All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4)

Abstract

The treatment of acute promyelocytic leukemia has improved considerably after recognition of the effectiveness of alltrans-retinoic acid (ATRA), anthracyclinebased chemotherapy, and arsenic trioxide (ATO). Here we report the use of all 3 agents in combination in an APML4 phase 2 protocol. For induction, ATO was superimposed on an ATRA and idarubicin backbone, with scheduling designed to exploit antileukemic synergy while minimizing cardiotoxicity and the severity of differentiation syndrome. Consolidation comprised 2 cycles of ATRA and ATO without chemotherapy, followed by 2 years of maintenance with ATRA, oral methotrexate, and 6-mercaptopurine. Of 124 evaluable patients, there were 4 (3.2%) early deaths, 118 (95%) hematologic complete remissions, and all 112 patients who commenced consolidation attained molecular complete remission. The 2-year rate for freedom from relapse is 97.5%, failure-free survival 88.1%, and overall survival 93.2%. These outcomes were not influenced by FLT3 mutation status, whereas failure-free survival was correlated with Sanz risk stratification

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

“…In the recent phase II APML4 study from Australia/New Zealand, 2 cycles of ATO and ATRA were used as consolidation in patients who achieved a CR after a 3-drug induction with ATRA, idarubicin, and ATO. 99 Among the patients who proceeded to consolidation (n = 112), all achieved molecular remission, and the 2-year DFS rate was 97.5%. The 2-year OS rate in all evaluable patients in this study (N = 124) was 93%.…”

“…All patients received prednisone (1 mg/kg/day for at least 10 days) regardless of initial WBC count as prophylaxis for differentiation syndrome. 99 The most common grade 3 or 4 nonhematologic adverse events during induction included infections (76%; including febrile neutropenia), hepatic toxicity (44%), gastrointestinal toxicity (28%), metabolic abnormalities (16%), and prolonged QTc interval (14%); grade 3 or 4 differentiation syndrome occurred in 14% of patients. Patients with a CR to induction received consolidation with 2 cycles of ATRA and ATO.…”

“…Maintenance therapy was administered for 2 years and consisted of eight 3-month cycles of treatment with ATRA, oral methotrexate, and 6-mercaptopurine. 99 Grade 3 or 4 adverse NCCN Guidelines Index AML In a recent phase III randomized trial of the Italian-German Cooperative Group, induction with ATRA combined with ATO was compared with the AIDA regimen in patients with newly diagnosed, low-or intermediate-risk APL (N = 162; APL0406 study). 100 Patients in Arm A received ATRA (45 mg/m 2 ) plus ATO (0.15 mg/kg) daily until CR, then ATO 5 days per week for 4 weeks every 8 weeks for a total of 4 courses, and ATRA daily for 2 weeks every 4 weeks for a total of 7 courses.…”

“…99 Patients received 1 cycle of induction therapy with ATRA (45 mg/m 2 days 1-36 in divided doses), age-adjusted idarubicin (6-12 mg/m 2 days 2, 4, 6, and 8), and ATO (0.15 mg/kg days 9-36 as a 2-hour IV infusion). All patients received prednisone (1 mg/kg/day for at least 10 days) regardless of initial WBC count as prophylaxis for differentiation syndrome.…”

Primed for the kill: occupying Bcl-2 to target death in acute myeloid leukaemia

“…The situation is far worse for elderly patients, who are largely palliated because of the unfavourable risk-benefit ratio associated with intensive chemotherapy in older populations. Therapies tailored to specific sub-groups of AML have been remarkably effective, such as all-trans retinoic acid and arsenic for acute promyelocytic leukaemia, which have emerged as frontline therapies for this disease [2]. Other attempts to "target" AML, such as with FLT3 inhibitors have been less successful, especially in the setting of chemotherapy failure [3].…”