Long-Term Outcome of All-Trans-Retinoic-Acid(ATRA)+Intensive Chemotherapy in Acute Promyelocytic Leukemia(APL),

ATRA has improved treatment of APL and particularly made remission induction therapy easier. However, there is no post-remission therapy that can surely cure APL. As ATRA alone is unlikely to cure the disease, a new combination therapy that uses ATRA and can attain a high rate of cure is needed. Objective: To cure APL by a combination of intensive remission induction therapy and post-remission therapy with ATRA. Also, to give supportive therapy under careful monitoring to avoid death due to chemotherapy. Subjects and Methods: Sixty-five consecutive patients with previously untreated APL who visited our hospital between January 2000 and January 2011 were treated. The t (15;17) or PML-RARA translocation was observed respectively in chromosome analysis and genotyping in all patients. The age range was 16 to 79 (median: 51). Nineteen were aged 60 or older. Thirty-four and thirty-one were men and women, respectively. Remission induction therapy was started with ATRA at 45 mg/m² (P.O.) immediately after diagnosis of APL. Idarubicin (IDR) at 10 mg/m² (Days 1, 3, 5, and 7) and behenoyl-ara-C (BH-AC) at 350 mg/m² (Days 1 through 7) were also administered. DIC was treated with continuous infusion of gabexate mesilate, platelet transfusion (to maintain a platelet count of ≥ 50,000/mm³), and frozen plasma transfusion (to maintain fibrinogen ≥ 100 mg/dL). The remission induction therapy was given in a sterile room. After completion of chemotherapy, macrophage colony-stimulating factor (M-CSF) was given for 10 days. Subsequently, granulocyte colony-stimulating factor (G-CSF) was administered until neutrophil recovery. After remission, the post-remission therapy commonly used in AML patients at our hospital (ASH, 2009, abstract, no. 1052) was given for 1 year. ATRA was given at 40 mg/body daily with chemotherapy. Patients received ATRA daily at the same dose for 3 years after completion of the post-remission therapy. The post-remission therapy involved high-dose-cytarabine (2 g/m² BID for 5 days but 1 g/m² × BID for 5 days for those aged 60 or older) combined with mitoxantrone (MIT) at 7 mg/m²/day for 3 days (HD-AC + MIT) given immediately after complete remission (CR). Subsequently, a combination of BH-AC at 350 mg/m² × 4 + aclarubicin at 20 mg/body × 6 and another combination of BH-AC at 350 mg/m² + IDR at 10 mg/m² × 1 were given repeatedly in an alternating manner (35 days each). M-CSF (for 7 days) was administered followed by G-CSF after completion of each chemotherapy combination. Each patient was transferred to a sterile room when the WBC count decreased below 1,000. Results: CR was achieved in 63/65(97%). Early deaths (ED) occurred in 2/65 (aged 74 and 79) due to interstitial pneumonia. The follow-ups of patients lasted from 3 to 142 months (median: 74 months). Three patients have experienced a relapse of APL, and relapse of hematological malignancy (myelodysplastic syndrome [MDS]) was seen in 5 patients. A chromosomal aberration not observed at first visit was found at relapse in all 5 patients who developed MDS. Six patients have died from relapsed APL (2), MDS (2), pneumonia following HD-AC + MIT (1), or liver cancer (1). For 63 patients who achieved CR, the overall survival (OS) calculated by the Kaplan-Meier method was 87% at 13 years. The disease-free survival (DFS) was 82% at 13 years. The OS and DFS for patients younger than 60 were respectively 93% and 80%. They were respectively 78% and 87% for patients aged 60 or older, showing no difference between the age groups. The DFS was 83% and 80% for patients treated with HDAC (52) and not treated with HDAC (11), respectively, showing little difference. When analyzed using the risk-based prognostic system of Sanz, et al., the OS was 70, 87, and 100% respectively for patients classified into the low (18), intermediate (27), and high risk (18) groups. The DFS was 72, 81, 94%, respectively. The analysis showed the best results for the high-risk group. Discussion: ATRA + intensive chemotherapy and long-term ATRA can attain a high rate of long-term survival (cure) for patients with APL regardless of age and risk group. Despite the use of intensive chemotherapy, only one patient died due to chemotherapy. This seems to be due to the selection of appropriate supportive therapy. Early diagnosis and bone marrow transplantation in patients with relapse (MDS) may further improve the rate of cure in patients with APL.

No relevant conflicts of interest to declare.