Abstract ID 6612

Health-related Quality of Life in Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia Patients Treated With Bosutinib or Imatinib
J. H. Lipton,1 P. Trask,2 D. Cella,3 L. Duvillie,4 C. Powell,5 M. V. Ramanan,6 Z. Maslyak,7 D-W. Kim8
1

Princess Margaret Hospital, Toronto, ON, Canada; 2Pzer Inc, New London, CT, USA; 3Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA; 4Pzer Global Research and Development, Paris, France; 5 Pzer Inc, Cambridge, MA, USA; 6Jehangir Hospital, Pune, India; 7SI Institute of Blood Pathology and Transfusion Medicine UAMS, Lviv, Ukraine; 8Seoul St. Marys Hospital, Seoul, South Korea.

*Presenting author.

INTRODUCTION
Chronic myelogenous leukemia (CML) is a rare cancer characterized by the uncontrolled growth 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, and blast; 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 a desired response, experience progression on, or are intolerant to, imatinib treatment.3 Second-generation tyrosine kinase inhibitors (TKIs), including bosutinib, a dual Src/Abl kinase inhibitor, have been developed with the goal of increasing the proportion of individuals who experience a response The recent phase 3 Bosutinib Efcacy and safety in newly diagnosed chronic myeloid LeukemiA (BELA) study4 compared patients treated with bosutinib with patients treated with imatinib 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 the bosutinib group, primarily due to adverse events (19% vs 5%) such as increased alanine aminotransferase (ALT), thrombocytopenia, and vomiting4

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

Adverse events may be associated with disease-related symptoms and inuence HRQoL; the treatment-emergent adverse events of any grade reported for at least 10% of patients are summarized in Table 2

Scale comparisons: raw scores At baseline, the mean FACT-Leu scores were not signicantly different between treatment arms (Table 3) Repeated measures mixed-effects models did not demonstrate any differences between the bosutinib and imatinib arms on any of the FACT-Leu subscales. This was true for each assessment 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 signicant improvements from baseline observed

Table 4. FACT-Leu Change From Baseline at 3- and 12-Month Assessments for Bosutinib and Imatinib Treatment Arms
Bosutinib FACT-Leu, mean (SD) Month 3 Subscale PWB SWB EWB FWB LEUS Summary scale FACT-G Total FACT-Leu Total FACT-TOI Month 12 Subscale PWB SWB EWB FWB LEUS Summary scale FACT-G Total 83.9 (14.1) 138.4 (22.2) 98.2 (15.5) 0.1 (12.1) 0.5 (19.1) 0.1 (14.8) 84.5 (17.1) 140.3 (23.9) 100.0 (16.5) 1.1 (13.0) 3.5 (18.8)* 3.0 (14.1)** 23.5 (3.9) 21.5 (5.5) 18.7 (4.0) 20.3 (5.4) 54.5 (8.5) 0.5 (4.1) 0.3 (4.5) 0.7 (4.1)* 0.1 (4.8) 0.7 (8.8) 23.8 (4.4) 21.5 (6.1) 18.9 (4.3) 20.4 (6.3) 55.8 (8.4) 0.3 (4.0) 0.6 (4.5)* 1.2 (3.8)++ 0.3 (5.6) 2.7 (7.7)++ 83.5 (14.2) 138.1 (20.7) 98.0 (15.4) n = 173b 0.4 (11.3) 0.3 (16.1) 0.1 (12.3) 84.1 (16.3) 139.0 (24.2) 98.4 (17.8) n = 201c 0.6 (10.7) 2.4 (16.7)* 1.7 (13.0)* 23.5 (4.1) 21.3 (6.1) 18.8 (3.7) 19.9 (5.4) 54.6 (8.5) 0.3 (3.9) 0.5 (5.5) 0.8 (3.6)+ 0.4 (4.3) 0.7 (7.3) 23.1 (4.9) 21.8 (5.6) 18.9 (4.2) 20.3 (5.9) 54.9 (9.2) 0.3 (3.9) 0.3 (3.8) 1.0 (3.6)++ 0.2 (4.3) 1.9 (7.7)++ Score n = 205 score Score n = 229a Imatinib score

