Oral Arsenic Trioxide without Chemotherapy as Maintenance Therapy for Patients with Acute Promyelocytic Leukemia in First Complete Remssion

ORAL arsenic TRIOXIDE without chemotherapy as MAINTENANCE THErAPY for patients with Acute promyelocytic leukemia in first complete remssion

Wing-Yan Au, Sidney Tam, Anskar Y.H. Leung, Eric Tse, Cyrus Kumana, Yok-Lam Kwong. Departments of Medicine and Clinical Biochemistry, Queen Mary Hospital, Hong Kong

Background. Conventional maintenance therapy for acute promyelocytic leukemia (APL) in first complete remission (CR1) comprises all-trans retinoic acid (ATRA), mercaptopurine and methotrexate. Arsenic trioxide (As₂O₃) is used predominantly in relapsed cases. The efficacy and safety of earlier use of As₂O₃ in maintenance remain undefined. The availability of oral-As₂O₃ makes As₂O₃ maintenance practical.

Materials and methods. From 2001–2008, 49 patients (24 men, 25 women, median age: 44 (16–73) years) with APL in CR1 (achieved after induction with ATRA, daunorubicin and cytosine arabinoside, and consolidated with daunorubicin and cytosine arabinoside) were studied. The following 2-year oral-As₂O₃ maintenance regimens were used: oral- As₂O₃ (10 mg/day × 14 Tevery 2 months, n=20), oral-As₂O₃ + ATRA (22.5–45 mg/m²/day × 14 every 2 months, n=20), and oral-As₂O₃ + ATRA + ascorbic acid (1 gm/day × 14, every 2 months, n=9). As₂O₃ regimens were approved by the institutional review board at Queen Mary Hospital. All As₂O₃ maintenance regimens were orally administered at home.

Results. At diagnosis, the presenting leucocyte count was > 10 × 10⁹/L in 9 cases, and platelet count < 40 × 10⁹/L in 32 cases. At a median follow-up of 25 (2–87) months, there were 4 relapses (risk group: high, n=3; low, n=1; relapse site: bone marrow, n=4; central nervous system, CNS, n=2; maintenance protocol: As₂O₃, n=2, As₂O₃+ATRA, n=2). CR2 was achieved in all patients with further As₂O₃-based therapy, although 2 patients ultimately relapsed again and died of refractory leukemia. Of the 45 patients in continuous CR1, 3 patients had died of unrelated causes (stroke at 62 months, nasopharyngeal carcinoma at 24 months, carcinoma of colon at 86 months). Three other solid tumors (carcinoma of colon, n=2; salivary gland cancer, n=1) were diagnosed. Of the 5 solid tumors found in this cohort, only 1 was diagnosed after commencement of As₂O₃-maintenance. The 3-year leukemia-free-survival and overall-survival were 89% and 77%. There was no difference in survival between patients receiving different oral-As₂O₃ maintenance regimens, and stratified according to risk factors. Adverse effects of the oral-As₂O₃ maintenance included headache (n=18), gastric discomfort (n=7), herpes zoster reactivation (n=10), reversible liver function derangement (n=12), menorrhagia (n=3), and rash (n=8). Clinical arrhythmias were not observed. There were no defaults in treatment due to side effects.

Conclusion. Oral-As₂O₃ maintenance is a simple regimen that is well tolerated, entirely oral and administered at home. This regimen considerably reduces exposure to anthracyclines, topoisomerase II inhibitors and anti-metabolites as used in other protocols, which is potentially advantageous for a curable leukemia, in view of chemotherapyinduced long-term complications. Although >60% of our patients belonged to intermediate and high-risk groups, this regimen was comparable to other multi-chemotherapy regimens in maintaining remission.