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Is CML Curable? We’ve been asked lately if CML is curable. Yes, CML is curable and here is why we think this is so. First, a Little History Did you know that the first case of CML was first diagnosed in Scotland in 1845 and then a second case was reported a few weeks later in Berlin? In 1872, it was observed that leukemic stem cells come from the bone marrow. However, it was in a lab in Philadelphia in 1962 that two researchers working together, Lowell and Hungerford located the Philadelphia Chromosome. This was a very significant event as it showed that cancer, and CML in this case, could be traced to a problem in the DNA. In 1972 Janet Rowley showed that there was a translocation, or exchange of gene material, between chromosomes 9 and 22 associated with leukemia, and specifically CML. Through the decades a variety of treatments have been helping most patients extend their lives. But it was a significant breakthrough by Alexander Levitzki who showed that ABL inhibitors could be effectively used in inhibiting tyrosine kinases and blocking cancer. Today we have three approved Tyrosine Kinase Inhibitors and another one far advanced in clinical trials (M. Deininger, ASH 2008, CML Educational Session). Most important thanks go to Dr. B. Druker for his tenacity while working with Signal Transductions Inhibitors, or STI 571, now known as Gleevec or Glivec, that proved the concept of targeted therapies and greatly improved the lives of CML patients. Dr. Druker’s worked rallied the entire CML community of scientist, doctors and patients as never before. Simply put, tyrosine Kinase inhibitors block the function of ATP, which is like an energy cell. Blocking the function of ATP in turn blocks the function of the protein generated by BCR ABL, which slows proliferation (which is what any cancer really is, over proliferation of cells that go un‐checked by the body’s immune system) of CML. This is a very simple description of it; there are other more technical and much more eloquently stated descriptions. Don’t hesitate to google and find the one that helps you understand the best. Before Tyrosine Kinase Inhibitors there was Interferon. Interferon is a biological immune modifier. Interferon on its own had a very difficult time to combat CML and BCR ABL outsmarted and overwhelmed it. Consequently many patients had to take incredibly high doses of Interferon to try to stop CML from progressing to its more deadly accelerated phases. A high dose of interferon induces an incredible amount of side effects that are very difficult to deal with and greatly diminish a patient’s quality of life. However, there was some good news; some patients, a small percentage, close to 12% by some reports, could be successfully treated with interferon and were able to stop taking the drug without relapsing. Some of these patients have been tracked for more than 20 years without relapse. These results added to the data of the patients who responded to an allogenic bone marrow transplant, suggest to us that CML is curable. We were all quite fortunate when Gleevec™, the world’s first Tyrosine Kinase Inhibitor started in Phase I trials and successfully went on to Phase II and expanded access programs. I am not going to expound too much on the success of these drugs, the data shows us that lives have been extended and with the newer drugs, quality of life is improving as well. For those who have the misfortune of developing resistance to one drug or another, we are lucky that there are second‐ generation drugs such as Sprycel™ and Tasigna™ as well as additional drugs in trials.

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Page 1: Is CML Curable - CmlSociety.org 2_files/Is CML Curable.pdf · Is CML Curable? We’ve been ... Philadelphia in 1962 that two researchers working together, Lowell and Hungerford located

IsCMLCurable?We’vebeenaskedlatelyifCMLiscurable.Yes,CMLiscurableandhereiswhywethinkthisisso.

