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2279

107 Chronic Myeloid Leukemia

Hagop Kantarjian and Jorge Cortes

S U M M A R Y O F K E Y P O I N T S

Incidence• About 5000 cases per year in the

United States; 15% of all leukemias• Median age 55 to 60 years at diagnosis

Clinical Findings• Common findings: fatigue, anemia,

abdominal discomfort, splenomegaly,leukocytosis

• 30% to 50% of patients asymptomaticat diagnosis

• White blood cell count usually greaterthan 50 × 109 cells/L, with a left-shifteddifferential, basophilia, thrombocytosis

Differential Diagnosis• Chronic myelomonocytic

leukemia

• Other myeloproliferative disorders• Leukemoid reactions

Evaluation• History and physical examination,

complete blood count with differentialand platelet count, and chemistries

• Bone marrow aspiration and biopsy• Testing for the presence of the

Philadelphia (Ph) chromosome bycytogenetic analysis or for the presenceof the BCR-ABL fusion gene byfluorescence in situ hybridization(FISH) or by reverse-transcriptionpolymerase chain reaction

Therapy• Hydroxyurea or imatinib mesylate

initially to control leukocytosis andthrombocytosis

• Imatinib induces a completehematologic and cytogenetic responsein most patients; estimated 5-year

survival rate 89%• New tyrosine kinase inhibitors

(dasatinib, nilotinib, bosutinib) activeafter imatinib failure

• Allogeneic stem cell transplantationmay be curative but is associated withconsiderable morbidity and mortality

INTRODUCTION

Chronic myeloid (or myelogenous) leukemia (CML) is a clonalhematopoietic stem cell disorder. It is characterized by overproduc-tion of myeloid cells, a result of excessive proliferation and reducedapoptosis. Clinical findings include fatigue, splenomegaly, leukocy-tosis, and anemia. Basophilia and thrombocytosis are common.1–3 CML is defined by the presence of a characteristic cytogenetic abnor-mality, the Philadelphia (Ph) chromosome, a reciprocal balancedtranslocation between the long arms of chromosome 9 and 22, t(9;22)(q34;q11.2). This results in the BCR-ABL–associated molecularevents, which are causally related to the disease pathophysiology.4–6

The typical course of CML is biphasic or triphasic. Most patientsare diagnosed in the indolent or chronic phase. If not treated appro-priately, CML progresses into the accelerated and blastic phases,

which are ominously fatal. Before the discovery of imatinib mesylate,

a selective Bcr-Abl tyrosine kinase inhibitor (TKI), the median sur-vival of patients with chronic-phase CML was 3 to 4 years withhydroxyurea, and 6 to 7 years with interferon-α (IFN-α). Imatinibhas resulted in a dramatic change in the prognosis of CML and isassociated with an estimated 5-year survival rate of 89%. Allogeneicstem cell transplantation is curative in CML but is associated withsignificant mortality and with serious morbidities. As the long-termresults with imatinib continue to mature positively, allogeneic stemcell transplantation, previously a frontline therapy among eligiblepatients, is now considered as a second-line strategy in CML afterfailure of TKI therapy.

INCIDENCE, EPIDEMIOLOGY,AND ETIOLOGY

CML accounts for 15% of cases of leukemia in the United States.There is a slight male preponderance (male-to-female ratio 1.6 : 1).Its annual incidence is about 1.5 cases per 100,000 individuals.

About 5000 cases of CML are diagnosed annually. This incidencehas not changed over in the past few decades, and it increases withage. The median age at diagnosis is 55 to 60 years; it is uncommonin children and adolescents; only 2.7% of CML cases are youngerthan 20 years.

Before imatinib therapy, the prevalence of CML was about 25,000cases in the United States. Now that the annual mortality followingimatinib therapy has been reduced to 2%, the prevalence of CML

will continue to rise, reaching a plateau (in the next 20 years) at about250,000 cases (when the annual incidence will equal the annual

mortality). This will change CML from an uncommon disorder to aprevalent one.There are no known familial associations in CML. Its risk is not

increased in monozygotic twins or in relatives of patients with CML.There are no known common etiologic agents incriminated in CML.Ionizing radiation (exposure to nuclear bombs or accidents; radiationtreatment of ankylosing spondylitis and cervical cancer) has increasedthe risk of CML. Its peak incidence is 5 to 10 years after exposureand is dose-related. The risk of CML is not increased in individuals

working in the nuclear industry. Radiologists working without ade-quate protection (before 1940) had an increased risk of developing



2280 Part III: Specific Malignancies

chronic myeloid leukemia, but no such risk has been found in recentstudies. Benzene exposure increases the risk of acute myelogenousleukemia but not of CML. CML is not a frequent secondary leukemiafollowing treatment of other cancers with radiation and/or alkylatingagents.7–10

PATHOGENESIS

Molecular Pathogenesis

The Ph chromosome abnormality is present in more than 90% of patients with typical CML (Fig. 107-1). It results from a balancedreciprocal translocation of genetic material between the long arms of chromosomes 9 and 22, t(9;22)(q34;q11.2). It is found in hemato-poietic cells but not in other human cells. Its origin is close to thepluripotent stem cell, and it is present in erythroid, myeloid, mono-cytic, and megakaryocytic cells, less commonly in B lymphocytes,rarely in T lymphocytes, but not in marrow fibroblasts. The break-point of chromosome 9 results in translocation of the cellular onco-gene ABL1 to a region on chromosome 22 coding for the majorbreakpoint cluster region (BCR ). ABL1 is a homologue of V-ABL,the Abelson virus that causes leukemia in mice. This juxtaposes a 5′ portion of BCR to a 3′ position of ABL1, and produces a new hybridoncogene, BCR-ABL. This codes for a novel Bcr-Abl oncoprotein of

molecular weight 210 kDa (p210BCR-ABL

). The p210BCR-ABL

oncopro-tein results in uncontrolled kinase activity, which causes excessiveproliferation and reduced apoptosis of CML cells,11–13 leads to agrowth advantage of CML cells over normal cells, and suppressesnormal hematopoiesis. The normal stem cells, although suppressed,persist and re-emerge after effective therapy of CML.

In Ph-positive acute lymphocytic leukemia, the breakpoint inBCR often occurs in a more centromeric region called minor BCR region (mBCR). This produces a smaller BCR gene opposing ABL1,and therefore a fusion gene, messenger RNA, and Bcr-Abl oncopro-

tein (p190BCR-ABL) of smaller sizes. A third rare breakpoint distal tothe major BCR region, called µ-BCR, produces a p230BCR-ABL hybridoncoprotein associated with a very indolent course of CML (seeFig. 107-1).14

The constitutive activation of BCR-ABL results in autophosphor-ylation and activation of downstream pathways that alter gene tran-scription, apoptosis, cytoskeletal organization, cytoadhesions, anddegradation of inhibitory proteins. These signal transduction path-

ways involve RAS, mitogen-activated protein (MAP) kinases, signaltransducers and activators of transcription (STAT), phosphatidylino-sitol 3-kinase (PI3K), MYC, and others. Many of these interactionsare mediated through tyrosine phosphorylation and require bindingof the BCR-ABL to adapter proteins such as GRB-2, CRK, CRK-likeprotein (CRKL) and SCR-homology containing proteins (SHC).Understanding the pathophysiology of these events could result in asuccessful development of targeted therapies that may synergize withimatinib to improve further the prognosis in CML.

