治癒CML

–

ABL酪胺酸激酶抑制劑CureofCMLwithtyrosinekinaseinhibitors木村晉也ShinyaKimuraMD,PhDHematologyandOncology,SagaUniversityDasatinibdiscontinuation(DADI)trialImatinib

顯著地改善CML

治療成效ImatinibimprovedCMLTx.drastically

イマチニブ(Druker,NatureMed2009)抗がん剤imatinibIFN-achemotherapy

臨床上

imatinib

不對CML

幹細胞起作用？Clinically,isimatinibnoteffectiveforCMLstemcells?Imatinib

中止試

驗STopIMatinibstudy(STIM)試驗

STIMrevealed41%

CMLPtscouldstopimatinibRelapse-freesurvivalwas45%at6mo,43%at12mo,and41%at24mo(Mahonetal.LancetOncol.2010)Survivalwithoutmolecular

relapseN=1000204060801000369121518212427100573628272320166Number

atRiskAccordingtoStopImatinib(A-STIM)試験Definitionofmolecularrelapse：onlyMMRloss

(eventhoughRQ-PCRpositive,stopimatinibcontinue)(Rousselotetal,JCO2014)MaywewaitforMMRloss?到CMRlossMMRlossNearly50%CMLPtscanstopimatinib

ifDMRsustainformorethan2years.ButOnly45%PtstreatedwithimatinibcanachieveDMR怎樣治癒更多的患者？

HowcanwecuremoreCMLpatients?a-phaseb-phase+a(Roederetal.NatMed,2006)各TKI對ABL

的親和性AffinityofeachTKIstoABLimatinibnilotinibdasatinibaffinity

x1x30

x325specificityInt.HighLowTypeITypeII各ABL抑制劑的標的蛋白imatinibnilotinibdasatinibbosutinibABLABLABLACKMAP4K5/KHS1ABL1ILKARGARGARGACTR2BMAPK11/p38betaSRCSTK4BCR-ABLBCR-ABLBCR-ABLACVR2MAPK14/p38alphaFYNTAOK3KITKITKITBRAFMYT1HCKPTK2PDGFRPDGFRPDGFREGFR/ERBB1NLKLYNPKMYT1DDR1DDR1SRCEPHA2,3,4,5,8PTK6/BrkBTKCAMK2GNQO2NQO2YESEPHB1,2,4,6QIKTECSYKFYNERBB2,4QSKMAP2K1ZAKLYNFAKRAF1MAP2K2HCKGAKRETMAP2K5LCKGCKRIPK2MAP3K1FGRHH498/TNNI3KSLKMAP3K2BLKILKSLK36/ULKMAP3K3FRKILMK1,2SYKMAP3K4CSKMAP2K5TAO3MAP4K1BTKMAP3K1TESK2MAP4K2TECMAP3K2TYK2MAP4K3BMXMAP3K3ZAKMAP4K4TXKMAP3K4MAPK14DDR1,2MAP4K1SrcSrcCumulativeincidenceofLGLexpansion(KimDHetal.Haematologica2009)

Dasatinib使用後LGL的增加產(chǎn)生更好的治療反應LGLexpansionbydasatinibcontributetoresponse48+13@2年ComparisonofresponsetodasatinibaccordingtothedevelopmentofLGLexpansionLGL増加(-)LGL=NK+CTL(MustjokiSWetal.Leukemia2009)Dasatinib

抑制Treg,誘發(fā)LGL增加DasatinibsuppressesTregandinducesLGLProportionnotprogressedProportionofaliveDasatinib

以外的TKIs

不誘發(fā)

LGLOtherTKIsexceptdasatinibdoesnotinduceLGL.※(MustjokiS,etal.

ASH2010)Firstlinedasatinib

在臨床有較好的效果

Firstlinedasatinibshowedmoreeffectsinclinic!

imatinibdasatinib

400mgQD100mgQDCCyR

3months31%54%6

months59%73%9months67%78%12ヶ月72%83%MMR

3

months0.40%8%6

months8%27%9

months18%39%12

months28%46%toAP/BC3.50%1.90%MoreRapid,Deeper!(Kantarjianetal,NEJM2010)更強有力,並兼有免疫調(diào)節(jié)功能Dasatinib

能增多治愈病例嗎？STOP

DASATINIB

(STD)TRIALFrenchigroupdidstopimatinibclinicaltrialStopImatinib

(STIM)XToinvestigatethe%oftreatment-freeremission(TFR)after1-3yearsofdasatinibdiscontinuationinCMLpatientswhosustaindeepmolecularresponse(DMR)atleast1yearwithsecondlinedasatinib.Wesimulatedthatthepowerof1yearofdasatinibisalmostequalto2yearsofimatinibaccordingtoseveralclinicaltrials.2yofimatinib=1yofdasatinib1year(DADI)2years(STIM)更有效的dasatinib

能把更多的患者治療到痊癒嗎？

Canmorepotent,dasatinibcuremoreCMLpatients?

