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Oral idasanutlin in patients with polycythemia vera

John Mascarenhas, Min Lu, Heidi Kosiorek, Elizabeth Virtgaym, Lijuan Xia, Lonette Sandy, Ruben Mesa, Bruce Petersen, Noushin Farnoud, Vesna Najfeld, Raajit Rampal, Amylou Dueck and Ronald Hoffman

Data supplements

Article Figures & Data

Figures

  • Figure 1.

    Baseline genomic alterations. The genomic profiles of 11 patients as determined by next-generation sequencing studies are shown. Each column represents an individual patient. Bars at the top indicate the number of alterations identified per patient. Mutated genes are listed on the right. Frequency of each mutation in these 11 patients is listed on the left. Type of alteration is denoted by key. Additionally, prior hydroxyurea (HU) exposure qualified by intolerance or resistance is shown below, and this is further coupled to the clinical, pathologic, and molecular response by ELN criteria for each patient. HR, histologic response; N/E, not evaluable; NR, no response.

  • Figure 2.

    Baseline MDM2 and day-5 plasma MIC-1 levels. (A) Baseline MDM2 levels were higher in patients with PV/ET compared with normal controls. The pretreatment MNC median MDM2 level was approximately fourfold higher in the PV/ET patients enrolled on the study compared with normal controls. (B) Plasma MIC-1 levels are increased on day 5 of idasanutlin therapy. p53 pathway activation is reflected by a 4.8-fold increase from baseline of MIC-1 protein levels by day 5 (P = .004).

  • Figure 3.

    Maximum TSS response on study. Nine patients treated with idasanutlin attained at least a 50% reduction in TSS. The cycle in which the best percentage reduction was first noted is shown in association with each patient response. NE, not evaluable; NR, no response.

  • Figure 4.

    JAK2 driver mutation response with idasanutlin therapy. The waterfall plots demonstrate the spectrum of molecular responses observed with idasanutlin therapy, and the cycle in which the maximal reduction in VAF was first noted is shown in association with the response bar. NE, not evaluable; NR, no response.

Tables

  • Table 1.

    Patient demographics and clinical variables by dose level

    100 mg (n = 6)150 mg (n = 6)Total (N = 12)
    Median age (range), y62 (32-83)63 (48-68)63.5 (32-83)
    Diagnosis, n (%)
     ET1 (16.7)0 (0.0)1 (8.3)
     PV5 (83.3)6 (100.0)11 (91.6)
    Female sex, n (%)5 (83.3)2 (33.3)7 (58.3)
    Median disease duration (range), mo41.6 (14.9-80.1)65.4 (21.0-154.3)43.9 (14.9-154.3)
    Previous thrombosis, n (%)3 (50.0)0 (0.0)3 (25.0)
    Prior hydroxyurea therapy, n (%)5 (83.3)5 (83.3)10 (83.3)
    Median spleen length by palpation (range), cm1.0 (1.0-7.0)2.5 (0.0-18.0)1.0 (0.0-18.0)
    Median leukocytes (range), ×109/L10.3 (4.9-15.9)12.2 (7.4-28.3)11.3 (4.9-28.3)
    Median hemoglobin (range), g/dL13.4 (12.8-15.6)13.7 (12.3-14.7)13.6 (12.3-15.6)
    Median hematocrit (range), %41.5 (38.3-46.7)43.0 (40.7-47.8)42.3 (38.3-47.8)
    Median platelets (range), ×109/L443.5 (118.0-1339.0)412.0 (153.0-700.0)443.5 (118.0-1339.0)
    Median LDH (range), U/L*252.0 (184.0-370.0)252.0 (177.0-616.0)252.0 (177.0-616.0)
    Median JAK2 V617F VAF (range), %23.7 (5.3-69.3)63.7 (6.3-88.6)40.6 (5.3-88.6)
    • * LDH, lactate dehydrogenase. Upper limit of normal for LDH is 220 U/L.

  • Table 2.