Evaluation of Patient-reported HRQoL

HRQoL was measured using the 44-item Functional Assessment of Cancer Therapy Leukemia (FACT-Leu)7 The FACT-Leu is a modular approach to assess patient HRQoL and leukemia-specic symptoms using a core set of questions (Functional Assessment of Cancer Therapy General Scale [FACT-G]), as well as a cancer site-specic subscale (leukemia symptoms [LEUS]) The FACT-G is a 27-item compilation of general questions scored on a 5-point scale ranging from 0 = not at all to 4 = very much. The items are divided into 4 primary HRQoL domains 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 concerns relating to leukemia 3 summary scales: FACTTrial Outcome Index (TOI; score range, 0124), composed of the PWB, 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 reective of better HRQoL Minimally important differences (MIDs) have been identied 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 7 points; FACT-G Total, 3 to 7 points; FACT-Leu Total, 6 to 12 points; and FACT-TOI, 5 to 6 points The FACT-Leu was completed at baseline, every 3 months on study, and at treatment completion

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

Adverse event,a % Any event Diarrhea Vomiting Nausea Increased ALT Thrombocytopenia Increased AST Anemia Rash Pyrexia Abdominal pain upper Increased lipase Neutropenia Abdominal pain Headache Upper respiratory tract infection Fatigue Leukopenia Hypophosphatemia Arthralgia Increased blood CPK Myalgia Muscle spasms Bone pain Peripheral edema Periorbital edema
a

Bosutinib (n = 248) All grades Grade 3/4 96 69 32 31 31 28 26 23 22 18 13 13 13 13 12 12 11 9 7 7 6 5 4 4 4 1 66 11 3 1 18 13 8 8 2 1 0 7 7 1 1 0 1 3 1 0 <1 0 0 0 0 0

Imatinib (n = 251) All grades Grade 3/4 96 22 14 35 7 27 8 21 17 10 7 10 27 6 10 7 12 21 15 10 15 11 22 10 11 14 52 1 0 0 2 14 2 6 1 1 0 5 16 0 0 0 1 6 8 <1 3 1 0 1 0 0

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 betweengroup differences in the average change from baseline scores on any of the scales Month 12 Statistically signicant 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 observed with the exception of the LEUS subscale (difference = 1.66, P = 0.026 adjusting for baseline, but not adjusting for multiple comparisons). Although statistically signicant, this difference between groups did not exceed the MID and is likely an artifact of uncorrected multiple comparisons

Health-related Quality of Life in CML

Patients with chronic phase (CP) CML are expected to remain on treatment for the rest of their lives. In a disease where patients frequently present without symptoms, the continued treatment 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 specic to patients with CML; only 1 of these included patients treated with a TKI5 In the International Randomized Study of Interferon Versus STI571 (IRIS), the Functional Assessment of Cancer TherapyBiological Response Modiers (FACT-BRM) was used to assess the HRQoL of patients with CML treated with interferon or imatinib at baseline and various times throughout treatment6 The data presented focused primarily on between-group differences and within-group longitudinal change from baseline, and did not specically list the actual baseline scores An examination of baseline scores estimated from the gures provided on 2 of the FACTBRM scales suggested that for patients with CML, there was relatively little impact on social/family well-being (SWB; score ~23) and emotional well-being (EWB; score ~17.5) With the development of second-generation TKIs and their expected long-term administration, understanding the impact of these treatments on a patients HRQoL is of paramount importance

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

60 Mean LEUS subscale score 50 40 30 20 10 0 Baseline Month 3 Month Month 6 9 Assessment Month 12 Month 18 Bosutinib Imatinib

FACT-Leu Total FACT-TOI

Statistics
Descriptive statistics were determined for patient-reported outcomes, without correction for missing information Paired t-tests and repeated measures mixed-effects models were used to assess within- and between-group differences over the course of the study

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase. Adverse events graded using the National Cancer Institute Common Terminology Criteria, version 3.0.

