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Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome–positive chronic myeloid leukemia patients with resistance or intolerance to imatinib

Jorge E. Cortes, Hagop M. Kantarjian, Tim H. Brümmendorf, Dong-Wook Kim, Anna G. Turkina, Zhi-Xiang Shen, Ricardo Pasquini, H. Jean Khoury, Steven Arkin, Angela Volkert, Nadine Besson, Richat Abbas, Junyuan Wang, Eric Leip and Carlo Gambacorti-Passerini
This article has an Erratum 122(14):2524

Data supplements

Article Figures & Data

Figures

  • Figure 1

    Disposition of patients. A total of 288 patients were enrolled in part 2, including 200 imatinib-resistant patients and 88 imatinib-intolerant patients. *AEs leading to withdrawal in 2 or more imatinib-resistant patients included thrombocytopenia (n = 6), aspartate aminotransferase elevation (n = 4), alanine aminotransferase elevation (n = 3), diarrhea (n = 3), neutropenia (n = 2), anemia (n = 2), leukopenia (n = 2), and vomiting (n = 2). AEs leading to withdrawal in 2 or more imatinib-intolerant patients included thrombocytopenia (n = 8), diarrhea (n = 3), alanine aminotransferase elevation (n = 3), aspartate aminotransferase elevation (n = 2), dyspnea (n = 2), neutropenia (n = 2), pancytopenia (n = 2), and rash (n = 2).

  • Figure 2

    Duration of CHR and MCyR with bosutinib treatment. Duration of CHR (A) and MCyR (B) were determined by the evaluable population; patients entering the study in CCyR were excluded. As of the data cutoff, 77% of the evaluable patients who achieved a CHR still retained their response (124/172 [72%] imatinib-resistant and 65/75 [87%] imatinib-intolerant patients), with a median duration of CHR not reached. Of the evaluable patients who achieved a MCyR, 78% still retained their MCyR as of the data cutoff (73/101 [72%] imatinib-resistant and 36/39 [92%] imatinib-intolerant patients), with the median duration of MCyR not reached.

  • Figure 3

    CHR and MCyR by Bcr-Abl mutation status at baseline. Mutations indicated as “unknown” included abnormalities not associated with known mutations (eg, nucleotide insertions or deletions, alternate splicing).

  • Figure 4

    PFS and overall survival with bosutinib treatment. PFS (A) and overall survival (B) are shown for chronic phase imatinib-resistant or -intolerant patients treated with bosutinib (all-treated population) at a median follow-up of 24.2 months.

  • Figure 5

    Mean plasma concentration vs time profiles after oral administration of bosutinib 500 mg on days 1 and 15.

Tables

  • Table 1

    Baseline patient demographic and disease characteristics

    CharacteristicImatinib resistant (n = 200)Imatinib intolerant (n = 88)Total (N = 288)
    No.%No.%No.%
    Age, y
        Median51.054.553.0
        Range18-8623-9118-91
    Sex, male11658384315453
    Hematologic analysis, 109/L
        White blood cell count
            Median6.75.96.5
            Range2.1-1512.1-160.72.1-151
        Platelet count
            Median261.5202.5237.5
            Range47-243648-225147-2436
    Duration of disease, y
        Median4.02.83.6
        Range0.1-15.10.1-13.60.1-15.1
    Treatment history
        No. of previous therapies*
            113166657419668
            2693523269232
        Previous IFN693523269232
        Previous stem cell transplantation632283
    Features of imatinib treatment
        Duration of previous imatinib treatment, y
            Median2.61.52.2
            Range0.4-8.8< 0.1-8.3< 0.1-8.8
        Previous complete hematologic response with imatinib16482556321976
        Reason for stopping imatinib
            Adverse event (intolerance)1186988733
            Disease progression163921116462
            Regimen completed740083
            Other741173
            Missing22022
        1 or more Bcr-Abl mutations detected§57/83698/322565/11557
    • * Includes previous tyrosine kinase inhibitor therapies. Percentages may not total 100% because of rounding.

    • Patients simultaneously meeting the protocol definitions for imatinib resistance and imatinib intolerance are categorized as having imatinib resistance.

    • The reason for stopping imatinib was not reported.

    • § Total of 83 imatinib-resistant and 32 imatinib-intolerant patients assessed for mutation status at baseline.

  • Table 2

    Hematologic response

    ResponseImatinib resistantImatinib intolerantTotal
    No.%No.%No.%
    Cumulative response
        Evaluable patients19988287
        Complete response17286758524786
    Cumulative response among patients with no baseline complete hematologic response
        Evaluable patients10041141
        Complete response7676348311078
    Reason for exclusion from analysis
        No baseline assessment101
  • Table 3

    Cytogenetic response

    ResponseImatinib resistantImatinib intolerantTotal
    No.%No.%No.%
    Response at 24 weeks
        All treated patients*20088288
        Major663324279031
            Complete452320236523
    Cumulative response
        Evaluable patients18680266
        Major10154394914053
            Complete7741334111041
    Reason for exclusion from evaluable analysis
        No baseline assessment14822
    Major cytogenetic response in evaluable patients by dose intensity
        Mean dose < 250 mg/d1/6170/601/128
        Mean dose 250 to < 350 mg/d12/24509/175321/4151
        Mean dose 350 to < 450 mg/d26/455812/215738/6658
        Mean dose 450 to < 550 mg/d53/945618/365071/13055
        Mean dose ≥ 550 mg/d9/17530/009/1753
    • * Patients without a baseline or week 24 assessment were counted as nonresponders.

