Oral Arsenic Trioxide in the Frontline Treatment of Newly-Diagnosed Acute Promyelocytic Leukemia: A 5-Year Prospective Cohort Study

Abstract

Introduction and objectivesIntravenous arsenic trioxide (As2O3) has been tested in the frontline treatment of newly-diagnosed acute promyelocytic leukemia (APL). We have formulated an oral preparation of As2O3 (oral-As2O3), and shown that it is efficacious for APL in when used in maintenance and re-induction protocol. In this study, we evaluated the use of oral-As2O3 in the frontline treatment of APL. The main objective of the study was to define the impact of upfront use of oral-As2O3 in newly-diagnosed patients.MethodsPatients. Patients with newly-diagnosed APL in eight regional hospitals in Hong Kong were identified.Arsenic-induction cohort. Induction comprised oral-As2O3 (10 mg/day, reduced to 5 mg/day in patients with serum creatinine >upper reference value; as 1 mg/ml solution), ATRA (45 mg/m2/day in 2 divided doses) and ascorbic acid (1 g/day) (AAA regimen), administered for six weeks. Three days of daunorubicin (50 mg/m2/day) were administered to patients aged <70 years, and omitted for those aged ≥70 years. For patients not receiving daunorubicin, if the white blood cell count (WBC) rose to >5 x 109/L, hydroxyurea (2-3 g/day) was used for cytoreduction.Consolidation regimen. On confirmation of CR1, two monthly consolidations comprising daunorubicin (50 mg/m2/day x 2) and cytarabine (100 mg/m2/day x 5) were administered to patients aged <70 years. For patients aged ≥70 years, consolidation with two monthly cycles of AAA (2 weeks/cycle) was instead administered. Bone marrow examination was performed two weeks after completion of consolidation.Maintenance regimen. All patients received maintenance AAA, given two weeks every eight weeks for two years.ResultsIn a 5-year period (January 1, 2013-March 31, 2018), there were 104 consecutive cases of newly-diagnosed APL. Five patients died at presentation due to disease complications.Arsenic-induction cohort. 62 newly-diagnosed patients (24 men, 38 women) at a median age of 52 (22-85) years, 36% having high-risk features, consented to and received oral-As2O3 induction. Complete remission (CR) rate was 100%. After a median of 29 (5-69) months, there were no relapses, so that conventional risks (age, leucocyte and platelet counts, FLT3 mutations) were not relevant. The leukemia-free survival (LFS) and overall survival (OS) at 3 years were both 100%. There was no leukemia- or treatment-related mortality. The most common non-hematologic AE was hepatotoxicity, presenting as transaminitis in all cases (grade 1/2, N=19, 30.6%; grade 3/4, N=16, 25.8%). Hyperbilirubinemia did not occur. In the sixteen cases with grade 3/4 transaminitis, oral-As2O3 was temporarily withheld for a median of 2 (1-5) days. With improvement in transaminases, oral-As2O3 was successfully re-administered without recurrence of transaminitis. Three patients developed QTc prolongation to a median maximum of 490 (480-496) ms. It was transient and self-limiting without need for oral-As2O3 dose interruption. Arrhythmias and heart failure were not observed. Headache, nausea and vomiting were other minor and less common AEs, which responded to symptomatic treatment.Non-arsenic-induction cohort. A contemporaneous cohort of 37 newly-diagnosed patients (15 men, 22 women; median age: 51, 23-78 years), 46% having high-risk features, did not consent to oral-As2O3 induction, and received similar induction (without oral-As2O3) and consolidation. CR rate was 100%. Most of them (89%) then received oral-As2O3 maintenance. After a median of 44 (6-69) months, there were three relapses (8%), all achieving remission again with oral-As2O3-containing salvage regimens.Arsenic induction versus non-arsenic induction. To define the role of oral-As2O3 during induction, we selected patients from the arsenic-induction cohort, who received daunorubicin induction, daunorubicin/cytarabine consolidation and AAA maintenance (N=50), and compared them with patients from the non-arsenic-induction cohort, who received the same induction, consolidation and AAA maintenance (N=32). The 5-year OS was comparable (arsenic-induction subgroup, 100% versus non-arsenic-induction subgroup, 96.8%; P=0.25). However, the 5-year LFS of the arsenic-induction subgroup was significantly superior to that of the non-arsenic-induction subgroup (100% versus 89.7%, P=0.04).ConclusionIn conclusion, oral-As2O3 induction for newly-diagnosed APL was safe and reduced relapses. DisclosuresNo relevant conflicts of interest to declare.