
  • This active agent can be a hematopoietic colony-stimulating factor.
  • Suitable hematopoietic colony stimulating factors include, but are not limited to filgrastim, sargramostim, molgramostim and epoietin alpha.
  • the chemotherapeutic compound is the cytarabine or the anthracycline.
  • treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subjects at risk of contracting the disease or suspected to have contracted the disease as well as subjects who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., disease manifestation, etc.]).
  • a fourth aspect of the invention relates to a therapeutic composition
  • a therapeutic composition comprising a chemotherapeutic compound and/or allogenic stem cells for allo-SCT according to the invention for use in the treatment of AML in patient with a bad prognosis as described above.
  • Any therapeutic agent of the invention may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions.
  • “Pharmaceutically” or “pharmaceutically acceptable” refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate.
  • a pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • compositions for example, the route of administration, the dosage and the regimen naturally depend upon the condition to be treated, the severity of the illness, the age, weight, and sex of the patient, etc.
  • compositions of the invention can be formulated for a topical, oral, intranasal, parenteral, intraocular, intravenous, intramuscular or subcutaneous administration and the like.
  • the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
  • the doses used for the administration can be adapted as a function of various parameters, and in particular as a function of the mode of administration used, of the relevant pathology, or alternatively of the desired duration of treatment.
  • compositions include, e.g. tablets or other solids for oral administration; time release capsules; and any other form currently can be used.
  • FIGURES are a diagrammatic representation of FIGURES.
  • Figure 1 NKp30 expression on peripheral NK cells at diagnosis predicts clinical outcome.
  • Figure 2 NKp30 expression stratifies patients with intermediate cytogenetic prognosis.
  • Figure 3 NKp30 expression stratifies patients with intermediate ELN.
  • FIG. 4 Threshold determination for NKp30 expression onNK cells (IPC prospective cohort).
  • A Distribution histograms of NKp30 mean fluorescence intensity (MFI) ratio (NKp30 MFI / isotype control MFI) in patients with AML at diagnosis. The curves are estimates of population density distribution.
  • B The volcano plot shows log of P value for overall survival according to threshold for NKp30 expression at diagnosis. The dashed line represents the threshold used in the rest of the study.
  • Figure 5 NKp30 recovery after CR is a better predictor of clinical outcome than NKp30 at diagnosis.
  • A The kinetics of NKp30 expression was assessed after CR (day 30, 60 and 90 after the last induction chemotherapy) in the IPC prospective cohort.
  • NKp30 expression Thirty-nine patients were tested for NKp30 expression at day 30, 28 patients at day 60 and 23 patients at day 90.
  • Table 1 Baseline patients characteristics - IPC prospective cohort
  • Allo-SCT allogeneic stem cell transplantation
  • Auto-SCT autologous stem cell transplantation
  • BM bone marrow
  • CR complete remission
  • FAB French- American-British classification
  • M male
  • F female
  • ITD internal tandem duplication
  • MDS myelodysplasia syndrome
  • NA not available
  • Nb number
  • t-AML therapy-related AML
  • s-AML secondary AML
  • OS overall survival
  • EFS event-free survival.
  • Table 2 Baseline patients characteristics - GOELAMS validation cohort Allo-SCT: allogeneic stem cell transplantation; Auto-SCT: autologous stem cell transplantation; BM: bone marrow; CR : complete remission ; FAB: French- American-British classification; M : male ; F : female; ITD: internal tandem duplication; MDS: myelodysplasia syndrome; NA : not available; Nb: number; t-AML: therapy-related AML; s-AML; secondary AML; OS: overall survival; EFS: event-free survival.
  • Allo-SCT allogeneic stem cell transplantation
  • Auto-SCT autologous stem cell transplantation
  • BM bone marrow
  • CR complete remission
  • FAB French- American-British classification
  • M male
  • F female
  • ITD internal tandem duplication
  • MDS myelodysplasia syndrome
  • NA not available
  • Nb number
  • t-AML
  • Multivariate Cox regression models were used to assess the predictive value of NKp30 expression while adjusting for the prognostic factors in the population (age at diagnosis, disease status, ELN, leukocytosis, and allogeneic stem cell transplantation as a time-dependent covariate).
  • NKp30 expression on NK cells at diagnosis was assessed in a total of 202 patients. Two cohorts of patients were analyzed.
  • the Paoli Calmettes Institute (IPC) prospective cohort included 116 patients with newly diagnosed non-acute promyelocytic leukemia (APL) AML admitted between November 2007 and November 2012, aged 18 to 65 years and treated with conventional 3+7 induction chemotherapy as previously described [Devillier R et al, 2015].
  • the Groupe ery d'Etude des Leucemies Aigues et harvest Maladies du Sang (GOELAMS) validation cohort included 86 patients from the LAM2006IR prospective multicenter randomized trial, included between November 2007 and April 2012 (NCT00860639).
  • For the GOELAMS validation cohort handling, conditioning and storing of patients samples were performed by the FILOtheque AML (N° BB-0033-00073), tumor bank of the FILO group, Cochin hospital, Paris. Analyses were performed in the Biopathology department and on the IPC Immunomonitoring platform. Assays were performed blinded to the study endpoint. Samples from the IPC prospective cohort and from the GOELAMS validation cohort were analyzed by independent experimenters.
  • NK cells from whole blood EDTA or frozen PBMC were immunostained with fluorescein isothiocyanate (FITC)-conjugated or Phycoerythrin-Texas Red-xTM (ECD)- conjugated anti-CD3, Phycoerythrin-Cyanine 7 (PC7)- or Allophycocyanin (APC) AF700- conjugated anti-CD56, and APC- or Krome OrangeTM (KO)-conjugated anti-CD45 antibodies.
  • FITC fluorescein isothiocyanate
  • ECD Phycoerythrin-Texas Red-xTM
  • PC7 Phycoerythrin-Cyanine 7
  • API Allophycocyanin
  • NKp30 triggering receptor expression was measured with Phycoerythrin (PE)-conjugated monoclonal antibodies. Isotype controls were mouse (PE)- conjugated monoclonal antibodies. All antibodies used were kindly provided by Beckman- Coulter, Marseille, France. Red blood cells were lysed with BD FACS Lysing solution (BD Biosciences, San Jose, CA) before acquisition.
  • the NKp30 mean fluorescence intensity (MFI) ratio (NKp30 MFI / isotype control MFI, referred to as rMFI) was calculated for each patient. NKp30 expression was assessed at diagnosis and after complete remission, at day 30, 60 and 90 after the last induction chemotherapy.
  • NKp30 low and NKp30 hlgh Patients were classified into two groups, NKp30 low and NKp30 hlgh , according to NKp30 rMFI.
  • Fig 4A displays inter- individual variability of NKp30 expression in AML patients.
  • the distribution of NKp30 expression was a juxtaposition of three Gaussian distributions. (d'Agostino and Pearson normality test and Kernel density estimation).
  • the threshold based on dispersion criteria was discriminant for survival analyses.
  • patients from both cohorts were classified into 2 distinct subgroups (NKp30 hlgh and NKp30 low phenotype) for survival analyses according to this threshold.
  • CIR Cumulative incidence of relapse
  • the patient characteristics, stratified by NKp30 expression groups, are summarized in Table 1 (IPC prospective cohort) and Table 2 (GOELAMS validation cohort).
  • IPC prospective cohort 21 patients had favorable cytogenetics (18.9%), 76 had intermediate cytogenetics (65.5%>) and 19 had unfavorable cytogenetics (16.4%).
  • the mean age ( ⁇ SD) at induction was 47.1 years ( ⁇ 10.6).
  • Median follow-up after diagnosis was 35.1 months.
  • the mean age ( ⁇ SD) at induction was 46.3 years ( ⁇ 11.0).
  • Median follow-up after diagnosis was 25.2 months.
  • Cytogenetic classification and European Leukemia Net (ELN) genetic classification FLT3/CEBPa/NPMl mutational status
  • NKp30 expression on Natural Killer (NK) cells was assessed by flow cytometry.
  • 70 (60.3%) had NKp30 hlgh phenotype, and 46 (39.7%) had low NKp30 low phenotype (Table 1).
  • 77 89.5%) NKp30 high phenotype and 9 (10.5%) had NKp30 low phenotype.
  • the frequency of patients with NKp30 high and low phenotype did not differ between age, cytogenetics or number of inductions.
  • NKp30 expression on peripheral NK cells at diagnosis predicts clinical outcome
  • NKp30 status stratifies patients with intermediate cytogenetic prognosis
  • N p30 recovery after CR is a better predictor of clinical outcome than N p30 at diagnosis
  • NKp30 expression was assessed in 39 patients from the IPC prospective cohort in CR after chemotherapy. Induction chemotherapy resulted in significant increase of NKp30 expression at day 30 that was maintained at least until day 90 (Fig 5A).
  • Fig 5A we then divided patients in two groups based on presence or absence of death 2 years after diagnosis.
  • Fig 5B NKp30 expression significantly increased at day 30 (Fig 5B). This increase remained significant until day 60.
  • Fig 5B no significant increase was evidenced compared to diagnosis (Fig 5B).
  • Fig 5B survival stratified by NKp30 expression at day 30.
  • Patel JP, Gonen M, Figueroa ME, et al Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. New England Journal of Medicine 366: 1079-1089, 2012 Slovak ML, Kopecky KJ, Cassileth PA, et al: Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 96:4075-4083, 2000.

