chronic myelogenous leukemia

CONTEMPO UPDATESLINKING EVIDENCE AND EXPERIENCE

Chronic Myelogenous LeukemiaMamta Kalidas, MDHagop Kantarjian, MDMoshe Talpaz, MD

Natural HistoryChronic myelogenous leukemia (CML)is a disorder of hematopoietic stemcells1 accounting for 15% of adult leu-kemias. The median age at presenta-tion is between 50 and 60 years; 12%to 30% of patients at diagnosis are olderthan 60 years.

Chronic myelogenous leukemia clas-sically progresses through 3 phases, be-coming more resistant to treatment ineach successive phase. The majority ofpatients present in the chronic phase,which may last 4 to 6 years and is oftenasymptomatic at diagnosis. In the accel-erated phase, symptoms become worseand immature blasts increase in the pe-ripheral blood. The duration of this phasemay last as long as a year. The final andfatal blastic phase (.30% blasts in thebone marrow or peripheral blood) hasfeatures of an acute leukemia includingfever, weight loss, bleeding, and ane-mia; this phase may last 3 to 6 months.

PathophysiologyThe Philadelphia (Ph9) chromosome wasfirst described in 1960 in patients withCML as a shortened chromosome thatwas later discovered to be chromosome22.2 In 1973 it was further character-ized as a t(9;22) translocation.3 Ninety-five percent of patients with CML havethis defining Ph9 chromosome from a re-ciprocal translocation t(9;22)(q34;q11).This translocation is also present in 15%to 30% of adult acute lymphoid leuke-mia (ALL) patients and 2% of acute my-eloblastic leukemia patients.4,5 The con-

sequence of this translocation is a fusionof the bcr (breakpoint cluster region)gene on chromosome 22 to the cellularabl (c-abl) gene on chromosome 9. Theresulting fusionprotein,Bcr-Abl, is a con-stitutively active cytoplasmic tyrosine ki-nase that can vary in size (185 kd-230kd) and can phosphorylate several sub-strates resulting in the initiation of mul-tiple signal cascades involved in cellgrowth, differentiation, adhesion, anddeath6 (FIGURE 1). Since this tyrosine ki-nase is constitutively active, the cells by-pass regulated growth and undergo a ma-lignant transformation to leukemia.

Monitoring With Bcr-AblPatients with CML currently may bemonitored by hematologic, cytogenetic(karyotype), and molecular tests such asFISH (fluorescence in situ hybridiza-tion)andRT-PCR(reverse transcriptase–polymerase chain reaction). Based onthese assays, therapy outcome may bedefined in terms of hematologic remis-sion (normalization of blood cell countsand spleen size), varying degrees of cyto-genetic response (decline in percentageof Ph9 cells), or a molecular remission(PCR negative). Cytogenetic analysis istedious, but has become useful in pre-dicting survival outcome.7-9 Polymerasechain reaction is a highly sensitive assayand can detect a single Ph9 cell in 10000to 100000 normal cells.10 Bcr-Abl mes-sengerRNA(mRNA)transcriptscannowbequantitatedand followedover timebynewly developed PCR assays to predicteventual relapse in patients who haveundergone transplantation,11 althoughthepredictive significanceof theseassaysin nontransplant therapies of CML hasnot been fully clarified.

Evolution of Therapy in CMLPrior to the 1950s, splenic irradiationwas the mainstay of CML therapy but

it had minimal effect on survival(TABLE).12 In 1953, busulfan was in-troduced for palliation of chronic-phase CML.14 Ten years later, hydroxy-urea, a ribonucleotide reductaseinhibitor, became available23 and wasfavored over busulfan because it hadfewer adverse effects and improved sur-vival.15,22 However, since neither drugaffected either cytogenetic response orprogression to blast crisis,15,22 more ef-fective therapy was needed. Alloge-neic stem cell transplantation (SCT) forCML was first performed in the 1970s,initially with identical twin trans-plants24 and subsequently with HLA-matched sibling transplants.25 Since fewpatients were eligible for SCT, alterna-tive treatment was desired, and in theearly 1980s a-interferon (IFN)–basedtherapy was introduced.26