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, Functional Assessment of Cancer Therapy General Scale; FACT-TOI, Functional Assessment of Cancer TherapyTrial Outcome Index. *P <0.05; **P <0.01; +P = 0.001; ++P <0.001. a n = 228 for LEUS subscale, FACT-Leu Total, and FACT-TOI. b n = 172 for LEUS subscale, FACT-Leu Total, and FACT-TOI. c n = 199 for PWB, SWB, and FACT-G Total; n = 197 for LEUS subscale; and n = 195 for FACT-Leu Total and FACT-TOI. Note: signicant differences are within group from baseline and not between groups. Patients were evaluable if they had baseline and post-baseline assessments to calculate a change score.

Patient-reported HRQoL and Disease-related Symptoms

RESULTS
Patients
A total of 250 and 252 patients were randomized to the bosutinib and imatinib arms, respectively Baseline characteristics, including ECOG status and Sokal risk score (a prognostic score completed at diagnosis to determine risk of a poor response; low risk is better) are presented in Table 1 Minimum follow-up after receiving the rst dose of either bosutinib or imatinib was 12 months Median duration of therapy for individuals in the bosutinib and imatinib arms, respectively, was 16.6 months (range, <0.130.4 months) and 16.8 months (range, 0.528.2 months)

Completion rates Baseline HRQoL data were available for 237/250 and 241/252 patients treated with bosutinib or imatinib, respectively Out of the number of patients remaining in the bosutinib and imatinib groups and for which FACT-Leu data were expected, respective completion rates were: at Month 3, 95% (205 patients) and 99% (229); at Month 6, 99% (192) and 98% (222); and at Month 12, 94% (173) and 95% (201)

CONCLUSIONS
This is one of the rst reports of HRQoL in patients with CP CML receiving rst-line treatment with second-generation TKI bosutinib in comparison to imatinib At baseline, rst-line patients with CP CML reported HRQoL that was similar to not only a general cancer sample, but also the general US population,9 and the sample of patients in the original IRIS trial.6 Patient scores on the PWB and FWB subscales, which measure such issues as lack of energy, presence of pain, ability to work, and ability to enjoy life, showed little impairment. This is important as it is difcult to meaningfully improve HRQoL that is already at a high level Similarly, symptoms of leukemia were few, and reective of the fact that 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 patients discontinued bosutinib than imatinib, a difference that may have resulted from the differential side effect prole and open-label design of the study. Although not reported here, a comparison of the HRQoL of patients who discontinued therapy prior to the 3- or 6-month assessment did not identify any differences in HRQoL from those who maintained treatment. Thus, the data are not articially inated due to sicker patients leaving the study In addition, over the course of treatment there were no clinically meaningful changes (improvements or deteriorations) in the HRQoL of patients with CP CML in either treatment group. There were also no differences in the average HRQoL of patients between treatment arms. This is particularly important given the fact that patients started with high levels of quality of life and both treatments have side effects that could potentially affect HRQoL The symptoms of leukemia were also minimal at baseline and remained so with treatment, a nding that would be expected given the 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 higher MMR rate and faster times to CCyR and MMR than those treated with imatinib, they also maintained their pre-treatment levels of HRQoL and did not experience an increase in their symptoms of leukemia

FACT-Leu, Functional Assessment of Cancer TherapyLeukemia; LEUS, leukemia symptoms.

