TY - JOUR
T1 - Sorafenib plus intensive chemotherapy in newly diagnosed FLT3-ITD AML
T2 - a randomized, placebo-controlled study by the ALLG
AU - Loo, Sun
AU - Roberts, Andrew W.
AU - Anstee, Natasha S.
AU - Kennedy, Glen A.
AU - He, Simon
AU - Schwarer, Anthony P.
AU - Enjeti, Anoop K.
AU - D'Rozario, James
AU - Marlton, Paula
AU - Bilmon, Ian A.
AU - Taper, John
AU - Cull, Gavin
AU - Tiley, Campbell
AU - Verner, Emma
AU - Hahn, Uwe
AU - Hiwase, Devendra K.
AU - Iland, Harry J.
AU - Murphy, Nick
AU - Ramanathan, Sundra
AU - Reynolds, John
AU - Ong, Doen Ming
AU - Tiong, Ing Soo
AU - Wall, Meaghan
AU - Murray, Michael
AU - Rawling, Tristan
AU - Leadbetter, Joanna
AU - Rowley, Leesa
AU - Latimer, Maya
AU - Yuen, Sam
AU - Ting, Stephen B.
AU - Fong, Chun Yew
AU - Morris, Kirk
AU - Bajel, Ashish
AU - Seymour, John F.
AU - Levis, Mark J.
AU - Wei, Andrew H.
AU - on behalf of the Australasian Leukaemia and Lymphoma Group (ALLG)
N1 - Funding Information:
This work was supported by grants from the Australian National Health and Medical Research Council ( 1048312 [A.H.W. and A.W.R.] and 2018071 [A.H.W.]) and Leukaemia Foundation Australia (A.H.W.).
Publisher Copyright:
© 2023 The American Society of Hematology
PY - 2023/12/7
Y1 - 2023/12/7
N2 - Sorafenib maintenance improves outcomes after hematopoietic cell transplant (HCT) for patients with FMS-like tyrosine kinase 3–internal tandem duplication (FLT3-ITD) acute myeloid leukemia (AML). Although promising outcomes have been reported for sorafenib plus intensive chemotherapy, randomized data are limited. This placebo-controlled, phase 2 study (ACTRN12611001112954) randomized 102 patients (aged 18-65 years) 2:1 to sorafenib vs placebo (days 4-10) combined with intensive induction: idarubicin 12 mg/m2 on days 1 to 3 plus either cytarabine 1.5 g/m2 twice daily on days 1, 3, 5, and 7 (18-55 years) or 100 mg/m2 on days 1 to 7 (56-65 years), followed by consolidation and maintenance therapy for 12 months (post-HCT excluded) in newly diagnosed patients with FLT3-ITD AML. Four patients were excluded in a modified intention-to-treat final analysis (3 not commencing therapy and 1 was FLT3-ITD negative). Rates of complete remission (CR)/CR with incomplete hematologic recovery were high in both arms (sorafenib, 78%/9%; placebo, 70%/24%). With 49.1-months median follow-up, the primary end point of event-free survival (EFS) was not improved by sorafenib (2-year EFS 47.9% vs 45.4%; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.51-1.51; P=.61). Two-year overall survival (OS) was 67% in the sorafenib arm and 58% in the placebo arm (HR, 0.76; 95% CI, 0.42-1.39). For patients who received HCT in first remission, the 2-year OS rates were 84% and 67% in the sorafenib and placebo arms, respectively (HR, 0.45; 95% CI, 0.18-1.12; P=.08). In exploratory analyses, FLT3-ITD measurable residual disease (MRD) negative status (<0.001%) after induction was associated with improved 2-year OS (83% vs 60%; HR, 0.4; 95% CI, 0.17-0.93; P=.028). In conclusion, routine use of pretransplant sorafenib plus chemotherapy in unselected patients with FLT3-ITD AML is not supported by this study.
AB - Sorafenib maintenance improves outcomes after hematopoietic cell transplant (HCT) for patients with FMS-like tyrosine kinase 3–internal tandem duplication (FLT3-ITD) acute myeloid leukemia (AML). Although promising outcomes have been reported for sorafenib plus intensive chemotherapy, randomized data are limited. This placebo-controlled, phase 2 study (ACTRN12611001112954) randomized 102 patients (aged 18-65 years) 2:1 to sorafenib vs placebo (days 4-10) combined with intensive induction: idarubicin 12 mg/m2 on days 1 to 3 plus either cytarabine 1.5 g/m2 twice daily on days 1, 3, 5, and 7 (18-55 years) or 100 mg/m2 on days 1 to 7 (56-65 years), followed by consolidation and maintenance therapy for 12 months (post-HCT excluded) in newly diagnosed patients with FLT3-ITD AML. Four patients were excluded in a modified intention-to-treat final analysis (3 not commencing therapy and 1 was FLT3-ITD negative). Rates of complete remission (CR)/CR with incomplete hematologic recovery were high in both arms (sorafenib, 78%/9%; placebo, 70%/24%). With 49.1-months median follow-up, the primary end point of event-free survival (EFS) was not improved by sorafenib (2-year EFS 47.9% vs 45.4%; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.51-1.51; P=.61). Two-year overall survival (OS) was 67% in the sorafenib arm and 58% in the placebo arm (HR, 0.76; 95% CI, 0.42-1.39). For patients who received HCT in first remission, the 2-year OS rates were 84% and 67% in the sorafenib and placebo arms, respectively (HR, 0.45; 95% CI, 0.18-1.12; P=.08). In exploratory analyses, FLT3-ITD measurable residual disease (MRD) negative status (<0.001%) after induction was associated with improved 2-year OS (83% vs 60%; HR, 0.4; 95% CI, 0.17-0.93; P=.028). In conclusion, routine use of pretransplant sorafenib plus chemotherapy in unselected patients with FLT3-ITD AML is not supported by this study.
UR - http://www.scopus.com/inward/record.url?scp=85175320170&partnerID=8YFLogxK
U2 - 10.1182/blood.2023020301
DO - 10.1182/blood.2023020301
M3 - Article
C2 - 37647654
AN - SCOPUS:85175320170
SN - 0006-4971
VL - 142
SP - 1960
EP - 1971
JO - Blood
JF - Blood
IS - 23
ER -