First,aLittleHistoryDidyouknowthatthefirstcaseofCMLwasfirstdiagnosedinScotlandin1845andthenasecondcasewasreportedafewweekslaterinBerlin?In1872,itwasobservedthatleukemicstemcellscomefromthebonemarrow.However,itwasinalabinPhiladelphiain1962thattworesearchersworkingtogether,LowellandHungerfordlocatedthePhiladelphiaChromosome.Thiswasaverysignificanteventasitshowedthatcancer,andCMLinthiscase,couldbetracedtoaproblemintheDNA.In1972JanetRowleyshowedthattherewasatranslocation,orexchangeofgenematerial,betweenchromosomes9and22associatedwithleukemia,andspecificallyCML.Throughthedecadesavarietyoftreatmentshavebeenhelpingmostpatientsextendtheirlives.ButitwasasignificantbreakthroughbyAlexanderLevitzkiwhoshowedthatABLinhibitorscouldbeeffectivelyusedininhibitingtyrosinekinasesandblockingcancer.TodaywehavethreeapprovedTyrosineKinaseInhibitorsandanotheronefaradvancedinclinicaltrials(M.Deininger,ASH2008,CMLEducationalSession).MostimportantthanksgotoDr.B.DrukerforhistenacitywhileworkingwithSignalTransductionsInhibitors,orSTI571,nowknownasGleevecorGlivec,thatprovedtheconceptoftargetedtherapiesandgreatlyimprovedthelivesofCMLpatients.Dr.Druker’sworkedralliedtheentireCMLcommunityofscientist,doctorsandpatientsasneverbefore.Simplyput,tyrosineKinaseinhibitorsblockthefunctionofATP,whichislikeanenergycell.BlockingthefunctionofATPinturnblocksthefunctionoftheproteingeneratedbyBCRABL,whichslowsproliferation(whichiswhatanycancerreallyis,overproliferationofcellsthatgoun‐checkedbythebody’simmunesystem)ofCML.Thisisaverysimpledescriptionofit;thereareothermoretechnicalandmuchmoreeloquentlystateddescriptions.Don’thesitatetogoogleandfindtheonethathelpsyouunderstandthebest.BeforeTyrosineKinaseInhibitorstherewasInterferon.Interferonisabiologicalimmunemodifier.InterferononitsownhadaverydifficulttimetocombatCMLandBCRABLoutsmartedandoverwhelmedit.ConsequentlymanypatientshadtotakeincrediblyhighdosesofInterferontotrytostopCMLfromprogressingtoitsmoredeadlyacceleratedphases.Ahighdoseofinterferoninducesanincredibleamountofsideeffectsthatareverydifficulttodealwithandgreatlydiminishapatient’squalityoflife.However,therewassomegoodnews;somepatients,asmallpercentage,closeto12%bysomereports,couldbesuccessfullytreatedwithinterferonandwereabletostoptakingthedrugwithoutrelapsing.Someofthesepatientshavebeentrackedformorethan20yearswithoutrelapse.Theseresultsaddedtothedataofthepatientswhorespondedtoanallogenicbonemarrowtransplant,suggesttousthatCMLiscurable.

WewereallquitefortunatewhenGleevec™,theworld’sfirstTyrosineKinaseInhibitorstartedinPhaseItrialsandsuccessfullywentontoPhaseIIandexpandedaccessprograms.Iamnotgoingtoexpoundtoomuchonthesuccessofthesedrugs,thedatashowsusthatliveshavebeenextendedandwiththenewerdrugs,qualityoflifeisimprovingaswell.Forthosewhohavethemisfortuneofdevelopingresistancetoonedrugoranother,weareluckythattherearesecond‐generationdrugssuchasSprycel™andTasigna™aswellasadditionaldrugsintrials.

Page 2: Is CML Curable - CmlSociety.org 2_files/Is CML Curable.pdf · Is CML Curable? We’ve been ... Philadelphia in 1962 that two researchers working together, Lowell and Hungerford located

Butwhataboutthecure?