DAsatinibDIscontinueTrial

(DADI

Trial：PI木村晉也)Allparticipants(n=63)Age(years)

59(24-84)SexFemale22(35%)Male41(65%)SokalriskLow41(65%)Intermediate9(14%)High9(14%)Missingdata4(6%)Reasonswhypatientsswitchedfromimatinibtodasatinibimatinib-resistant13(21%)imatinib-intolerant36(57%)Patient'schoice14(22%)BestresponsetopriorimatinibCHR6(10%)CCyR5(8%)MMR49(78%)Missingdata3(5%)進行dasatinib中斷試驗患者的背景資料Baseline

characteristicsofpatients(Imagawa,LancetHematol2015) DADItrial

的

Studydesign8830632533Dasatinib

中斷之后的TFR比率Treatment-FreeRemission(TFR)afterdiscontinuationofdasatinibＮ＝63Atamedianfollow-upof20monthsafter

discontinuation,theestimatedTFRrateswere49%at6monthsand48%at12months.(Imagawa,LancetHematol2015) 按照換成dasatinib不同原因其TFR

比率之差別TFRsurvivalaccordingtothereasonswhypatientsswitchedfromimatinibtodasatinibTheTFRrateat12monthswassignificantlypoorerinimatinib-resistantpatients(8%)thaninotherpatients(58%).分子學復發(fā)患者再次使用

dasatinib治療的效果Molecularresponsesafterdasatinibreintroductionformolecularlyrelapsedpatients.Monthsafterdasatinibreintroduction*01369

120.10.010.00691(n=33)DMRlevelMMRlevelBCR-ABL1leveloninternationalscale(%)AllmolecularlyrelapsedpatientsreturnedquicklytoDMRwithin6monthsafterdasatinibreintroduction.放心Imatinib-resistant造成難以中斷

dasatinib

治療Estimatedtreatment-freeremissionsurvival

at12months%

(95%CI)Hazardratio(95%CI)

pvalueAge<45years29.4(10.71-51.15)54.3(39.01-67.37)0.558(0.274-1.136)0.079≥45yearsGenderMale39.0(24.34-53.44)63.6(40.29-79.88)0.573(0.258-1.271)0.135FemaleSokalriskscoreLow51.2(35.15-65.17)22.2(3.37-51.31)44.4(13.59-71.93)0.817(0.306-2.180)1.894(0.598-5.999)0.6860.277IntermediateHighReasonswhypatientsswitchedfromimatinibtodasatinibimatinib-resistant7.7(0.48-29.20)2.895(1.111-7.541)0.732(0.295-1.814)0.0290.500imatinib-intolerant61.1(43.35-74.82)patient'schoice50.0(22.86-72.21)HistoryofinterferonatherapyNointerferona46.0(31.88-59.01)0.806(0.333-1.952)0.606interferona53.8(24.77-75.99)Totaldurationofbothimatinibanddasatinibtreatments<50months35.3(14.48-57.04)0.592(0.286-1.225)0.123≥50months52.2(36.96-65.36)Totaldosageofdasatinibduringaperiodof1yearbeforedrugdiscontinuation<37,236mg50.0(34.93-63.33)41.2(18.58-62.64)1.239(0.589-2.605)0.542≥37,236mgTotaldosageofdasatinibfromthetimeofdruginitiation(mg)<64,700mg55.6(39.98-68.60)1.966(0.974-3.969)0.038≥64,700mg27.8(10.11-48.87)雖然在dasatinib治療變成

DMR了但是.年齢、性別對

dasatinib

治療後

TFR的影響

ImpactofageandgenderonTFRafterdasatinibTx.年齢性別Dasatinib治療後的TFR和淋巴球種類TFRafterdasatinibTxandlymphocyteprofiles(Imagawa,etal.LancetHaematol,2015)為什麼

regulatoryT

Cell

減少,NK

cell

增加的話容易中止治療？(推測)調(diào)整性T細胞調(diào)整性T細胞dasatinibＸＸＸＸＸＸNK細胞NK細胞NKcell不要欺負癌細胞因為Treg可以抑制NK細胞攻擊癌細胞當

