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Blood, 1 July 2003, Vol. 102, No. 1, pp. 407-408 To the editor:Oral arsenic trioxide in the treatment of relapsed acute promyelocytic leukemiaOral potassium arsenite used to be an important antileukemic agent1 until the 1950s, when it was surpassed by modern chemo-therapeutic 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 As2O3,4 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 As2O3-induced 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 x 109/L [range, 62-120 x 109/L]) requiring idarubicin (6 mg/m2/d x 5, given when white cell count > 15 x 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 normalized after temporary cessation of treatment, and further oral As2O3 therapy was not compromised. Mild skin rashes (grade I) developed in 5 patients and subsided with symptomatic treatment. Headache developed in 2 patients on oral As2O3/ATRA, and subsided when the dose of ATRA was split. None of our patients showed ECG abnormalities of the types previously reported.8 Our preliminary results in this pilot study showed that oral As2O3 was highly active in relapsed APL, with an efficacy comparable with intravenous As2O3.9 The side effects, including the frequency and severity of leucocytosis, LFT derangement, and skin rashes, were also comparable with intravenous As2O3.2,3 Cardiac arrhythmias were not found, which was similar to a previous study of intravenous As2O3 in Chinese patients, where arrhythmia was seen in only 1 of 58 patients.2 It is important to note that only 4 patients received oral As2O3 as a single agent for CR induction, with the rest having received ATRA or idarubicin before CR was reached. With this limitation, our results showed that oral As2O3 had a short-term efficacy and safety profile similar to intravenous As2O3. A recent study also showed that oral tetra-arsenic tetrasulfide was highly efficacious in APL.10 However, the long-term efficacy and safety of oral As2O3 compared with intravenous As2O3 will require longer follow-up. Finally, although oral or intravenous As2O3 and hematopoietic stem cell transplantation are effective treatment modalities for patients with relapsed APL, their relative merits are undefined, and further randomized trials will be needed to address this issue.
Correspondence: Y.-L. Kwong, University Department of Medicine, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong; e-mail: ylkwong{at}hkucc.hku.hk
The University of Hong Kong has filed a temporary patent for the use of oral arsenic trioxide in the treatment of acute promyelocytic leukemia.
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