OBJECTIVE
The primary objective in the BELA study was to determine the rate of CCyR at 12 months. Secondary objectives included evaluating the rate of MMR at 12 months and the duration of CCyR, MMR, and complete hematological response (CHR). One of the exploratory objectives of the study was to evaluate the impact of bosutinib and imatinib on HRQoL, leukemiaspecic symptoms, and the health status of patients with newly diagnosed CP CML. Outcomes from this exploratory analysis are reported here

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

Table 1. Patient Characteristics, ITT Population

Characteristic, n (%) Age, y Mean (SD) Median Age category <65 y 65 y Sex Male Female Race Asian Black or African American White Other ECOG Performance Status, n (%) 0 1 Sokal risk score Low Intermediate High Bosutinib (n = 250) 47.4 (14.4) 48.0 220 (88) 30 (12) 149 (60) 101 (40) 64 (26) 2 (1) 160 (64) 24 (10) 185 (74) 65 (26) 88 (35) 117 (47) 45 (18) Imatinib (n = 252) 45.6 (14.8) 47.0 225 (89) 27 (11) 135 (54) 117 (46) 57 (23) 3 (1) 164 (65) 28 (11) 181 (72) 71 (28) 89 (35) 118 (47) 45 (18)

Subscale PWB SWB EWB FWB LEUS Summary scale FACT-G Total FACT-Leu Total FACT-TOI 83.8 (12.0) [82.3, 85.4] 137.8 (18.6) [135.4, 140.2] 98.0 (14.1) [96.2, 99.8] 83.5 (14.9) [81.6, 85.4] 136.4 (23.0) [133.5, 139.3] 96.5 (17.2) [94.3, 98.7] 69.7 (14.6) 108.9 (23.8) 69.4 (20.0) 80.4 (15.9) 80.1 (18.1) 23.9 (3.9) [23.4, 24.3] 21.8 (5.1) [21.2, 22.5] 18.0 (4.0) [17.5, 18.5] 20.1 (4.5) [19.5, 20.7] 53.8 (8.3) [52.8, 54.9] 23.5 (4.3) [22.9, 24.0] 22.1 (5.1) [21.4, 22.7] 17.9 (4.4) [17.3, 18.4] 20.1 (5.7) [19.4, 20.8] 53.0 (9.6) [51.7, 54.2] 15.6 (6.3) 22.3 (5.2) 17.1 (4.9) 14.7 (5.4) 39.1 (11.2) 21.2 (6.2) 22.3 (4.8) 18.1 (4.5) 18.8 (6.4) 22.7 (5.4) 19.1 (6.8) 19.9 (4.8) 18.5 (6.8)

METHODS
Patients
Cytogenetic diagnosis of Philadelphia chromosomepositive (Ph+) CP CML diagnosed for no more than 6 months Adequate hepatic and renal function Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Aged at least 18 years (20 years in Japan)

REFERENCES
1. Redaelli A, et al. Expert Rev Anticancer Ther. 2004;4(1):85-96. 2. O'Brien SG, et al. N Engl J Med. 2003;348(11):994-1004. 3. Druker BJ, et al. N Engl J Med. 2006;355(23):2408-2417. 4. Gambacorti-Passerini C, et al. Oral presentation at: 52nd American Society of Hematology Annual Meeting and Exposition; December 47, 2010; Orlando, FL. Abstract #208. 5. Efcace F, et al. Eur J Cancer. 2008;44(11):1497-1506. 6. Hahn EA, et al. J Clin Oncol. 2003;21(11):2138-2146. 7. Webster K, et al. Qual Life Res. 2002;11(7):678. 8. Arnold B, et al. Poster presented at: 12th Annual Conference of the International Society for Pharmacoeconomics and Outcomes Research; October 2427, 2009; Paris, France. 9. Brucker PS, et al. Eval Health Prof. 2005;28(2):192-211.

ACKNOWLEDGMENTS
This study (Study 3160A4-3000 [ClinicalTrials.gov Identier: NCT00574873]) was supported by Pzer. Editorial/medical writing support was provided by Wilson Joe, PhD, at MedErgy and was funded by Pzer.

