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R. Aplenc et al.
Table 4. Targeted toxicity by phase of therapy. Phase of therapy
Treatmentarm
Toxicity N
Induction I Induction II Intensification I Intensification II ArmA ArmB Avs.B ArmA ArmB Avs.B ArmA ArmB Avs.B ArmA ArmB Avs.B
PPPP
574 580 518 529 460 469 373 361
Cardiac Heartfailure 4 4 3 6 5 10 10 13
EF decreased Cardiac LVSD
0.7% 0.7% 4 6 0.7% 1.0% 5 8 0.9% 1.4% 6 20
1.000 0.753 0.413
0.6% 1.1% 15 0.2% 0.9% 44 0.8% 0.8% 4 17 0.8% 3.2%
0.506 0.218 1.000
1.1% 2.1% 8 19 1.7% 4.1% 13 15 2.8% 3.2% 8 14 1.7% 3.0%
0.206 0.036 0.740 0.212
2.7% 3.6% 4 11 1.1% 3.0% 9 16 2.4% 4.4% 5 10 1.3% 2.8%
0.474 0.059 0.132 0.171 0.119 0.624 0.648 0.435 1.000 0.492 0.627
0.356
0.955
Neurologic
Pulmonary
Renal
Microbiologically
documented
sterile site infections (at least 1 occurrence)
Dosereductions
PICU admissions
Peripheral neuropathy/ Paresthesia/neuralgia 1.0% 3.4%
0.005 0.495 1.000 0.490 1.000 0.124 1.000 0.750
0.299
0.006
Seizure 21 10 00 03
ARDS
Hypoxia Respiratory failure
Acute kidney injury
Creatinine increased
Viridans group
Streptococcus
Gram Negative Bacilli Fungi
0.3% 0.2%
2 12
0.3% 2.1% 21 35 3.7% 6.0% 10 18 1.7% 3.1% 9 10 1.6% 1.7% 0 5 0.0% 0.9% 21 25 3.7% 4.3%
9 16 1.6% 2.8% 16 7 2.8% 1.2% 8 31
0.623
0.008 0.060 0.133 0.835 0.062 0.572
0.165
0.2% 0.0%
23
0.4% 0.6% 7 10 1.4% 1.9% 2 3 0.4% 0.6% 04 0.0% 0.8% 1 2 0.2% 0.4% 55 53 10.6% 10.0%
23 31 4.4% 5.9% 37
0.0% 0.0%
63
1.3% 0.6% 7 24 1.5% 5.1% 4 5 0.9% 1.1% 16 0.2% 1.3% 0 2 0.0% 0.4% 70 78 15.2% 16.6%
41 49 8.9% 10.4% 02
1.000
0.337 0.002 1.000 0.124 0.500 0.556
0.429
0.0% 0.8%
31
0.8% 0.3% 15 17 4.0% 4.7% 8 5 2.1% 1.4% 21 0.5% 0.3% 0 1 0.0% 0.3% 83 75 22.3% 20.8%
53 43 14.2% 11.9% 66
0.055 0.6% 1.3% 8 33
0.342 0.0% 0.4% 4 37
0.500 1.6% 1.7% 9 47
1.4% 5.3% <0.001 1.5% 6.2% <0.001 0.9% 7.9% <0.001 2.4% 13.0% <0.001
121 155 43 66 53 84 72 71
21.1% 26.7% 0.025 8.3% 12.5% 0.027 11.5% 17.9% 0.006 19.3% 19.7% 0.901
ARDS: adult respiratory distress syndrome; EF: ejection fraction; LVSD: left ventricular cystolic dysfunction; PICU: pediatric intensive care unit.
study populations, including characteristics such as obesi- ty, molecularly-defined risk differences between study populations, efficacy of the backbone treatment regimen, variations in supportive care practices, and the potential impact of structural differences in the provision of health services. Additional analyses including comparisons focus- ing on the efficacy of dexrazoxane as a cardioprotectant,24 specific cytogenetic abnormalities (MLL translocation sub- groups), the use of MRD testing for outcome prediction, optimizing risk classification, the intensification of Induction II therapy with cytarabine and mitoxantrone, and the role of allogeneic donor SCT, are ongoing.
Second, COG, in partnership with the Cancer Therapy Evaluation Program (CTEP) can conduct complex clinical trials that contain phase I, phase II, and phase III compo- nents. The sorafenib study arm, which will be reported separately, served as a phase I trial of the feasibility and
initial efficacy assessment of incorporating sorafenib into pediatric AML. Moreover, at the initiation of AAML1031, the only published data for bortezomib in pediatric AML was as a single agent.17 While limited safety data were available during the 2-year planning process prior to the opening of the AAML1031 trial in June, 2011, full safety and efficacy data were not available until the subsequent closure of the AAML07P1 trial in December, 2011.18 Given these limited toxicity data, the AAML1031 trial included a planned targeted toxicity (ARDS and TRM) analyses after the randomization of 100 patients to the bortezomib treatment arm. The successful monitoring of bortezomib-associated toxicities on the AAML1031 trial highlights the ability of COG, in partnership with the CTEP, to conduct complex clinical trials that provide definitive efficacy testing of a novel agent in the setting of limited preliminary toxicity data.
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haematologica | 2020; 105(7)