Sorafenib plus intensive chemotherapy in newly diagnosed FLT3-ITD AML: a randomized, placebo-controlled study by the ALLG

Loo, S; Roberts, AW; Anstee, NS; Kennedy, GA; He, S; Schwarer, AP; Enjeti, AK; D&#39;Rozario, J; Marlton, P; Bilmon, IA; Taper, J; Cull, G; Tiley, C; Verner, E; Hahn, U; Hiwase, DK; Iland, HJ; Murphy, N; Ramanathan, S; Reynolds, J; Ong, DM; Tiong, IS; Wall, M; Murray, M; Rawling, T; Leadbetter, J; Rowley, L; Latimer, M; Yuen, S; Ting, SB; Fong, CY; Morris, K; Bajel, A; Seymour, JF; Levis, MJ; Wei, AH; Australasian; Leukaemia and Lymphoma Group

Author(s): Loo, S; Roberts, AW; Anstee, NS; Kennedy, GA; He, S; Schwarer, AP; Enjeti, AK; D'Rozario, J; Marlton, P; Bilmon, IA; Taper, J; Cull, G; Tiley, C; Verner, E; Hahn, U; Hiwase, DK; Iland, HJ; Murphy, N; Ramanathan, S; Reynolds, J; Ong, DM; Tiong, IS; Wall, M; Murray, M; Rawling, T; Leadbetter, J; Rowley, L; Latimer, M; Yuen, S; Ting, SB; Fong, CY; Morris, K; Bajel, A; Seymour, JF; Levis, MJ; Wei, AH; Australasian; Leukaemia and Lymphoma Group;
Details: Publication Year 2023-12-07,Volume 142,Issue #23,Page 1960-1971
Journal Title: Blood
Publication Type: Research article
Abstract: 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.
Keywords: Humans; Sorafenib; fms-Like Tyrosine Kinase 3/genetics; *Hematopoietic Stem Cell Transplantation; Retrospective Studies; *Leukemia, Myeloid, Acute/drug therapy/genetics
Department(s): Clinical Haematology; Pathology
Publisher's Version: https://doi.org/10.1182/blood.2023020301
Open Access at Publisher's Site: https://doi.org/10.1182/blood.2023020301
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-01-19 03:10:19

Last Modified: 2024-01-19 03:11:30