WO2010054298A1 - Method for optimizing the treatment of chronic myeloid leukemia with abl tyrosine kinase inhibitors - Google Patents
Method for optimizing the treatment of chronic myeloid leukemia with abl tyrosine kinase inhibitors Download PDFInfo
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Definitions
- the present invention relates to a method of treating chronic myeloid ieukemia (CML) in a human patient population.
- CML chronic myeloid ieukemia
- ABSC ATP-binding cassette
- c-Myc was a direct regulator and physically associated with the promoter of tested ABC genes, as assessed by Chromatin immunoprecipitation in a eel! Sine derived from a Ph+ CML patient
- our findings supported the model of a direct and coordinate regulation of a large set of ABC genes by the c-Myc transcription factor.
- Our study also supported prior findings that deregulation of specific set of ABC genes could be an important molecular mechanism altering imatinib transport.
- St is hence an object of the present invention to identify novel prognostic indicators to improve both an initial assessment and subsequent monitoring of CML patients, it is a further object of present invention to specify a patient population for the treatment of CML, in particular by estimating treatment response. It is a further object of present invention to improve success of treatment of CML. It is a further object of present invention to improve success of treatment of CML with imatinib. it is a further object of present invention to predict achievement of major molecular response (MMR) in CML patients.
- MMR major molecular response
- the "ASCC3 level, as used herein, relates to the ABCC3 expression i ⁇ vel relative to the expression of at least one reference gene.
- the expression level of ABCC3 is quantified by quantity PCR and normaiized to the PCR products of three reference genes, i.e. GUSB, b-actin and GAPDH,
- the term “A8CC3 level” as used herein is defined as the ABCC3 expression level relative to the expression of GAPDH gene, measured by quantitative PCR
- the ⁇ Ct is calculated as the difference between the Ct of ABCC3 and Ct of GAPDH, when the PCR reaction has an efficiency higher than 90% and the Cf has been determined in the linearity range of the PCR curves.
- the low ABCC3 level refers to ⁇ Ct higher than 4, more preferred to ⁇ Ct higher than 5-
- the Sow ABCC3 levei refers to ⁇ Ct from 4 to 100, 5 to 100, 8 to 100, 10 to 100,
- the expression level of A8CC3 before the imatinib treatment may be used to predict CML patients likely to respond well to standard dose imatinib mesylate, and those who would be most iikely to benefit from a higher dose of Imatinib mesylate.
- the present invention pertains to the use of ABCC3 as a biomarker for CML patients.
- the level of ABCC3 is indicative for the therapeutic efficacy of imatinib or a pharmaceutically acceptable salt thereof.
- the level of ABCC3 in a CML patient can be used for the assessment of the therapeutic amount of imatinib or pharmaceutically acceptable salt thereof.
- a level of ABCC3 level referring to ⁇ Ct higher than 4 is indicative for raising the therapeutic amount of imatinib or a pharmaceutically acceptable salt thereof, preferably to at least 150% of the standard dosage prescribed for CML patients.
- the present invention pertains the use of ABCC3 as a biomarker for CML patients for determining the therapeutic efficacy of imatinib or a pharmaceutically acceptable salt thereof.
- present invention relates to an ex vivo method for determining the ABCC3 level, comprising the steps of a) determining the mRNA level of ABCC3 from a sample; b) determining the mRNA level of GAPDH; c) normalizing ABCC3 mRNA to GAPDH mRNA.
- such sample is a blood sample, even more preferred a sample of peripheral blood.
- the ABCC3 level is preferably determined with Q-PCR as described herein.
- a further aspect of present invention relates to the use of the above ex vivo method for screening CML patients to determine appropriate treatment with imatinib, or a pharmaceutically acceptable salt thereof.
- appropriate treatment in this context means to obtain more efficient treatment of CML, in particular in patients with lower response to imatinib.
- Lower response to imatinib or its pharmaceutically salts means a ABCC3 level referring to ⁇ Ct higher than 4.
- Appropriate treatment includes increasing therapeutic amount of imatinib or a pharmaceutically acceptable salt thereof.