What causes the BCR-ABL molecular rearrangement is unknown.Molecular techniques that amplify detection of BCR-ABL to 1 in 108 detect it in marrow cells of 25% to 30% of normal adults, in 5% of infants, but not in cord blood.15 Because CML develops in only 1.5of 100,000 individuals (i.e., 1 to 2 per 25,000 to 30,000 individuals

who express BCR-ABL in their bone marrow), additional molecularevents or lack of immune recognition of the clonal cells may contrib-

ute to the development of CML.The fusion BCR-ABL gene and the p210 protein can be found insome patients with typical morphologic CML, in whom thet(9;22)(q34;q11.2) is not identified. These patients have a responseto therapy and a survival similar to Ph+ cases. Patients with Ph− andBCR-ABL− CML (discussed later) constitute a different entity (atyp-ical CML) and have a worse prognosis.16,17 The molecular patho-physiology of CML transformation is poorly understood. Severalmolecular events have been associated with CML transformation,including point mutations or deletions in the p53 tumor suppression

m-bcr

B

M-bcr

µ-bcr

e11b

1a

a2a3

a11

e1a2

b2a2

b3a2

e19a2

p190bcr-abl

p210bcr-abl

p230bcr-abl

e19

b1

b5

e1e2 5

3

5

3

BCR

Chromosome 22 Chromosome 9

ABL

229

46,XY,t(9;22)()q34;q11.2)A

Figure 107-1 • The Philadelphia (Ph) chromosome, initially described as a minute chromosome, was later identified as a balanced reciprocal trans-location between the long arms of chromosomes 9 and 22, t(9;22) (q34;q11.2). This results in the translocation of the ABL1 gene from chromosome 9in proximity to the breakpoint cluster region (BCR ) on chromosome 22. Depending on the breakpoint site on chromosome 22, three resultant Bcr-Abloncoproteins are generated: (1) P210BCR-ABL, which occurs in the large majority of patients with Ph+ CML; (2) P190 BCR-ABL, present in two thirds of patients with Ph+ acute lymphocytic leukemia (the other one third have the P210 BCR-ABL product); and (3) P230 BCR-ABL, which is found rarely (1% to2%) in patients with an indolent course of Ph+ CML. The three breakpoints on chromosome 22, M-Bcr (P210), m-bcr (P190), µ-bcr (P230), whichcorrespond to the three resultant Bcr-Abl oncoproteins are shown.



Chronic Myeloid Leukemia • CHAPTER 107

gene, p35, c- Myc amplification, deletions in the p16 tumor suppres-sor gene, alteration of retinoblastoma (Rb) gene, and others. Howeverthe causal relation of these events to transformation is not clear.

Animal Models of Chronic Myeloid Leukemia

Experimental models have established a causal relationship betweenthe BCR-ABL molecular events and the development of CML. Trans-genic mice that express BCR-ABL developed acute leukemia. A BCR-

ABL–expressing retrovirus used to infect murine bone marrow cellsthat later repopulate irradiated mice, resulted in myeloproliferativedisorders, including a CML-like syndrome.18–20 BCR-ABL, under thecontrol of a tetracycline-repressible promoter, expressed in mice,resulted in a lymphoid leukemia that reversed in the presence of tetracycline,21 attesting to the leukemic potential of BCR-ABL as asole oncogenic abnormality. The recapitulation of CML-like disor-ders in animal models mediated by the BCR-ABL molecular eventsestablished them as a root cause for CML and a legitimate moleculartarget for therapeutic interventions with TKIs.

DISEASE MANIFESTATIONS

Chronic Phase

About 30% to 50% of patients with CML diagnosed in the UnitedStates are asymptomatic. The disease is found on routine physicalexamination or blood tests.

Common signs and symptoms of CML, when present, result fromanemia and splenomegaly. These include fatigue, weight loss, malaise,easy satiety, and left upper quadrant fullness or pain (Table 107-1).Rare manifestations include bleeding (associated with a low plateletcount and/or platelet dysfunction), thrombosis (associated withthrombocytosis and/or marked leukocytosis), gouty arthritis (fromelevated uric acid levels), priapism (usually with marked leukocytosisor thrombocytosis), retinal hemorrhages, and upper gastrointestinalulceration and bleeding (from elevated histamine levels due to baso-philia). Leukostatic symptoms (dyspnea, drowsiness, loss of coordina-tion, confusion) due to sludging in the pulmonary or cerebral vessels,are uncommon in chronic phase despite white blood cell (WBC)counts exceeding 100 × 109 cells/L.

Splenomegaly is the most consistent physical sign in CML and isdetected in 50% to 60% of cases. Hepatomegaly is less common(10% to 20%). Lymphadenopathy, infiltration of skin or othertissues, is uncommon. When present, these findings may suggestaccelerated or blastic phases of CML, or Ph− CML. Headaches, bonepain, arthralgias, pain from splenic infarction, and fever are morefrequent with CML transformation.

Laboratory features of untreated CML include leukocytosis withpredominance of neutrophils, and a left shift extending to blast cells.Basophils and eosinophils are increased. Thrombocytosis is common;thrombocytopenia is rare and, if present, suggests a worse prognosis.

Anemia (hemoglobin < 11 g/dL) is present in one third of patients.Biochemical abnormalities include a low leukocyte alkaline phospha-tase score, which also occurs in some patients with agnogenic myeloidmetaplasia. Serum levels of vitamin B12, lactate dehydrogenase, uricacid, and lysozyme are often increased. Some patients demonstrate a

cyclic oscillation of the WBC count.The bone marrow is hypercellular with marked myeloid hyper-plasia. The myeloid-to-erythroid ratio is usually 15 : 1 to 20 : 1. About15% of patients have 5% or more blast cells in the peripheral bloodor bone marrow at diagnosis. Increased reticulin fibrosis is common(30% to 40% grade 3–4 reticulin fibrosis by silver staining), butcollagen fibrosis is rare at presentation.22 Interestingly, whereas the“spent phase” of myelofibrotic CML was commonly reported in thepast (with busulfan therapy) as an end-stage CML event, it hasbecome uncommon in the eras of IFN-α and imatinib therapies.Imatinib effectively reduces myelofibrosis in CML.23,24

Accelerated and Blastic Phases

The definitions of accelerated and blastic phases of CML are shownin Table 107-2. In most patients the transformation from chronic toadvanced phase is insidious, the disease becoming more difficult tocontrol. This is referred to as the accelerated phase . The criteria of accelerated phase are variable. In one study, features that correlated

with a median survival of 18 months or less were blast percentageequal or greater than 15%, blasts plus promyelocytes equal or greaterthan 30%, basophils equal or greater than 20%, and a platelet countless than 100 × 109 cells/L unrelated to therapy, and cytogeneticclonal evolution.25 Features of accelerated-phase CML should berevisited, because some (e.g., clonal evolution more favorable, blasts>10% less favorable) have different prognostic implications fromrecent studies (Fig. 107-2).26 About 5% to 10% of patients present

in the accelerated phase. The accelerated phase is also associated with worsening anemia and splenomegaly, organ infiltration (liver, lymphnodes, skin, bones, or other tissues), and constitutional symptoms(aches, fever, malaise, weight loss).

Blastic-phase CML is diagnosed by the presence of 30% or moreblasts in the bone marrow and/or peripheral blood, or by the presenceof extramedullary blastic disease. The blastic-phase CML resemblesacute leukemia. Patients may develop fever, bone aches, bleeding,infections, weight loss, and increasing splenomegaly. Approximately 70% of patients develop a myeloid or undifferentiated blastic phaseand 30% a B-cell lymphoid blastic phase.27

Table 107-1 Features of Patients with NewlyDiagnosed Ph+ Chronic MyelogenousLeukemia Referred to M.D.Anderson Cancer Center*

Parameter Percentage

Age ≥60 years (median) 18 (55)

Female gender 41

Splenomegaly 37

Hepatomegaly 10

Lymphadenophathy 6

Other extramedullary disease 7

Hemoglobin <10 g/dL 13

Platelets

>450 × 109 cells/L 34

4<100 × 109 cells/L

WBC ≥50 × 109 cells/L 45

Marrow

≥5% blasts 7

14≥5% basophilsPeripheral blood

≥3% blasts 13

14≥7% basophils

Cytogenetic clonal evolution other than the Phchromosome

7

Sokal risk

Low 61

Intermediate 27

High 12

*From 1970 to present (N = 2172)




Most patients evolve into the accelerated phase before blasticphase, but 20% of patients transit into a blastic phase without

warning. Most patients in accelerated or blastic phase have additionalchromosomal abnormalities, such as a double Ph, trisomy 8, or iso-chromosome 17. Extramedullary blastic phase of CML can occur inthe lymph nodes, skin, meninges (especially in lymphoid blasticphase), bone, and other sites.

DIAGNOSIS

The diagnosis of typical CML is simple and consists of document-ing, in the setting of persistent unexplained leukocytosis (or occa-sionally thrombocytosis), the presence of the Ph chromosomet(9;22)(q34;q11.2), by routine cytogenetics, or the corresponding

BCR-ABL rearrangement by FISH analysis or by molecularstudies. A FISH analysis relies on the colocalization of large genomic

probes specific to the BCR and ABL1 genes. Comparison of simul-taneous marrow and blood samples by FISH analysis shows highconcordance. FISH studies may have a false-positive range of 1% to10% depending on the probes used.

