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For those in the older patient cohort who
received monthly maintenance therapy, a fiveyear CIR of 69 percent (95% CI 61-75) and a
five-year survival of 27 percent (95% CI 21-33)
were observed.
Five-year survival rates for the younger
cohort were 28 percent in the TAD-HAM cohort
(95% CI 17-39) and 31 percent in the HAMHAM cohort (95% CI 19-43; p=0.65) compared
with 29 percent (95% CI 20-38) and 25 percent
(95% CI 17-33; p=0.9), respectively, in the older
cohort.
Whether or not patients received granulocyte-colony stimulating factor (G-CSF) did not
significantly impact outcomes for either patient
cohort.
See TABLE 2 for a comparison of outcomes
between younger and older patients who
were assigned to receive and were receiving
S:7”
significantly different therapy-intensities.
BOSULIF® (bosutinib) tablets for oral use
Initial U.S. Approval: 2012
Brief summary of Prescribing Information
INDICATIONS AND USAGE
BOSULIF is indicated for the treatment of adult patients with chronic, accelerated, or blast phase
Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML) with resistance or
intolerance to prior therapy.
DOSAGE AND ADMINISTRATION
Recommended Dosing: The recommended dose and schedule of BOSULIF is 500 mg orally once daily with
food. Continue treatment with BOSULIF until disease progression or patient intolerance. If a dose is missed
beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day.
Dose Escalation: Consider dose escalation to 600 mg once daily with food in patients who do not reach
complete hematological response (CHR) by week 8 or a complete cytogenetic response (CCyR) by week 12,
who did not have Grade 3 or higher adverse reactions, and who are currently taking 500 mg daily.
Dose Adjustments for Non-Hematologic Adverse Reactions: Elevated liver transaminases: If elevations in
liver transaminases greater than 5 x institutional upper limit of normal (ULN) occur, withhold BOSULIF until
recovery to less than or equal to 2.5 x ULN and resume at 400 mg once daily thereafter. If recovery takes
longer than 4 weeks, discontinue BOSULIF. If transaminase elevations greater than or equal to 3 x ULN occur
concurrently with bilirubin elevations greater than 2 x ULN and alkaline phosphatase less than 2 x ULN
(Hy’s law case definition), discontinue BOSULIF. Diarrhea: For NCI CTCAE Grade 3-4 diarrhea (increase of greater
than or equal to 7 stools/day over baseline/pretreatment), withhold BOSULIF until recovery to Grade
less than or equal to 1. BOSULIF may be resumed at 400 mg once daily. For other clinically significant,
moderate or severe non-hematological toxicity: Withhold BOSULIF until the toxicity has resolved, then
consider resuming BOSULIF at 400 mg once daily. If clinically appropriate, consider re-escalating the dose
of BOSULIF to 500 mg once daily. Dose Adjustments for Myelosuppression: Dose reductions for severe
or persistent neutropenia and thrombocytopenia are as follows: If absolute neutrophil count (ANC) is
less than 1000x106/L or platelets are less than 50,000x106/L: Withhold BOSULIF until ANC is greater than
or equal to 1000x106/L and platelets are greater than or equal to 50,000x106/L. Resume treatment with
BOSULIF at the same dose if recovery occurs within 2 weeks. If blood counts remain low for greater than 2
weeks, upon recovery, reduce dose by 100 mg and resume treatment. If cytopenia recurs, reduce the dose
by an additional 100 mg upon recovery and resume treatment. Doses less than 300 mg/day have not been
evaluated. Concomitant Use With CYP3A Inhibitors: Avoid the concomitant use of strong or moderate
CYP3A inhibitors with BOSULIF as an increase in bosut inib plasma concentration is expected (strong CYP3A
inhibitors include boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/
ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin,
and voriconazole. Moderate CYP3A inhibitors include amprenavir, aprepitant, atazanavir, ciprofloxacin,
crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit products,
imatinib, and verapamil). Concomitant Use With CYP3A Inducers: Avoid the concomitant use of strong
or moderate CYP3A inducers with BOSULIF as a large reduction in exposure is expected (strong CYP3A
inducers include carbamazepine, phenytoin, rifampin, and St. John’s Wort. Moderate CYP3A inducers
include bosentan, efavirenz, etravirine, modafinil, and nafcillin). Hepatic Impairment: In patients
with mild (Child-Pugh A), moderate (Child-Pugh B), or severe (Child-Pugh C) hepatic impairment, the
recommended dose of BOSULIF is 200 mg daily. Renal Impairment: If creatinine clearance (CrCL) is
30 to 50 mL/min, the recommended starting dose of BOSULIF is 400 mg daily. If CrCL is <30 mL/min, the
recommended starting dose of BOSULIF is 300 mg daily.