- a further aspect of present invention relates to a diagnostic kit comprising a) means for determining the mRNA level of ABCC3 from a sample; b) means for determining the mRNA level of GAPDH; c) means for normalizing ABCC3 mRNA to GAPDH mRNA.
- a diagnostic kit comprising a) means for determining the mRNA level of ABCC3 from a sample; b) means for determining the mRNA level of GAPDH; c) means for normalizing ABCC3 mRNA to GAPDH mRNA.
- sample is as defined above.
- a further aspect of present invention relates to the use of imatinib, or a pharmaceutically acceptable sait thereof, for the treatment of a CML patient with a ABCC3 level referring to ⁇ Ct higher than 4, preferably wherein the ABCC3 level refers to ⁇ Ct higher than 5,
- the present invention pertains to a method of treating CML patient comprising the steps of
- said daily dose of imatinib mesylate is 150%, 200%, 250% or 300% of the standard dosage prescribed for CML patients.
- the daily dose to be administered to patients having lower ABCC3 is between about 600 and 1200 mg of Imatinib mesylate, e.g. 600 mg/day, 800 mg/day, 1000 rng/day or 1200 mg/day.
- the information regarding standard dosage prescribed for CML patients can be normally obtained from the label contained in the drug package.
- Preferred amounts of imatinib mesylate in case of a SHP1 level lower than 3 are 600 mg/day to 1200 mg/day. Further preferred lower limits are 650 mg/day, 700 mg/day, 750 mg/day, ⁇ OO mg/day and 850 mg/day. Further preferred upper limits are 1150 mg/day, 1100 mg/day, 1050 mg/day, 1000 mg/day, 950 mg/day and 900 rng/day. It is to be understood that each combination of upper and lower limits are comprised in present invention, "
- step (b) a daily dose of lmatinib mesylate is administered orally, Th ⁇ collecting of a blood sample from CML patients required under step (a) of the methods described herein can be accomplished by standard procedures being slate of the art.
- the Q- PCR is performed as generally practiced in the art and the level is normalized to reference to PCR products of reference genes.
- CCR complete cytogenic response
- Imatinib is genericaiiy and specifically disclosed in the patent applications US 5,521,184, in particular in Example 21 , the subject-matter of which is hereby incorporated into the present application by reference, imatinib can also be prepared in accordance with the processes disclosed in WO03/086613.
- Imatinib is preferably applied in the form of its mono-mesylate salt
- lmatinib mono-mesyiate can be prepared in accordance with the processes disclosed in US 6,694,051 the subject-matter of which is hereby incorporated into the present application by reference. Comprised are likewise the corresponding polymorphs, e.g. crystal modifications, which are disclosed therein.
- fmatinib mono-mesyiate can be administered in dosage forms as described in US 5,521 ,184, US 6,894,051 or US 2005-0267125.
- the present invention provides a combination for simultaneous, separate or sequential use which comprises (a) imatinib free base or any pharmaceutically acceptable salt thereof, preferably imatinib mesylate, and (b) an agent that releases ABCC3 from expression suppression.
- the combination is a fixed combination.
- the agent that releases ABCC3 from expression suppression is a DNA demethyiating agent, in one embodiment, the agent that releases ABCC3 from expression suppression is an inhibitor of chromatin condensation or an agent that releases chromatin from condensation.
- the invention provides a use of the combination of the present invention for the treatment of a patient suffering from chronic lymphocytic leukemia.
- the patient is non-responder or s ⁇ boptima! responder to imatinib standard dose treatment.
- the patient is non-responder or subopiima! responder to imatinib treatment with the dosage of at least 150%, or at least 200% of the standard dose.
- the present invention provides a pharmaceutical composition comprising a combination of the present invention and at least one pharmaceutically acceptable carrier.
- Figure 1 ABC transporter genes expression in newly diagnosed CP-CML patients treated with Imatinib (400 mg/day).