    Treatment information by dose level of idasanutlin

    100 mg (n = 6)150 mg (n = 6)Total (N = 12)
    Median n of cycles (range)9 (7-14)13.0 (5-20)10.5 (5-20)
    Median duration on study (range), wk36.7 (29.0-131.1)77.6 (23.1-105.0)54.2 (23.1-131.1)
    DLT, n*000
    N of patients with treatment holiday, n of cycles
     1011
     2-3134
     >311
    N of patients continuing on part A (cycle 7+)347
    N of patients eligible for and receiving treatment on part B314
    Pegylated IFN-α2a (part B)(n = 3)(n = 1)(n = 4)
     Median n of cycles (range)2.5 (2-3)153 (2-15)
    Reason for discontinuation of treatment
     Patient refusal224
     Investigator decision213
    • * DLT defined as nonhematologic AE of grade 3+ or hematologic AE of grade 2+ thrombocytopenia or grade 3+ neutropenia or anemia during cycle 1 and evaluated for 56 d.

  • Table 3.

    Treatment-emergent AEs occurring in at least 2 patients regardless of attribution

    n (%)
    100 mg (n = 6)150 mg (n = 6)Total (N = 12)
    Grade 1/2Grade 3Grade 1/2Grade 3All grades
    Diarrhea5 (83.3)1 (16.7)5 (83.3)11 (91.7)
    Fatigue4 (66.7)2 (33.3)3 (50.0)1 (16.7)10 (83.3)
    Constipation6 (100)4 (66.7)10 (83.3)
    Nausea5 (83.3)5 (83.3)10 (83.3)
    Headache4 (66.7)1 (16.7)2 (33.3)7 (50)
    Abdominal pain4 (66.7)2 (33.3)6 (50)
    Upper respiratory tract infection1 (16.7)4 (66.7)5 (41.7)
    Dry skin2 (33.3)2 (33.3)4 (33.3)
    Pain2 (33.3)1 (16.7)1 (16.7)4 (33.3)
    Pruritus2 (33.3)2 (33.3)4 (33.3)
    Vomiting3 (50.0)1 (16.7)4 (33.3)
    Arthralgia3 (50)3 (25)
    Dizziness3 (50)3 (25)
    Cough2 (33.3)1 (16.7)3 (25.0)
    Decreased appetite2 (33.3)1 (16.7)3 (25.0)
    Dyspepsia2 (33.3)1 (16.7)3 (25.0)
    Flushing2 (33.3)1 (16.7)3 (25.0)
    Oropharyngeal pain1 (16.7)2 (33.3)3 (25.0)
    Dysgeusia1 (16.7)2 (33.3)3 (25.0)
    Dyspepsia2 (33.3)1 (16.7)3 (25.0)
    Epistaxis1 (16.7)1 (16.7)2 (16.7)
    Weight gain1 (16.7)1 (16.7)2 (16.7)
    Alopecia1 (16.7)1 (16.7)2 (16.7)
    Anorexia1 (16.7)1 (16.7)2 (16.7)
    Back pain1 (16.7)1 (16.7)2 (16.7)
    Chest pain2 (33.3)2 (16.7)
    Disorientation2 (33.3)2 (16.7)
    Eye infection1 (16.7)1 (16.7)2 (16.7)
    Flatulence1 (16.7)1 (16.7)2 (16.7)
    GERD1 (16.7)1 (16.7)2 (16.7)
    Heartburn1 (16.7)1 (16.7)2 (16.7)
    Rash2 (33.3)2 (16.7)
    Sinusitis2 (16.7)2 (16.7)
    • GERD, gastroesophageal reflux disease.

  • Table 4.

    Response outcomes for parts A and B

    NENRPRCROverall response (PR + CR), n (%)
    Part A (n = 12)1*4347 (58)
    Part B (n = 4)2112 (50)
    Part A + B ORR9 (75)
     95% CI, %42.8-94.5
    • NE, not evaluable; NR, no response.

    • * NE due to patient decision to withdraw from study after 4 cycles because of gastrointestinal toxicity.

    • Four patients from part A who had NR entered part B combination idasanutlin + IFN-α.

    • Residual splenomegaly likely resulting from known portal vein thrombosis in 1 patient, likely a CR (n = 1).