Currently, allogeneic matched sib-ling SCT is favored for young (,30-40years old) patients in chronic phase whoare within 1 year of diagnosis. These pa-tients can have “cure” rates of 50% to55% at 10 years.27 For older patients, thetransplant-associated mortality rate is30% to 50%, which is higher than themortality rate in younger patients.28,29

Even with the long-term event-free sur-vival rates seen with allogeneic SCT, 10%to 20% of the patients who receive onewill experience a disease relapse, whichgenerally occurs within 3 years of trans-

See also Patient Page.

Author Affiliations: Departments of Bioimmuno-therapy (Drs Kalidas and Talpaz) and Leukemia (DrKantarjian), M.D. Anderson Cancer Center, Hous-ton, Tex.Financial Disclosure: Dr Kantarjian received grants orfunding from Novartis and Schering Plough; Dr Tal-paz received grants or funding (including lecture spon-sorships) from Novartis, Schering Plough, and Hoff-mann LaRoche.Corresponding Author and Reprints: Moshe Talpaz,MD, Department of Bioimmunotherapy, M.D. Ander-son Cancer Center, 1515 Holcombe Blvd, Box 422,Houston, TX 77030 (e-mai l : mtalpaz@mai l.mdanderson.org).Contempo Updates Section Editors: Alice T. D.Hughes, MD; Janet M. Torpy, MD, Fishbein Fellows.

©2001 American Medical Association. All rights reserved. (Reprinted) JAMA, August 22/29, 2001—Vol 286, No. 8 895

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plantation.30 Treatment choices in-clude a-IFN, infusion of donor lympho-cytes, or a second SCT. Infusion of donorlymphocytes is most effective when givenwithin the first 2 years of the SCT.31 Lym-phocytes from the original donor aretransfused and induce complete remis-sion through graft-vs-tumor effect in 60%to 80% of patients who relapse with ac-tive chronic-phase CML.31

Although allogeneic SCT from sib-lings is the best chance for cure for CMLpatients in chronic phase, only 15% to20% of patients are candidates for thistreatment given the limitations of age orlack of HLA-matched related donors fail-ing to provide therapeutic solutions forthe majority of patients with CML. Forpatients not eligible for SCT, a-IFN plushydroxyurea and/or cytarabine can beused.32 Combination therapy with a-IFNand cytarabine has a slight survival ad-vantage over a-IFN alone.7,20,33,34

a-Interferon was first used clinicallyin 1983 after reports of activity in CML.26

A single-center study later demon-strated that a-IFN induced complete he-matologic (80%) and complete cytoge-netic (26%) responses in patients withchronic-phase CML21 and similar re-sponses were confirmed by other inves-tigators.9,33-35 Median time to completehematologic remission is 6 to 7 monthsand 12 to 17 months for complete cy-togenetic remission.21 Survival ratesare higher in patients receiving a-IFNthan in patients receiving busulfan orhydroxyurea alone.20,22,34 The most re-markable impact on survival has beendemonstrated among patients withlow-risk disease, where survival rateshave exceeded 9 years.7,19-22,36,37 Further-more, greater than 80% of those whodemonstrate a complete cytogenetic re-sponse to a-IFN are alive for more than10 years.7,21 However, a-IFN therapy isassociated with considerable adverse ef-fects, which include fever, chills, fa-tigue, arthralgias, anorexia, and weightloss, and is discontinued in 4% to 18%of patients due to toxicity.34

Novel TherapiesThe search for more effective treatmenthas continued because of the limita-

