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Use of Arsenic Trioxide (As2O3 ) in the Treatment of Acute Promyelocytic Leukemia (APL): II. Clinical Efficacy and Pharmacokinetics in Relapsed Patients

Zhi-Xiang Shen, Guo-Qiang Chen, Jian-Hua Ni, Xiu-Shong Li, Shu-Min Xiong, Qian-Yao Qiu, Jun Zhu, Wei Tang, Guan-Lin Sun, Kan-Qi Yang, Yu Chen, Li Zhou, Zhi-Wen Fang, Yan-Ting Wang, Jun Ma, Peng Zhang, Ting-Dong Zhang, Sai-Juan Chen, Zhu Chen and Zhen-Yi Wang

Article Figures & Data

Figures

  • Fig. 1.

    Overall survival (top) and disease-free survival (bottom) curves of 14 relapsed APL patients after As2O3-induced CR.

  • Fig. 2.

    Dynamic changes of peripheral WBC counts during As2O3 treatment in five patients presenting hyperleukocytosis.

  • Fig. 3.

    Plasma pharmacokinetic curves after one dose (10 mg) of As2O3 in relapsed APL patients. (A) The mean plasma arsenic concentration time curve for eight patients. Bar, SD. (B) Pharmacokinetic curves obtained on day 1 and day 30 of As2O3 remission induction in patient no. 6. (C) Pharmacokinetic curves determined on day 1 of remission induction and day 1 of consolidation therapy in patient no. 13.

  • Fig. 4.

    Contents of As2O3 excreted every 24 hours in the urine among six patients. Arrows point out the time when drug was withdrawn. The sign “*” marks the time when consolidation therapy was begun.

  • Fig 5. Dynamic changes of As2O3 contents in hair (A) and nail (B) after As2O3 remission induction and/or consolidation treatment in APL patients. The number at the end of each curve indicates the patient case number. Solid lines represent the time when patients were under As2O3 treatment; dotted lines correspond to the days when drug was not used.

Tables

  • Table 1.

    Patients' Clinical Data at Diagnosis

    Patient No.Sex/AgeHBWBC (×109/L)Platelet (×1012/L)APL Cell % in BMt(15; 17)/PML-RARαPrevious Treatment Protocol
    (g/L)CR-InductionConsolidation
    1F/40107.00.98.439.5+/NDATRA (40 mg × 30 d)HA + DA
    2M/34138.03.38.696.0+/L(+)ATRA (40 mg × 22 d)HA + DA + AA
    3M/4184.00.852.019.5+/L(+)ATRA (30 mg × 51 d)HA + AA
    4M/4376.03.456.932.0+/L(+)ATRA (40 mg × 30 d)HA + AA
    5M/34126.01.57.770.0+/L(+)ATRA (60 mg × 30 d)AA
    6F/15108.051.04.095.0+/L(+)ATRA (30 mg × 30 d)DA
    7M/5375.04.05.085.0−/L(−)S(−)ATRA (80 mg × 70 d)HA + ATRA
    8F/1575.03.876.072.0ND/L(+)ATRA (15 mg × 30 d)DA + ATRA
    9M/32112.09.84.859.0NDATRA (60 mg × 47 d)DA
    10M/14127.03.123.690.0NDATRA (30 mg × 30 d)HA
    11F/2764.015.248.081.5+/S(+)ATRA (80 mg × 30 d)HA
    ATRA (60 mg × 30 d)* HA + AA + DA
    12M/42115.04.013.612.5ND/L(+)BHAC-DMPMTX + Ara-c
    BHAC-DMP* MTX + Ara-c
    ATRA (70 mg × 24 d) BHAC-DMP
    13F/53122.04.610.844.0+/L(+)ATRA (80 mg × 48 d)DA + HA
    ATRA (40 mg × 68 d)* DA
    14M/4965.00.64.071.0NDBHAC-DMPMTX + Ara-c
    BHAC-DMP* MTX + Ara-c
    ATRA (70 mg × 24 d) BHAC-DMP
    15M/45105.067.54.272.0+/L(+)ATRA (30 mg × 50 d)DA + HA
    • Patients No. 11 and 13 were diagnosed at second relapse; patients No. 12 and 15 were diagnosed at third relapse; all other cases were at first relapse. For PML-RARα, L and S denote the long and short type isoforms of the fusion mRNA, respectively.12

    • Abbreviations: ND, not done; DA, Daunorubicin + Ara-C; HA, Harringtonin + Ara-C; AA, Aclamycin + Ara-C; BHAC-DMP, Benenoyl-Ara-C + daunomycin + 6-MP + Prednisone.

    • * Protocol used for the second CR.

    • Protocol used for the third CR.

  • Table 2.

    Remission Induction With As2O3

    Patient No.Treatment ResultsTotal Doses of As2O3 UsedDays to Achieve CRAdditional Treatment
    1CR28028
    2CR41041
    3CR28028
    4CR28028
    5CR28028
    6CR30030
    7NR540
    8CR38038
    9CR44044
    10CR28028
    11CR28028Daunorubicin (40 mg/d × 3 d) + Ara-C (150 mg/d × 5 d)
    12CR39039ATRA 30 mg/d, from day 11 to CR
    13CR53053Hydroxyurea (3 g/d × 15 d)
    14CR42042ATRA 30 mg/d, from day 3
    to CR
    15CR54054Harringtonine (4 mg × 25 d) + Ara-C (200 mg/d × 9 d)
    • Abbreviation: NR, no remission.

  • Table 3.

    Main Side Effects With As2O3 Treatment

    Side EffectsFrequency (%)
    Skin dryness, itching, or erythematous changes26.7 (4/15)
    Headache6.7 (1/15)
    EKG change
    (1) low-flat T-wave6.7 (1/15)
    (2) sinal tachycardia and I0 A-V inductive block6.7 (1/15)
    Nausea, vomiting, or loss of appetite accompanied with lassitude26.7 (4/15)
    Liver function*
    GPT increased6.7 (1/15)
    GOT increased13.3 (2/15)
    AKP increased13.3 (2/15)
    γ-GTP increased6.7 (1/15)
    Total bilirubin increased6.7 (1/15)
    Enlargement of salivary gland 6.7 (1/15)
    Thyrophyma without thyroidism†‡ 6.7 (1/15)
    Arthralgia or musculogia13.3 (2/15)
    Teeth ache13.3 (2/15)
    Oral ulcer6.7 (1/15)
    Hemorrhage of teeth, nose, or skin13.3 (2/15)
    • These signs were observed in *the same two patients, †the same patient, and ‡during consolidation.

  • Table 4.

    Pharmacokinetic Parameters After Intravenous Drip of As2O3 in Relapsed APL Patients

    Patient No.Cpmax (μmol/L)t1/2αt1/2βVc (L)CL(s) (L/h)AUC (μmol/h/L)
    (h)(h)
    66.010.556.383.831.3836.20
    64-150 6.281.0513.614.331.2938.70
    88.181.0116.662.931.3443.95
    84-151 6.220.8711.263.821.4035.70
    97.700.4912.363.441.2739.55
    94-150 6.080.828.023.811.7029.40
    106.621.1511.654.101.5332.60
    104-150 6.221.0010.034.311.4934.30
    116.820.6210.463.981.4334.85
    125.540.9311.174.301.8127.60
    136.621.1616.524.151.3337.55
    134-151 6.891.429.564.941.4434.75
    157.301.2111.863.891.3337.70
    • F4-150 On day 30 of remission induction.

    • F4-151 On day 1 of consolidation treatment.