Reverse transcriptase–polymerase chain reaction (RT-PCR)amplifies the region around the junction between BCR and ABL1. Itis highly sensitive for the detection of minimal residual disease. PCR testing can either be qualitative, providing information aboutthe presence of the BCR-ABL transcript, or quantitative, assessingthe amount of BCR-ABL transcripts. Qualitative PCR may beuseful for diagnosis of CML; quantitative PCR is ideal for monitor-ing residual disease and is usually performed by real-time PCR.Simultaneous peripheral blood and marrow PCR studies show a high

level of concordance. False-positive and false-negative results canhappen with PCR. False-negative results may be from poor-quality RNA or failure of the reaction; false-positive results can be due tocontamination. A 0.5- to 1-log coefficient of variability in somesamples can occur depending on testing procedures, sample handling,and laboratory experience.28,29

The Ph chromosome is usually present in 100% of metaphases,often as the sole abnormality. Between 10% and 15% of patientshave additional chromosomal changes (clonal evolution) involvingtrisomy 8, isochromosome 17, additional loss of material from thesecond chromosome 22 (double Ph), or others.

Table 107-2 Definitions of the Accelerated and Blastic Phases of Chronic Myelogenous Leukemia

Criteria M.D. Anderson Cancer CenterInternational Bone MarrowTransplant Registry World Health Organization

ACCELERATED PHASE

Percent blasts 15–29 10–29 10–19

Percent blasts + promyelocytes ≥30 ≥20 NA

Percent basophils ≥20 ≥20% (basophils + eosinophils) ≥20

Platelets (×109 /L) <100 Unresponsive ↑, persistent ↓ <100 or >1000 unresponsive

Cytogenetics CE CE CE not at diagnosis

WBC NA Difficult to control, or doubling in<5 days

NA

Anemia NA Unresponsive NA

Splenomegaly NA Increasing NA

Other Chloromas, myelofibrosis Megakaryocyte proliferation, fibrosis

BLASTIC PHASE

30% or more blasts; or extramedullary blastic disease, except for the WHO classification, which requires 20% or more.

CE, clonal evolution; NA, not applicable; WBC, white blood cells.

0 12 24 36 48 60 72 84 96

0.0

0.2

0.4

0.6

0.8

1.0

CE at diagnosis

Chronic phase at referral

Platelets > 1000 x 109 /L, no Rx

CE not at diagnosis

Accelerated phase

Blasts 10% to 14%

Splenomegaly and WBC>10 x 10q/L, and/or platelets

>1000 x 10q/L, unresponsiveto therapy

Blasts 20% to 29%

Blasts ≥30%

Months

P r o p o r t i o n w i t h p r o g r e s s i o n - f r e e s u r v i v a l

Figure 107-2 • Progression-free survival in CML by different character-istics, highlighting that clonal evolution (CE) at diagnosis is not associated

with adverse prognosis. CE during the course of CML has a slight adverseprognostic impact but cannot be considered an accelerated-phase feature,because the associated estimated 4-year progression-free survival rate is 68%,

similar to that of chronic phase. Similarly thrombocytosis (>1000 × 109 cells/L) is associated with an estimated 4-year progression-free survivalrate of 84%. The estimated 4-year progression-free survival rate in acceleratedphase (classical standard criteria) is 45%. The figure also highlightsthat whereas a blast percentage of 20% to 29% is associated with anadverse accelerated phase–like prognosis, it cannot be considered a blasticphase feature (as proposed by the World Health Organization), because itseems to be closer in outcome to accelerated than to blastic phase. Patients

who present with 10% to 14% blasts have an adverse prognosis similar toaccelerated phase. Therefore, the proposed new criteria of accelerated phasemay exclude clonal evolution, but include patients with blast percentagesabove 10%.




Eighty-five percent of patients have a typical t(9;22) translocation;5% have variant translocations which can be simple (involving chro-mosome 22 and a chromosome other than chromosome 9), orcomplex (involving one or more chromosomes in addition to chro-mosomes 9 and 22). With imatinib, patients with Ph variants haveresponse to therapy and prognosis similar to Ph+ CML.

Diagnostic and Monitoring Procedures in Chronic

Myeloid Leukemia

The improved rates of complete cytogenetic response and of molec-ular response with imatinib now require new techniques that measurethese responses more accurately (rather than relying on evaluation of only 20 metaphases by routine cytogenetic studies), with less painfulprocedures (peripheral blood rather than marrow samples), and withmethods that measure minimal disease below the level of detectionby routine karyotypic analysis (molecular studies). FISH studies canassess rapidly disease status in 200 cells, and can be performed onblood specimens. Quantitative PCR studies usually measure the ratioof the abnormal message, BCR-ABL, to a normal message (e.g., ABL).

A BCR-ABL/ ABL ratio of less than 0.1% (approximately a 3-logreduction of disease from a standardized baseline) has been associated

with a low risk of relapse and with favorable progression-free survival. A negative PCR analysis (undetectable BCR-ABL transcripts; usually

a 4.5-log reduction or more) may be technique-dependent and isreferred to as complete molecular response.Monitoring response to imatinib-based therapy may use different

approaches depending on the investigators’ experience, patientage, whether changes of residual disease affect subsequent therapy,availability of methodologies, and other factors. In general, patients

with newly diagnosed CML require an initial bone marrow analysis(to evaluate the percentage of blasts and basophils, and whetherclonal evolution is present), then once a year (to detect cytogeneticabnormalities in both the Ph+ and Ph− cell). Some experts recom-mend bone marrow studies every 3 to 6 months in the first yearbecause of the prognostic significance of the Ph+ status from routinemarrow cytogenetic studies. Practically, peripheral blood FISHstudies every 3 to 4 months provide a reasonable estimate of theresponse profile in the first year. Once Ph+ cells are less than 5% by FISH, the complete cytogenetic response can be confirmed by a

bone marrow analysis with routine cytogenetics, and subsequentmonitoring of minimal residual disease performed by peripheralblood real-time PCR studies. In a patient in stable complete cytoge-netic response, real-time PCR studies may be performed every 6months. If concerns arise regarding changes in PCR values, thestudy can be repeated more frequently (e.g., every 2 to 3 months).Some investigators suggest a two-fold or 0.5-log increase in transcriptlevels may correlate with the development of mutations or withrelapse.30–32 However, these analyses stem from individual laborato-ries with significant expertise and may not apply to routine practice.In general, in a patient in complete cytogenetic response, a riseof transcript levels by real-time PCR should be repeatedly confirmedbefore a change of therapy is considered, which may be minor (e.g.,increasing the dose of imatinib), rather than drastic (e.g., allogeneicstem cell transplant).

Monitoring for mutations in the Bcr-Abl kinase domain (Abl

mutations) that are associated with resistance is also an evolvingconcept. Assessing mutation status before therapy or in respondingpatients has no prognostic or therapeutic value. Mutation studies areimportant in patients who exhibit cytogenetic-hematologic relapse orresistance. In them, detection of a threonine-to-isoleucine mutationat codon 315 (T315I) will indicate a change of therapy to non-TKIs(e.g., allogeneic stem cell transplant, specific T315I inhibitors, com-binations of chemotherapy). Particular mutations may favor the useof one TKI over others, based on preclinical studies and early clinicalexperience. For example, V299L and F317L mutations are lessresponsive to dasatinib, whereas some P-loop mutations may be less

sensitive to nilotinib. Otherwise, mutation analysis at present hasminimal impact on current practice in CML.31,32

DIFFERENTIAL DIAGNOSIS

CML can be confused with leukemoid reactions. These are usually transient, have a temporal cause (severe infection, steroids, stress),show modest rises of WBC counts up to 50 × 109 cells/L with toxic

granulocytic vacuolation and Döhle bodies in the granulocytes, anda normal or increased leukocyte alkaline phosphatase level. Cortico-steroids can rarely cause self-limiting extreme neutrophilia with a leftshift.

CML should be differentiated from other myeloproliferative dis-orders or myelodysplastic syndromes like chronic myelomonocyticleukemia, proliferative myelodysplastic syndrome, agnogenic myeloidmetaplasia, polycythemia rubra vera, and essential thrombocytosis.

