Table S1. Cytogenetic and Molecular Response by Dose Intensity

Table S1. Cytogenetic and Molecular Response by Dose Intensity

CP2L/IM-R / CP2L/IM-I / CP2L Total
MCyR response by dose intensity, n/N (%)
Mean dose <250 mg/d / 0 / 2/3 (67) / 2/3 (67)
Mean dose 250−<350 mg/d / 0/4 / 11/12 (92) / 11/16 (69)
Mean dose 350−<450 mg/d / 3/5 (60) / 11/12 (92) / 14/17 (82)
Mean dose 450−<550 mg/d / 2/3 (67) / 2/4 (50) / 4/7 (57)
Mean dose ≥550 mg/d / 2/2 (100) / 0 / 2/2 (100)
MMR response by dose intensity, n/N (%)
Mean dose <250 mg/d / 0 / 0/3 / 0/3
Mean dose 250−<350 mg/d / 0/4 / 7/12 (58) / 7/16 (44)
Mean dose 350−<450 mg/d / 3/5 (60) / 9/12 (75) / 12/17 (71)
Mean dose 450−<550 mg/d / 2/3 (67) / 2/4 (50) / 4/7 (57)
Mean dose ≥550 mg/d / 1/2 (50) / 0 / 1/2 (50)

CP2L=chronic phase second line; IM-I=imatinib intolerant; IM-R=imatinib resistant/refractory; MCyR=major cytogenetic response; MMR=major molecular response.

Table S2. Cytogenetic and Molecular Response by Dose Reduction

CP2L Total
Patients reducing dose to 400 mg,a n (%) / 43 (77)
Attained/maintained MCyR, n (%) / 33 (77)
First MCyR following reduction / 29 (88)
MCyR before and after reduction / 4 (12)
MCyR before but not after reduction / 0
Attained/maintained MMR, n (%) / 22 (51)
First MMR following reduction / 19 (86)
MMR before and after reduction / 3 (14)
MMR before but not after reduction / 0
Patients reducing dose to 300 mg, n (%) / 32 (51)
Attained/maintained MCyR, n (%) / 23 (72)
First MCyR following reduction / 11 (48)
MCyR before and after reduction / 11 (48)
MCyR before but not after reduction / 1 (4)
Attained/maintained MMR, n (%) / 14 (44)
First MMR following reduction / 7 (50)
MMR before and after reduction / 7 (50)
MMR before but not after reduction / 0

CP2L=chronic phase second line; MCyR=major cytogenetic response; MMR=major molecular response.

aPatients who started on 400 mg were excluded from this analysis.

Table S3 Summary of Patients with Emergent BCR-ABL Mutations Detected at Baseline or at Treatment Discontinuation

Molecular / Cytogenetic / Discontinuation From Treatment
Cohort / Mutation at Baseline / Mutation at End of Treatment / Response at Baseline / Best Response Achieved / Response at End of Treatment / Response at Baseline / Best Response Achieved / Response at End of Treatment
CP2L/IM-R / G250E / No / N/D / CMR / CMR / PCyR / CCyR / CCyR
E281K / No / N/D / CMR / CMR / PCyR / CCyR / CCyR
T315I / T315I / N/D / N/A / N/D / MiCyR / MiCyR / MiCyR / Disease progression
F359C / No / N/D / CMR / CMR / No response / CCyR / CCyR
H396R / No / N/D / CMR / CMR / PCyR / CCyR / CCyR / Symptomatic deterioration
E292V / E292V / N/D / No response / Unknown / No response / MiCyR / MiCyR / Disease progression
F359I / F359I / No response / No response / No response / MiCyR / MiCyR / No response / Adverse event: Increased alanine aminotransferase, increased aspartate aminotransferase
F317L / F317L / No response / No response / No response / No response / No response / No response / Adverse event: increased lipase
CP2L/IM-I / F317L / No / N/D / N/A / N/D / No response / N/A / N/D / Subject request
E255K / E255K / No response / No response / No response / MiCyR / CCyR / PCyR
N96S / No / No response / CMR / CMR / PCyR / CCyR / CCyR
K285R / No / No response / CMR / MMR / MiCyR / CCyR / CCyR
CP3L / NO / T315I / N/D / MMR / No response / CCyR / CCyR / CCyR / Investigator request
ADV / G250E, E279K / G250E / No response / No response / No response / PCyR / CCyR / CCyR / Disease progression
E459K / E459K / No response / No response / No response / No response / MiCyR / No response / Adverse event: thrombocytopenia
Y253H, T315I / No / No response / N/A / N/D / No response / N/A / N/D / Disease progression: death
E255V, T315I / T315I / No response / N/A / Unknown / MiCyR / N/A / N/D / Disease progression
E459K / T315I / No response / No response / No response / No response / CCyR / No response / Disease progression
F359V, E459K / F359V, E459K / No response / No response / No response / No response / No response / No response / Adverse event: thrombocytopenia

