Optimizing Outcomes Through Pharmaceutical Advances in the Treatment of Chronic Myeloid Leukemia

BACkgrOund: Chronic myeloid leukemia (CML) is a potentially fatal stem cell cancer that comprises approximately 14% of all leukemias. Although it is estimated that 4,600 people will be diagnosed with CML in the united States in 2007, only 12% of those individuals will die from the disease. That low mortality rate is due to the availability and efficacy of the new kinase inhibitors that target the BCr-ABL oncogene and other targets to hold disease progression in check. OBjeCTIve: To review the molecular pathogenesis of CML, describe the clinical course of the disease, and explain the current application of cyto-genetics and molecular testing for diagnosis and treatment. SuMMAry: CML is caused by the translocation of chromosomes 9 and 22 to create what is called the Philadelphia chromosome. This translocation removes a critical regulatory domain from the tyrosine kinase, ABL, such that its protein product is constitutively active. This means that the cell escapes the constraints of normal cell growth and proliferates uncontrol-lably. The modified protein is known as BCr-ABL, and it causes CML by phosphorylating numerous downstream proteins involved in the activation of cell division, among other functions. during the earliest phase of the disease, the chronic phase, kinase inhibitors that target BCr-ABL are effective in stopping disease progression. However, a minority of patients remain unresponsive to this therapy. Laboratory tests are thus of great importance for this disease. not only are they required for the diagnosis of CML, but during therapy they can establish the degree of response. That response, in turn, can supply the clinician with a good estimate of the prognosis for the patient. The tests used for CML include complete blood count (CBC) with platelets, cytogenetic analysis, fluorescence in situ hybridization (FISH), and quantitative polymerase chain reaction (PCr). These tests vary in the difficulty of application and in the sensitivity. CBC is commonplace within the average hospital laboratory, whereas cytogenetic analysis, FISH, and PCr require specialized equipment, personnel, and training. Hematologic counts are the least sensitive measures of disease, with a limit of detection of a leukemic burden of 1011 cells. Cytogenetics can detect a burden of 109 cells. Finally, quantitative PCr can detect a burden of as few as 105 leukemic cells. The current costs of these tests range from approximately $375 to $1,500 and must be performed every 3 to 6 months to follow the patient’s response to therapy. COnCLuSIOn: The advent of kinase inhibitor therapy for CML has greatly increased the importance of sensitive analysis of disease burden. Subsequent testing during therapy greatly improves the ability of the clinician to predict the therapeutic outcome. Signs of early treatment failure can give the patient time to switch therapies before the disease progresses to an advanced stage.

SuMMAry: CML is caused by thetranslocation of chromosomes9and 22 to create what is called thePhiladelphia chromosome. This translocation removesacritical regulatorydomainfromthe tyrosine kinase,ABL,such that itsprotein productisconstitutivelyactive. This meansthatthe cell escapes theconstraints of normal cell growth andproliferatesuncontrollably.The modifiedprotein is knownasBCr-ABL,and it causes CML by phosphorylatingnumerousdownstream proteinsinvolvedinthe activation of cell division, amongother functions. during theearliest phaseof thedisease, thechronic phase, kinase inhibitorsthattargetBCr-ABL are effectiveinstopping disease progression. However, aminorityofpatients remain unresponsive to this therapy.
Finally, themostsensitive assessmentisquantitative PCR. The result of this assessment is referred to as themolecular response. PCRr esults areo ften reported as 10-fold( log) reductions, as showninthe Figure.Currently,our finallimit of detectionisan approximate load of 105leukemiccells.
Cytogenetics( karyotyping) is performedo nab onem arrow biopsy.The cellsderivedfromthe biopsy areculturedf or 1to3 days,allowingsomeofthemtoenter themetaphasestate of mitosis, wherethe chromosomesare condensed andwhere cytogeneticsc an be assessed.A tt hisp oint thec ells ares tained andt he chromosomesa re then identified on theb asis of characteristic bandsoflight anddarkstaining. The sizesand patterns of these bandsallow thei dentificationn ot only of normal chromosomes butalsoo ft ranslocations, amplifications,and deletions.T he Ph is thus identified by itsuniquepattern of bands.
Thec ost of this test at EmoryH ealthcare is approximately $1,500.I ti sac rucial test andi sa lwaysd onea td iagnosis.N ot only does it enablethe identification of theP hb ut it also shows thepresenceofother cytogenetic abnormalities.Thistestwill be essential in determiningw hether clonal evolutionh as occurred within theb onem arrows tem cell poola nd thus whether the patienth as progressed beyond theC P. Furthermore,i ti sa n essential test to be performedifdisease progressionissuspected. The5 -years urvivald ataf romt he IRIS trials howt hatp atients with CMLw ho have no CR at 24 months have an 82%c hance of survival at 5y ears. 11 In comparison,p atientsw ithC ML who achieveaC CR at 24 months have a 99%chanceo fsurvivala t5 years. If thepatient hasnot beguntorespond to therapywithin 12 months andpossiblyasearly as 3months, guidelines recommend thattherapy be switchedatthispoint rather thanatalater date.