Although the clinical syndromes may overlap, cytogenetic and molec-ular studies demonstrating the presence of Ph or the BCR-ABL rear-rangement clarify the diagnosis.

A difficult diagnostic situation may arise in patients with a typicalmorphologic picture of CML (splenomegaly, leukocytosis) but whodo not have the Ph chromosome. In some, the BCR-ABL hybrid genecan be demonstrated by molecular studies. Patients who are Ph− andBCR-ABL− often have chronic myelomonocytic leukemia. Patients

may rarely have myeloid hyperplasia, with selective involvement of the neutrophil, eosinophil, or basophilic cell lineages. These aredescribed as having chronic neutrophilic, eosinophilic, or basophilicleukemia and do not have evidence of the Ph chromosome or BCR-

ABL fusion gene. Occasionally, patients with Ph+ CML may presentlike essential thrombocytosis (marked thrombocytosis without leuko-cytosis). Cytogenetic studies are required in all pat ients with essentialthrombocytosis to identify the occasional patient with Ph+ CML andessential thrombocytosis-like presentation.

PROGNOSIS

Prognosis in CML has changed drastically over the past 5 to 10 years.Before imatinib, the median survival of patients with CML inchronic phase (85% to 90% of newly diagnosed patients) was 6 to 7years with IFN with or without cytarabine. For candidates for allo-

geneic stem cell transplantation, the expected 20-year survival rate was 40% to 50% in younger patients with a matched related donor. With imatinib therapy the estimated 5-year survival rate in chronicphase is 89%.33 With an annual mortality of 1% to 2% in the first5 years (if this positive trend is maintained in later years), the esti-mated median survival may exceed 25 years (Fig. 107-3).33–35 Thus,chronic-phase CML may have now changed to an indolent disorderin which most patients may survive normally with continued oralimatinib therapy. Imatinib therapy has also changed the prognosis inaccelerated phase. The median survival has increased from 1 to 2years before imatinib to an estimated 4-year survival rate of 60%.36

Among patients with accelerated-phase CML who have an early cytogenetic response to imatinib, the estimated 4-year survival rate is80%. Similarly, patients with clonal evolution as the only sign of accelerated disease have an estimated 5-year survival rate of 80%.37 Survival in blastic phase is also better with imatinib therapy, but only

modestly so (median survival improved from 3–6 months to 12–15months). Prognosis of lymphoid blastic phase is slightly more favor-able, with a response rate to anti–acute lymphoid leukemia chemo-therapy and imatinib of 60%, and a median survival of 12 to 18months.

Before imatinib, several prognostic models (Sokal, Hasford)divided patients in chronic phase into low-, intermediate-, and high-risk groups based on pretreatment adverse prognostic factors includ-ing: older age, splenomegaly, thrombocytosis, higher percentage of blasts and basophils, and presence of cytogenetic clonal evolution.38,39 Imatinib therapy has now altered the prognostic significance of




several of these factors, including deletion of derivative chromosome9, age, and myelofibrosis.23,24,40,41 The latter in fact resolves quiteeffectively with imatinib therapy.23 Currently, the most relevant prog-nostic factor on imatinib therapy is the degree of cytogenetic andmolecular response to initial imatinib therapy (in the first 3 to 12months).33,42,43 Thus, the introduction of imatinib therapy in CML

will require new definitions of the accelerated phase and the adversefactors/risk models in CML.

MANAGEMENT OF CHRONIC MYELOGENOUSLEUKEMIA IN CHRONIC PHASE

In the 1980s to 1990s, the two frontline therapies in CML wereIFN-α–based regimens and allogeneic stem cell transplantation.There was ongoing controversy about the best approach in newly diagnosed patients who were candidates for allogeneic stem cell trans-plantation. In general, allogeneic stem cell transplantation was rec-

ommended for younger patients with matched related donors, whereas older patients and those with unrelated donors (i.e., higherrisk for stem cell transplantation–related mortality) were offereda trial of IFN-based therapies before considering allogeneic stemcell transplantation.44 The maturing positive results with imatinibtherapy have now convinced most investigators and patients to useimatinib as initial therapy, and to delay allogeneic stem cell trans-plantation to a second-line strategy after failure of imatinib and/orother TKIs.

Imatinib

The role of imatinib therapy in CML was established in a series of pivotal trials of imatinib following IFN-α failure in chronic, acceler-ated, and blastic phases, and later in a frontline InternationalRandomized Study of Interferon plus cytarabine versus STI571(IRIS trial).33,42,45–53

Imatinib mesylate, a 2-phenylaminopyrimidine derivative, bindsto the canonical adenosine triphosphate (ATP)-binding site of the

ABL kinase domain. It blocks phosphorylation of tyrosine residueson substrate protein. Blocking ATP binding inactivates the ABLkinase, because it cannot transfer phosphate to its substrate. Inhibit-ing phosphorylation prevents activation of signal transduction path-

ways that cause CML (Fig. 107-4). Imatinib inhibits several tyrosinekinases including p210BCR-ABL, p190BCR-ABL, v-ABL, c-ABL, c-Kit, andplatelet-derived growth factor receptor (PDGF-R).

In the IRIS study 1106 patients with newly diagnosed CML wererandomized to imatinib 400 mg orally daily versus IFN-α plus cyta-rabine. Imatinib was associated with significantly higher rates of major (Ph positivity <35%; 85% vs. 22%) and complete cytogeneticresponses (74% vs. 8%), and lower rates of progression (3% vs. 20%)and transformation (1.5% vs. 7%) after 12 months of therapy.42 An

Imatinib1991–20001981–19901970–1980

Year

258925456184

12329340180

Total Dead92%

0 2 4 6 8 10 12 14 16 18

1.0

0.8

0.6

0.4

0.2

0.0

Years from referral

P r o p o r t i o n a l i v e

Figure 107-3 • Survival of all patients with newly diagnosed Ph+ CMLin chronic phase referred to M.D. Anderson Cancer Center since 1970 (N = 1823). The estimated 6-year survival rate with recent imatinib therapy is92%. Patients treated between 1970 and 1980 received mostly hydroxyurea-based therapy; their median survival was about 4 years. Patients treated

between 1981 and 2000 received mostly interferon (IFN)-based therapy Themedian survival of patients treated with IFN-based therapy from 1981 to1990 is about 6.5 years; it is about 10 years for patients treated between 1991and 2000 because of the added benefit of sequential therapy with imatiniblate in their course.

PATP PP

P

P

PATP PP

P

Substrate

Effectors

Signal

Effectors

Signal

Substrate

ADP Imatinib

Bcr-Abl Bcr-Abl

Figure 107-4 • The Bcr-Abl oncopro-tein has constitutive tyrosine kinase activity compared with the tightly regulated tyro-sine kinase activity of the normal ABLproduct. The Bcr-Abl kinase activates mul-tiple substrates and binding partners,resulting in activation of downstream sig-naling pathways. This results in increased

proliferation and reduced apoptosis of CML cells. By binding to the Abl kinasedomain, imatinib prevents the phosphory-lation of Bcr-Abl, thus interrupting theactivation of the CML pathways.




update of the 5-year follow-up in the 553 patients treated with ima-tinib continued to show excellent results: projected complete cytoge-netic response rate (single-time response) 87%; annual rate of progression to accelerated-blastic phase 4%; annual mortality rate 1%to 2%. At the 5-year follow-up time, 368 patients (67%) were stillon imatinib on study. Rates of transformation and mortality seem tohave been reduced in years 4 and 5 compared with the first 3 years.The estimated 5-year survival rate was 89%. The estimated 5-year

survival rate excluding non-CML-related deaths was 95%.33

Survival was also better with imatinib versus IFN + cytarabine (estimated 5-year survival rates 89% vs. 86%; P = 0.049). The difference was notvery drastic, however, because of the crossover design of the IRISstudy and the commercial availability of imatinib, both resulting ina change from IFN + cytarabine to imatinib in about 90% of patients

within a median of 9 months from start of therapy. Comparison of imatinib results to historical experience with IFN therapy demon-strates more significant survival differences.34,35

