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INTRODUCTION Chronic myelogenousleukemia (CML)isa rare cancer characterizedby the uncontrolled

growth of white bloodcells. CML represents7% to 20% of all leukemia cases,with aworldwide incidence projectedat 1 to 2per 100,000people 1

UntreatedCML commonlyprogressesthrough 3disease phases:chronic,accelerated, and

blast;each corresponding to increasing leukemic blast countsandclinical severity

Since the approval of imatinib in2001, a disease that wasultimatelyfatal isnow considereda manageable,chronic disease with long periodsof remission2

Despite the successof imatinib,however, some patients(17%25%)fail to achieve adesiredresponse, experience progressionon,or are intolerant to,imatinib treatment.3

Second-generationtyrosine kinase inhibitors(TKIs), including bosutinib,a dual Src/Abl kinaseinhibitor,have been developedwith the goal of increasing the proportionof individualswho

experience a response

The recent phase 3Bosutinib Efficacyandsafety innewly diagnosedchronic myeloidLeukemiA(BELA)study 4 comparedpatients treatedwith bosutinib with patientstreated with

imatinibAt 12months, patientstreated with bosutinib showed

Ahigher rate of complete cytogenetic response (CCyR) inthe evaluable population

(78% vs68%)

Higher ratesof major molecular response (MMR)inthe intent-to-treat population(39%vs26%) andin the evaluable population(43% vs27%)

Ashorter time to CCyR (12.9weeksvs 24.6weeks) anda shorter time to MMR(37.1weeksvs72.3weeks)thanimatinib

However, a larger proportionof patients(29% vs20%) were discontinuedfrom the

bosutinib group,primarilydue to adverse events(19% vs5%) such asincreasedalanineaminotransferase (ALT),thrombocytopenia, andvomiting 4

Health-relatedQualityofLifeinCML

Patientswith chronic phase (CP)CML are expectedto remain ontreatment for the rest oftheir lives. Ina disease where patientsfrequentlypresent without symptoms,the continued

treatment raisesthe questionof what impact treatment hason health-relatedquality of life(HRQoL)

Little informationonthe HRQoL of patientswith CML hasbeenreported. Areview of HRQoL

inpatientswith leukemia between1980and2007revealedonly3studiesspecific topatientswith CML;only1 of these includedpatients treatedwith a TKI5

Inthe International RandomizedStudy of InterferonVersus STI571(IRIS), the FunctionalAssessment of Cancer TherapyBiological Response Modifiers(FACT-BRM)wasused to

assessthe HRQoL of patientswith CML treatedwith interferonor imatinib at baseline andvarioustimes throughout treatment6

The data presentedfocused primarilyon between-groupdifferences andwithin-group

longitudinal change from baseline,anddid not specificallylist the actual baseline scores

An examinationof baseline scoresestimatedfrom the figuresprovided on2 of the FACT-BRM scalessuggestedthat for patientswith CML,there wasrelatively little impact on

social/familywell-being (SWB;score ~23)ande motional well-being (EWB;score ~17.5)

With the development of second-generationTKIs andtheir expectedlong-term

administration,understanding the impact of these treatmentsona patients HRQoL isofparamount importance

OBJECTIVE The primaryobjective in the BELAstudywas to determine the rate of CCyR at 12months.Secondaryobjectives includedevaluating the rate of MMR at 12monthsand the durationofCCyR,MMR, andcomplete hematological response (CHR). One of the exploratoryobjectives

of the studywasto evaluate the impact of bosutinib andimatinib onHRQoL,leukemia-specific symptoms,andthe health statusof patientswith newlydiagnosed CP CML.

