Treatment of Relapsed Acute Promyelocytic Leukemia with Oral Arsenic Trioxide: An Eleven-Year Experience

Background. For patients with relapsed acute promyelocytic leukemia (APL), the optimal therapy after arsenic trioxide (As₂O₃)-induced complete remission (CR) is unclear. Autologous or allogeneic hematopoietic stem cell transplantation (HSCT) has been advocated. These strategies are associated with morbidity and considerable mortality, and not all patients are eligible. The role of maintenance therapy with As₂O₃ remains undefined.

Materials and methods. From 1997–2008, 50 consecutive APL patients (25 men, 25 women, median age: 35 (12–72) years) in relapse (R1, n=47; R2, n=3) were treated with As₂O₃ until CR. This was followed by idarubicin consolidation (6 mg/m²/day × 9) in 43 patients. Seventeen patients did not receive maintenance treatment. Thirty-two patients received oral-As₂O₃ maintenance (10 mg/day × 14 every 2 months). All-trans retinoic acid (ATRA, 45 mg/m²/day) maintenance was used together with oral-As₂O₃ in 27 patients. As₂O₃ protocol was approved by the institutional review board at Queen Mary Hospital. All maintenance treatment was given in the outpatient clinic as oral medication.

Results. Of 50 relapsed cases, As₂O₃-induced CR was achieved in 49 patients, 1 patient dying of pneumonia. At a median follow-up of 61 (6–122) months, 27 patients (19 with and 8 without As₂O₃ maintenance) had remained in remission. Further relapses (R2, n=20; R3, n=2.) occurred in 22 patients (13 with and 9 without As₂O₃ maintenance), at a median of 16 (6–28) months. Concomitant central nervous system (CNS) relapse occurred in 8 cases. Treatment of post-As₂O₃ relapses included oral-As₂O₃ (10 mg/day) + ATRA (45 mg/m²/day) with (n=10) or without (n=10) ascorbic acid (1 gm/day) until CR, and then maintenance with As₂O₃ + ATRA +/− ascorbic acid. Leucocytosis during treatment was controlled with mitoxantrone. In these 22 cases of post-As₂O₃ relapses, further remission was still achieved in 19 patients (CR3, n=18; CR4, n=1), with 3 patients dying from cerebral bleeding. At a median follow-up of 88 (8–98) months, 8 patients had remained in remission. Further relapses occurred in 11 patients. Salvage therapy consisted of As₂O₃+ATRA+ascorbic acid, together with chemotherapy (mitoxantrone, n=8; amascrine, n=3), gemtuzumab ozogamicin (n=4), and autologous HSCT (n=1). Eight patients finally died of refractory leukemia after a median of 6 (2–33) months. Three patients had remained in remission (CR4, n=2, CR5 n=1) at a median of 41 (26–102) months. On an intention-totreat basis, our oral-As₂O₃ treatment/maintenance regimen for patients with relapsed APL resulted in a 4-year overall survival of 71%, and event-free-survival of 53%.

Conclusion. Our findings showed that an oral-As₂O₃-based treatment/maintenance strategy resulted in durable remission in a significant proportion of patients with relapsed APL. As most of the treatment is administered at home, this regimen involves much less financial, personnel and emotional costs as compared with HSCT strategies. Further improvement should be directed towards prevention of CNS relapses with appropriate prophylaxis in high-risk patients. For remissions at or beyond CR3, consideration of HSC harvest and storage at molecular remission should be considered. The use of demethylation agents and histone deacetylase inhibitors in combination with As₂O₃ remains to be investigated.