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Randomized trial of 10 days of decitabine ± bortezomib in untreated older patients with AML: CALGB 11002 (Alliance)

Gail J. Roboz, Sumithra J. Mandrekar, Pinkal Desai, Kristina Laumann, Alison R. Walker, Eunice S. Wang, Jonathan E. Kolitz, Bayard L. Powell, Eyal C. Attar, Wendy Stock, Clara D. Bloomfield, Jessica Kohlschmidt, Krzysztof Mrózek, Duane C. Hassane, Levi Garraway, Judit Jané-Valbuena, Michele Baltay, Adam Tracy, Guido Marcucci, Richard M. Stone and Richard A. Larson

Data supplements

Article Figures & Data

Figures

Tables

  • Table 1.

    Patient characteristics

    Characteristicn (%)P*
    Arm A: decitabine (n = 82)Arm B: decitabine + bortezomib (n = 81)Total (N = 163)
    Age stratification, y1.0
     60-6931 (37.8)31 (38.3)62 (38.0)
     ≥7051 (62.2)50 (61.7)101 (62.0)
    Age, y.59
     Median72.472.972.4
     Range60.7-92.360.5-90.060.5-92.3
    Sex.06
     Male51 (62.2)62 (76.5)113 (69.3)
     Female31 (37.8)19 (23.5)50 (30.7)
    Race1.0
     Unknown3 (3.7)2 (2.5)5 (3.1)
     White74 (90.2)73 (90.1)147 (90.2)
     Black/African American3 (3.7)4 (4.9)7 (4.3)
     Asian0 (0.0)1 (1.2)1 (0.6)
     Native Hawaiian or Pacific Islander1 (1.2)0 (0.0)1 (0.6)
     Not reported1 (1.2)0 (0.0)1 (0.6)
     Multiple races reported0 (0.0)1 (1.2)1 (0.6)
    Ethnicity.76
     Non-Hispanic77 (93.9)77 (95.1)154 (94.5)
     Not reported3 (3.7)1 (1.2)4 (2.5)
     Unknown2 (2.4)3 (3.7)5 (3.1)
    ECOG PS.49
     022 (26.8)21 (25.9)43 (26.4)
     141 (50.0)48 (59.3)89 (54.6)
     216 (19.5)11 (13.6)27 (16.6)
     33 (3.7)1 (1.2)4 (2.5)
    Clinical onset of AML.58
     De novo57 (69.5)53 (65.4)110 (67.5)
     Therapy related10 (12.2)8 (9.9)18 (11.0)
     MDS related/AHD15 (18.3)20 (24.7)35 (21.5)
    ELN classificationn = 71n = 76n = 147.37
     Normal20 (28.2)28 (36.8)48 (32.7)
     Intermediate-II19 (26.8)22 (28.9)41 (27.9)
     Adverse32 (45.1)26 (34.2)58 (39.5)
    Creatinine, mg/dLn = 82n = 80n = 162.24
     Median0.91.01.0
     Range0.0-7.00.0-2.20.0-7.0
     ≥1.512 (14.6)11 (13.8)23 (14.2)1.0
    LVEF, %n = 79n = 76n = 155.68
     Median61.060.060.0
     Range30.0-74.029.0-81.029.0-81.0
     <453 (3.8)4 (5.3)7 (4.5).72
    • AHD, antecedent hematologic disorder; ECOG, Eastern Cooperative Oncology Group; ELN, European LeukemiaNet; LVEF, left ventricular ejection fraction; MDS, myelodysplastic syndrome.

    • * For continuous variables, Kruskal-Wallis test; for discrete variables, Fisher’s exact test.

  • Table 2.

    Patient outcomes

    Arm A: decitabine (n = 82)Arm B: decitabine + bortezomib (n = 81)P (2 sided)
    n (%; 95% CI) achieving CR + CRi rate32 (39; 28-50)31 (38; 28-50).91*
    Median (range) time to response, mo3.6 (0.9-17.2)2.3 (1.7-7.9).32
    Median (95% CI) duration of response, CR + CRi, mo10.9 (5.7-19.6)15.3 (10.4-NA).15§
    Median (95% CI) OS, mo9.3 (5.8-12.2)8.9 (3.8-14.3).18
    Median (95% CI) OS after transplantation, moNA (n = 9)31.1 (4.6-NA).98§
    • NA, not attained.

    • * Mantel-Haenszel test.

    • Two-sided rank sum test.

    • Kaplan-Meier estimate.

    • § Two-sided stratified log-rank test.

    • One-sided stratified log-rank test.

    • Landmark Kaplan-Meier estimate from time of transplantation to death resulting from any cause.

  • Table 3.

