Page 138 - 2020_07-Haematologica-web

R. Aplenc et al.
ence disease recurrence.3,4 Moreover, treatment-related mortality limits the ability to further intensify therapy.5 Thus, new therapies are needed to improve the outcomes of children with AML.
The development and evaluation of targeted therapies for children with AML is the highest clinical research pri- ority for the Myeloid Committee in the Children’s Oncology Group (COG).6 After successfully demonstrat- ing an improvement in event-free survival (EFS) in chil- dren treated with gemtuzumab,3,4 COG sought to evalu- ate the efficacy of bortezomib, a first-generation protea- some inhibitor approved for multiple myeloma and non- Hodgkin lymphoma. Bortezomib was selected based on preliminary data demonstrating that AML blasts have increased proteasomes and are more sensitive to protea- some inhibitor-mediated apoptosis,7 AML stem cells have increased NF-kB that is selectively targeted with protea- some inhibitors,8-11 preclinical data from the pediatric pre- clinical testing program showing activity against leukemia cell lines,12,13 and studies in adults with AML demonstrat- ing clinical benefit.14-16 At the time of the opening of the AAML1031 study, a COG pediatric phase I single agent bortezomib trial had determined the single agent maxi- mum tolerated dose,17 and a phase II trial (AAML07P1), combining bortezomib with AML chemotherapy for patients with relapsed AML, was nearing completion.18
Since the available safety and efficacy data for combin- ing bortezomib with standard AML chemotherapy was limited, COG, in collaboration with the Cancer Therapy Evaluation Program (CTEP), designed AAML1031 as a definitive efficacy phase III trial with an interim toxicity analysis to ensure that combining bortezomib with stan- dard AML chemotherapy was safe. The primary objective of AAML1031 was to definitively assess the impact of bortezomib in combination with standard AML chemotherapy on EFS for children with newly diagnosed AML without high allelic ratio (HAR) FLT3 ITD. A second objective was to evaluate the impact of bortezomib on overall survival (OS). Based on the available preliminary data at the time of study initiation, bortezomib was hypothesized to improve both EFS and OS. Multiple sec- ondary objectives included an expanded safety assess- ment, multiple biology correlative studies, and secondary clinical data analyses.
Methods
The AAML1031 study was an open-label multi-center random- ized trial including patients aged 0 to 29.5 years with previously untreated primary AML. Exclusion criteria were: prior chemother- apy, acute promyelocytic leukemia [t(15;17)], juvenile myelomonocytic leukemia, bone marrow failure syndromes, or secondary AML. The National Cancer Institute’s central institu- tional review board (IRB) and IRB at each enrolling center approved the study; patients and families provided informed con- sent or assent as appropriate. The trial was conducted in accor- dance with the Declaration of Helsinki. The trial was registered at clinicaltrials.gov identifier: NCT01371981.
Patients were randomly assigned at enrollment to either stan- dard AML treatment or standard treatment with bortezomib. Randomization was conducted in blocks of four. Bortezomib was administered at a dose of 1.3 mg/m2 once on days 1, 4, and 8 of each chemotherapy course.
Patients with high allelic ratio FLT3 ITD were offered enroll-
ment on a phase I sorafenib treatment arm if that arm was open. Patients with HAR FLT3 ITD who declined enrollment in the sorafenib arm, or who enrolled while the arm was suspended, continued to receive treatment according to their initial random- ization. These patients were included in safety analyses but were excluded from all efficacy analyses.
Patients were classified as low- or high-risk after Induction I. Low-risk patients received four courses of chemotherapy and high-risk patients received three courses of chemotherapy fol- lowed by allogeneic SCT. High-risk patients without an appropri- ate donor received four courses of chemotherapy.
The primary end point was EFS from study entry. EFS was defined as the time from study entry until death, refractory dis- ease, or relapse of any type, whichever occurred first. The second- ary end points were OS, remission rates, relapse risk, post induc- tion disease-free survival (DFS), and treatment-related mortality (TRM). OS was defined as time from study entry until death. Relapse risk was defined as the time from the end of Induction II for patients in complete remission (CR) to relapse, where deaths without a relapse were considered competing events. DFS was defined as the time from end of Induction II for patients in CR until relapse or death. Refractory disease was defined as the per- sistence of central nervous system (CNS) disease after Induction I, or the presence of morphologic bone marrow blasts ≥5% or any extramedullary disease at the end of Induction II. Patients with refractory disease were removed from protocol therapy. TRM was defined as the time from either study entry, or from end of Induction II for patients in CR, to deaths without a relapse, with relapses considered as competing events. Patients without an event were censored at their date of last known contact. However, for TRM analyses, patients were censored 30 days post end of therapy or 200 days post SCT.
Statistical analysis
The study was designed with 1-sided testing and 2.5% type I error rate and 80% power to detect a 9% difference in EFS plateaus (52% vs. 61%, hazard ratio = 0.78) between patients without HAR FLT3 ITD randomized to standard therapy versus bortezomib/standard combination therapy. All P-values are two- sided. Please see the Online Supplementary Appendix for additional details of the methods used.
Results
Between February 2011 and January 2016, 1,231 patients were enrolled on the AAML1031 study; patients were aged 0 to 29.5 years and had previously untreated primary AML at 184 institutions. Data for this analysis were frozen at December 31, 2017, with a median follow- up period of 3.0 years (range, 0-6.0 years) for patients alive at last contact. A total of 132 patients were excluded: 32 patients not meeting eligibility criteria, 102 patients with HAR FLT3 ITD who either enrolled (n=60) or did not enroll (n=42) on the phase I sorafenib treatment arm that concluded enrollment on July 31, 2017; this left 1,097 patients eligible for analysis. Figure 1 illustrates the rea- sons for exclusion and shows that 555 participants were randomized to the bortezomib arm and 542 to the control arm.
Accrual to the main randomization was completed on January 15, 2016. As of March 14, 2016, the projected relapse event horizon was reached and outcome analyses indicated that the addition of bortezomib did not improve EFS, DFS or OS, but did demonstrate a higher incidence of
1880
haematologica | 2020; 105(7)