Chemotherapy-free Regimen Successful in Acute Promyelocytic Leukemia 

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For the first time, a chemotherapy-free regimen was superior to conventional cytotoxic chemotherapy for the treatment of acute promyelocytic leukemia (APL). The combination of all-trans retinoic acid (ATRA) plus arsenic trioxide (Trisenox) achieved significantly superior overall survival compared to ATRA plus chemotherapy: 98.7% vs 91.1%, respectively. Patients who received ATRA plus arsenic trioxide had a 2-year event-free survival of 97% vs 86.7% for those who received ATRA plus chemotherapy (idarubicin followed by anthracycline-based consolidation and maintenance therapy).

New Strategy

“APL is a rare but aggressive subtype of acute myeloid leukemia (AML). Recent research suggests that malignant cells can be transformed rather than killed, and this means that acute leukemia may be curable without chemotherapy,” stated Francesco Lo-Coco, MD, Chair of the APL subcommittee of the Italian GIMEMA group and Professor of Hematology at University Tor Vergata, Rome, Italy.

 “Our results are an important step toward the further utilization of targeted therapies for other types of leukemia, as we begin to focus on improving the overall treatment experience for patients by offering new strategies that deliver the same efficacy as traditional options with considerably less toxicity,” he stated.

Intergroup Study

APL 0406 was an intergroup study conducted by GIMEMA (Gruppo Italiano Malattie EMatologiche dell’Adulto), SAL (Study Alliance Leukemia Group), and AMSLG (German-Austrian AML Study Group), designed as a noninferiority trial to compare arsenic trioxide plus ATRA vs ATRA plus chemotherapy (the standard of care at the time the trial was initiated). APL 0406 randomly assigned 162 patients with standard-risk APL in a 1:1 ratio to both arms.

“This was the first randomized controlled trial to compare these two regimens in APL,” Dr. Lo-Coco noted.

Patients in the ATRA/arsenic trioxide group received both drugs daily until complete remission was achieved; then arsenic trioxide 5 days per week, 4 weeks on/4 weeks off, for a total of 4 courses and ATRA 2 weeks on/2 weeks off for a total of 7 courses, for a total duration of 28 weeks. Standard treatment was ATRA/idarubicin as induction, followed by three cycles of ATRA/anthracycline and ATRA/mitoxantrone consolidation therapy, followed by ATRA plus low-dose chemotherapy maintenance therapy for 2 years.

Complete remission was achieved in 100% of the ATRA/arsenic trioxide arm vs 95% of the ATRA/chemotherapy arm. Two-year event-free survival was achieved in 97% in the ATRA/arsenic trioxide arm (with one death and two relapses) vs 86.7% in the ATRA/chemotherapy arm (seven deaths and four relapses). Disease-free survival rates were 97% and 90%, respectively. Cumulative incidence of relapse rates were 1.4% vs 5.6%, respectively.

Fewer side effects, including significantly less fever, neutropenia, and thrombocytopenia (P < .001 for all three effects), were reported in the chemotherapy-free arm, Dr. Lo-Coco said.

Continuous Progress

“There has been continuous progress in treating APL. In the early 1990s, ATRA was found to be highly effective when combined with chemotherapy, making it the standard of care for APL. In 1996, response to arsenic trioxide was seen, creating the potential for a regimen that would avoid the toxicity of chemotherapy-based regimens. Now the chemotherapy-free combination of ATRA plus arsenic trioxide has been shown to improve outcomes even further,” he commented.

“APL is still a fulminant disease that needs to be promptly diagnosed and treated; otherwise patients will die within hours or days,” he stated. “This represents success in transforming malignant cells into ‘good guys’ through ATRA, to become terminally differentiated cells that die. It represents the demolition of dogma, with a remarkable cure rate with ATRA plus arsenic trioxide.”

‘Huge’ Step Forward in APL

Commenting on this study, press conference moderator William G. Woods, MD, Pediatric Hematology/Oncology Director and the Daniel P. Amos Children’s Chair, Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, said, “This is the first curative treatment for APL that does not include myelosuppressive chemotherapy. This is a huge step forward in the front-line treatment of APL.” ■

Disclosure: Dr. Lo-Coco is a member of the advisory committee for Boehringer Ingelheim, and a member of the speakers bureau for Cephalon. Dr. Woods reported no potential conflicts of interest.


1. Lo-Coco F, Avvisati G, Orlando SM, et al: ATRA and arsenic trioxide (ATO) versus ATRA and idarubicin (AIDA) for newly diagnosed, non-high risk acute promyelocytic leukemia (APL): Results of the phase III, prospective, randomized, intergroup APL0406 study led by the Italian-German cooperative groups GIMEMA-SAL-AMLSG. 2012 ASH Annual Meeting. Abstract 6. Presented December 9, 2012.

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