ADV=advanced phase; CCyR=complete cytogenetic response; CMR=complete molecular response; CP2L=chronic phase second line; CP3L=chronic phase third line; IC50=relative concentration that inhibits 50%; IM-I=imatinib intolerant; IM-R=imatinib resistant/refractory; MiCyR=minor cytogenetic response; MMR=major molecular response; N/A=not applicable; N/D=not determined; PCyR=partial cytogenetic response.

Sensitive mutations are noted in green and were defined as IC50 values ≤2-fold higher versus wild-type BCR-ABL; insensitive mutations are noted in red and were defined as IC50 values >2-fold higher than wild-type BCR-ABL [13, 14]. The bosutinib sensitivity of all other mutations is unknown.

Table S4. AEs Leading to Treatment Discontinuation by Yeara

Year 1
(n=63) / Year 2
(n=41) / Year 3
(n=35) / Year 4
(n=27) / Year 5
(n=24) / Year 6‒8
(n=14) / Total
(N=63)
Any AEb, n (%) / 14 (22) / 1 (2) / 1 (3) / 1 (4) / 1 (4) / 0 / 18 (29)
Increased AST / 3 (5) / 0 / 0 / 1 (4) / 0 / 0 / 4 (6)
Abnormal hepatic function / 3 (5) / 0 / 0 / 0 / 0 / 0 / 3 (5)
Increased ALT / 3 (5) / 0 / 0 / 0 / 0 / 0 / 3 (5)
Thrombocytopenia / 3 (5) / 0 / 0 / 0 / 0 / 0 / 3 (5)
Abnormal liver function test / 1 (2) / 0 / 0 / 0 / 0 / 0 / 1 (2)
Bladder cancer / 0 / 1 (2) / 0 / 0 / 0 / 0 / 1 (2)
Blast cell crisis / 1 (2) / 0 / 0 / 0 / 0 / 0 / 1 (2)
Cerebral hemorrhage / 0 / 0 / 0 / 0 / 1 (4) / 0 / 1 (2)
Increased lipase / 1 (2) / 0 / 0 / 0 / 0 / 0 / 1 (2)
Liver injury / 1 (2) / 0 / 0 / 0 / 0 / 0 / 1 (2)
Posterior reversible encephalopathy syndrome / 0 / 0 / 1 (3) / 0 / 0 / 0 / 1 (2)
Rash / 1 (2) / 0 / 0 / 0 / 0 / 0 / 1 (2)

AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase.

a1 year = 365.25 days; bpatients could have reported ≥1 AE as AE leading to treatment discontinuation.

Table S5. Characteristics and Management of Diarrhea and Hepatic AEs (N=63)

Diarrhea / Increased ALT / Increased AST
Patient with event, n (%) / 60 (95) / 24 (38) / 19 (30)
Median time to onset, d (range) / 1 (1‒24) / 17 (7‒120) / 21 (7‒337)
Median cumulative duration, d (range) / 28 (1‒2180) / 64 (6‒1245) / 29 (6‒682)
Event resolved, n (%) / 52 (87) / 21 (88) / 16 (84)
AE management, n (%)
Received dose reduction / 6 (10) / 12 (50) / 4 (21)
Received dose interruption / 8 (13) / 12 (50) / 7 (37)
Reinitiated / 8 (100) / 12 (100) / 5 (71)
Successfully reinitiated / 8 (100) / 10 (83) / 4 (80)

AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase.

