Photo by Bill Branson
Child with leukemia
Consolidation therapy that includes arsenic trioxide (ATO) can decrease anthracycline dosing by about 40% in children and young adults with acute promyelocytic leukemia (APL), according to new research.
And it can accomplish this without compromising survival in standard-risk patients.
Outcomes for high-risk patients compared favorably to other pediatric APL trials, the research indicated.
Investigators compared ATO consolidation in the AAML0631 trial to the historic control trial AIDA0493 and reported the results in the Journal of Clinical Oncology.
The AAML0631 phase 3 trial, conducted by the Children’s Oncology Group, compared newly diagnosed pediatric APL patients receiving ATO consolidation to the benchmark of event-free survival (EFS) in standard-risk (SR) patients established by the AIDA0493 trial.
AIDA0493 enrolled patients between January 1993 and June 2000. The protocol involved treatment with all-trans retinoic acid (ATRA), anthracyclines, and high-dose cytarabine. The trial resulted in overall survival (OS) of approximately 90%.
AAML0631
AAML063 investigators defined SR as a white blood cell count (WBC) at presentation less than 10,000 cells/μL. They defined high risk (HR) as a WBC count of 10,000 cells/μL or more.
AAML0631 patients had to be at least 2 years old and younger than 22, and their de novo APL had to be confirmed by PML-RARα polymerase chain reaction.
The patients could have had no prior leukemia treatment, except for steroids, hydroxyurea, or leukapheresis.
AAML0631 did not exclude patients based on organ function or performance status. AIDA0493, however, excluded patients with performance status of 4 or liver function tests greater than 3 times the upper limit of normal.
Patients were excluded from AAML0631 if they had preexisting prolonged QT syndrome because of the risk of QT interval prolongation with ATO.
AAML0631 treatment protocol
All patients received ATRA during induction, each consolidation course, and maintenance.
Induction therapy consisted of ATRA and idarubicin.
All patients received 2 cycles of ATO during the first consolidation. SR patients received an additional 2 consolidation courses, and HR patients received 3 consolidation courses that included high-dose cytarabine and anthracycline.
Maintenance therapy consisted of ATRA, oral methotrexate, and 6-mercaptopurine for 2 years.
Patients also received prophylactic treatment with intrathecal cytarabine.
Patient demographics
Investigators enrolled 108 patients between March 2009 and November 2012, of which 101 (66 SR and 35 HR) were evaluable.
Patients were a median age of 15.04 years (range, 2.01 – 21.34), 56% were female, 80% were white, 10% black, 2% Native American, 3% Asian, and 5% unknown.
Three quarters of the patients had an ECOG score of 0 or 1, median WBC counts of 3.8 x 1000 cells/uL (range, 0.4 – 173.8), and median platelet counts of 21.5 x 1000/uL (range, 3 – 198).
Almost two-thirds of patients (63%) had the classic translocation (15;17), and 37% had an additional 1 or more cytogenetic abnormalities.
The SR patients in AAML0631 had similar characteristics to the patients in AIDA0493 except for the distribution of performance status scores and differences in racial/ethnic diversity.
Efficacy
After a median follow-up of 3.73 years (range, 0.003 – 5.97), the 3-year overall survival (OS) was 94% ± 5% and the 3-year EFS was 91% ± 6%.
For SR patients, the OS was 98% ± 3% and the EFS 95% ± 5%.
For HR patients, the OS was 86% ± 12% and the EFS was 83% ± 13%.
SR patients had a 2-year EFS of 97%. This compared with 91% for patients in the AIDA0493 trial, which means that therapy with ATO was not inferior to therapy in the historic comparator trial (P=0.93).
And these results were achieved with a cumulative anthracycline dosing of idarubicin at 51 mg/m2 (SR) and 61 mg/m2 (HR) and mitoxantrone at 20 mg/m2.
This compared with the AIDA0493 cumulative anthracycline dosing of 80 mg/m2 of idarubicin and 50 mg/m2 of mitoxantrone.
The cumulative daunorubicin equivalent in the AAML0631 trial was 335 mg/m2 (SR) and 385 mg/m2 (HR) compared with 600 mg/m2 in the AIDA 0493 trial.
Toxicity
The percentage of patients with adverse events varied according to treatment cycle and was highest during induction and high-dose cytarabine-containing courses.
The most common adverse events were fever/neutropenia and infection.
Differentiation syndrome occurred in 20% of patients during induction, 31% in HR patients and 13% in SR patients. ATRA was held for 15 of these patients during induction. It was subsequently re-started at a lower dose and increased to the full dose.
QTc interval prolongation of grade 1 or 2 occurred in 16% (n=15) and 12% (n=11) during the ATO cycles.
One patient experienced grade 3 QTc interval prolongation during ATO consolidation. There were no grade 4 or 5 events for this toxicity.
One event of grade 1 ventricular arrhythmia and 1 event of grade 1 left ventricular systolic dysfunction occurred during ATO consolidation.
Two off-therapy cardiac events have been reported: a grade 1 QTc interval prolongation and a grade 2 ventricular arrhythmia.
No cardiac deaths have occurred, and liver toxicity was minimal during ATO cycles.
The investigators believe the favorable results of this study provide a new benchmark for outcomes in pediatric APL.
The Children’s Oncology Group is currently accruing pediatric APL patients to further investigate similar treatment approaches.