    • Major cytogenetic response = complete + partial cytogenetic response.

  • Table 4

    Cytogenetic response by best previous response to imatinib

    ResponseImatinib resistantImatinib intolerantTotal
    No.%No.%No.%
    Best previous cytogenetic response with imatinib*
        Major cytogenetic response8040394411941
            Complete512631358228
            Partial2915893713
        No major cytogenetic response10653232612945
            Minor15833186
            Minimal2412673010
            None673414168128
        Missing14726304014
    Major cytogenetic response by best previous response to imatinib
        Major cytogenetic response on imatinib previously51/806418/394669/11958
        No major cytogenetic response on imatinib previously45/106428/233553/12941
        Missing data on response to imatinib previously5/143613/265018/4045
    Complete cytogenetic response by best previous response to imatinib
        Major cytogenetic response on imatinib previously46/805817/394463/11953
        No major cytogenetic response on imatinib previously27/106255/232232/12925
        Missing data on response to imatinib previously4/142911/264215/4038
    • * Percentages may not total 100% because of rounding.

    • Major cytogenetic response = complete + partial cytogenetic response.

  • Table 5

    Molecular response among patients achieving complete cytogenetic response

    ResponseImatinib resistantImatinib intolerantTotal
    No.%No.%No.%
    Cumulative response*
        Patients in subgroup analysis552378
        Major356415655064
            Complete274914614153
    Reason for exclusion from analysis
        No assessment702191
        Did not achieve complete cytogenetic response7544119
    • * Major molecular response = ≥ 3 log reduction from standardized baseline Bcr-Abl:Abl ratio. Complete molecular response = undetectable Bcr-Abl, with a sensitivity of ≥ 5 log. Molecular response was not assessed according to the International Scale.

    • Because of logistical constraints, 4 countries (China, India, Russia, and South Africa) did not evaluate molecular response.

  • Table 6

    Treatment-emergent adverse events and laboratory abnormalities

    EventImatinib resistant (n = 200)Imatinib intolerant (n = 88)Total (N = 288)
    AllGr 3/4AllGr 3/4AllGr 3/4
    No.%No.%No.%No.%No.%No.%
    Nonhematologic TEAEs occurring with any grade in 10% or more of patients
        Diarrhea169851587484111324384269
        Nausea8442004450451284441
        Rash*8543179414791012644269
        Vomiting6734323439671013593
        Abdominal pain442221212411652331
        Upper abdominal pain381900161800541900
        Fatigue422100222522642221
        Pyrexia48241112140060211< 1
        Cough341700121400461600
        Headache291500171900461600
        Edema28141114160042151< 1
        Arthralgia26130013151139141< 1
        Decreased appetite251321121400371321
        Constipation1790015171132111< 1
        Back pain12600161800281000
        Nasopharyngitis191000101100291000
    Hematologic laboratory abnormalities (all grades)
        Anemia18291201076861618258903613
        Thrombocytopenia§13166392060682933191666824
        Neutropenia7437281442482528116405318
    Other laboratory abnormalities occurring with grade 3/4 severity in 4% or more of patients
        Elevated ALT11156201058661011169593010
        Elevated AST95488446526714149145
        Hypophosphatemia884418936416712443248
        Elevated uric acid894512631355612042176
        Hypocalcemia75385340455611540103
        Elevated lipase50251892933677927248
        Hypermagnesemia47241682630182073253412
        Elevated INR522632192245712572
        Hypomagnesemia442211121400561910
    • ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; Gr, grade; INR, international normalized ratio; and TEAE, treatment-emergent adverse event.

    • * Rash includes acne, allergic dermatitis, erythema, exfoliative rash, folliculitis, heat rash, rash, rash erythematous, rash macular, rash papular, rash pruritic, and skin exfoliation.

    • Edema includes edema, face edema, localized edema, edema peripheral, periorbital edema, and pitting edema.

    • At baseline, anemia was reported by 125 (63%) imatinib-resistant patients and 45 (51%) imatinib-intolerant patients.

    • § At baseline, thrombocytopenia was reported by 34 (17%) imatinib-resistant patients and 19 (22%) imatinib-intolerant patients.

    • At baseline, neutropenia was reported by 18 (9%) imatinib-resistant patients and 13 (15%) imatinib-intolerant patients.

  • Table 7

    Mean pharmacokinetic parameters on days 1 and 15 after oral administration of bosutinib 400, 500, and 600 mg

    DoseDayMeasureCmax, ng/mLTmax, h*T1/2, hAUC, ng·h/mL
    400 mg1No.3333
    Mean77.23.0 (3-4)NA1487
    CV%76.317.3109.472.2
    15No.3323
    Mean157.36.0 (6-24)22.62851
    CV%17.686.624.416.6
    500 mg1No.3333
    Mean100.96.0 (6-6)22.12064
    CV%35.3010.124.8
    15No.3323
    Mean200.36.0 (4-8)21.93660
    CV%6.033.327.911.4
    600 mg1No.12121112
    Mean119.94.0 (2-48)24.72074
    CV%33.5159.054.120.0
    15No.1010610
    Mean208.26.0 (3-8)27.03360
    CV%35.230.4100.843.5
    • AUC indicates area under the curve; Cmax, maximum concentration; CV%, coefficient of variation; NA, not available; Tmax, time to maximum concentration; and T1/2, elimination half life.

    • * For Tmax, median (range) values are shown instead of mean values.