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Bortezomib combined with pediatric AML chemotherapy
3-year OS from study entry were 63.6%±4.5% versus 67.2%±4.3% (P=0.356). Similar outcomes by randomiza- tion arm were observed for the cumulative incidence of relapse, 1-year TRM, and DFS/OS from the end of Induction II (Table 2).
Subgroup analyses by risk group (Online Supplementary Table S2) showed similar outcomes between treatment arms for both low- and high-risk patients. Combining the two arms, 3-year DFS and OS for low-risk patients was 52.9%±3.7% and 74.1%±3.4%, respectively while 3-year DFS and OS for high-risk patients was 27.8%±6.6% and 36.9%±7.6%. Subgroup analyses by NPM, CEBPA, CBF, and KMT2A molecular subtypes (Online Supplementary Table S3) and by age category (Online Supplementary Table S4) did not show any evidence of subtype- or age-specific bortezomib responses.
Univariable and multivariable Cox analyses from study entry and end of Induction II are shown in Table 3 and Online Supplementary Table S5. Initial white blood cell count (WBC) >100x109/L was significantly associated with an increased risk of relapse, treatment-related mor- tality, and decreased survival from study entry. Age greater or equal to 11 years old was associated with a decreased risk of relapse and increased survival. Black race, a previously observed risk factor,3,19 was no longer a significant risk factor for relapse or death. The magnitude and significance of these associations remained stable between univariate and multivariable analyses.
Interim analyses of TRM and acute respiratory distress syndrome (ARDS) after 100 patients were randomized to bortezomib did not cross predefined toxicity thresholds. Overall TRM and targeted toxicity data are shown in Table 4 and Online Supplementary Table S6. No differences were observed in overall or course-specific TRM. While most toxicity rates did not differ by treatment arm, peripheral neuropathy, dose reductions, and pediatric Intensive Care Unit (PICU) admissions were consistently increased in patients receiving bortezomib in combination with standard chemotherapy. Course-specific increased rates of ARDS and hypoxia were observed in the patients treated with bortezomib together with standard chemotherapy. However, the reported rates of these toxi-
cities was relatively low and did not differ from rates in patients treated with standard chemotherapy alone. No differences in infectious complications, renal toxicities, or decline in shortening fraction/ejection fraction were observed between treatment arms (Online Supplementary Table S7). Subgroup toxicity analyses by patient age demonstrated increased toxicities in Arm B patients with increasing age (Online Supplementary Table S8) amongst patients who completed all four courses of chemotherapy.
Discussion
The AAML1031 trial data demonstrate that the addition of bortezomib to standard chemotherapy does not improve EFS or OS. However, bortezomib caused addi- tional treatment-related toxicity, specifically peripheral neuropathy, dose reductions, and PICU admissions. Given the lack of clinical benefit and increased toxicity observed in the bortezomib treatment arm, bortezomib was discon- tinued in all patients who remained on protocol mandated therapy. While the preliminary data regarding bortezomib efficacy in adults with AML was promising,14-16 and pedi- atric preclinical models demonstrated a potential biologi- cal rationale for combining bortezomib with pediatric AML chemotherapy,12,13 the results of AAML1031 do not support the addition of bortezomib to current pediatric AML chemotherapy. This trial result illustrates the need for specific pediatric clinical trials in AML, even in the con- text of a promising efficacy signal in adult AML.
Several important additional conclusions may be drawn from these data. First, the outcomes seen on the AAML1031 trial are generally similar to those seen on the standard arm of the immediately antecedent phase III trial, AAML0531, and are slightly inferior to outcomes reported in other pediatric co-operative oncology groups.3,20-22 The observed differences in outcomes between other pediatric co-operative oncology group clinical trials and AAML1031 are still not completely understood but stem, in part, from the elimination of chemotherapy cycle 5 (Capizzi AraC) for low-risk patients with uninformative molecular fea- tures.23 Further investigations will evaluate differences in
Table 3. Multivariable analyses.
Treatment arm Arm A
Arm B
Age at diagnosis, years
2-10 0-1 ≥11
WBC at diagnosis, x109/L ≤ 100
> 100
Race
Non-black
Black
OS from study entry
N HzR 95%CI P HzR 95%CI P
TRM from study entry HzR 95%CI P
EFS from study entry
482 1 487 0.91
318 1 209 1.26 442 0.86
805 1 164 1.42
832 1
137 1.30
0.73 - 1.13
0.94 - 1.68
0.66 - 1.11
1.08 - 1.86
0.97 - 1.75
1 0.383 0.95
1 0.118 1.21 0.231 0.78
1 0.013 1.64
1
0.084 1.02
0.80 - 1.13
0.96 - 1.53
0.64 - 0.96
1.32 - 2.03
0.79 - 1.31
0.567
0.100
0.017
<0.001
0.884
1
0.87 0.49 - 1.57
1
0.80 0.32 - 1.99 1.25 0.65 - 2.40
1
1.79 0.92 - 3.48
1
1.86 0.95 - 3.62
0.652
0.638
0.498
0.089
OS: overall survival; EFS: event-free survival; TRM: treatment-related mortality; HzR: hazard ratio; CI: confidence interval; WBC: white blood cell count.
0.068
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