- X axis represents different patient groups: Pre Sub / Post Sub: 15 patients who didn't show a partial cytogenetic response (CgR) by 6 months nor a complete CgR by 12 months (suboptimal responders according to European LeukemiaNet recommendations), before frnafjnib treatment (Pre-Sub) and the same patients analysed after Imatinib treatment (Post-Sub); Post Resp, 5 patients treated with Imatinib who achieved a stable major molecular response (MMR) by 12 months (responders ⁇ .
- Y axis represents deita threshold cycle (Ct) values which were caiculated as the difference between Ct of the ABC mRNA and Ct of the GAPDH mRNA used for normalization.
- Ct threshold cycle
- Results are reported as delta Ct values which were calculated as the difference between Ct of the ABC mRNA and Ct of the GAPDH mRNA used for normalization. Assay were done using the ABi PRISM 7900 Sequence detection System (Applied Biosystems, Foster City, CA). One-way Anova statistical test was also applied to results in order to confirm that the expression level of analysed genes is significantly different between the two groups of patients .Our results show that suboptimai responders display high expression levels of ABCG2 ( ⁇ 0.01 ) and very low levels of ABCC3 (p ⁇ 0.0001) as compared to patients with responders. Interestingly, when ABC expression profile of the same patient was evaluated before starting imatinib treatment and compared with a measurement obtained at the time of suboptima! response, we could not observe any significant difference between the two conditions
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Abstract
The present invention relates to a method of treating chronic myeloid leukemia (CML) in a human patient population. In particular, present invention relates to the use of ABCC3 as a biomarker for CML patients
Description
Method for Optimizing the Treatment of Chronic Myeloid Leukemia with AbI Tyrosine Kinase inhibitors
The present invention relates to a method of treating chronic myeloid ieukemia (CML) in a human patient population.
The success of treatment with imatinib mesylate in the majority of chronic phase CML patients is wei! documented. Improving treatment outcomes for those patients who perform less well however requires a detailed understanding of the critical determinants of treatment response.
The deregulation of ATP-binding cassette (ABC) transporters responsible for the efflux of anticancer agents may involve mutations or single nucieotide polymorphisms (SNPs) or an increase in their expression level. Consequently, chemoresistance may develop. We have previously shown that the expression level and transcription of ABC drug transporters in CML celis is affected by c-Myc. Our results demonstrated that c-Myc is highly expressed in CD34+ ceils from newly diagnosed chronic phase (CP)-CML patients, and that it can significantly upregulate the expression of several ABC genes, particularly, the ABCC1 , ABCC4 and ABCG2, while it downregulates the expression of ABCC3. We have also demonstrated that c-Myc was a direct regulator and physically associated with the promoter of tested ABC genes, as assessed by Chromatin immunoprecipitation in a eel! Sine derived from a Ph+ CML patient Taken together, our findings supported the model of a direct and coordinate regulation of a large set of ABC genes by the c-Myc transcription factor. Our study also supported prior findings that deregulation of specific set of ABC genes could be an important molecular mechanism altering imatinib transport.
St is hence an object of the present invention to identify novel prognostic indicators to improve both an initial assessment and subsequent monitoring of CML patients, it is a further object of present invention to specify a patient population for the treatment of CML, in particular by estimating treatment response. It is a further object of present invention to improve success of treatment of CML. It is a further object of present invention to improve success of treatment of CML with imatinib. it is a further object of present invention to predict achievement of major molecular response (MMR) in CML patients.
Definitions;
In principle, the "ASCC3 level, as used herein, relates to the ABCC3 expression iβvel relative to the expression of at least one reference gene. By way of example, the expression level of ABCC3 is quantified by quantity PCR and normaiized to the PCR products of three reference genes, i.e. GUSB, b-actin and GAPDH, However, and for sake of clarity, the term "A8CC3 level" as used herein is defined as the ABCC3 expression level relative to the expression of GAPDH gene, measured by quantitative PCR,
Thereby, the ΔCt is calculated as the difference between the Ct of ABCC3 and Ct of GAPDH, when the PCR reaction has an efficiency higher than 90% and the Cf has been determined in the linearity range of the PCR curves.