    Nonhematological adverse events in >10% of patients, regardless of attribution

    Adverse event* by armn (%)
    Grade 3Grade 4Grade 5Total
    Fatigue
     A12 (14.8)0012 (14.8)
     B16 (20)0016 (20)
    Infections and infestations
     A10 (12.3)1 (1.2)1 (1.2)12 (14.7)
     B10 (12.5)01 (1.3)11 (13.8)
    Sepsis
     A011 (13.6)5 (6.2)16 (19.8)
     B05 (6.3)6 (7.5)11 (13.8)
    Lung infection
     A16 (19.8)2 (2.5)2 (2.5)20 (24.8)
     B20 (25)02 (2.5)22 (27.5)
    Hyperglycemia
     A10 (12.3)3 (3.7)013 (16)
     B13 (16.3)0013 (16.3)
    Hypoalbuminemia
     A16 (19.8)0016 (19.8)
     B10 (12.5)0010 (12.5)
    Hypocalcemia
     A7 (8.6)3 (3.7)010 (12.3)
     B3 (3.8)1 (1.3)04 (5.1)
    Hypokalemia
     A10 (12.3)3 (3.7)013 (16)
     B12 (15)1 (1.3)013 (16.3)
    Hypophosphatemia
     A9 (11.1)009 (11.1)
     B6 (7.5)006 (7.5)
    Peripheral sensory neuropathy
     A0000
     B8 (10)2 (2.5)010 (12.5)
    Dyspnea
     A9 (11.1)009 (11.1)
     B10 (12.5)1 (1.3)011 (13.8)
    Hypoxia
     A6 (7.4)1 (1.2)07 (8.6)
     B8 (10)01 (1.3)9 (11.3)
    Hypertension
     A6 (7.4)006 (7.4)
     B14 (17.5)0014 (17.5)
    Hypotension
     A11 (13.6)3 (3.7)014 (17.3)
     B10 (12.5)4 (5)014 (17.5)
    • Excludes hematological toxicity and febrile neutropenia, which were observed in all patients.

    • * Regardless of attribution, per National Cancer Institute Common Toxicity Criteria (version 4.0).

    • 161 patients were evaluated for adverse events: arm A (decitabine), n = 81; arm B (decitabine + bortezomib), n = 80.

  • Table 4.

    Number of mutations per patient by treatment arm

    No. of mutations per patientn (%)
    Arm A: decitabine (n = 56)Arm B: decitabine + bortezomib (n = 62)All patients (N = 118)
    02 (3.6)4 (6.5)6 (5.1)
    115 (26.8)12 (19.4)27 (22.9)
    213 (23.2)19 (30.6)32 (27.1)
    316 (28.6)8 (12.9)24 (20.3)
    47 (12.5)12 (19.4)19 (16.1)
    52 (3.6)4 (6.5)6 (5.1)
    61 (1.8)2 (3.2)3 (2.5)
    70 (0.0)1 (1.6)1 (0.8)
    Median (range)2 (0-6)2 (0-7)2 (0-7)
  • Table 5.

    CR and 1-y survival by mutational status and treatment arm

    Mutationn (%; 95% CI) of patientsFisher’s exact P (2 sided)
    Arm A: decitabine (n = 56)Arm B: decitabine + bortezomib (n = 62)
    ASXL1n = 14n = 13
     CR*2 (14; 2-43)2 (15; 2-45)1.0
     1-y survival6 (43; 23-79)7 (54; 33-89).71
    No ASXL1n = 42n = 49
     CR*8 (19; 9-34)13 (27; 15-41).46
     1-y survival16 (42; 29-60)23 (47; 35-63).52
    DNMT3An = 9n = 14
     CR*1 (11; 0-48)3 (21; 5-51)1.0
     1-y survival3 (33; 7-70)7 (50; 23-77).67
    No DNMT3An = 47n = 48
     CR*9 (19; 9-33)12 (25; 14-40).62
     1-y survival19 (40; 26-56)23 (48; 33-63).54
    IDH2n = 8n = 9
     CR*2 (25; 3-65)2 (22; 3-60)1.0
     1-y survival5 (63; 24-91)7 (78; 40-97).62
    No IDH2n = 48n = 53
     CR*8 (17; 7-30)13 (25; 14-40).46
     1-y survival17 (35; 22-51)23 (43; 30-58).42
    NPM1n = 6n = 11
     CR*2 (33; 4-78)3 (27; 6-61)1.0
     1-y survival3 (50; 12-88)7 (64; 31-89).64
    No NPM1n = 50n = 51
     CR*8 (16; 7-29)12 (24; 13-37).46
     1-y survival19 (38; 25-53)23 (45; 31-60).55
    RUNX1n = 9n = 10
     CR*2 (22; 3-60)1 (10; 0-45).58
     1-y survival5 (56; 21-86)5 (50; 19-81)1.0
    No RUNX1n = 47n = 52
     CR*8 (17; 8-31)14 (27; 67-41).33
     1-y survival17 (36; 23-51)25 (48; 34-62).31
    TET2n = 8n = 12
     CR*1 (13; 0-53)3 (25; 5-57).62
     1-y survival3 (38; 9-76)6 (50; 21-79).67
    No TET2n = 48n = 50
     CR*9 (19; 9-33)12 (24; 13-38).63
     1-y survival19 (40; 26-55)24 (48; 34-63).42
    TP53n = 14n = 12
     CR*3 (21; 5-51)2 (17; 2-48)1.0
     1-y survival3 (27; 11-66)2 (17; 5-59)1.0
    No TP53n = 42n = 50
     CR*7 (17; 7-31)13 (26; 15-40).32
     1-y survival19 (47; 34-65)28 (56; 44-72).40
    • * Binomial estimate for subgroups with ≤10 patients in a comparison.

    • Kaplan-Meier estimate.