In late chronic-phase CML after IFN-α failure, among 454 eval-uable patients receiving imatinib, the cumulative complete cytoge-netic response rate was 57%, and the estimated 5-year survival rate79%.45,46 In accelerated phase the complete cytogenetic response rate

was 40%, and the estimated 4-year survival rate 60%.49,50 In blasticphase response rates were lower and more transient, and the mediansurvival duration only 6 to 12 months (Table 107-3).51

In the IRIS study, a major molecular response (3-log reductionof transcript levels) was observed in 38% of patients in the originalupdate,43 and in 70% of patients with longer follow-up.48,54 Achiev-ing a major molecular response in complete cytogenetic response at18 months was associated with an estimated transformation-free sur-vival and survival rates of 100% at 5 years versus 95% for completecytogenetic response without a major molecular response (P = 0.007).33 Disappearance of BCR-ABL was initially observed in aminority of patients (5%) but is now reported with longer termfollow-ups in 30% to 50% of patients.54,55 This rate depends onthe sensitivity of the molecular test, because in general, a reductionof transcript levels by 4.5 log or more (or a BCR-ABL/ABL ratioof <0.003) may reach levels below detection in most molecularlaboratories.31,32

Higher doses of imatinib 600 to 800 mg daily may overcomeresistance to standard-dose imatinib in some patients.53 In accelerated

phase, high-dose imatinib was associated with higher response ratesand longer survival.49 In chronic-phase CML, imatinib 800 mg daily was also associated with higher rates of complete cytogenetic response,major and complete molecular response, and better progression-freesurvival rates.48,55

Imatinib is associated with mild-moderate side effects includingnausea, vomiting, diarrhea, skin rashes, muscle cramps, bone aches,periorbital or leg edema, and weight gain. Serious but uncommonside effects (1% to 2%) include hepatic, renal, or cardiopulmonary dysfunction. These are manageable with dose reductions or treatmentinterruptions.56,57 Drug-related myelosuppression occurs in 10% to

30% of patients in newly diagnosed CML. This is managed withbrief treatment interruptions and/or dose modifications, or withgrowth factors (erythropoietin for anemia, filgrastim for neutrope-nia). Chromosomal abnormalities may appear in the Ph− cells in 5%to 10% of responding patients. These include some abnormalitiesobserved in myelodysplastic syndrome and acute myeloid leukemiasuch as chromosome 5 or 7 abnormalities, trisomy 8, 20q- and others.These chromosomal abnormalities are probably due to unmasking of

a fragile stem cell prone to development of CML or to genetic insta-bility. Such changes disappear spontaneously in up to 70% of cases.Evolution to a Ph− myelodysplastic syndrome or acute myeloid leu-kemia is rare and probably part of the new natural course of CML.58

Imatinib therapy (400 mg daily) is started as soon as the diagno-sis of CML is established. Allopurinol is recommended until the

WBC count is less than 10 × 109 cells/L. Tumor lysis syndrome israre, except in occasional patients in advanced-phase disease whorequire hydration and closer monitoring. With imatinib the WBCand platelet counts decrease in the first 2 to 4 weeks and normalize

within 1 to 2 months. Complete blood counts are recommended weekly during the first month of therapy, then every 1 to 2 months.For patients with accelerated or blastic phases, complete blood countsshould be performed more frequently, and as indicated clinically.Imatinib therapy should be continued indefinitely; treatment discon-

tinuation even among patients with durable complete molecularresponses (>2 years) has been associated with molecular relapse inabout half.59 High-dose imatinib (i.e., 600–800 mg daily) may beconsidered in CML transformation or Ph+ acute lymphoid leukemia(in combination with chemotherapy), in patients with an unsatisfac-tory response to standard-dose imatinib, or with cytogenetic relapseon imatinib.

Allogeneic Stem Cell Transplantation

Allogeneic stem cell transplantation is curative in selected patients with CML. It is most effective during the chronic phase. Amongpatients in first chronic phase transplanted from matched siblings,the estimated 20-year survival rate is 40% to 50% (Fig. 107-5).60 Thereport from the International Bone Marrow Transplant Registry (IBMTR), compiling data from over 6000 patients undergoing trans-

plants, showed a 5-year survival rate of 60% for first chronic phase/sibling donor, but a 20-year survival rate of 40% to 45%.60 Most of the 10% to 15% additional deaths between years 5 and 20 were dueto transplant-associated complications rather than CML relapse.Chronic morbidities for stem cell transplantation include graft-versus-hose disease (GVHD), infertility, cataracts, hip necrosis,second cancers, and GVHD-associated organ damage (pulmonary,hepatic) or immune-mediated complications. Transplant-relatedmortality ranges from 5% to 50%, depending on several factorsincluding patient age, whether the donor is related or unrelated, thedegree of matching, and other factors such as positivity for cyto-

Table 107-3 Results of Imatinib Therapy in Chronic Myelogenous Leukemia

CML Phase

PERCENTAGE

CHR/HR

CYTOGENETIC RESPONSE MOLECULAR RESPONSE

Major Complete Major Complete % Estimated Survival (at X year)

Chronic—newly diagnosed 90/98 90 87 70 20–40 89–92 (5–6)

Chronic—after interferon failure 60/80 67 57 NA NA 79 (5)

Accelerated 50–60/80 40 30 NA NA 60 (4)

Blastic 20/40 30 10 NA NA 10–20 (2)

CHR, complete HR; CML, chronic myeloid leukemia; HR, hematologic response; NA, not available.

Data extracted from references 33, 45–52.




megalovirus (CMV), preparative and post-transplant regimens, andinstitutional expertise.61–67 Disease-free survival rates with relatedallogeneic stem cell transplantation are 40% to 80% in chronic-phaseCML. The disease-free survival rates are 60% to 80% among patientsyounger than 30 to 40 years of age and 30% to 40% in patients olderthan age 50 years. Disease-free survival rates range from 30% to 60%in accelerated-phase CML, and from 5% to 30% in blastic-phaseCML. Patients with clonal evolution as the only accelerated-phasecriterion have disease-free survival rates of 60%. Patients transplantedin second chronic phase have also favorable disease-free survival ratesof about 40%.

A major limitation of allogeneic stem cell transplantation is

the availability of related donors. Human leukocyte antigen (HLA)–compatible unrelated donors can be found in 50% of patients; themedian time from donor search to transplant is 3 to 6 months. Ingeneral, unrelated donor stem cell transplantation is associated

with higher rates of GVHD and transplant-related complicationsand mortality, and with lower rates of disease-free survival andsurvival. Results of unrelated stem cell transplantation in selectcenters, with molecularly matched donors and optimally managedpatients, seem similar to those achieved with related donor stem celltransplantation.62

Nonmyeloablative preparative regimens have expanded the use of allogeneic stem cell transplantation to older patients and have reducedtransplant-associated complications, organ damage, and mortality.Results in general show high degrees of engraftment, less morbidity and mortality, but perhaps higher incidences of persistent residualdisease, and similar degrees of chronic GVHD.66

Improving Results of Allogeneic Stem Cell Transplantation

Allogeneic stem cell transplantation is safest and results are best inyounger patients with an HLA-identical sibling donor. Improvementof stem cell transplantation results can be achieved through: (1) bettermolecular characterization of the HLA phenotype and genotype andmatching of unrelated donors, (2) improved management of compli-cations, including viral infections (CMV),67 (3) performing stem celltransplantation before CML evolution to accelerated-blastic phases,(4) treatment of relapse after stem cell transplantation before overtdisease occurs (i.e., at time of molecular relapse), and (5) safer andbetter conditioning regimens.63

Monitoring Outcome after Allogeneic Stem CellTransplantation and Treatment of Relapse

Most CML relapses after stem cell transplantation manifest in thefirst 3 to 5 years. Thereafter, the relapse rate is very low but may sometimes occur even after 10 to 15 years from transplant. Patientsusually exhibit molecular relapse before cytogenetic or hematologicrelapse. Increasing BCR-ABL transcript levels usually predict for cyto-genetic and hematologic relapse.68,69

If relapse occurs, withdrawal of immunosuppression (cyclospo-rine, steroids) can induce remission (especially if molecular relapse)by favoring graft-versus-leukemia effect. However, this also may exac-erbate GVHD. If relapse persists, it can be managed effectively withimatinib, donor lymphocyte infusions, IFN-α, or a second stem celltransplantation.70,71 Imatinib results in remission rates of 40% to60% if the relapse is molecular or cytogenetic in chronic phase. It isless effective if CML relapse is hematologic or in transformation.Donor lymphocyte infusions induce durable remission rates of 60%

with molecular or cytogenetic relapse, but may exacerbate GVHD(which can be fatal), and result in intense myelosuppression in 20%of patients.