Preferably, the low ABCC3 level refers to ΔCt higher than 4, more preferred to ΔCt higher than 5- In one embodiment, the Sow ABCC3 levei refers to ΔCt from 4 to 100, 5 to 100, 8 to 100, 10 to 100,
The word "about", as used herein and throughout the application, refers to a value that can vary within a range from of -10% to +10% of the indicated vaiue. PreferabSy from -5% to +5% of the indicated value. in the present application we disciose the role of ABC transport genes expression in newly diagnosed CP-CML patients treated with imatinib mesylate using RNtA extracted from white biood ceiSs of patients who achieved a stable major molecular response (MMR) by 12 months (responders) and patients who didn't show a partial cytogenetic response (CgR) by 6 months nor a complete CgR by 12 months (suboptima! responders according to European LeukemiaNet recommendations). All patients were enrolled on GIMEMA CML Working Party-sponsored ciinicai trials of imatinib. A pane! of ABC genes including ABCB1, ABCBθ, ABCC1 , ABCC3, ABCC4, ABCE1 and ABCG2 was interrogated by Q-PCR for the ievei of expression. Results were normalized to the expression of three reference genes, i.e., GUSB, b-actin and GAPDH. We have surprisingly found that suboptimal responders display very low leveis of ABGC3 (p<0,0001) as compared to patients with responders.
Importantly, the expression level of A8CC3 before the imatinib treatment may be used to predict CML patients likely to respond well to standard dose imatinib mesylate, and those who would be most iikely to benefit from a higher dose of Imatinib mesylate.
Hence, in one aspect, the present invention pertains to the use of ABCC3 as a biomarker for CML patients. Thereby., the level of ABCC3 is indicative for the therapeutic efficacy of imatinib or a pharmaceutically acceptable salt thereof. The level of ABCC3 in a CML patient can be used for the assessment of the therapeutic amount of imatinib or pharmaceutically acceptable salt thereof. In particular, a level of ABCC3 level referring to ΔCt higher than 4 is indicative for raising the therapeutic amount of imatinib or a pharmaceutically acceptable salt thereof, preferably to at least 150% of the standard dosage prescribed for CML patients.
Hence, in one aspect the present invention pertains the use of ABCC3 as a biomarker for CML patients for determining the therapeutic efficacy of imatinib or a pharmaceutically acceptable salt thereof.
In a further aspect, present invention relates to an ex vivo method for determining the ABCC3 level, comprising the steps of a) determining the mRNA level of ABCC3 from a sample; b) determining the mRNA level of GAPDH; c) normalizing ABCC3 mRNA to GAPDH mRNA.
Preferably, such sample is a blood sample, even more preferred a sample of peripheral blood. The ABCC3 level is preferably determined with Q-PCR as described herein.
A further aspect of present invention relates to the use of the above ex vivo method for screening CML patients to determine appropriate treatment with imatinib, or a pharmaceutically acceptable salt thereof. The term "appropriate treatment" in this context means to obtain more efficient treatment of CML, in particular in patients with lower response to imatinib. Lower response to imatinib or its pharmaceutically salts means a ABCC3 level referring to ΔCt higher than 4. "Appropriate treatment" includes increasing therapeutic amount of imatinib or a pharmaceutically acceptable salt thereof.
A further aspect of present invention relates to a diagnostic kit comprising a) means for determining the mRNA level of ABCC3 from a sample;
b) means for determining the mRNA level of GAPDH; c) means for normalizing ABCC3 mRNA to GAPDH mRNA. Preferably, the term "sample" is as defined above.
A further aspect of present invention relates to the use of imatinib, or a pharmaceutically acceptable sait thereof, for the treatment of a CML patient with a ABCC3 level referring to ΔCt higher than 4, preferably wherein the ABCC3 level refers to ΔCt higher than 5,
Hence, the present invention pertains to a method of treating CML patient comprising the steps of
(a) determining the ABCC3 level before the treatment of Imatinib mesylate in biood of a patient suffering from CML1 and
(b) administering a daily dose of lmatinib mesylate to the patient suffering from CML showing low ABCC3 level wherein low ABCC3 level refers to ΔCt higher than 4, and preferabiy higher than 5, wherein said daily dose of lmatinib mesylate is at least 150% of the standard dosage prescribed for CIVSL patients.
