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Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib

Farrukh T. Awan, Anna Schuh, Jennifer R. Brown, Richard R. Furman, John M. Pagel, Peter Hillmen, Deborah M. Stephens, Jennifer Woyach, Elena Bibikova, Prista Charuworn, Melanie M. Frigault, Ahmed Hamdy, Raquel Izumi, Bolan Linghu, Priti Patel, Min Hui Wang and John C. Byrd

Article Figures & Data

Figures

  • Figure 1.

    Patient flow through the study. CNS, central nervous system.

  • Figure 2.

    Change in ibrutinib-related AEs during acalabrutinib treatment. *An additional 6 events of unknown grade (rash, diarrhea, hemorrhage, decreased appetite, dyspnea, and weight decreased) did not recur.

  • Figure 4.

    Acalabrutinib pharmacodynamics in ibrutinib-intolerant patients. (A) BTK occupancy for ibrutinib-intolerant patients with day-1 (D1) predose (Pre) signal/noise ratio ≥5 (n = 4 patients excluded for this reason). For the box plots, the horizontal line in the center of the box shows the median, and the upper and lower edges of the box show the 25th and 75th percentiles, respectively. The I bars (whiskers) represent 1.5× the interquartile range, with symbols showing outliers according to the Tukey method. (B) BCR-induced BTK phosphorylation (p) shown as fold over D1 predose plus exogenous acalabrutinib control. Filtered on D1 predose fold change >1.5 (n = 15 patients excluded for this reason; n = 2 patients had insufficient cells to perform the assay). Significance was determined using a paired, 2-tailed, parametric Student t test comparing time points with D1 predose. ***P < .001, ****P < .0001. C, cycle; Post, postdose; SD, standard deviation.

Tables

  • Table 1.

    Baseline characteristics of all treated patients (N = 33)

    Characteristicn or n/N (%)
    Age, y
     Median64
     Range50-82
    Male sex20 (61)
    ECOG performance status ≤132 (97)
    Rai stage III-IV9 (27)
    Bulky disease ≥5 cm10/32 (31)
    β2-microglobulin >3 mg/L21/27 (78)
    No. of prior therapies
     Median4
     Range2-13
    Ibrutinib as most recent prior therapy*30 (91)
    Duration of prior ibrutinib treatment, mo
     Median12
     Range1-62
    Time from ibrutinib end to acalabrutinib start, d
     Median47
     Range3-331
    Baseline cytopenias
     ANC ≤1.5 × 109/L4 (12)
     Hemoglobin ≤11.0 g/dL9 (27)
     Platelets ≤100 × 109/L13 (39)
    Genomic status
     del(11q)7/32 (22)
     del(17p)12/32 (38)
     del(13q)21/27 (78)
    TP53 mutation8/27 (30)
    NOTCH1 mutation2/27 (7)
    SF3B1 mutation4/27 (15)
     Unmutated IGHV25/31 (81)
    • ANC, absolute neutrophil count; ECOG, Eastern Cooperative Oncology Group.

    • * Other most recent prior therapies: venetoclax, n = 1; methylprednisolone with rituximab, n = 1; investigational drug (TG02), n = 1.

  • Table 2.

    AEs experienced during acalabrutinib treatment (≥15% any grade) for all treated patients (N = 33)

    AEn (%)
    Any gradeGrade 1Grade 2Grade 3Grade 4
    Diarrhea19 (58)15 (45)4 (12)00
    Headache13 (39)9 (27)4 (12)00
    Cough11 (33)6 (18)5 (15)00
    Weight increased10 (30)6 (18)3 (9)1 (3)0
    Nausea9 (27)6 (18)2 (6)1 (3)0
    Contusion8 (24)5 (15)3 (9)00
    Upper respiratory tract infection8 (24)2 (6)5 (15)1 (3)0
    Arthralgia7 (21)6 (18)1 (3)00
    Pyrexia7 (21)5 (15)1 (3)1 (3)0
    Vomiting7 (21)5 (15)2 (6)00
    Fatigue6 (18)3 (9)3 (9)00
    Myalgia6 (18)2 (6)3 (9)00
    Rash6 (18)5 (15)1 (3)00
    Constipation5 (15)4 (12)1 (3)00
    Dizziness5 (15)3 (9)2 (6)00
    Ecchymosis5 (15)4 (12)1 (3)00
    Fall5 (15)3 (9)2 (6)00
    Noncardiac chest pain5 (15)3 (9)1 (3)1 (3)0
  • Table 3.

    Investigator-assessed responses in treated patients (N = 33)

    Best responsen (%)
    CR (bone marrow confirmed)1 (3.0)
    PR19 (57.6)
    PRL5 (15.2)
    Stable disease6 (18.2)
    ORR (≥ PR)20 (60.6)
     95% CI*42.1-77.1
    ORR (≥ PRL)25 (75.8)
     95% CI*57.7-88.9
    • * 95% exact binomial confidence interval (CI).