MANAGEMENT OF PATIENTS WITH IMATINIB RESISTANCE

“Resistance” to imatinib therapy can be defined as failure to achievethe following endpoints: (1) complete hematologic response (CHR)after 3 months of therapy, (2) any cytogenetic response after 6months, (3) a major cytogenetic response (Ph positivity > 35%) after12 months, or (4) a complete cytogenetic response after 18 months.In addition, patients experiencing cytogenetic or hematologic relapseat any time on treatment are considered to have secondary resistanceto imatinib.31

The annual resistance rate to imatinib is about 3% to 4% in thefirst 5 years. Resistance can be primary (mostly due to BCR-ABL–independent mechanisms; i.e., with persistent inhibition of the Bcr-

Abl kinase), or secondary (after an initial response, most often dueto Bcr-Abl–dependent mechanisms, i.e., with reactivation of the Bcr-

Abl kinase).31,32 Several Bcr-Abl–dependent mechanisms of imatinibresistance have been proposed including amplification of BCR-ABL

oncogene or transcript levels, multidrug resistance-dependentpumping of imatinib out of the cell, shifts of Bcr-Abl localization inthe CML cells, and mutations of the Abl kinase domain. Bcr-Ablpoint mutations (>40 described so far), account for about 40% to50% of resistance. Mutations that can occur at the ATP-binding site(P-loop), at contact points with imatinib, or at other Bcr-Abl sites(catalytic domain, activating loop) can produce relative or absoluteresistance to imatinib; some mutations are not relevant to resistance.Mutations with relative resistance to imatinib can be overcome withhigher doses of imatinib; others do not respond to increasing theimatinib dose but respond to treatment with the more potent second-generation TKIs. A particular mutation, T315I, confers absoluteresistance to imatinib and to the second-generation TKIs (i.e., dasat-inib, nilotinib, bosutinib) but may be responsive to new inhibitors

with different binding requirements.Patients who develop imatinib resistance have several treatment

options including allogeneic stem cell transplant, treatment with thenew-generation TKIs, and others. Imatinib resistance in chronicphase is associated with an estimated 4-year survival rate of 60%.However, if progression is in accelerated or blastic phases, the prog-nosis is poor.72 For patients in accelerated or blastic phase afterimatinib resistance, every attempt should be made to refer them toallogeneic stem cell transplantation. If patients develop resistance toimatinib but are still in chronic phase, allogeneic stem cell transplan-tation is an appropriate second-line option if the patient is youngerand/or has a related matched donor. In the interim, or if the patientis older and/or has an unrelated matched donor, a trial of one of thenew-generation TKIs is reasonable. Subsequent therapy may be based

Figure 107-5 • Probability of survival of patients undergoing allogeneicstem cell transplant according to the International Bone Marrow TransplantRegistry (N = 6548). Patients transplanted in first chronic phase (CP1) withan HLA-matched sibling (Sib) had the best outcome. Those transplanted

with unrelated donors or not in CP1 had a worse outcome. The estimated

20-year survival rate of patients transplanted from a sibling donor in CP1 was 45%.

1: Sib + CP1 (N = 3372)2: Sib + Not CP1 (N = 1141)3: Other donor + CP1 (N = 1302)4: Other donor + Not CP1 (N = 725)5: All patients (N = 6548)

0 4 8 12 2018

1.0

0.8

0.6

0.4

0.2

0.0

Years

P r o

b a b i l i t y




on the early response to that therapy. In all cases of imatinib resis-tance, mutational analysis is recommended to identify patients withT315I or other mutations that can be selectively nonresponsive toone of the new-generation TKIs. If a T315I mutation is identified,second-generation TKIs are not effective and the patient should bereferred for allogeneic stem cell transplantation as soon as possible,and in the interim be controlled with hydroxyurea, cytarabine, com-binations of standard older therapies, or investigational agents that

might be effective against T315I mutations. A treatment algorithmfor CML is proposed in Figure 107-6.

Dasatinib

Dasatinib (Sprycel; BMS354825) is a newly approved potent oralmultitargeted kinase inhibitor of critical oncogenic kinases includingBcr-Abl, Src, C-kit, and PDGF-R. This dual Abl/Src inhibitor is 300times more potent than imatinib in preclinical models, and is effec-tive against all imatinib-resistant kinase domain mutations exceptT315I. Following the positive phase I studies of dasatinib demon-strating safety and efficacy in Ph+ leukemias after imatinib failure,73 pivotal phase II studies, referred to as START (Src/Abl Tyrosinekinase inhibition Activity Research Trials of dasatinib), were con-ducted in all phases of CML after imatinib failure and in Ph+ acutelymphocytic leukemia. This led to the US Food and Drug Adminis-

tration’s approval of dasatinib for this indication in 2006. In 387patients with chronic-phase CML after imatinib failure, dasatinib70 mg orally twice daily produced a CHR rate of 90%, a majorcytogenetic response rate of 52%, a complete cytogenetic responserate of 39%, and an estimated 10-month progression-free survivalrate of 92%.74 Response rates were higher in patients with imatinibintolerance versus resistance but were similar by whether mutations

were present or absent. Results were similarly encouraging in acceler-ated-blastic phases and in Ph+ acute lymphocytic leukemia (Table107-4).75–77 A randomized study of dasatinib 70 mg orally twice daily versus high-dose imatinib (400 mg orally twice daily) in patients withCML chronic phase after failure on imatinib 400 to 600 mg daily accrued 150 patients (2 : 1 randomization).77 Dasatinib was associated

with higher rates of complete cytogenetic response at 3 months (22%vs. 8%), overall major cytogenetic response (52% vs. 33%; P = 0.02),

and overall complete cytogenetic response (40% vs. 16%, P = 0.004).

The difference in response rates was most evident in patients withfailure on imatinib 600 mg daily (major cytogenetic response rates49% vs. 24%) but not in patients with failure on imatinib 400 mga day (major cytogenetic response rates 58% vs. 53%). Progression-free survival was better with dasatinib (estimated 12-month rates94% vs. 70%; P < 0.0001). Dasatinib was associated with higherrates of grade 3 to 4 cytopenias (55% to 59%) compared with high-dose imatinib (14% to 39%), and with pleural effusions (17% vs.0%). In a single-institution review of the dasatinib experience, pleuraleffusions were observed in 48 of 138 patients (37%) treated withdasatinib. Pleural effusions were often exudates and were managed

with treatment interruptions, diuretics and short courses of steroids,and resumption of dasatinib at lower dose schedules.78 Myelosuppres-sion was also managed with dose interruptions and reductions. A four-arm randomization study of different dasatinib dose schedules(50 mg twice daily, 100 mg single-dose daily, 70 mg twice daily,

140 mg single-dose daily) showed that a single daily dasatinib doseof 100 mg produced equivalent treatment results with fewer sideeffects.79

Nilotinib

Nilotinib (Tasigna, AMN107) was rationally designed by replace-ment of the N -methylpiperazine binding group of imatinib to opti-mize the binding affinity and selectivity for the Abl kinase. Nilotinib,a selective Bcr-Abl kinase inhibitor, was 30 times more potent thanimatinib in preclinical models, and was active against all imatinib-resistant mutations except T315I. Similar to dasatinib, the phase Istudy with imatinib showed safety and activity after imatinib failure.80 The pivotal phase II studies with imatinib 400 mg orally twice daily have been completed. In the phase II pivotal trial of nilotinib in 316patients in chronic phase after imatinib failure, the CHR rate was

74%, the major cytogenetic response rate 52%, and the completecytogenetic response rate 34%. The estimated 1-year survival rate was95%. Side effects were modest, including grade 3 to 4 myelosuppres-sion in 20% to 30%; no pleural effusions were observed. Responserates were similar in patients with imatinib resistance versus intoler-ance and in patients with or without mutations.81

The activity of nilotinib in CML accelerated and blastic phaseafter imatinib failure were also encouraging, although response rates

were lower and response durations shorter (Table 107-5).82,83 Nilo-tinib recently has been approved by the Food and Drug Administra-tion (October 2007) for the treatment of CML in chronic oraccelerated phases following imatinib failure.