In a preferred embodiment said daily dose of imatinib mesylate, is 150%, 200%, 250% or 300% of the standard dosage prescribed for CML patients.
For example, in the case when standard dosage prescribed for CML patients is 400mg, the daily dose to be administered to patients having lower ABCC3 is between about 600 and 1200 mg of Imatinib mesylate, e.g. 600 mg/day, 800 mg/day, 1000 rng/day or 1200 mg/day.
The information regarding standard dosage prescribed for CML patients can be normally obtained from the label contained in the drug package.
Preferred amounts of imatinib mesylate in case of a SHP1 level lower than 3 are 600 mg/day to 1200 mg/day. Further preferred lower limits are 650 mg/day, 700 mg/day, 750 mg/day, δOO mg/day and 850 mg/day. Further preferred upper limits are 1150 mg/day, 1100 mg/day, 1050 mg/day, 1000 mg/day, 950 mg/day and 900 rng/day. It is to be understood that each combination of upper and lower limits are comprised in present invention, "
In an embodiment, in step (b) a daily dose of lmatinib mesylate is administered orally,
Thø collecting of a blood sample from CML patients required under step (a) of the methods described herein can be accomplished by standard procedures being slate of the art. The Q- PCR is performed as generally practiced in the art and the level is normalized to reference to PCR products of reference genes.
The term "complete cytogenic response (CCR)" as used herein means 0 % Philadelphia- chromosome positive metaphases among at least 20 or 25 ceiis in metaphase in the bone marrow aspirate {Colombat M, Fort MP, Choilet C, et al. Molecular remission in chronic myeloid leukemia patients with sustained complete cytogenetic remission after imatinib mesylate treatment HaematoSogica 2006;91 : 162-8.).
Imatinib is genericaiiy and specifically disclosed in the patent applications US 5,521,184, in particular in Example 21 , the subject-matter of which is hereby incorporated into the present application by reference, imatinib can also be prepared in accordance with the processes disclosed in WO03/086613.
For the purpose of the present invention, Imatinib is preferably applied in the form of its mono-mesylate salt, lmatinib mono-mesyiate can be prepared in accordance with the processes disclosed in US 6,694,051 the subject-matter of which is hereby incorporated into the present application by reference. Comprised are likewise the corresponding polymorphs, e.g. crystal modifications, which are disclosed therein.
fmatinib mono-mesyiate can be administered in dosage forms as described in US 5,521 ,184, US 6,894,051 or US 2005-0267125.
Our findings suggest that profiling of ABC drug transporter genes in CML patients could provide a novel modality of investigating their responsiveness to imatinib. Analysis of a larger series of patients is ongoing to further explore the potential predictive value of this expression profile. Hence A8CC3, which is strongly repressed possibly through a typical epigenetic mechanisms such as promoter hypermethyiation and /or chromatin condensation, could be re-activated by means of demethySating agents or inhibitors of chromatin condensation.
Thus the present invention provides a combination for simultaneous, separate or sequential use which comprises (a) imatinib free base or any pharmaceutically acceptable salt thereof,
preferably imatinib mesylate, and (b) an agent that releases ABCC3 from expression suppression.
In one preferred embodiment, the combination is a fixed combination.
In one embodiment, the agent that releases ABCC3 from expression suppression is a DNA demethyiating agent, in one embodiment, the agent that releases ABCC3 from expression suppression is an inhibitor of chromatin condensation or an agent that releases chromatin from condensation.
In one aspect, the invention provides a use of the combination of the present invention for the treatment of a patient suffering from chronic lymphocytic leukemia. In one further embodiment, the patient is non-responder or sυboptima! responder to imatinib standard dose treatment. In one further embodiment, the patient is non-responder or subopiima! responder to imatinib treatment with the dosage of at least 150%, or at least 200% of the standard dose.
The present invention provides a pharmaceutical composition comprising a combination of the present invention and at feast one pharmaceutically acceptable carrier.