Outcomesfrom thisexploratory analysisare reportedhere

METHODSPatients

Cytogenetic diagnosisof Philadelphia chromosomepositive (Ph+)CP CML diagnosedfor nomore than6months

Adequate hepatic andrenal function

EasternCooperative OncologyGroup (ECOG)Performance Statusof 0or 1

Agedat least 18years(20yearsinJapan)

StudyDesign

Phase 3,multicenter,ope n-label studywith newlydiagnosedpatients with CP CMLrandomized1:1 to bosutinib or imatinib

Patientswere randomlyassigned to receive bosutinib 500mg or imatinib400 mg once daily

Dose interruptionor discontinuationcould occur for toxicity

Patientsreceived treatment until diseaseprogression or unacceptable toxicity

Evaluationof Patient-reportedHRQoL

HRQoL wasmeasured using the 44-item Functional Assessment of Cancer TherapyLeukemia (FACT-Leu)7

The FACT-Leuisa modular approach to assesspatient HRQoL andleukemia-specific

symptomsusing a core set of questions(Functional Assessment of Cancer TherapyGeneralScale [FACT-G]),aswell asa cancer site-specific subscale(leukemia symptoms[LEUS])

The FACT-Gisa 27-item compilationof general questions scoredon a 5-point scale rangingfrom 0= not at all to 4= verymuch. The items are dividedinto 4primaryHR QoL

domains

Physical well-being (PWB;7 items;range, 028)

Social/familywell-being (7items; range,028)

Emotional well-being (6items; range,024)

Functional well-being (FWB;7 items;range, 028)

The LEUS module consistsof 17items(score range,068) that assesspatient concerns

relating to leukemia

3summary scales:FACTTrial Outcome Index (TOI;score range,0124), composedof the

PWB,FWB, andLEUS scales;FACT-GTotal (scorerange, 0108);and theFACT-Leu Total(score range,0176),can also be calculated

Higher scoresare reflective of better HRQoL

Minimallyimportant differences(MIDs)have beenidentified for the different FACT-Leu

scales:PWB,2to 3points;SWB,not available;EWB,2points;FWB,2to 3points;LEUS,4 to 7points;FACT-GTotal,3to 7points;FACT-LeuTotal,6to 12points;andFACT-TOI,5 to 6points

The FACT-Leuwascompletedat baseline,every3monthsonstudy,andat treatment

completion

Statistics

Descriptive statisticswere determinedfor patient-reportedoutcomes,without correctionfor

missing information

Pairedt-testsand repeatedmeasures mixed-effects modelswere usedto assesswithin- andbetween-groupdifferences over thecourse of the study

RESULTSPatients

Atotal of 250and252 patientswere randomizedto the bosutinib andimatinib arms,respectively

Baseline characteristics,including ECOG status andSokal risk score (a prognostic scorecompletedat diagnosisto determine risk of a poor response;low risk isbetter) are presented

in Table 1

Minimum follow-upafter receiving thefirst dose of either bosutinib or imatinib was12months

Medianduration of therapyfor individualsin the bosutiniband imatinibarms, respectively,

was16.6months(range,

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INTRODUCTION Chronic myelogenous leukemia (CML) is a rare cancer characterized by the uncontrolledgrowth of white blood cells. CML represents 7% to 20% of all leukemia cases, with a

worldwide incidence projected at 1 to 2 per 100,000 people1

Untreated CML commonly progresses through 3 disease phases: chronic, accelerated, andblast; each corresponding to increasing leukemic blast counts and clinical severity

Since the approval of imatinib in 2001, a disease that was ultimately fatal is now considered

a manageable, chronic disease with long periods of remission2

Despite the success of imatinib, however, some patients (17%25%) fail to achieve adesired response, experience progression on, or are intolerant to, imatinib treatment.3

Second-generation tyrosine kinase inhibitors (TKIs), including bosutinib, a dual Src/Abl kinaseinhibitor, have been developed with the goal of increasing the proportion of individuals whoexperience a response

The recent phase 3 Bosutinib Efficacy and safety in newly diagnosed chronic myeloidLeukemiA (BELA) study4 compared patients treated with bosutinib with patients treated withimatinib

At 12 months, patients treated with bosutinib showed

A higher rate of complete cytogenetic response (CCyR) in the evaluable population(78% vs 68%)

Higher rates of major molecular response (MMR) in the intent-to-treat population (39%vs 26%) and in the evaluable population (43% vs 27%)

A shorter time to CCyR (12.9 weeks vs 24.6 weeks) and a shorter time to MMR(37.1 weeks vs 72.3 weeks) than imatinib