Any cytogenetic response at 3 monthsMajor cytogenetic response at 12 months

Allogeneicstem cell

transplantation

New TKIs, other investigationalcombinations

Imatinib

Yes

Fail

Yes No

No

If stem celltransplantationmortality high

Stem cell transplantation candidate

Continue

Figure 107-6 • Proposed treatment algorithm for patients with newly diagnosed CML. Patients achieving any cytogenetic response after 6 months,a major cytogenetic response after 12 months of therapy, and a completecytogenetic response in the second year of therapy should continue on ima-tinib until there is evidence of resistance. High-dose imatinib could beattempted in patients with unsatisfactory response. In case of resistance,allogeneic stem cell transplantation can be considered as the next option if the transplant-related mortality is acceptable to the patient. If not, the patientcan consider treatment with the new-generation tyrosine kinase inhibitors(dasatinib, nilotinib, bosutinib), or with other investigational therapies,before proceeding to allogeneic stem cell transplant.

Table 107-4 Results of Dasatinib Phase II Studiesin CML and Ph+ ALL after ImatinibFailure

Disease N

RESPONSE RATE (%)

CHR/HR

CYTOGENETIC RESPONSE

Major Complete

CML, chronic 387 90/90 52 39

CML, accelerated 107 39/64 33 24

CML, blastic 116 26/47 38 33

Ph+ ALL 46 33/51 57 54

CML chronic,randomized

Dasatinib 101 93 52 40

High-dose imatinib 49 82 33 16

ALL, acute lymphoid leukemia; CHR, complete hematologic response; CML,

chronic myeloid leukemia; HR, hematologic response; Ph, Philadelphia chromosome.

Data extrapolated from r eferences 74–77.




Bosutinib

Bosutinib (SKI606) is an orally available dual Src/Abl inhibitor thatis 30 to 200 times more potent than imatinib. It has minimal inhib-itory activity against c-Kit and PDGF-R (therefore expected to

produce less myelosuppression and pleural effusions). In a phase I/IIstudy of 69 patients with CML treated after imatinib failure, theCHR rate among 48 patients in chronic phase was 84%, andthe cytogenetic response rate 81%, (major 52%, complete 33%).84 The median follow-up on study was short. Grade 3 to 4 toxicities

were minimal, including skin rashes in 6% and thrombocytopenia in6%. Mild to moderate diarrhea was common at the phase II doseselected of 500 mg orally daily.

Other Agents

MK0457 is an aurora kinase inhibitor with inhibitory activity against T3151 mutant CML. In a preliminary experience in patients

with advanced phases of CML and T315I mutations, MK0457showed encouraging results.85 Other aurora kinase inhibitors withpotential activity against T315I mutant CML include AT9283 andKW2449.

Other classes of agents that have shown reasonable activity againstCML after imatinib failure include farnesyl transferase inhibitors(tipifarnib), decitabine, and homoharringtonine.86–88

SELECTION OF SEQUENTIAL THERAPIESIN PATIENTS WITH CHRONICMYELOGENOUS LEUKEMIA

The longer term follow-up results of imatinib in newly diagnosedCML are reassuring. With its modest toxicity profile and absence of treatment-related mortality, imatinib is now frontline CML therapy in all patients regardless of age. Allogeneic stem cell transplantationis associated with mortality rates of 5% to 50% in the first year and

with significant chronic morbidities including GVHD-related com-plications, cataracts, infertility, second cancers, and a 15% mortality

between years 5 and 20 of follow-up that may be related to subtlebut continuous transplant-related organ damage and some laterelapses. Patients with imatinib resistance may consider allogeneicstem cell transplantation as second-line therapy if they are youngerand/or have a matched related donor (i.e., expected low stem celltransplantation-related mortality). Among patients with expectedhigh stem cell transplantation-related mortality, a trial of a second-generation kinase inhibitor may be attempted, and consideration of transplant based on the early response profile to the treatment.Patients with T315I mutations should be referred to allogeneic stemcell transplantation. Patients with imatinib resistance in accelerated

or blastic phase, either de novo or after chronic phase, should also bereferred to allogeneic stem cell transplantation as soon as possibleregardless of their response to the second-generation TKIs (eventhough such attempts may debulk the transformed disease andimprove the outcome after stem cell transplantation).

Old Traditional Standards of Care Revisited

Busulfan (1,4-dimethane-sulfonyl-oxybutane) is the first alkylatingagent that demonstrated activity in CML. Busulfan therapy wasassociated with significant toxicities, including severe and prolongedmyelosuppression. Busulfan should be used today only as part of some conditioning regimens in allogeneic stem cell transplantation,and must be avoided in any patients awaiting allogeneic stem celltransplantation because of the associated adverse outcome.

Hydroxyurea, a ribonucleotide reductase inhibitor, is a well-toler-ated oral cytotoxic agent that can control blood counts rapidly inmost patients with CML. Rare side effects include nausea, rashes,mouth ulcers, and hand or leg ulcers. Hydroxyurea is usually givenat a daily dose of 1 to 10 g, depending on the degree of leukocytosis,and the dose adjusted to keep the WBC count between 2 × 109 and10 × 109 cells/L. Hydroxyurea may be used for initial cytoreduction,as a temporary measure to control counts in between definitive ther-apies, or part of a combination approach with imatinib or other TKIs.It should not be used alone as a definitive treatment in CML, becauseit rarely suppresses Ph+ cells.

IFN-α showed anti-CML activity in the 1980s and was a standardof care in CML until the discovery of imatinib. IFN-α induced CHR rates of 50% to 80% in untreated chronic-phase CML, and cytoge-netic response rates of 40% to 60% (major in 10% to 40%; completein 5% to 30%).89 A meta-analysis of randomized studies of IFN-α versus hydroxyurea or busulfan, showed that IFN-α therapy wasassociated with better survival than hydroxyurea or busulfan (5-yearsurvival rates 57% vs. 42% , P < .00001).90 IFN-α has minimalactivity in accelerated or blastic phases of CML. It is associated

with significant side effects including flu-like symptoms, fever,chills, myalgias, fatigue, depression, neuropathy, diarrhea, memory problems, immune-mediated complications, myelosuppression, andothers.91

Achievement of a major or complete cytogenetic response withIFN-α is associated with significantly better long-term survival.92 Combinations of IFN-α and low-dose cytarabine improve resultsover IFN-α alone.93

New formulations of IFN-α attached to polyethylene glycol(PEG) prolong its half-life, allow weekly administration, reduce tox-icities, and may also improve results (at least with a particularpegylated IFN-α2a formulation, Pegasys).94

MANAGEMENT OF ACCELERATEDAND BLASTIC PHASES OF CHRONICMYELOGENOUS LEUKEMIA

Imatinib, dasatinib, and nilotinib have all shown activity in CML intransformation. The single-agent activity is more encouraging anddurable in accelerated phase, but less so in blastic phase.

In accelerated phase, imatinib produces a hematologic response

rate of 80%, a CHR rate of 40%, a major cytogenetic response rateof 30%, and an estimated 4-year survival rate of 60%. In accelerated-phase CML after imatinib failure, dasatinib is associated with ahematologic response rate of 64%, a cytogenetic response rate of 40%, and an estimated 18-month survival rate of 70%. The second-generation TKIs probably produce better results than imatinib, eitheralone or in combinations.

Whereas the three TKIs have shown activity in blastic-phase CMLand two of them (imatinib and dasatinib) have been approved forthe indication, the results are modest, and combination modalitiesshould be pursued. These include acute myeloid leukemia regimens

Table 107-5 Results of Nilotinib Phase II Studiesin CML and Ph+ ALL after ImatinibFailure

Disease N

RESPONSE (%)

CHR

CYTOGENETIC RESPONSE

Major Complete

CML, chronic 316 74 52 34

CML, accelerated 64 17 31 17

CML, blastic 96 13 NR NR

Ph+ ALL 34 6 NR NR

ALL, acute lymphoid leukemia; CHR, complete hematologic response; CML,

chronic myeloid leukemia; NR, not reported; Ph, Philadelphia chromosome.