Study Design
Phase 3, multicenter, open-label study with newly diagnosed patients with CP CML randomized 1:1 to bosutinib or imatinib

ITT, intent-to-treat; SD, standard deviation; ECOG, Eastern Cooperative Oncology Group.

FACT-Leu, Functional Assessment of Cancer TherapyLeukemia; SD, standard deviation; CI, condence 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 of Cancer 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.

P O S T E R P R E S E N T E D AT T H E A N N U A L M E E T I N G O F T H E A M E R I C A N S O C I E T Y O F C L I N I C A L O N C O L O G Y ( A S C O ) , J U N E 3 7 , 2 0 1 1 , C H I C A G O , I L L I N O I S .

INTRODUCTION
Chronic myelogenous leukemia (CML) is a rare cancer characterized by the uncontrolled growth 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, and blast; 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 a desired response, experience progression on, or are intolerant to, imatinib treatment.3 Second-generation tyrosine kinase inhibitors (TKIs), including bosutinib, a dual Src/Abl kinase inhibitor, have been developed with the goal of increasing the proportion of individuals who experience a response The recent phase 3 Bosutinib Efcacy and safety in newly diagnosed chronic myeloid LeukemiA (BELA) study4 compared patients treated with bosutinib with patients treated with imatinib 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 the bosutinib 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 of their lives. In a disease where patients frequently present without symptoms, the continued treatment 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 specic to patients with CML; only 1 of these included patients treated with a TKI5 In the International Randomized Study of Interferon Versus STI571 (IRIS), the Functional Assessment of Cancer TherapyBiological Response Modiers (FACT-BRM) was used to assess the HRQoL of patients with CML treated with interferon or imatinib at baseline and various times throughout treatment6 The data presented focused primarily on between-group differences and within-group longitudinal change from baseline, and did not specically list the actual baseline scores An examination of baseline scores estimated from the gures provided on 2 of the FACTBRM scales suggested that for patients with CML, there was relatively little impact on social/family well-being (SWB; score ~23) and emotional well-being (EWB; score ~17.5) With the development of second-generation TKIs and their expected long-term administration, understanding the impact of these treatments on a patients HRQoL is of paramount importance

OBJECTIVE
The primary objective in the BELA study was to determine the rate of CCyR at 12 months. Secondary objectives included evaluating the rate of MMR at 12 months and the duration of CCyR, MMR, and complete hematological response (CHR). One of the exploratory objectives of the study was to evaluate the impact of bosutinib and imatinib on HRQoL, leukemiaspecic symptoms, and the health status of patients with newly diagnosed CP CML. Outcomes from this exploratory analysis are reported here

METHODS
Patients
Cytogenetic diagnosis of Philadelphia chromosomepositive (Ph+) CP CML diagnosed for no more than 6 months Adequate hepatic and renal function Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Aged at least 18 years (20 years in Japan)

Study Design
Phase 3, multicenter, open-label study with newly diagnosed patients with CP CML randomized 1:1 to bosutinib or imatinib

 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 Therapy Leukemia (FACT-Leu)7 The FACT-Leu is a modular approach to assess patient HRQoL and leukemia-specic symptoms using a core set of questions (Functional Assessment of Cancer Therapy General Scale [FACT-G]), as well as a cancer site-specic subscale (leukemia symptoms [LEUS]) The FACT-G is a 27-item compilation of general questions scored on a 5-point scale ranging from 0 = not at all to 4 = very much. The items are divided into 4 primary HRQoL domains 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 concerns relating to leukemia 3 summary scales: FACTTrial Outcome Index (TOI; score range, 0124), composed of the PWB, 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 reective of better HRQoL Minimally important differences (MIDs) have been identied 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 7 points; FACT-G Total, 3 to 7 points; FACT-Leu Total, 6 to 12 points; and FACT-TOI, 5 to 6 points The FACT-Leu was completed at baseline, every 3 months on study, and at treatment completion

Statistics
Descriptive statistics were determined for patient-reported outcomes, without correction for missing information Paired t-tests and repeated measures mixed-effects models were used to assess within- and between-group differences over the course of the study

