Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710

Abstract

Arsenic trioxide (As 2 O 3 ) is a highly effective treatment for patients with relapsed acute promyelocytic leukemia (APL); its role as consolidation treatment for patients in first remission has not been defined. We randomized 481 patients (age > 15 years) with untreated APL to either a standard induction regimen of tretinoin, cytarabine, and daunorubicin, followed by 2 courses of consolidation therapy with tretinoin plus daunorubicin, or to the same induction and consolidation regimen plus two 25-day courses of As 2 O 3 consolidation immediately after induction. After consolidation, patients were randomly assigned to one year of maintenance therapy with either tretinoin alone or in combination with methotrexate and mercaptopurine. Ninety percent of patients on each arm achieved remission and were eligible to receive their assigned consolidation therapy. Event-free survival, the primary end point, was significantly better for patients assigned to receive As 2 O 3 consolidation, 80% compared with 63% at 3 years (stratified logrank test, P < .0001). Survival, a secondary end point, was better in the As 2 O 3 arm, 86% compared with 81% at 3 years (P ‫؍‬ .059). Disease-free survival, a secondary end point, was significantly better in the As 2 O 3 arm, 90% compared with 70% at 3 years (P < .0001). The addition of As 2 O 3 consolidation to standard induction and consolidation therapy significantly improves event-free and diseasefree survival in adults with newly diagnosed APL. This trial was registered at clinicaltrials.gov (NCT00003934).

How to manage acute promyelocytic leukemia

“…According to the recent data of this important trial (Leukemia Intergroup Study C9710), the addition of ATO is an important improvement to the treatment strategy since the 3-year EFS reached 80%, 76 which is consistent with our point of view that the treatment of APL should target both PML and RARa to fulfill a maximum efficacy. In this study, both of the two randomized groups were given the same induction therapy (ATRA, Ara-C and daunorubicin).…”

Acute myeloid leukemia—Major progress over four decades and glimpses into the future

“…Based on these experiences and the results of single agent anti-APL efficacies of ATRA and arsenic trioxide [59], investigators evaluated the addition of ATRA to chemotherapy during both induction and/or consolidation [60][61][62], the addition of arsenic trioxide during consolidation therapy [63], and the use of nonchemotherapy regimens including ATRA, arsenic trioxide, and GO. Comparative studies showed that the addition of ATRA to chemotherapy during induction and or consolidation improved survival [60][61][62], and that the addition of arsenic trioxide during consolidation in CR also improved survival.…”

Comparable outcomes between autologous and allogeneic transplant for adult acute myeloid leukemia in first CR

“…Unlike the other regimens, the APML4 trial does not use cytarabine during induction. In light of these new studies, the panel recommends initial induction with ATRA plus daunorubicin and cytarabine 81,83,84 ; ATRA plus idarubicin alone 85 ; ATRA plus idarubicin and ATO 100 ; or enrollment in a clinical trial. In addition, the panel recommends the administration of prophylactic corticosteroids (eg, dexamethasone) in patients with a WBC count greater than 10,000/mcL (or in patients receiving induction with both ATRA and ATO, regardless of WBC count) to prevent differentiation syndrome (see Supportive Care on page AML-C).…”

“…84 In this trial, patients who were randomized to receive 2 courses of 25 days of ATO (5 days a week for 5 weeks) immediately after entering CR and NCCN Guidelines Index AML Table of Contents Discussion…”

“…83 The second North American Intergroup trial also used ATRA (45 mg/m 2 ), daunorubicin (50 mg/m 2 per day for 4 days,) and cytarabine (200 mg/m 2 per day for 7 days) with a similar initial CR rate (90%). 84 Consolidation in this trial differed in that 2 cycles of a novel agent, arsenic trioxide (ATO) were given following induction and prior to the final 2 cycles of anthracycline.…”