ACkNOwlEDgMENT
The author thanksRobertScheinman,PhD,for hisassistanceindeveloping this manuscript.
The author disclosesnopotentialbiasorconflictofinterest relating to this research.
OBjeCTIve: This review will outlinethe evolution of therapyinCML.Preimatinib andimatinib-based treatmentstrategies,clinicalefficacy,and the mechanism of imatinib resistance will be discussed.
Imatinib functions by competingwithadenosine triphosphate (ATP)for bindingtothe BCr-ABL tyrosine kinase.Inthe absence of ATP, BCr-ABL is notabletoactivate downstream effector tyrosine kinase moleculesthat drivewBC proliferation.The International randomizedInterferonversus STI571 clinicaltrial wasthe firsttodocument theefficacy of imatinib as a first-line therapyfor patients in CP.Morethan90% of these patients hada CHr. Toxicities associated with this therapyare low. response in patients with advancedCML is less pronouncedthaninCPand is shorterlived, with less than 30%ofpatients achieving aCHr.For patients with CML in BP,the only viabletherapy is to attemptatemporaryreduction in disease burden with asalvage chemotherapyregimen, suchasvAC (etoposide, cytarabine,and carboplatin).The goal of this inductionchemotherapyisto induce asecondremission;thenthe patientmay be consideredfor allogeneic BMT.
OBjeCTIve: This review will outlinethe evolution of therapyinCML.Preimatinib andimatinib-based treatmentstrategies,clinicalefficacy,and t he mechanism of imatinib resistance will be discussed.
Imatinib functions by competingwithadenosine triphosphate (ATP)for bindingtothe BCr-ABL tyrosine kinase.Inthe absence of ATP, BCr-ABL is notabletoactivate downstream effector tyrosine kinase moleculesthat drivewBC proliferation.The International randomizedInterferonversus STI571 clinicaltrial wasthe firsttodocument theefficacy of imatinib as a first-line therapyfor patients in CP.Morethan90% of these patients hada CHr. Toxicities associated with this therapyare low. response in patients with advancedCML is less pronouncedthaninCPand is shorterlived, with less than 30%ofpatients achieving aCHr.For patients with CML in BP,the only viabletherapy is to attemptatemporaryreduction in disease burden with asalvage chemotherapyregimen, suchasvAC (etoposide, cytarabine,and carboplatin).The goal of this inductionchemotherapyisto induce asecondremission;thenthe patientmay be consideredfor allogeneic BMT.
COnCLuSIOn:For themajorityofpatients with CML in CP,the standard of care is to maintain thepatientinCPwithimatinib therapy. Clinicaltrials have been extraordinarilysuccessful, with 5-year survival ratesgreater than 90%. Allogeneic BMTcontinuestobeanoption forthose whocannot tolerate imatinib or when CML progresses on imatinib therapy.

■■ Pre-imatinib Therapies
CytoreductiveTher apy Busulfan wasone of theinitialagentstotreat CML. It hasefficacy in controlling elevated whiteb lood cell (WBC)c ountso vera period of severaly ears.H owever,b usulfant herapyi sn ot without toxicity.Perhapsthe most well-known toxicity is pulmonary fibrosis,commonlytermed"busulfan lung." This toxicity appears to be related to thed urationo fe xposure to thed rug. Patients progressed to AP andBP, with amedian survival of 45 months.

OtherToxicities
Nauseaand vomitingcan be largelya voided by taking imatinib with food.M yalgia anda rthralgiam ay be treated with nonsteroidal anti-inflammatoryd rugs,w itht he caveat thatt he plateletc ount cannot be low. Rash is common.T he patientc an be rechallengedorthe imatinibdose lowered. Novartis will supply, on request, av erys pecifica lgorithm forr estartingt herapy at a lowerd oset ot ry to minimize recurrence of ther ash. Finally, imatinibinhibitscytochrome P450 3A4and thus hasn umerous drug interactions with otherd rugs usingt hisl iverm etabolic pathway.