RESULTS
Patients
A total of 250 and 252 patients were randomized to the bosutinib and imatinib arms, respectively Baseline characteristics, including ECOG status and Sokal risk score (a prognostic score completed at diagnosis to determine risk of a poor response; low risk is better) are presented in Table 1 Minimum follow-up after receiving the rst dose of either bosutinib or imatinib was 12 months Median duration of therapy for individuals in the bosutinib and imatinib arms, respectively, was 16.6 months (range, <0.130.4 months) and 16.8 months (range, 0.528.2 months)

Table 1. Patient Characteristics, ITT Population

Characteristic, n (%) Age, y Mean (SD) Median Age category <65 y 65 y Sex Male Female Race Asian Black or African American White Other ECOG Performance Status, n (%) 0 1 Sokal risk score Low Intermediate High Bosutinib (n = 250) 47.4 (14.4) 48.0 220 (88) 30 (12) 149 (60) 101 (40) 64 (26) 2 (1) 160 (64) 24 (10) 185 (74) 65 (26) 88 (35) 117 (47) 45 (18) Imatinib (n = 252) 45.6 (14.8) 47.0 225 (89) 27 (11) 135 (54) 117 (46) 57 (23) 3 (1) 164 (65) 28 (11) 181 (72) 71 (28) 89 (35) 118 (47) 45 (18)

ITT, intent-to-treat; SD, standard deviation; ECOG, Eastern Cooperative Oncology Group.

 Adverse events may be associated with disease-related symptoms and inuence HRQoL; the treatment-emergent adverse events of any grade reported for at least 10% of patients are summarized in Table 2

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

Adverse event,a % Any event Diarrhea Vomiting Nausea Increased ALT Thrombocytopenia Increased AST Anemia Rash Pyrexia Abdominal pain upper Increased lipase Neutropenia Abdominal pain Headache Upper respiratory tract infection Fatigue Leukopenia Hypophosphatemia Arthralgia Increased blood CPK Myalgia Muscle spasms Bone pain Peripheral edema Periorbital edema
a

Bosutinib (n = 248) All grades Grade 3/4 96 69 32 31 31 28 26 23 22 18 13 13 13 13 12 12 11 9 7 7 6 5 4 4 4 1 66 11 3 1 18 13 8 8 2 1 0 7 7 1 1 0 1 3 1 0 <1 0 0 0 0 0

Imatinib (n = 251) All grades Grade 3/4 96 22 14 35 7 27 8 21 17 10 7 10 27 6 10 7 12 21 15 10 15 11 22 10 11 14 52 1 0 0 2 14 2 6 1 1 0 5 16 0 0 0 1 6 8 <1 3 1 0 1 0 0

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase. Adverse events graded using the National Cancer Institute Common Terminology Criteria, version 3.0.

Patient-reported HRQoL and Disease-related Symptoms

Completion rates Baseline HRQoL data were available for 237/250 and 241/252 patients treated with bosutinib or imatinib, respectively Out of the number of patients remaining in the bosutinib and imatinib groups and for which FACT-Leu data were expected, respective completion rates were: at Month 3, 95% (205 patients) and 99% (229); at Month 6, 99% (192) and 98% (222); and at Month 12, 94% (173) and 95% (201)