CONTRAINDICATIONS
Hypersensitivity to BOSULIF. In the BOSULIF clinical trials, anaphylactic shock occurred in less than 0.2% of
treated patients.
WARNINGS AND PRECAUTIONS
Gastrointestinal Toxicity: Diarrhea, nausea, vomiting, and abdominal pain occur with BOSULIF treatment.
Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, and fluid
replacement. In the single-arm Phase 1/2 clinical trial, the median time to onset for diarrhea (all grades)
was 2 days and the median duration per event was 1 day. Among the patients who experienced diarrhea,
the median number of episodes of diarrhea per patient during treatment with BOSULIF was 3 (range
1-221). To manage gastrointestinal toxicity, withhold, dose reduce, or discontinue BOSULIF as necessary.
Myelosuppression: Thrombocytopenia, anemia, and neutropenia occur with BOSULIF treatment.
Perform complete blood counts weekly for the first month of therapy and then monthly thereafter, or
as clinically indicated. To manage myelosuppression, withhold, dose reduce, or discontinue BOSULIF as
necessary. Hepatic Toxicity: One case consistent with drug-induced liver injury (defined as concurrent
elevations in ALT or AST greater than or equal to 3 x ULN with total bilirubin greater than 2 x ULN and
alkaline phosphatase less than 2 x ULN) occurred in a trial of BOSULIF in combination with letrozole. The
patient recovered fully following discontinuation of BOSULIF. This case represented 1 out of 1209 patients
in BOSULIF clinical trials. In the 546 patients from the safety population, the incidence of ALT elevation
was 17% and AST elevation was 14%. Twenty percent of the patients experienced an increase in either ALT
or AST. Most cases of transaminase elevations occurred early in treatment; of patients who experienced
transaminase elevations of any grade, more than 80% experienced their first event within the first 3
months. The median time to onset of increased ALT and AST was 30 and 33 days, respectively, and the
median duration for each was 21 days. Perform hepatic enzyme tests monthly for the first three months
of BOSULIF treatment and as clinically indicated. In patients with transaminase elevations, monitor liver
enzymes more frequently. Withhold, dose reduce, or discontinue BOSULIF as necessary.
Fluid Retention: Fluid retention occurs with BOSULIF and may manifest as pericardial effusion, pleural
effusion, pulmonary edema, and/or peripheral edema. In the single-arm, Phase 1/2 clinical trial in 546
patients with CML treated with prior therapy, severe fluid retention was reported in 14 patients (3%).
Specifically, 9 patients had a Grade 3 or 4 pleural effusion, 3 patients experienced both Grade 3 or Grade 4
pleural and pericardial effusions, 1 patient experienced Grade 3 peripheral and pulmonary edema, and
1 patient had a Grade 3 edema. Monitor and manage patients using standards of care. Interrupt, dose
reduce, or discontinue BOSULIF as necessary. Renal Toxicity: An on-treatment decline in estimated
glomerular filtration rate (eGFR) has occurred in patients treated with BOSULIF. The table identifies
the shift from baseline to lowest observed eGFR during BOSULIF therapy for patients in the global Ph+
Leukemia studies. The median duration of therapy with BOSULIF was approximately 17 months (range,
0.03 to 95) for patients in these studies.
“These data indicate that within the age span
of 57 to 63 years, numbers of induction and
consolidation courses; intensity of cytarabine
therapy; and additions of mitoxantrone, G-CSF,
and an autoHCT had no significant impact on
therapy outcomes.” the authors concluded, suggesting that “age, rather than therapy intensity is
the strongest determinant of therapy-outcomes
under these conditions.”