However, a larger proportion of patients (29% vs 20%) were discontinued from thebosutinib group, primarily due to adverse events (19% vs 5%) such as increased alanine

aminotransferase (ALT), thrombocytopenia, and vomiting4

Health-related Quality of Life in CML

Patients with chronic phase (CP) CML are expected to remain on treatment for the rest oftheir lives. In a disease where patients frequently present without symptoms, the continuedtreatment raises the question of what impact treatment has on health-related quality of life

(HRQoL) Little information on the HRQoL of patients with CML has been reported. A review of HRQoL

in patients with leukemia between 1980 and 2007 revealed only 3 studies specific topatients with CML; only 1 of these included patients treated with a TKI5

In the International Randomized Study of Interferon Versus STI571 (IRIS) the Functional

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Patients were randomly assigned to receive bosutinib 500 mg or imatinib 400 mg once daily

Dose interruption or discontinuation could occur for toxicity

Patients received treatment until disease progression or unacceptable toxicity

Evaluation of Patient-reported HRQoL

HRQoL was measured using the 44-item Functional Assessment of Cancer TherapyLeukemia (FACT-Leu)7

The FACT-Leu is a modular approach to assess patient HRQoL and leukemia-specific

symptoms using a core set of questions (Functional Assessment of Cancer Therapy GeneralScale [FACT-G]), as well as a cancer site-specific subscale (leukemia symptoms [LEUS])

The FACT-G is a 27-item compilation of general questions scored on a 5-point scale rangingfrom 0 = not at all to 4 = very much. The items are divided into 4 primary HRQoLdomains

Physical well-being (PWB; 7 items; range, 028)

Social/family well-being (7 items; range, 028)

Emotional well-being (6 items; range, 024)

Functional well-being (FWB; 7 items; range, 028)

The LEUS module consists of 17 items (score range, 068) that assess patient concernsrelating to leukemia

3 summary scales: FACTTrial Outcome Index (TOI; score range, 0124), composed of thePWB, FWB, and LEUS scales; FACT-G Total (score range, 0108); and the FACT-Leu Total(score range, 0176), can also be calculated

Higher scores are reflective of better HRQoL

Minimally important differences (MIDs) have been identified for the different FACT-Leu

scales: PWB, 2 to 3 points; SWB, not available; EWB, 2 points; FWB, 2 to 3 points; LEUS, 4 to 7points; FACT-G Total, 3 to 7 points; FACT-Leu Total, 6 to 12 points; and FACT-TOI, 5 to 6points

The FACT-Leu was completed at baseline, every 3 months on study, and at treatmentcompletion

Statistics

Descriptive statistics were determined for patient-reported outcomes, without correction formissing information

Paired t-tests and repeated measures mixed-effects models were used to assess within- andbetween-group differences over the course of the study

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Adverse events may be associated with disease-related symptoms and influence HRQoL; thetreatment-emergent adverse events of any grade reported for at least 10% of patients aresummarized in Table 2

Table 2. Treatment-emergent Adverse Events Occurring in 10% of Patients,Safety Population

Bosutinib (n = 248) Imatinib (n = 251)

Adverse event,a % All grades Grade 3/4 All grades Grade 3/4

Any event 96 66 96 52

Diarrhea 69 11 22 1

Vomiting 32 3 14 0

Nausea 31 1 35 0

Increased ALT 31 18 7 2

Thrombocytopenia 28 13 27 14

Increased AST 26 8 8 2

Anemia 23 8 21 6

Rash 22 2 17 1

Pyrexia 18 1 10 1

Abdominal pain upper 13 0 7 0

Increased lipase 13 7 10 5

Neutropenia 13 7 27 16

Abdominal pain 13 1 6 0

Headache 12 1 10 0

Upper respiratory

tract infection12 0 7 0

Fatigue 11 1 12 1

Leukopenia 9 3 21 6

Hypophosphatemia 7 1 15 8

Arthralgia 7 0 10

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Table 3. FACT-Leu Baseline Scores for Bosutinib and Imatinib Treatment Arms and FACT-G Normative Data

FACT-Leu, mean (SD) [95% CI] Bosutinib (n = 237) Imatinib (n = 241) FACT-Leu validation sample8 2002 General cancer sample9 General US adult population norms9