Figure 1 : ABC transporter genes expression in newly diagnosed CP-CML patients treated with Imatinib (400 mg/day). X axis represents different patient groups: Pre Sub / Post Sub: 15 patients who didn't show a partial cytogenetic response (CgR) by 6 months nor a complete CgR by 12 months (suboptimal responders according to European LeukemiaNet recommendations), before frnafjnib treatment (Pre-Sub) and the same patients analysed after Imatinib treatment (Post-Sub); Post Resp, 5 patients treated with Imatinib who achieved a stable major molecular response (MMR) by 12 months (responders}. Y axis represents deita threshold cycle (Ct) values which were caiculated as the difference between Ct of the ABC mRNA and Ct of the GAPDH mRNA used for normalization.
Examples
The following examples are illustrative, but do not serve to limit the scope of the invention described herein. The examples are meant only to suggest a method of practicing the pre-
sent invention. The data shown below were collected from samples of CML patients in the TIDEL trial.
ABC transporter genes expression in newiy diagnosed CP-CML patients treated with lmatinib (400 mg/day).
Relative expression of ABC genes (ABCB1 , ABCB9, ABCC1, ABCC3, ABCC4, ABCE1 and ABCG2) was compared in two different groups of patients; Pre Sub / Post Sub: 15 patients who didn't show a partial cytogenetic response (CgR) by 6 months nor a compietβ CgR by 12 months (suboptima! responders according to European LeukemiaNet recommendations), before lmatinib treatment (Pre-Sub) and the same patients analysed after fmatinib treatment (Post-Sub); Post Resp, 5 patients treated with Smatinib who achieved a stable major molecular response (MMR) by 12 months (respoπders). Total RNA was extracted from 350μL of guaπidium isothiocyaπate solution (GITC) mononuclear eel! using RNeasy Mini kits (Quiagen, Craweiy, UK) according to the manufacturer's instructions. The samples were reverse transcribed from total RNA using the High Capacity cDNA Reverse Transcription Kit (Applied Biosystems). Target amplification, using cDNA as the template, were done using TaqMan Gene Expression Assays and GAPDH was seiected and used as a contra! gene. Each samples was analyzed in duplicate and threshold cycle (Ct) values were averaged. Results are reported as delta Ct values which were calculated as the difference between Ct of the ABC mRNA and Ct of the GAPDH mRNA used for normalization. Assay were done using the ABi PRISM 7900 Sequence detection System (Applied Biosystems, Foster City, CA). One-way Anova statistical test was also applied to results in order to confirm that the expression level of analysed genes is significantly different between the two groups of patients .Our results show that suboptimai responders display high expression levels of ABCG2 (ρ<0.01 ) and very low levels of ABCC3 (p<0.0001) as compared to patients with responders. Interestingly, when ABC expression profile of the same patient was evaluated before starting imatinib treatment and compared with a measurement obtained at the time of suboptima! response, we could not observe any significant difference between the two conditions
Claims
1. Use of ABCC3 as a biomarker for CML patients.
2. The use according to claim 1 , for determining the therapeutic efficacy of imatinib or a pharmaceutically acceptable salt thereof,
3. An ex vivo method for determining the A8CC3 level, comprising the steps of a) determining the mRNA levei of ABCC3 from a sample; b) determining the mRNA level of GAPDH; c) normalizing ABCC3 mRNA to GAPDH roRNA,
4. Use of the method according to claim 3 for screening CML patients to determine appropriate treatment with imatinib, or a pharmaceutically acceptable salt thereof.
5. A diagnostic kit comprising a} means for determining the mRNA levei of A8CC3 from a sample; b) means for determining the mRNA level of GAPDH; c) means for normalizing ABCC3 mRNA to GAPDH mRNA,
6. Use of imatinib, or a pharmaceutically acceptable salt thereof, for the treatment of a CML patient with a ABCC3 level referring to ΔCt higher than 4,
7. Use according to claim 6, wherein the A8CC3 ievei refers to ΔCt higher than 5,
8. A method of treating a CML patient comprising the steps of
(a) determining the ABCC3 level before the treatment of Imatinib. free base or any pharmaceutically acceptable salt thereof, in blood of a patient suffering from CML, and
(b) administering a daily dose of imatinib, free base or any pharmaceutically acceptable salt thereof, to the patient suffering from CML showing low ABCC3 level , wherein tow ABCC3 level refers to ΔCt higher than 4, wherein said daily dose of imatinib, free base or any pharmaceutically acceptable salt thereof is at least 150% of the standard dosage prescribed for CML patients.