The limited age range of the patients in
Shift from Baseline to Lowest Observed eGFR Group During Treatment
Safety Population in Clinical Studies (n=818)*
Baseline
Renal Function
Status
Normal
Mild
Mild to Moderate
Moderate to Severe
Severe
Total
n
Normal
n (%)
Mild
n (%)
274
438
79
24
1
816
53 (19)
10 (2)
0
0
0
63 (8)
174 (64)
170 (39)
4 (5)
1 (4)
0
349 (43)
Follow Up
Mild to Moderate
Moderate to Severe
n (%)
n (%)
30 (11)
14 (5)
177 (40)
63 (14)
28 (35)
37 (47)
1 (4)
6 (25)
0
0
236 (29) 120 (15)
Severe
n (%)
1 (<1)
14 (3)
10 (13)
15 (63)
0
40 (5)
Kidney
Failure
n (%)
1 (<1)
2 (1)
0
1 (4)
1 (100)
5 (1)
Notes: Grading is based on Modification in Diet in Renal Disease method (MDRD).
KDIGO Classification by eGFR: Normal: greater than or equal to 90, Mild: 60 to less than 90, Mild to Moderate: 45 to less than 60,
Moderate to Severe: 30 to less than 45, Severe: 15 to less than 30, Kidney Failure: less than 15 mL/min/1.73 m2.
*Among the 818 patients, eGFR was missing in 5 patients at baseline or on-therapy. There were no patients with kidney failure
at baseline.
Monitor renal function at baseline and during ther apy with BOSULIF, with particular attention to those patients
who have preexisting renal impairment or risk factors for renal dysfunction. Consider dose adjustment
in patients with baseline and treatment emergent renal impairment. Embryofetal Toxicity: There are no
adequate and well controlled studies of BOSULIF in pregnant women. BOSULIF can cause fetal harm when
administered to a pregnant woman. Bosutinib caused embryofetal toxicities in rabbits at maternal exposures
that were greater than the clinical exposure at the recommended bosutinib dose of 500 mg/day. Females of
reproductive potential should be advised to avoid pregnancy while being treated with BOSULIF. If this drug
is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be
apprised of the potential hazard to the fetus.
ADVERSE REACTIONS
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions,
adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in
the clinical trials of another drug and may not reflect the rates observed in practice. Serious adverse
reactions reported include anaphylactic shock, myelosuppression, gastrointestinal toxicity (diarrhea),
fluid retention, hepatotoxicity, and rash. Adverse reactions of any toxicity grade reported for greater
than 20% of patients in the Phase 1/2 safety population (n=546) were diarrhea (82%), nausea (46%),
thrombocytopenia (41%), vomiting (39%), abdominal pain (37%), rash (35%), anemia (27%), pyrexia (26%),
and fatigue (24%). Adverse Reactions in Patients with Imatinib-Resistant or -Intolerant Ph+ Chronic Phase
(CP), Accelerated Phase (AP), and Blast Phase (BP) CML: The single-arm, Phase 1/2 clinical trial enrolled
patients with Ph+ chronic, accelerated, or blast phase chronic myelogenous leukemia (CML) with resistance
or intolerance to prior therapy. The safety population (received at least 1 dose of BOSULIF) included 546
CML patients. Within the safety population there were 287 patients with CP CML previously treated with
imatinib only who had a median duration of BOSULIF treatment of 24 months and a median dose intensity
of 484 mg/day; 119 patients with CP CML previously treated with both imatinib and at least 1 additional TKI
who had a median duration of BOSULIF treatment of 9 months and a median dose intensity of 475 mg/day;
and 140 patients with advanced phase CML, including 76 patients with AP CML and 64 patients with BP CML.
In the patients with AP CML and BP CML, the median duration of BOSULIF treatment was 10 months and 3
months, respectively. The median dose intensity was 483 mg/day and 500 mg/day in the AP CML and BP
CML cohorts, respectively.
Adverse Reactions (10% or Greater) in Patients with CML in Study 1
Chronic Phase CML
N=406
Diarrhea
Nausea
Abdominal Paina
Thrombocytopenia
Vomiting
Rashb
Fatiguec
Anemia
Pyrexia
Increased alanine aminotransferase
Headache
Cough
Increased aspartate aminotransferase
Neutropenia
Edemad
Arthralgia
Decreased appetite
Respiratory tract infectione
Nasopharyngitis
Advanced Phase CML
N=140
All Grades
(%)
Grade 3/4
(%)
All Grades
(%)
Grade 3/4
(%)
84
46
40
40
37
34
26
23
22
20
20
20
16
16
14
14
13
12
12
9
1
1
26
3
8
1
9
<1
7
1
0
4
11
<1
<1
1
<1
0
76
47
29
42
42
35
20
37
36
10
18
21
11
19
14
13
14
10
5
5
2
5
37
4
4
4
26
3
5
4
0
3
18
1
0
0
0
0
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G:.5”