Oral arsenic trioxide in the treatment of relapsed acute promyelocytic leukemia.

Oral potassium arsenite used to be an important antileukemic agent1 until the 1950s, when it was surpassed by modern chemotherapeutic drugs. The use of arsenic resurged when its high efficacy was shown in acute promyelocytic leukemia (APL).2,3 However, to date, only intravenous As2O3 has been used. We have recently redeveloped an oral preparation of As2O3, which achieved total blood cell and plasma levels of elemental arsenic comparable with those of intravenous As2O3. Treated with oral As2O3 were 12 consecutive unselected patients with relapsed APL (Table 1). The relapse was confirmed morphologically ( 30% blasts abnormal promyelocytes in the marrow) and cytogenetically (presence of t(15;17), with none of the cases showing additional karyotyic aberrations) or molecularly (presence of PML/RARA). The treatment was given with informed consent, and the protocol was approved by the institutional review board of the University of Hong Kong. All patients had a pretreatment Karnofsky score higher than 80%. Routine monitoring included alternate daily blood counts and renal/liver function tests (LFTs), and electrocardiography (ECG) daily in the initial week, then weekly. There were 8 patients in first relapse (R1) treated with oral As2O3 (10 mg/d) until complete remission (CR; 5% of abnormal promyelocytes blasts in the marrow), followed by consolidation with idarubicin (6 mg/m2/d, 5 days in the first month, then 2 days per month for 2 months).5 Cases 1, 2, 3, 5, and 7 received one day of intravenous As2O3 as part of the initial pharmacokinetic study.4 All patients achieved CR2 with oral As2O3, given for a median of 37 days (range, 22-59 days). At a median follow-up of 14 months (range, 6-18 months), 7 patients were in continuous CR2. In R2, 5 patients (including case 1, who relapsed after CR2) were treated with a combination of oral As2O3 (10 mg/d) and all-trans retinoic acid (ATRA; 45 mg/m2/d) until remission,6 followed by 6 consolidation courses with As2O3 and ATRA (As2O3: 10 mg/d; ATRA: 45 mg/m2/d, for 2 weeks every 2 months). With oral As2O3/ATRA given for a median of 31 days (range, 28-37 days), 4 patients achieved CR3. At a median follow-up of 17 months (range, 14-19 months), all had remained in CR3. Patient 1 died of cerebral hemorrhage 76 days after treatment, without achieving CR3. PML/RARA remained positive in all patients after As2O3induced CR. However, PML/RARA became negative in 11 cases 3 to 6 months after remission, and remained negative until the latest bone marrow examination. Polymerase chain reaction (PCR) in patient 1 became positive shortly before R2. Of the patients, 4 (cases 1, 4, 10, and 12) developed leucocytosis (median, 74 109/L [range, 62-120 109/L]) requiring idarubicin (6 mg/m2/d 5, given when white cell count 15 109/L) for control. However, symptomatology similar to the ATRA syndrome7 was not observed. Impairment of LFTs occurred in 5 patients, peaking at a median of 11 days (range, 5-21 days). LFTs