Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia. Morphologically, it is identified as the M3 subtype of acute myeloid leukemia by the French-American-British classification and cytogenetically is characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the fusion between promyelocytic leukemia (PML) gene and retinoic acid receptor ␣ (RAR␣). It seems that the disease is the most malignant form of acute leukemia with a severe bleeding tendency and a fatal course of only weeks. Chemotherapy (CT; daunorubicin, idarubicin and cytosine arabinoside) was the front-line treatment of APL with a complete remission (CR) rate of 75% to 80% in newly diagnosed patients. Despite all these progresses, the median duration of remission ranged from 11 to 25 months and only 35% to 45% of the patients could be cured by CT. Since the introduction of all-trans retinoic acid (ATRA) in the treatment and optimization of the ATRA-based regimens, the CR rate A historical view of acute promyelocytic leukemia (APL)Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML; Figure 1). Morphologically, it is identified as AML-M3 by the French-American-British (FAB) classification. Cytogenetically, APL is characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the fusion between the promyelocytic leukemia (PML) gene and retinoic acid receptor ␣ (RAR␣). Variant chromosomal translocations (eg, t(11;17), t(5;17)) can be detected in no more than 2% of APL patients. As a special entity, APL was first described in 1957 by a Swedish author, Hillestad, 1 when he reported 3 patients characterized by "a very rapid fatal course of only a few weeks'duration," with a white blood cell (WBC) picture dominated by promyelocytes and a severe bleeding tendency. He concluded that the disease "seems to be the most malignant form of acute leukemia." More detailed features of APL were described by Bernard et al 2 in 1959, and the severe hemorrhagic diathesis has been ascribed to disseminated intravascular coagulation (DIC) or hyperfibrinolysis.In 1973, Bernard et al 3 demonstrated that APL leukemic cells were relatively sensitive to chemotherapy (CT: daunorubicin) that yielded a complete remission (CR) rate of 19 (55%) in 34 patients with APL. From then on, CT composed of an anthracycline (daunorubicin, idarubicin, or others) and cytosine arabinoside (Ara-C) was the frontline treatment of APL, and the CR rates could reach 75% to 80% 4,5 in newly diagnosed patients. However, the frequently observed aggravation of bleeding syndrome by CT, leading to high early death rate, necessitated intensive platelet and fibrinogen support. Despite such progress, the median duration of remission ranged from 11 to 25 months and only 35% to 45% of the patients could be cured by CT alone as judged by the criterion of 5-year disease-free survival (5-year DFS). 6,39 In 1985, the introduction of all-trans retinoic acid (ATRA) opened a new...

The therapeutic effect of arsenic trioxide (As2O3 ) in the treatment of acute promyelocytic leukemia (APL) was evaluated among 15 APL patients at relapse after all-trans retinoic acid (ATRA) induced and chemotherapy maintained complete remission (CR). As2O3 was administered intravenously at the dose of 10 mg/d. Clinical CR was achieved in nine of 10 (90%) patients treated with As2O3 alone and in the remaining five patients treated by the combination of As2O3 and low-dose chemotherapeutic drugs or ATRA. During the treatment with As2O3 , there was no bone marrow depression and only limited side effects were encountered. Pharmacokinetic studies, which were performed in eight patients, showed that after a peak level of 5.54 μmol/L to 7.30 μmol/L, plasma arsenic was rapidly eliminated, and the continuous administration of As2O3 did not alter its pharmacokinetic behaviors. In addition, increased amounts of arsenic appeared in the urine, with a daily excretion accounting for approximately 1% to 8% of the total daily dose administered. Arsenic contents in hair and nail were increased, and the peak content of arsenic could reach 2.5 to 2.7 μg/g tissue at CR. On the other hand, a decline of the arsenic content in hair and nail was observed after withdrawal of the drug. We conclude that As2O3 treatment is an effective and relatively safe drug in APL patients refractory to ATRA and conventional chemotherapy.

Fifty-eight acute promyelocytic leukemia (APL) patients (11 newly diagnosed and 47 relapsed) were studied for arsenic trioxide (As2O3) treatment. Clinical complete remission (CR) was obtained in 8 of 11 (72.7%) newly diagnosed cases. However, As2O3 treatment resulted in hepatic toxicity in 7 cases including 2 deaths, in contrast to the mild liver dysfunction in one third of the relapsed patients. Forty of forty-seven (85.1%) relapsed patients achieved CR. Two of three nonresponders showed clonal evolution at relapse, with disappearance of t(15;17) and PML-RAR fusion gene in 1 and shift to a dominant AML-1-ETO population in another, suggesting a correlation between PML-RAR expression and therapeutic response. In a follow-up of 33 relapsed cases over 7 to 48 months, the estimated disease-free survival (DFS) rates for 1 and 2 years were 63.6% and 41.6%, respectively, and the actual median DFS was 17 months. Patients with white blood cell (WBC) count below 10 × 109/L at relapse had better survival than those with WBC count over 10 × 109/L (P = .038). The duration of As2O3-induced CR was related to postremission therapy, because there was only 2 of 11 relapses in patients treated with As2O3 combined with chemotherapy, compared with 12 of 18 relapses with As2O3 alone (P = .01). Reverse transcription polymerase chain reaction (RT-PCR) analysis in both newly diagnosed and relapsed groups showed long-term use of As2O3 could lead to a molecular remission in some patients. We thus recommend that ATRA be used as first choice for remission induction in newly diagnosed APL cases, whereas As2O3 can be either used as a rescue for relapsed cases or included into multidrug consolidation/maintenance clinical trials.