Figure 1. Production of the Bcr-Abl Gene and Protein

Chromosome 9 Chromosome 9

Chromosome 22

TRANSFORMED HEMATOPOIETIC PROGENITOR CELL

Philadelphia Chromosome

Translocation

Bcr-Abl Fusion Protein

Bcr-Abl Fusion Protein

Tyrosine Kinase Domain

AblBcr

DNA Binding Sites

IncreasedCell Survival

UnregulatedCell Proliferation

AbnormalCell Adhesion

q34

q11

N C

Bcr-AblFusion Gene

abl Gene

bcr Gene

TranslationBcr-AblmRNA

Transcription of Bcr-Abl Fusion Gene

After the translocation between chromosomes 9 and 22, the Bcr-Abl fusion gene undergoes transcription. Theresulting chimeric Bcr-Abl messenger RNA (mRNA) is then translated into the Bcr-Abl tyrosine kinase protein,which enhances altered cell proliferation, adhesion, and survival.

Table. Evolution of Discoveries and Therapies in Chronic Myelogenous Leukemia*

Era Discovery TreatmentMedian

Survival, mo

1900-1920 Characterization ofdisease morphology

3112

1920-1950 Splenic irradiation 2812,13

1950-1960 Busulfan 35-4514,15

1960 Ph chromosome Hydroxyurea 48-6715-17

1970-present Allogeneic SCT 50%-60%cure rate18†

1980-present Bcr-Abl gene, protein,and cellular signaling

Interferons 55-897,19-22

1998-present STI-571 (specific targetedtherapy)

. . .‡

*SCT indicates stem cell transplant; STI-571, signal transduction inhibitor 571.†Only for patients eligible for SCT.‡Ellipses indicate not yet available.

CHRONIC MYELOGENOUS LEUKEMIA RESEARCH AND TREATMENT

896 JAMA, August 22/29, 2001—Vol 286, No. 8 (Reprinted) ©2001 American Medical Association. All rights reserved.


tionsofcurrenttherapies—manypatientsare not eligible for a potentially curativeallogeneic SCT, SCT is associated withlife-threatening toxicities, and a-IFN isseldom curative and also associated withmorbidity. In 1996, this effort led to thedevelopment of relatively specific Bcr-Abl tyrosine kinase inhibitors.38 One ofthese, a 2-phenylaminopyrimidine, wasa potent relatively selective inhibitor ofthe Bcr-Abl tyrosine kinase. This com-pound, CGP 57148B (Novartis, Basel,Switzerland),demonstrated inhibitionofproliferation of Bcr-Abl expressing cellsaswell as inhibitionofBcr-Abl (+) tumorformation in profoundly immunodefi-cient mice.38 CGP 57148B (later namedSTI-571, signal transduction inhibitor571) had little in vivo toxicity in ani-mals and did not hinder the growth ofnormal cells.38 Further investigation ofthis compound has revealed that STI-571binds to theadenosinetriphosphate–binding site of Abl, thus inhibiting thephosphorylation of substrates and sub-sequent malignant transformation39

(FIGURE 2). Although STI-571 is rela-tivelyspecific forBcr-Abl tyrosinekinasesand is active against platelet-derivedgrowth factor receptor kinase40 and c-kitreceptor kinase,41 it is inactive against alarge number of other tyrosine kinases.38

Because of the promising in vitro andin vivo data, a phase 1 study of STI-571began in patients with chronic-phaseCML resistant to or intolerant of a-IFN.A total of 53 of 54 patients experiencedcomplete hematologic remissions.42 Cy-togenetic responses, were seen in 54% ofpatients.42 Complete hematologic remis-sions have continued in 51 of the 53 pa-tients after a median follow-up of 265days.42 These results are surprising inlight of the fact that these patients hadlong-standing disease (3 years on aver-age from diagnosis). The adverse ef-fects of STI-571 observed in the study in-cluded nausea, vomiting, and fluidretention; a maximal tolerated dose wasnot reached.40,42 Preliminary data froma phase 2 study of STI-571 evaluating cy-togenetic responses in patients with Ph(+) CML for whom a-IFN had not beensuccessful are also promising. After 6months of therapy, a major cytogenetic