Treg

細胞消失的時候,這裡可以攻擊了被抑制了正在日本進行的主要的

ABLTKIstop試驗Imatinib

stop

試驗

STIM-213:stop復發(fā)後→imatinibDOMEST:

stop復發(fā)後

→dasatinib

DasatiniborNilotinib

stop

試驗

DADI:

secondline（third）dasatinib、1年DMRD-Stop:secondlinedasatinib、2年DMR1st-DADI:firstlinedasatinib、1年

DMRNilo-St:secondline

nilotinib、2年

DMR總結(jié):

DADItrialAfterconfirmationofDMRformorethan1year,secondlinedasatinibtreatmentwasdiscontinued.theestimatedTFRrateswere49%at6monthsand48%at12months.TheTFRrateat12monthswassignificantlypoorerinimatinib-resistantpatients(8%)thaninotherpatients(58%).

AllmolecularlyrelapsedpatientsreturnedquicklytoDMRwithin6monthsafterdasatinibre-introduction.HighNK-cellandlowregulatoryT-cellcountsbeforediscontinuationweresignificantlycorrelatedwithsuccessfultherapydiscontinuation.Jun Imagawa Dept.ofHaematologyandOncology,HiroshimaUniversity

Hideo Tanaka Dept.ofHaematology,HiroshimaCityAsaHospitalMasaya Okada Dept.ofInternalMedicine,HyogoCollegeofMedicineHirohisa Nakamae Dept.ofHaematology,GraduateSchoolofMedicine,OsakaCityUniversityMasayuki Hino Dept.ofHaematology,GraduateSchoolofMedicine,OsakaCityUniversityKazunori Murai Dept.ofHaematologyandOncology,IwateMedicalUniversityYoji Ishida Dept.ofHaematologyandOncology,IwateMedicalUniversityTakashi Kumagai Dept.ofHaematology,OhmeMunicipalGeneralHospitalSeiichi Sato Dept.ofInternalMedicine,FujimotoSogoHospitalKazuteru Ohashi HematologyDivision,KomagomeHospitalHisashi Sakamaki HematologyDivision,KomagomeHospitalHisashi Wakita Div.ofHaematologyandOncology,JapaneseRedCrossNaritaHospitalNobuhiko Uoshima Dept.ofHaematology,MatsushitaMemorialHospitalYasunori Nakagawa Dept.ofHaematology,JapaneseRedCrossMedicalCentreYosuke Minami Div.ofBloodTransfusionKobeUniversityHospitalMasahiro Ogasawara Dept.ofHaematology,SapporoHokuyuHospitalTomoharu Takeoka DivisionofHaematologyandImmunology,OtsuRedCrossHospitalHiroshi Akasaka Dept.ofHaematology,ShinkoHospitalTakahiko Utsumi Dept.ofHaematology,ShigaMedicalCentreforAdultsNaokuni Uike DivisionofHaematology,NationalKyushuCancerCentreTsutomu Sato

4thDept.ofInternalMedicine,SapporoMedical,UniversitySchoolofMedicineSachiko Ando Dept.ofHaematology,TeineKeijinkaiHospitalKensuke Usuki Dept.ofHaematology,NTTMedicalCentreTokyoMasato Shikami Dept.ofHaematology,DaiyukaiGeneralHospitalHisashi Fukutani Dept.ofHaematology,AichiCancerCenterAichiHospitalYokiko Ohe Dept.ofHaematology,UegaharaHospitalNaoyuki Tange Dept.ofHaematology,OgakiMunicipalHospitalHirohiko Shibayama Dept.ofHaematologyandOncology,OsakaUniversityHospitalYasuhiro Maeda Dept.ofHaematology,NationalHospitalOrganizationOsaka-MinamiMedicalToshihiro Fukushima Dept.ofHaematologyandImmunology,KanazawaMedicalUniversityHospitalNaomi Sugimori Dept.ofHaematologyandOncology,KanazawaUniversityHospitalKazuo Tsubaki Dept.ofHaematology,NaraHospitalKinkiUniversityToshimasa

Kukita

Dept.ofHaematology,ImamuraHospitalYok