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 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 × 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 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.