Table S6. Preferred Terms Included in Cardiac, Vascular, and Renal AE Clusters

Cluster / Definition
System Organ Class
High-Level Group Term
High-Level Term
Preferred Term
Cardiac / Cardiac disorders
Cardiac arrthymiasa
Heart failuresa
Congenital, familial, and genetic disorders
Cardiac and vascular disorders congenital
Cardiac disorders congenital NEC
Long QT syndrome congenital
Investigations
Cardiac and vascular investigations (excluding enzyme tests)
Cardiac function diagnostic procedures
Ejection fraction decreased
Cardiac imaging proceduresb
ECG investigations
ECG QT interval abnormal
ECG QT prolonged
General disorders and administration site conditions
Fatal outcomes
Death and sudden death
Cardiac death
Sudden cardiac death
Sudden death
Vascular / Cardiac disorders
Coronary artery disordersa
Investigations
Cardiac and vascular investigations (excluding enzyme tests)
Vascular imaging procedures NECb
Nervous system disorders
CNS vascular disorders
CNS hemorrhages and cerebrovascular accidentsb
CNS vascular disorders NECb
Transient cerebrovascular eventsb
Surgical and medical procedures
Vascular therapeutic procedures
Arterial therapeutic procedure (excluding aortic) b
Vascular therapeutic procedures NECb
Vascular disorders
Arteriosclerosis, stenosis, vascular insufficiency and necrosisa
Embolism and thrombosisa
Vascular disorders NEC
Non-site-specific vascular disorders NECb
Peripheral vascular disorders NEC (excluding flushing and hot flash)b
Renal / Acute prerenal failure
Anuria
Crush syndrome
Diabetic end stage renal disease
Neonatal anuria
Oliguria
Pancreatorenal syndrome
Postrenal failure
Prerenal failure
Renal failure
Renal failure
Acute kidney injury
Chronic kidney disease
Renal failure neonatal
Renal impairment
Renal impairment neonatal
Scleroderma renal crisis
Blood creatinine abnormal
Blood creatinine increased
Creatinine renal clearance abnormal
Creatinine renal clearance decreased
Glomerular filtration rate abnormal
Glomerular filtration rate decreased
Blood urea increased

AE=adverse event; CNS=central nervous system; ECG=electrocardiogram; NEC=not elsewhere classified.

aAll high-level terms included in this high-level group term (and all preferred terms associated with the high-level term) were included in the analysis; ball preferred terms included in this high-level term were included in the analysis.

Table S7. Definition of Clusters

Cluster / Definition
Hepatotoxicity / SMQ: hepatic disorders
sub-SMQ (narrow): cholestasis and jaundice of hepatic origin ‒ sub-SMQ (narrow): hepatic failure, fibrosis and cirrhosis and other liver damage‒related conditions
sub-SMQ (narrow): cholestasis and jaundice of hepatic origin ‒ sub-SMQ (narrow): hepatitis, noninfectious
sub-SMQ (narrow): liver-related investigations, signs and symptoms ‒ selected relevant PTs
Gastrointestinal toxicity / MedDRA PTs: nausea, regurgitation, retching, vomiting, projectile vomiting, diarrhea, defecation urgency, frequent bowel movements, gastrointestinal hypermotility
Hypersensitivity / MedDRA HLGT: allergic conditions
Fluid retention / MedDRA SMQ (narrow): hemodynamic edema, effusions and fluid overload
Bone marrow suppression / MedDRA SMQ: hematopoietic cytopenias
sub-SMQ (narrow): hematopoietic cytopenias affecting >1 type of blood cell
sub-SMQ (narrow): hematopoietic erythropenia
sub-SMQ (narrow): hematopoietic leukopenia
sub-SMQ (narrow): hematopoietic thrombocytopenia
sub-SMQ (broad): relevant PTs
Cardiotoxicity (including QT prolongation) / SMQ: torsade de pointes/QT prolongation (narrow)
MedDRA HLGT: cardiac arrhythmias
MedDRA HLGT: heart failures
MedDRA HLGT: coronary artery disorders
MedDRA HLGT: pericardial disorders
MedDRA SOC: general disorders and administration site conditions ‒SOC ‒ relevant PTs
Infection / SOC: infections and infestations
Hemorrhage / MedDRA SMQ: hemorrhages
sub-SMQ (narrow): hemorrhage terms (excluding laboratory terms)
sub-SMQ (narrow): hemorrhage laboratory terms ‒ relevant PTs
Rash / MedDRA HLT: rashes, eruptions and exanthems NEC
MedDRA HLT: erythemas
MedDRA HLT: acnes
MedDRA HLT: dermatitis and eczema
Pancreatitis/increased lipase / MedDRA SMQ (narrow): acute pancreatitis
MedDRA PTs: pancreatitis chronic
MedDRA PTs: lipase increased
Renal dysfunction / MedDRA HLT: renal failure and impairment
MedDRA HLT: renal function analyses ‒ relevant PTs
Interstitial lung disease / MedDRA SMQ (narrow): interstitial lung disease

HLGT=high-level group term; HLT=high level term; MedDRA=Medical Dictionary for Regulatory Activities; NEC=not elsewhere classified; PT=preferred term; SMQ=standardized MedDRA queries; SOC=system organ class; sub-SMQ=subordinate standardized MedDRA queries.