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Abstract

La présente invention concerne un procédé de prédiction du temps de survie d'un patient souffrant d'une leucémie myéloïde aiguë (LAM). La gestion thérapeutique des patients, classée comme intermédiaire dans la classification ELN, est difficile. En suivant des études sur une cohorte de 202 patients, les inventeurs montrent que NKp30 pourrait être utile pour reclasser 40 % de patients sur un pronostic intermédiaire dans le groupe de pronostic défavorable. Le biomarqueur de l'invention permet ainsi de rendre les patients éligibles pour une thérapie post-rémission appropriée (c'est-à-dire une chimiothérapie et une allogreffe). Ainsi, la présente invention concerne un procédé de prédiction du temps de survie d'un patient souffrant d'une leucémie myéloïde aiguë (LAM) et classé comme intermédiaire dans la classification cytogénétique et dans la classification ELN comprenant la détermination dans un échantillon (par exemple, des échantillons de sang périphérique total frais ou des cellules mononucléaires du sang périphérique) du niveau d'expression de NKp30. Typiquement, le niveau est déterminé par cytométrie en flux.
PCT/EP2018/053248 2017-02-10 2018-02-09 Biomarqueur de pronostic chez des patients atteints de lam WO2018146239A1 (fr)

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WO2022013256A1 (fr) * 2020-07-15 2022-01-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation de cd160 en tant que biomarqueur dans la leucémie aiguë myéloïde

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