Subscale

PWB23.9 (3.9)

[23.4, 24.3]23.5 (4.3)

[22.9, 24.0]15.6 (6.3) 21.2 (6.2) 22.7 (5.4)

SWB21.8 (5.1)

[21.2, 22.5]22.1 (5.1)

[21.4, 22.7]22.3 (5.2) 22.3 (4.8) 19.1 (6.8)

EWB18.0 (4.0)

[17.5, 18.5]17.9 (4.4)

[17.3, 18.4]17.1 (4.9) 18.1 (4.5) 19.9 (4.8)

FWB20.1 (4.5)

[19.5, 20.7]20.1 (5.7)

[19.4, 20.8]14.7 (5.4) 18.8 (6.4) 18.5 (6.8)

LEUS53.8 (8.3)

[52.8, 54.9]

53.0 (9.6)

[51.7, 54.2]39.1 (11.2)

Summary scale

FACT-G Total83.8 (12.0)[82.3, 85.4]

83.5 (14.9)[81.6, 85.4]

69.7 (14.6) 80.4 (15.9) 80.1 (18.1)

FACT-Leu Total137.8 (18.6)

[135.4, 140.2]136.4 (23.0)

[133.5, 139.3]108.9 (23.8)

FACT-TOI

98.0 (14.1)

[96.2, 99.8]

96.5 (17.2)

[94.3, 98.7] 69.4 (20.0)

FACT-Leu, Functional Assessment of Cancer TherapyLeukemia; SD, standard deviation; CI, confidence interval; PWB, physical well-being; SWB, social/family well-being; EWB, emotional well-being; FWB, functional well-being; LEUS, leukemia symptoms; FACT-G, Functional Assessment ofCancer Therapy General Scale; FACT-TOI, Functional Assessment of Cancer TherapyTrial Outcome Index; HRQoL, health-realted quality of life.

Maximum values for scales: PWB = 28; SWB = 28; EWB = 24; FWB = 28; LEUS = 68; FACT-G Total = 108; FACT-Leu Total = 176; FACT-TOI = 124. Higher scores = fewer symptoms/better HRQoL.

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Scale comparisons: raw scores

At baseline, the mean FACT-Leu scores were not significantly different between treatmentarms (Table 3)

Repeated measures mixed-effects models did not demonstrate any differences betweenthe bosutinib and imatinib arms on any of the FACT-Leu subscales. This was true for eachassessment point up to and including the Month 18 assessment

Between-group differences in the LEUS subscale over time are shown in Figure 1

Scale comparisons: change from baseline scores

Month 3 Statistically significant improvements from baseline observed

In the bosutinib arm, in the EWB subscale

In the imatinib arm, in the EWB, LEUS, FACT-Leu Total, and FACT-TOI scales

These improvements did not exceed the MID for either arm, and there were no between-

group differences in the average change from baseline scores on any of the scales

Month 12

Statistically significant improvements from baseline were observed

In the bosutinib arm, in the EWB subscale

In the imatinib arm, in the SWB, EWB, LEUS, FACT-Leu Total, and FACT-TOI scales

As with the Month 3 assessment, improvements from baseline did not exceed the MID(Table 4)

No between-group differences in the average change from baseline scores were observedwith the exception of the LEUS subscale (difference = 1.66, P = 0.026 adjusting forbaseline, but not adjusting for multiple comparisons). Although statistically significant,

this difference between groups did not exceed the MID and is likely an artifact ofuncorrected multiple comparisons

40

50

60 Bosutinib Imatinib

escore

Figure 1. FACT-Leu leukemia symptom scores over 18 months of treatment.