Table 3. FACT-Leu Baseline Scores for Bosutinib and Imatinib Treatment Arms and FACT-G Normative Data
FACT-Leu, mean (SD) [95% CI] Subscale PWB SWB EWB FWB LEUS Summary scale FACT-G Total FACT-Leu Total FACT-TOI 83.8 (12.0) [82.3, 85.4] 137.8 (18.6) [135.4, 140.2] 98.0 (14.1) [96.2, 99.8] 83.5 (14.9) [81.6, 85.4] 136.4 (23.0) [133.5, 139.3] 96.5 (17.2) [94.3, 98.7] 69.7 (14.6) 108.9 (23.8) 69.4 (20.0) 80.4 (15.9) 80.1 (18.1) 23.9 (3.9) [23.4, 24.3] 21.8 (5.1) [21.2, 22.5] 18.0 (4.0) [17.5, 18.5] 20.1 (4.5) [19.5, 20.7] 53.8 (8.3) [52.8, 54.9] 23.5 (4.3) [22.9, 24.0] 22.1 (5.1) [21.4, 22.7] 17.9 (4.4) [17.3, 18.4] 20.1 (5.7) [19.4, 20.8] 53.0 (9.6) [51.7, 54.2] 15.6 (6.3) 22.3 (5.2) 17.1 (4.9) 14.7 (5.4) 39.1 (11.2) 21.2 (6.2) 22.3 (4.8) 18.1 (4.5) 18.8 (6.4) 22.7 (5.4) 19.1 (6.8) 19.9 (4.8) 18.5 (6.8) Bosutinib (n = 237) Imatinib (n = 241) FACT-Leu validation sample8 2002 General cancer sample9 General US adult population norms9

FACT-Leu, Functional Assessment of Cancer TherapyLeukemia; SD, standard deviation; CI, condence 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 of Cancer 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.

 Scale comparisons: raw scores At baseline, the mean FACT-Leu scores were not signicantly different between treatment arms (Table 3) Repeated measures mixed-effects models did not demonstrate any differences between the bosutinib and imatinib arms on any of the FACT-Leu subscales. This was true for each assessment 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 signicant 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 betweengroup differences in the average change from baseline scores on any of the scales Month 12 Statistically signicant 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 observed with the exception of the LEUS subscale (difference = 1.66, P = 0.026 adjusting for baseline, but not adjusting for multiple comparisons). Although statistically signicant, this difference between groups did not exceed the MID and is likely an artifact of uncorrected multiple comparisons

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

60 Mean LEUS subscale score 50 40 30 20 10 0 Baseline Month 3 Month Month 6 9 Assessment Month 12 Month 18 Bosutinib Imatinib

FACT-Leu, Functional Assessment of Cancer TherapyLeukemia; LEUS, leukemia symptoms.

Table 4. FACT-Leu Change From Baseline at 3- and 12-Month Assessments for Bosutinib and Imatinib Treatment Arms
Bosutinib FACT-Leu, mean (SD) Month 3 Subscale PWB SWB EWB FWB LEUS Summary scale FACT-G Total FACT-Leu Total FACT-TOI Month 12 Subscale PWB SWB EWB FWB LEUS Summary scale FACT-G Total FACT-Leu Total FACT-TOI 83.9 (14.1) 138.4 (22.2) 98.2 (15.5) 0.1 (12.1) 0.5 (19.1) 0.1 (14.8) 84.5 (17.1) 140.3 (23.9) 100.0 (16.5) 1.1 (13.0) 3.5 (18.8)* 3.0 (14.1)** 23.5 (3.9) 21.5 (5.5) 18.7 (4.0) 20.3 (5.4) 54.5 (8.5) 0.5 (4.1) 0.3 (4.5) 0.7 (4.1)* 0.1 (4.8) 0.7 (8.8) 23.8 (4.4) 21.5 (6.1) 18.9 (4.3) 20.4 (6.3) 55.8 (8.4) 0.3 (4.0) 0.6 (4.5)* 1.2 (3.8)++ 0.3 (5.6) 2.7 (7.7)++ 83.5 (14.2) 138.1 (20.7) 98.0 (15.4) n = 173b 0.4 (11.3) 0.3 (16.1) 0.1 (12.3) 84.1 (16.3) 139.0 (24.2) 98.4 (17.8) n = 201c 0.6 (10.7) 2.4 (16.7)* 1.7 (13.0)* 23.5 (4.1) 21.3 (6.1) 18.8 (3.7) 19.9 (5.4) 54.6 (8.5) 0.3 (3.9) 0.5 (5.5) 0.8 (3.6)+ 0.4 (4.3) 0.7 (7.3) 23.1 (4.9) 21.8 (5.6) 18.9 (4.2) 20.3 (5.9) 54.9 (9.2) 0.3 (3.9) 0.3 (3.8) 1.0 (3.6)++ 0.2 (4.3) 1.9 (7.7)++ Score n = 205 score Score n = 229a Imatinib score

