Eradication of Chronic Myeloid Leukemia Stem Cells A Novel Mathematical Model Predicts No Therapeutic Benefit of Adding G-CSF to Imatinib 英文参考文献.docVIP

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Eradication of Chronic Myeloid Leukemia Stem Cells A Novel Mathematical Model Predicts No Therapeutic Benefit of Adding G-CSF to Imatinib 英文参考文献.doc

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Eradication of Chronic Myeloid Leukemia Stem Cells A Novel Mathematical Model Predicts No Therapeutic Benefit of Adding G-CSF to Imatinib 英文参考文献

EradicationofChronicMyeloidLeukemiaStemCells:A NovelMathematicalModelPredictsNoTherapeutic BenefitofAddingG-CSFtoImatinib JasmineFoo1,MarkW.Drummond2,BayardClarkson3,TessaHolyoake2,FranziskaMichor1* 1Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America, 2Section of Experimental Haematology, MedicalFaculty,UniversityofGlasgow,Glasgow,UnitedKingdom,3MolecularPharmacologyandChemistryProgram,MemorialSloan-KetteringCancerCenter,NewYork, NewYork,UnitedStatesofAmerica Abstract Imatinib mesylate induces complete cytogenetic responses in patients with chronic myeloid leukemia (CML), yet many patientshavedetectableBCR-ABLtranscriptsinperipheralbloodevenafterprolongedtherapy.Bonemarrowstudieshave shown that this residual disease resides within the stem cell compartment. Quiescence of leukemic stem cells has been suggestedasamechanismconferringinsensitivitytoimatinib,andexposuretotheGranulocyte-ColonyStimulatingFactor (G-CSF),togetherwithimatinib,hasledtoasignificantreductioninleukemicstemcellsinvitro.Inthispaper,wedesigna novelmathematicalmodelofstemcellquiescencetoinvestigatethetreatmentresponsetoimatinibandG-CSF.Wefind thattheadditionofG-CSFtoanimatinibtreatmentprotocolleadstoobservableeffectsonlyifthemajorityofleukemic stemcellsarequiescent;otherwiseitdoesnotmodulatetheleukemiccellburden.Thelatterscenarioisinagreementwith clinical findings in apilot study administering imatinib continuously or intermittently, with or without G-CSF (GIMI trial). Furthermore, our model predicts that the addition of G-CSF leads to a higher risk of resistance since it increases the productionofcyclingleukemicstemcells.Althoughthepilotstudydidnotincludeenoughpatientstodrawanyconclusion with statistical significance, there were more cases of progression in the experimental arms as compared to continuous imatinib.OurresultssuggestthattheadditionaluseofG-CSFmaybedetrimentaltopatientsintheclinic. Citation: FooJ,DrummondMW,ClarksonB,