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CONCLUSIONS This is one of the first reports of HRQoL in patients with CP CML

receiving first-line treatment with second-generation TKI bosutinibin comparison to imatinib

At baseline, first-line patients with CP CML reported HRQoL thatwas similar to not only a general cancer sample, but also thegeneral US population,9 and the sample of patients in the originalIRIS trial.6 Patient scores on the PWB and FWB subscales, whichmeasure such issues as lack of energy, presence of pain, ability towork, and ability to enjoy life, showed little impairment. This isimportant as it is difficult to meaningfully improve HRQoL that isalready at a high level

Similarly, symptoms of leukemia were few, and reflective of the factthat for many of these patients, the disease is discovered in the

absence of disease-related symptoms

Over the course of treatment, a greater proportion of patientsdiscontinued bosutinib than imatinib, a difference that may haveresulted from the differential side effect profile and open-labeldesign of the study. Although not reported here, a comparison ofthe HRQoL of patients who discontinued therapy prior to the 3- or

6-month assessment did not identify any differences in HRQoL fromthose who maintained treatment. Thus, the data are not artificiallyinflated due to sicker patients leaving the study

In addition, over the course of treatment there were no clinicallymeaningful changes (improvements or deteriorations) in the HRQoLof patients with CP CML in either treatment group. There were alsono differences in the average HRQoL of patients between treatmentarms. This is particularly important given the fact that patientsstarted with high levels of quality of life and both treatments haveside effects that could potentially affect HRQoL

The symptoms of leukemia were also minimal at baseline andremained so with treatment, a finding that would be expected giventhe fact that the majority of patients at the 12-month assessment

were reporting a CCyR

Thus, not only did patients treated with bosutinib achieve a higherMMR rate and faster times to CCyR and MMR than those treatedwith imatinib, they also maintained their pre-treatment levels ofHRQoL and did not experience an increase in their symptoms ofleukemia

Table 4. FACT-Leu Change From Baseline at 3- and 12-Month Assessments for Bosutinib and Imatinib Treatment Arms

Bosutinib Imatinib

FACT-Leu, mean (SD) Score score Score score

Month 3 n = 205 n = 229a

Subscale

PWB 23.5 (4.1) 0.3 (3.9) 23.1 (4.9) 0.3 (3.9)

SWB 21.3 (6.1) 0.5 (5.5) 21.8 (5.6) 0.3 (3.8)

EWB 18.8 (3.7) 0.8 (3.6)+ 18.9 (4.2) 1.0 (3.6)++

FWB 19.9 (5.4) 0.4 (4.3) 20.3 (5.9) 0.2 (4.3)

LEUS 54.6 (8.5) 0.7 (7.3) 54.9 (9.2) 1.9 (7.7)++

Summary scale

FACT-G Total 83.5 (14.2) 0.4 (11.3) 84.1 (16.3) 0.6 (10.7)

FACT-Leu Total 138.1 (20.7) 0.3 (16.1) 139.0 (24.2) 2.4 (16.7)*

FACT-TOI 98.0 (15.4) 0.1 (12.3) 98.4 (17.8) 1.7 (13.0)*

Month 12 n = 173b n = 201c

Subscale

PWB 23.5 (3.9) 0.5 (4.1) 23.8 (4.4) 0.3 (4.0)

SWB 21.5 (5.5) 0.3 (4.5) 21.5 (6.1) 0.6 (4.5)*

EWB 18.7 (4.0) 0.7 (4.1)* 18.9 (4.3) 1.2 (3.8)++

FWB 20.3 (5.4) 0.1 (4.8) 20.4 (6.3) 0.3 (5.6)

LEUS 54.5 (8.5) 0.7 (8.8) 55.8 (8.4) 2.7 (7.7)++

Summary scale

FACT-G Total 83.9 (14.1) 0.1 (12.1) 84.5 (17.1) 1.1 (13.0)

FACT-Leu Total 138.4 (22.2) 0.5 (19.1) 140.3 (23.9) 3.5 (18.8)*

FACT-TOI 98.2 (15.5) 0.1 (14.8) 100.0 (16.5) 3.0 (14.1)**

FACT-Leu, Functional Assessment of Cancer TherapyLeukemia; SD, standard deviation; , change (month X baseline); PWB, physical well-being; SWB, social/family well-being; EWB, emotional well-being; FWB, functional well-being; LEUS, leukemia symptoms; FACT-G, FunctionalAssessment of Cancer Therapy General Scale; FACT-TOI, Functional Assessment of Cancer TherapyTrial Outcome Index.

*P