■■ Imatinib Resistance
Acquired resistance refers to theability of CMLtodevelop resistancetoimatinibovertime. Disease progressiondespite imatinib is inevitablei np atientsw ho acquirethese mutations. The most common causeisthe mutation of BCR-ABLt oaf ormthatisn o longer sensitive to imatinib. This is them ost common form of resistance,a nd numerous mutationsc ausing resistance have been identified andc haracterized.A nother mechanism leading to resistance is gene amplification. Herethe number of BCR-ABL proteins produced exceedsthe ability of imatinibtoinhibit.
OBjeCTIve: To review themechanismsbywhich CML becomesresistant to imatinib andtodiscuss thenew therapeuticalternatives to imatinib and when they should be considered.
SuMMAry: Managed careweighsadvances andassociated costs to determinTheintroduction of imatinib hasindefinitely lengthened the survival time of patientswithCML,transformingthisintoachronic disease condition.However,care must be taken to avoid theappearance of imatinib-resistant clones.resistance can manifest through1ofseveral mechanisms, includingincreasedplasmaprotein binding, increaseddrugefflux, theappearance of BCr-ABL mutantsthathavelow affinity forimatinib,the appearance of BCr-ABL independentproliferation signals,and theamplification of theBCr-ABL gene. Subtherapeuticdosingishighlylikelytoresult in theselection of aresistant clone;thus, it is of paramount importance to ensure theimatinib dose is sufficient. Measurements of plasma levels of imatinib areproving to be predictiveofoutcomes,suggestingthatthe monitoring of imatinib levels will be an important andnecessary aspect of monitoring disease.Several clinicaltrials have shown that high-doseimatinib provides greaterand fasterresponse rates. This alsomay lead to betterlong-term blockade of disease progression. waiting untildiseaseprogressionbeginsappears to lead to greaterresistance to high-doseimatinib andshould be avoided. dasatinib is anext-generation kinase inhibitor that bindstoboth SrC andtomultipleconformationsofBCr-ABL.Itiscapable of blocking severalBCr-ABL mutantsthatare resistant to imatinib.Clinical trials have shown dasatinib is effective in maintainingpatients in CP and can return apercentage of patients with advancedCML to CP.economic analysisindicates that thecost-efficacy ratiofor imatinib is approximately $40,000 per year andcompares favorably with thecosts of accepted procedures,suchasdialysis.datahaveshown that tyrosine kinases also have better mortalityratesthanallogeneic bone marrowtransplantfor thefirst 8years andappeartoalso be more cost-effectivethantransplantation for this time frame.  6 Blood samples hadbeen obtained from 551p atientswithC ML on day1( trough sampletaken 24 hoursafter thefirst dose)and at steady stateo nday 29 of treatment.M olecular response ratesa fter 1y ears howedt hato nly 25%o fp atientsw ithl evels< 647n g/mL went into am olecular response,whereas 40%ofpatientswithlevels>647ng/mL went into am olecular response.After 4y ears,5 3% of patients with a lowCmin achieved an MMR versus 80%ofpatientswithahigh Cmin.Eachofthese patients wasgiven an imatinibdoseof400 mg,b ut theirp lasmal evels, as well as theirr esponses,v aried considerably.

■■ Conclusions
Imatinibh as turned CMLf romar elativelyr apidly fatalc ondition into am anageablec hronic disease.A sw itha ll chronic conditions,disease management must be optimized. Costsmust be containedb ye stablishinga ppropriate dosagesa nd identifyingt he importantd isease parameters to monitor. Recent data strongly supportthe monitoring of imatiniblevelstoestablish the effectived ose, as well as high-dosei matinibt herapyt oa chieve more rapid responsesa nd to potentiallya void them orer apid developmento fr esistant disease.D asatinibi san ewer kinase inhibitorthatbinds to BCR-ABLinthe active andinactiveconformations, as well as to theSRC kinase,and thus canovercome the resistance caused by severalcommonCML mutations. Clinicaltrialshavebeen quitesuccessful, notonlyfor patients in CP buttoalesser extent,for patients in advancedstagesofthe disease. This is most likelybecause of thea bility of dasatinibt o block SRCand BCR-ABLkinases.Economic analysis showsthat imatiniband dasatinibtherapies have acost-efficacyratio closeto thatofdialysis, amarkerfor accepted costsofquality-of-life years. The cost-efficacyratio is farsuperiortothe olderchemotherapies, such as hydroxyureaand IFN ∂ ,and also appears to be superior to BMT. Finally, it appears possible thatsomepatientswho have achieved aCMR with imatinibcan stop therapywithoutrelapse. More time is needed before it canbed etermined whetherthese drugsindeed have acurative effect.