Data extrapolated from references 80–83.




plus TKIs (e.g., idarubicin + cytarabine + imatinib) in myeloid-undifferentiated blastic phase, and acute lymphoid leukemia regi-mens plus TKIs (e.g., hyper-CVAD + imatinib or dasatinib) inlymphoid blastic phase.95,96 In the latter, central nervous system pro-phylaxis should be included, because about 30% of patients may develop central nervous system disease. In all such instances patientsshould be referred to allogeneic stem cell transplant as soon aspossible.

Allogeneic stem cell transplantation in accelerated phase results in5-year disease-free survival rates of 15% to 30%. If transplant is donein a second chronic phase the results are better, with disease-freesurvival rates of 40% to 50%. In blastic phase, survival after alloge-neic transplant is 5% to 15%.97

SPECIAL CONSIDERATIONS

Ph - Chronic Myelogenous Leukemia

Among 10% of patients with morphologic CML without a detectablePh chromosome, a third have the BCR-ABL molecular abnormality detected by FISH or PCR. These patients (Ph−, BCR-ABL+ CML)have similar clinical features, response to imatinib therapy, and prog-nosis as Ph+ CML. Patients who lack the BCR-ABL fusion gene(Ph−, BCR-ABL−; atypical CML according to the WHO classifi-

cation) have heterogeneous conditions, including proliferativemyelodysplastic syndrome, chronic myelomonocytic leukemia, ormyeloproliferative disorders. They tend to be older, exhibit moreoften anemia, thrombocytopenia, and monocytosis, and do not show basophilia, eosinophilia, or thrombocytosis. They do not respond toimatinib therapy and have poor prognosis with a median survival of 18 to 24 months. Ph− and BCR-ABL− CML often overlaps clinically

with chronic myelomonocytic leukemia. Patients die from infectionsand bleeding with marrow failure, or from transformation to acuteleukemia (50%).

Pregnancy

If CML is diagnosed in a pregnant woman, she can be managed withleukopheresis if indicated during the first trimester of pregnancy,

with hydroxyurea subsequently until delivery, then with more defin-itive therapy. Anecdotal reports of successful deliveries after IFNtherapy during pregnancy have been reported; however, IFN is anti-angiogenic and may have adverse affects on the fetus that are not

evident with reports including only few patients. If a woman becomespregnant while on imatinib therapy, the drug should be discon-tinued. Partners of men on imatinib have delivered normalbabies. However, the numbers are too small to make definitiveconclusions.98

Other Considerations

Severe thrombocytosis not responding to imatinib or other TKIs may be controlled with the addition of hydroxyurea, anagrelide, or otherchemotherapeutic agents (thio-TEPA, 6 mercaptopurine).

Splenectomy or splenic irradiation is rarely used in current man-agement of CML. A rare indication for splenectomy is disease pro-gression and painful, massive splenomegaly with hypersplenism;splenectomy may provide temporary benefit. Splenic irradiationshould be avoided because of its transient effects and the resultantadhesions, which make subsequent splenectomy risky.

Leukapheresis is also rarely indicated for control of severe symp-tomatic leukocytosis during the first trimester of pregnancy, or forleukostasis-induced complications such as priapism. The latter canalso be managed surgically through decompression of the penile veinor with brief local irradiation.

FUTURE DIRECTIONS

Targeted therapy with TKIs has significantly improved prognosis inCML, particularly for patients in chronic phase. Emergence of resis-tance in a minority of patients with newly diagnosed CML suggeststhe complex interactions in CML pathophysiology and the need toimprove therapy. Long-term therapy with imatinib is expensive andpresents a socioeconomic issue. Current and future studies are explor-ing the role of the new TKIs (dasatinib, nilotinib, bosutinib) asfrontline therapy in CML to reduce or prevent emergence of resis-tance due to mutations or other mechanisms. Combinations of TKIs

with each other (simultaneous, sequential), or with other activeagents that may target the downstream events, should also be explored.These include inhibitors of pathways involving Raf, farnesylation,mTOR, JAK/STAT, MEK/MAPK, PI3K/AKT, or others. Combina-tions of TKIs with such classical anticancer agents as hydroxyurea,cytarabine, homoharringtonine, and others are in progress. Vaccinestrategies in the setting of minimal residual disease may eradicatedormant resistant clones and provide a potential for long-term event-free survival or cure without the need for indefinite therapy.99,100

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78. Quintás-Cardama A, Kantarjian H, O’Brien S,et al: Pleural effusion in patients with chronicmyelogenous leukemia treated with dasatinib afterimatinib failure. J Clin Oncol 2007;25:3908–3914.

79. Hochhaus A, Kim DW, Rousselot P, et al:Dasatinib (SPRYCEL®) 50 mg or 70 mg BID

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81. le Coutre P, Bhalla K, Giles F, et al: A phase II

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82. Kantarjian H, Giles F, Gattermann N, et al:Nilotinib (formerly AMN107), a highly selectiveBCR-ABL tyrosine kinase inhibitor, is effective inpatients with Philadelphia chromosome–positivechronic myelogenous leukemia in chronic phasefollowing imatinib resistance and intolerance.Blood 2007;110:3540–3546.

83. Ottmann O, Kantarjian H, Larson R, et al: A phase II study of nilotinib, a novel tyrosine kinaseinhibitor administered to imatinib resistant orintolerant patients with chronic myelogenousleukemia (CML) in blast crisis (BC) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL)[abstract 1862]. Blood (ASH Annual Meeting Abstracts) 2006;108.

84. Cortes J, Kantarjian HM, Baccarani M, et al: A phase 1/2 study of SKI-606, a dual inhibitor of Srcand Abl kinases, in adult patients withPhiladelphia chromosome positive (Ph+) chronicmyelogenous leukemia (CML) or acutelymphocytic leukemia (ALL) relapsed, refractory orintolerant of imatinib [abstract 168]. Blood (ASH Annual Meeting Abstracts) 2006;108.

85. Giles FJ, Cortes JE, Jones D, et al: MK-0457, anovel kinase inhibitor, is active in patients withchronic myeloid leukemia or acute lymphocyticleukemia with the T315I BCR-ABL mutation.Blood 2007;109:500–502.

86. Cortes J, Albitar M, Thomas D, et al: Efficacy of the farnesyl transferase inhibitor R115777 inchronic myeloid leukemia and other hematologic

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90. Chronic Myeloid Leukemia Trialists’ CollaborativeGroup: Interferon alfa versus chemotherapy forchronic myeloid leukemia: a meta-analysis of sevenrandomized trials. J Natl Cancer Inst 1997;89:1616.

91. O’Brien S, Kantarjian H,Talpaz M: Practicalguidelines for the management of chronicmyelogenous leukemia with interferon alpha. Leuk Lymphoma 1996;23:247.

92. Kantarjian H, O’Brien S, Cortes J, et al: Completecytogenetic and molecular responses to interferon-α-based therapy for chronic myelogenous leukemiaare associated with excellent long-term prognosis.Cancer 2003;97:1033–1041.

93. Guilhot F, Chastang C, Michallet M, et al:Interferon alfa-2B combined with cytarabine versusinterferon alone in chronic myelogenous leukemia:French Chronic Myeloid Leukemia Study Group.N Engl J Med 1997;337:223–229.

94. Lipton JH, Khoroshko ND, Golenkov AK, et al: A randomized multicenter comparative study of peginterferon alfa-2a (40kD) vs interferon-alfa-2ain patients with treatment naive chronic-phasechronic myelogenous leukemia [abstract 782a].Blood 2002;100.

95. Oki Y, Kantarjian H, Gharibyan V, et al: Phase IIstudy of low-dose decitabine in combination withimatinib mesylate in patients with accelerated ormyeloid blastic phase of chronic myelogenousleukemia. Cancer 2007;109:899–906.

96. Quintás-Cardama A, Kantarjian H, Garcia-ManeroG, et al: A pilot study of imatinib, low-dosecytarabine and idarubicin for patients with chronicmyeloid leukemia in myeloid blast phase. Leuk Lymphoma 2007:48:283–289.

97. Clift RA, Buckner CD, Thomas ED, et al:Marrow transplantation for patients in acceleratedphase of chronic myeloid leukemia. Blood1994;84:4368–4373.

98. Ault P, Kantarjian H, O’Brien S, et al: Pregnancy among patients with chronic myeloid leukemiatreated with imatinib. J Clin Oncol 2006;24:

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