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Adding arsenic trioxide to standard therapy for acute promyelocytic leukemia improved overall and event-free survival in the phase III randomized North American Intergroup Protocol C9710 trial.
Estimated overall survival at 3 years was 86% for the experimental arm versus 79% for adults and 86% for children given standard treatment without arsenic trioxide (Trisenox), the lead investigator, Dr. Bayard L. Powell, reported in a plenary talk. The arsenic-based therapy was associated with acceptable toxicity, and benefits were observed in all risk groups.
"Arsenic trioxide is definitely established today in the first-line treatment of APL," Dr. Bob Lowenberg, professor of hematology and chair of the department of hematology at Erasmus University in Rotterdam, the Netherlands, responded in a subsequent discussion.
Arsenic trioxide is approved for second-line treatment of acute promyelocytic leukemia (APL).
While APL patients with white blood counts greater than 10,000/mcL at diagnosis had a higher rate of death during initial therapy, "arsenic trioxide does substantially reduce the relapse rate for this high-risk group," said Dr. Powell, professor and section head, hematology and oncology, Comprehensive Cancer Center, Wake Forest University, Winston-Salem, N.C.
After enrollment, 537 patients received initial induction therapy with oral tretinoin 45 mg/m² per day for 7 days plus cytarabine 200 mg/m² as a continuous infusion for 7 days, and daunorubicin 50 mg/m² for 4 days for those aged 3 years and older or 1.5 mg/m² as a continuous infusion for those less than 3 years of age.
The investigators then randomized 243 adults who had achieved complete or partial remission after induction therapy to two courses of arsenic trioxide 0.15 mg/kg per day. Patients received this course as a first consolidation therapy for 5 days each week for 5 weeks with a 2-week rest between cycles.
Subsequent consolidation therapy for all patients included two courses of oral tretinoin 45 mg/m² for 7 days plus 3 days of daunorubicin 50 mg/m² for patients 15 years and older (2 days for those younger than 15 years).
All patients still in remission after completing consolidation therapy were further randomized to 1 year of maintenance therapy with daily oral tretinoin repeated every other week alone or with 6-mercaptopurine 60 mg/m² daily plus methotrexate 20 mg/m² weekly.
In all, 243 adults were randomized to arsenic trioxide therapy. Randomized to standard therapy were 237 adults and 57 children less than 15 years of age. Based on white blood cell counts, 53 adults in the experimental arm were high risk, as were 58 adults and 14 children in the standard arm.
Remissions occurred in 90% of patients randomized to each arm; 7% died during induction, and 3% had insufficient data to determine response.
The Kaplan-Meier estimate for event-free survival at 3 years was better for patients randomized to arsenic trioxide than for adults randomized to standard therapy (81% vs. 66%) (P = .0007). The 3-year event-free survival for pediatric patients (62%) was not significantly different from that of adults who also received no arsenic trioxide.
Complete remission rates, death during induction, and relapse within 1 year were all similar between low- and intermediate-risk patients, but were inferior in high-risk patients.
Among the 243 patients randomized to arsenic trioxide, 16 died during induction, there were insufficient data for 7, and 2 did not achieve remission. Of the other 218 eligible for arsenic therapy, 202 received at least one course and 5 (2%) have relapsed.
Toxicity did not increase during consolidation therapy, nor were there lethal events. There were no grade 3-4 increases in the Q-T interval, which has been previously reported with arsenic trioxide.
In his discussion, Dr. Lowenberg suggested two potential implications of the C9710 trial. First, a dose reduction of anthracyclines used in traditional APL therapy might be possible without compromising outcomes, provided arsenic trioxide is introduced. Second, the addition of arsenic to full-dose optimal standard chemotherapy will allow for improved outcomes in high-risk patients.
Better ways are needed to exploit the therapeutic potential of arsenic, including method and time of application; integration into induction, consolidation, and/or maintenance therapy; whether a higher dose should be used; and how arsenic trioxide could serve patients such as the elderly in whom full-dose chemotherapy is contraindicated.
Powell B.L. et al. Effect of consolidation with arsenic trioxide (As2O3) on event-free survival (EFS) and overall survival (OS) among patients with newly diagnosed acute promyelocytic leukemia (APL): North American Intergroup Protocol C9710. Abstract 2.
Commentary |
Although acute promyelocytic leukemia accounts for only 10% of the cases of acute myeloid leukemia, it is often feared due to frequent complications, including life-threatening coagulopathy. Understanding of the critical role of the fusion protein PML-RARa in the pathophysiology of the disease and introduction of the differentiating agent all-trans retinoic acid (ATRA) into clinical practice almost 20 years ago revolutionized treatment. Over 70% of patients are now cured by the combination of cytotoxic therapy and ATRA. Arsenic trioxide is also a useful drug for APL patients in relapse. When it is used as a single agent in this setting, more than 80% of individuals achieve remission. Dr. Bayard Powell presented the results of the latest North American Intergroup study on APL. This randomized phase III study asked whether the addition of two courses of postremission arsenic trioxide reduced the relapse risk for previously untreated patients. The final results confirmed the benefit of arsenic trioxide when given along with standard therapy. Not only event-free but also overall survival was significantly prolonged in the group that received arsenic trioxide. The therapy was well tolerated, and benefited patients in all risk categories. This study should change clinical practice. All patients with previously untreated APL should receive arsenic trioxide as one part of their treatment course. Improvements are still needed for high-risk patients with an initial WBC count higher than 10,000. Subsequent Intergroup studies will specifically target this patient population, and will also test whether lower-risk patients can omit maintenance therapy entirely. — Steven E. Coutré, M.D.
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