TY - JOUR
T1 - Sorafenib in Combination With Standard Chemotherapy for Children With High Allelic Ratio FLT3 /ITD+ Acute Myeloid Leukemia
T2 - A Report From the Children's Oncology Group Protocol AAML1031
AU - Pollard, Jessica A.
AU - Alonzo, Todd A.
AU - Gerbing, Robert
AU - Brown, Patrick
AU - Fox, Elizabeth
AU - Choi, John
AU - Fisher, Brian
AU - Hirsch, Betsy
AU - Kahwash, Samir
AU - Getz, Kelly
AU - Levine, John
AU - Brodersen, Lisa Eidenschink
AU - Loken, Michael R.
AU - Raimondi, Susana
AU - Tarlock, Katherine
AU - Wood, Andrew
AU - Sung, Lillian
AU - Kolb, E. Anders
AU - Gamis, Alan
AU - Meshinchi, Soheil
AU - Aplenc, Richard
N1 - Publisher Copyright:
© American Society of Clinical Oncology.
PY - 2022/6/20
Y1 - 2022/6/20
N2 - PURPOSE: High allelic ratio (HAR)
FLT3/ITD (AR > 0.4) mutations confer poor prognosis in pediatric acute myeloid leukemia (AML). COG AAML1031 studied the feasibility and efficacy of adding sorafenib, a multikinase tyrosine kinase inhibitor to standard chemotherapy and as single-agent maintenance therapy in this population.
MATERIALS AND METHODS: Patients were treated in three cohorts. The initial safety phase defined the maximum tolerated dose of sorafenib starting in induction 2. Cohorts 2 and 3 added sorafenib in induction and as single-agent maintenance. Clinical outcome analysis was limited to n = 72 patients in cohorts 2/3 and compared with n = 76 HAR
FLT3/ITD+ AML patients who received identical chemotherapy without sorafenib. Sorafenib pharmacokinetics and plasma inhibitory activity were measured in a subset of patients.
RESULTS: The maximum tolerated dose of sorafenib was 200 mg/m
2 once daily; dose-limiting toxicities included rash (n = 2; 1 grade 3 and 1 grade 2), grade 2 hand-foot syndrome, and grade 3 fever. Pharmacokinetics/plasma inhibitory activity data demonstrated that measured plasma concentrations were sufficient to inhibit phosphorylated FLT3. Although outcomes were superior with sorafenib in cohorts 2 and 3, patients treated with sorafenib also underwent hematopoietic stem-cell transplant more frequently than the comparator population. Multivariable analysis that accounted for both hematopoietic stem-cell transplant and favorable co-occurring mutations confirmed sorafenib's benefit. Specifically, risk of an event was approximately two-fold higher in HAR
FLT3/ITD+ patients who did not receive sorafenib (event-free survival from study entry: hazard ratio [HR] 2.37, 95% CI, 1.45 to 3.88,
P < .001, disease-free survival from complete remission: HR 2.28, 95% CI, 1.08 to 4.82,
P = .032, relapse risk from complete remission: HR 3.03, 95% CI 1.31 to 7.04,
P = .010).
CONCLUSION: Sorafenib can be safely added to conventional AML chemotherapy and may improve outcomes in pediatric HAR
FLT3/ITD+ AML.
AB - PURPOSE: High allelic ratio (HAR)
FLT3/ITD (AR > 0.4) mutations confer poor prognosis in pediatric acute myeloid leukemia (AML). COG AAML1031 studied the feasibility and efficacy of adding sorafenib, a multikinase tyrosine kinase inhibitor to standard chemotherapy and as single-agent maintenance therapy in this population.
MATERIALS AND METHODS: Patients were treated in three cohorts. The initial safety phase defined the maximum tolerated dose of sorafenib starting in induction 2. Cohorts 2 and 3 added sorafenib in induction and as single-agent maintenance. Clinical outcome analysis was limited to n = 72 patients in cohorts 2/3 and compared with n = 76 HAR
FLT3/ITD+ AML patients who received identical chemotherapy without sorafenib. Sorafenib pharmacokinetics and plasma inhibitory activity were measured in a subset of patients.
RESULTS: The maximum tolerated dose of sorafenib was 200 mg/m
2 once daily; dose-limiting toxicities included rash (n = 2; 1 grade 3 and 1 grade 2), grade 2 hand-foot syndrome, and grade 3 fever. Pharmacokinetics/plasma inhibitory activity data demonstrated that measured plasma concentrations were sufficient to inhibit phosphorylated FLT3. Although outcomes were superior with sorafenib in cohorts 2 and 3, patients treated with sorafenib also underwent hematopoietic stem-cell transplant more frequently than the comparator population. Multivariable analysis that accounted for both hematopoietic stem-cell transplant and favorable co-occurring mutations confirmed sorafenib's benefit. Specifically, risk of an event was approximately two-fold higher in HAR
FLT3/ITD+ patients who did not receive sorafenib (event-free survival from study entry: hazard ratio [HR] 2.37, 95% CI, 1.45 to 3.88,
P < .001, disease-free survival from complete remission: HR 2.28, 95% CI, 1.08 to 4.82,
P = .032, relapse risk from complete remission: HR 3.03, 95% CI 1.31 to 7.04,
P = .010).
CONCLUSION: Sorafenib can be safely added to conventional AML chemotherapy and may improve outcomes in pediatric HAR
FLT3/ITD+ AML.
KW - Child
KW - Hematopoietic Stem Cell Transplantation/adverse effects
KW - Humans
KW - Leukemia, Myeloid, Acute/drug therapy
KW - Mutation
KW - Phenylurea Compounds/adverse effects
KW - Protein Kinase Inhibitors/adverse effects
KW - Remission Induction
KW - Sorafenib/therapeutic use
KW - fms-Like Tyrosine Kinase 3/genetics
UR - http://www.scopus.com/inward/record.url?scp=85130999898&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85130999898&partnerID=8YFLogxK
U2 - 10.1200/JCO.21.01612
DO - 10.1200/JCO.21.01612
M3 - Article
C2 - 35349331
AN - SCOPUS:85130999898
SN - 0732-183X
VL - 40
SP - 2023
EP - 2035
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 18
ER -