response was observed in 56% of the 290evaluable patients.43 Phase 2 studies thatincluded patients with accelerated-phase CML have demonstrated an over-all hematological response rate of 78%;a complete hematologic remission hasbeen demonstrated in 22 patients.40 STI-571 has also been evaluated in patientswith blastic-phase CML and Ph (+) ALL.Fifty-five percent of patients with CMLin blastic phase demonstrated a re-sponse; 22% of these were complete re-sponses.44 Even though 14 of 20 pa-tients with Ph (+) ALL or lymphoid blastcrisis experienced a response, all but 1have relapsed while receiving therapy.44

A phase 3 trial is under way to investi-gate the use of STI-571 as front-line treat-ment of newly diagnosed patients withCML in chronic phase. It will compareSTI-571 with the combination of a-IFNand cytarabine.

In May 2001, the Food and Drug Ad-ministration approved STI-571 underthe name Gleevec (Novartis, East Ha-nover, NJ) for patients with chronic-

phase CML who are resistant to or in-tolerant of a-IFN as well as for patientswith more advanced stages of CML.

New AgentsA number of novel agents are still un-der investigation for the treatment ofCML. Homoharringtonine, a plant alka-loid, has shown activity in patients in theearly and late chronic phases of CML.45

A potent hypomethylating agent calleddecitabine has also demonstrated activ-ity in patients with CML in acceleratedand blastic phases.46 Of 5 patients withblastic-phase CML treated with troxa-citabine, a cytosine analog, 2 have re-turned to chronic phase.47 Immuno-therapy with specific vaccines is alsounder investigation.48

ConclusionsOver the past century, our understand-ing of CML pathogenesis and therapeu-tic strategies for CML has evolved con-siderably. Chronic myelogenousleukemia is one of the few diseases in

Figure 2. Structure and Mechanism of Action of STI-571

Substrate

Substrate

Malignant Transformation

Bcr-Abl Protein

Bcr-Abl Protein

Phosphorylation

No Phosphorylation

Chemical Structure of STI-571

C29H31N7O • CH4SO3

H

O

CH3

H

ATP

STI-571

ATP

Binds at ATP Binding Site

N

N

N N N

CH3

N

N

A B

A, After adenosine triphosphate (ATP) binds to the Bcr-Abl protein, the cell substrate becomes phosphory-lated and initiates a chain of signal cascades leading to malignant transformation of the cell. B, STI-571 bindsto the Bcr-Abl tyrosine kinase protein at its ATP binding site, thus preventing phosphorylation of the substrateand subsequent malignant transformation.


©2001 American Medical Association. All rights reserved. (Reprinted) JAMA, August 22/29, 2001—Vol 286, No. 8 897


which a specific cytogenetic and mo-lecular abnormality has been impli-cated in the pathogenesis of the disease.The presence of a constitutively activeBcr-Abl tyrosine kinase in the tumor cellshas led to the first targeted moleculartherapy of its kind.This drug has the ad-vantage, compared with traditional an-tineoplastic agents, of being able to tar-get abnormal cells and spare normal cells.

Clinical trials have shown verypromising results of STI-571 in Bcr-Abl (+) leukemias in all phases. Themost durable responses have beenseen in patients with chronic-phaseCML who are resistant to or intolerantof a-IFN, but remarkable responseshave also been seen in accelerated andblastic phases of the disease. The suc-cess of this inhibitor has underscored

the significance of molecular basedtherapy. It may be the first in a seriesof new compounds that operate in asimilar mode of action in a variety ofother malignancies. Additionalresearch should help determine theoptimal role for STI-571, whether it bealone, in combination with a-IFN andcytarabine, or as first-line therapyfor CML.

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chronic myelogenous leukemia

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