9. The method of claim 8, wherein said imatinib, free base or any pharmaceutically acceptable salt thereof, is imatinib mesylate.
10. The method of claim 8 or 9, wherein said low ABCC3 level refers to ΔCt higher than 5.
10. Package insert for a medicament comprising imatinib, or a pharmaceutically acceptable salt thereof, characterized that it contains instructions for the use for patients with a ABCC3 level refers to ΔCt higher than 4.
8. A method of treating CML patient comprising the steps of
(a) determining the ABCC3 level before the treatment of Smatinib, free base or any pharmaceutically acceptable salt thereof, in biood of a patient suffering from CML, and
(b) administering a daily dose of imatsnib, free base or any pharmaceutically acceptable salt thereof, to the patient suffering from CML showing iow ABCC3 Seve! , wherein low ABCC3 ievel refers to ΔCt higher than 4, wherein said daily dose of lmatinib mesylate is at least 150% of the standard dosage prescribed for CML patients.
9. The method of claim 8, wherein said imatinib, free base or any pharmaceutically acceptable salt thereof, is imatinib mesylate.
10. The method of claim 8 or 9, wherein said low ABCC3 level refers to ΔCt higher than 5,
11. A combination for simultaneous, separate or sequential use which comprises (a) imatinib free base or any pharmaceutically acceptable salt thereof, and (b) an agent that releases ABCC3 from expression suppression.
12. The combination of claim 11 , wherein said imatinib, free base or any pharmaceutically acceptable salt thereof, is imatinib mesylate.
13. The combination of claim 11 or 12, wherein said combination is a fixed combination.
14. The combination of any one of the claims 11-13, wherein said agent that releases ABCC3 from expression suppression is a DNA demethylattng agent.
15. The combination of any one of the claims 11-13, wherein said agent that releases ABCC3 from expression is an inhibitor of chromatin condensation or an agent that releases chromatin from condensation.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11284608P | 2008-11-10 | 2008-11-10 | |
| US61/112,846 | 2008-11-10 | ||
| US11870108P | 2008-12-01 | 2008-12-01 | |
| US61/118,701 | 2008-12-01 |
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| WO2010054298A1 true WO2010054298A1 (en) | 2010-05-14 |
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| PCT/US2009/063707 WO2010054298A1 (en) | 2008-11-10 | 2009-11-09 | Method for optimizing the treatment of chronic myeloid leukemia with abl tyrosine kinase inhibitors |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050164196A1 (en) * | 2002-04-17 | 2005-07-28 | Dressman Marlene M. | Methods to predict patient responsiveness to tyrosine kinase inhibitors |
| US20070154931A1 (en) * | 2005-12-15 | 2007-07-05 | Radich Jerald P | Genes associate with progression and response in chronic myeloid leukemia and uses thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050164196A1 (en) * | 2002-04-17 | 2005-07-28 | Dressman Marlene M. | Methods to predict patient responsiveness to tyrosine kinase inhibitors |
| US20070154931A1 (en) * | 2005-12-15 | 2007-07-05 | Radich Jerald P | Genes associate with progression and response in chronic myeloid leukemia and uses thereof |
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| IRACI NUNZIO ET AL: "Expression Profiling of ABC Transporter Genes in Chronic Myeloid Leukemia (CML) and Responsiveness to Imatinib", BLOOD, vol. 112, no. 11, 16 November 2008 (2008-11-16), 50TH ANNUAL MEETING OF THE AMERICAN- SOCIETY-OF-HEMATOLOGY; SAN FRANCISCO, CA, USA; DECEMBER 06 -09, 2008, pages 1096, XP002573032, ISSN: 0006-4971 * |
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