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, Functional Assessment of Cancer Therapy General Scale; FACT-TOI, Functional Assessment of Cancer TherapyTrial Outcome Index. *P <0.05; **P <0.01; +P = 0.001; ++P <0.001. a n = 228 for LEUS subscale, FACT-Leu Total, and FACT-TOI. b n = 172 for LEUS subscale, FACT-Leu Total, and FACT-TOI. c n = 199 for PWB, SWB, and FACT-G Total; n = 197 for LEUS subscale; and n = 195 for FACT-Leu Total and FACT-TOI. Note: signicant differences are within group from baseline and not between groups. Patients were evaluable if they had baseline and post-baseline assessments to calculate a change score.

CONCLUSIONS
This is one of the rst reports of HRQoL in patients with CP CML receiving rst-line treatment with second-generation TKI bosutinib in comparison to imatinib At baseline, rst-line patients with CP CML reported HRQoL that was similar to not only a general cancer sample, but also the general US population,9 and the sample of patients in the original IRIS trial.6 Patient scores on the PWB and FWB subscales, which measure such issues as lack of energy, presence of pain, ability to work, and ability to enjoy life, showed little impairment. This is important as it is difcult to meaningfully improve HRQoL that is already at a high level Similarly, symptoms of leukemia were few, and reective of the fact that 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 patients discontinued bosutinib than imatinib, a difference that may have resulted from the differential side effect prole and open-label design of the study. Although not reported here, a comparison of the HRQoL of patients who discontinued therapy prior to the 3- or 6-month assessment did not identify any differences in HRQoL from those who maintained treatment. Thus, the data are not articially inated due to sicker patients leaving the study In addition, over the course of treatment there were no clinically meaningful changes (improvements or deteriorations) in the HRQoL of patients with CP CML in either treatment group. There were also no differences in the average HRQoL of patients between treatment arms. This is particularly important given the fact that patients started with high levels of quality of life and both treatments have side effects that could potentially affect HRQoL The symptoms of leukemia were also minimal at baseline and remained so with treatment, a nding that would be expected given the 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 higher MMR rate and faster times to CCyR and MMR than those treated with imatinib, they also maintained their pre-treatment levels of HRQoL and did not experience an increase in their symptoms of leukemia

REFERENCES
1. Redaelli A, et al. Expert Rev Anticancer Ther. 2004;4(1):85-96. 2. O'Brien SG, et al. N Engl J Med. 2003;348(11):994-1004. 3. Druker BJ, et al. N Engl J Med. 2006;355(23):2408-2417. 4. Gambacorti-Passerini C, et al. Oral presentation at: 52nd American Society of Hematology Annual Meeting and Exposition; December 47, 2010; Orlando, FL. Abstract #208. 5. Efcace F, et al. Eur J Cancer. 2008;44(11):1497-1506. 6. Hahn EA, et al. J Clin Oncol. 2003;21(11):2138-2146. 7. Webster K, et al. Qual Life Res. 2002;11(7):678. 8. Arnold B, et al. Poster presented at: 12th Annual Conference of the International Society for Pharmacoeconomics and Outcomes Research; October 2427, 2009; Paris, France. 9. Brucker PS, et al. Eval Health Prof. 2005;28(2):192-211.

ACKNOWLEDGMENTS
This study (Study 3160A4-3000 [ClinicalTrials.gov Identier: NCT00574873]) was supported by Pzer. Editorial/medical writing support was provided by Wilson Joe, PhD, at MedErgy and was funded by Pzer.