AtASH2008therewasanupdateonthestudythatwasstartedbyDr.MahoneinFranceanditisquiteexciting.Therewere15patientsinFrancewhodecidedtostoptreatmentwithGleevec™foronereasonoranother,sotheopportunitywastakentoobservewhatwouldhappentothem.7ofthepatientsrelapsedwithin6months,however,8ofthepatientsinthisverysmallcohortpilotstudy,didnotrelapse.Thesepatientshavebeenfollowedformorethan37months.Interestinglyitwasnotedthatthesepatientshadbeen“pre‐treated”withinterferon.Coulditbethatpretreatmentwithinterferonconferssomeadvantage?Thatwasthehypothesis,butthehypothesiswouldneedfurthertesting,sotheyenrolledanother69patientsfrom22differentcentersinFrance.ThecriterionwasthattheyhadtohavebeeninacompletemolecularremissionandPCRundetectablefortwoyearsconsecutively,beforebeingallowedtostopGleevec™.Ofthese69patients,27patientshaverelapsed;13werepretreatedwithIFN,and14wereonlytreatedwithGleevec™.Thebignewsisthatat9monthsfollowup46%(orapproximately31)ofthesepatientsarestillinremission,ofthose46%patients,53%werepretreatedwithinterferonand39%are“denovo”patients(haveonlybeentreatedwithGleevec™).EarlierwementionedthatonInterferonalone,somesourcesreportedupto12%ofpatientscouldbetakenoffthedrug.Addedwiththisnewinformation,wecanexplorethehypothesisthattheearlyresultswithinterferonalonecouldbegreatlyimprovedwiththeadditionofatargetedtherapylikeGleevec™.TheothergoodnewsisthatmostpatientswhorelapsedafterstoppingGleevec™quicklyregainedtheirmolecularresponse:“Dr.MahonalsoemphasizedthatallofthepatientswhorelapsedweresensitivetoImatinibafteritwasrestarted.Someoftherelapsedpatientswentbackintoremissionveryquickly,butforothers,itisaslowerprocess.Althoughthefollow‐upinthisparticularstudy(69patients,22centers)isshort,patientsinthepilotstudyhavenowbeenfollowedforseveralyears.“TheresultsfrombothofthesetrialsconfirmthatcompletemolecularresponsecanbesustainedafterImatinibisdiscontinued.Thisisparticularlytrueforpatientswhohavebeenpretreatedwithinterferon,saidDr.Mahon”.ItseemspossiblethatthecombinationofbothGleevec™andotherTyrosineKinaseInhibitor’sforthatmatter,withsomethinglikeInterferoncanimprovethepotentialforpatientstoenjoyarelapsefreeanddrugfreeremission.Notsureifthatistheexactsamethingasacure,butwewouldliketoseewhatitisliketonothavetothinkaboutonedrugoranother,wouldn’tyou?Earlierinthisessay,itwasmentionedthatCMLcouldbetracedtoaproblemintheDNA.Thisisverygoodnews,becausenowweknowthatourDNAdoesn’texactly“sealourfate”asweoncethoughtitdid.Thereisnewresearchaboutepigenomes.Thereallybasictakeawayaboutepigenesisthattheycanbeswitchedoneway,andthatmeansthattheycanbeswitchedbacktoo!Readthereallycoolarticleaboutthishere:Whew!YourDNAIsn'tYourDestiny

TherearenowmorecentersparticipatinginallowingpatientstotrytostopGleevec™andwethinkthatthisisveryexciting.Importantly,thereisresearchgoingoninmanyareasthathelpsusalltolearnmoreaboutthisdisease.ThisisvitallyimportanttousasthesedrugsareveryexpensiveandarecreatingasignificantsocioeconomichardshipforCMLpatientsandtheirfamilies.ThiswasevidentwiththeresultsoftheinternationalCMLpatientssurveypresentedatasatellitesymposiumatASHinDecember2008.VisittheCMLSocietywebsiteforthevideopresentation.

SayingCMLisn’tcurablewouldbeignoringthegreatsuccesseswehavehadinhelpingpeoplewithCMLtoenjoyimprovedsurvivalrates.Sostayhealthy,continuetolearnalongwithusandimportantly,stayinformed.

IsCMLCurable?Wecancertainlysaywearecountingonit!

Disclaimers:Pleasenotetheclinicaltrialdatapresentedherewasfromarelativelysmallcohortofpatientswhoweregoodresponderstotherapy.Whiletheresultsseemquitepositive,donotattempttostopyourtherapy.Ifyouhaveanyquestionsaboutyourcurrenttreatment,pleasediscussthemwithyourdoctor.

GleevecandTasignaaretrademarksofNovartisOncologySprycelistheTrademarkofBristolMyersSquibb


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