Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial.

Abstract

BACKGROUND:

Findings of retrospective studies suggest that sorafenib maintenance post-transplantation might reduce relapse in patients with FLT3 internal tandem duplication (FLT3-ITD) acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation. We investigated the efficacy and tolerability of sorafenib maintenance post-transplantation in this population.

METHODS:

We did an open-label, randomised phase 3 trial at seven hospitals in China. Eligible patients (aged 18-60 years) had FLT3-ITD acute myeloid leukaemia, were undergoing allogeneic haematopoietic stem-cell transplantation, had an Eastern Cooperative Oncology Group performance status of 0-2, had composite complete remission before and after transplantation, and had haematopoietic recovery within 60 days post-transplantation. Patients were randomly assigned (1:1) to sorafenib maintenance (400 mg orally twice daily) or non-maintenance (control) at 30-60 days post-transplantation. Randomisation was done with permuted blocks (block size four) and implemented through an interactive web-based randomisation system. The primary endpoint was the 1-year cumulative incidence of relapse in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02474290; the trial is complete.

FINDINGS:

Between June 20, 2015, and July 21, 2018, 202 patients were enrolled and randomly assigned to sorafenib maintenance (n=100) or control (n=102). Median follow-up post-transplantation was 21·3 months (IQR 15·0-37·0). The 1-year cumulative incidence of relapse was 7·0% (95% CI 3·1-13·1) in the sorafenib group and 24·5% (16·6-33·2) in the control group (hazard ratio 0·25, 95% CI 0·11-0·57; p=0·0010). Within 210 days post-transplantation, the most common grade 3 and 4 adverse events were infections (25 [25%] of 100 patients in the sorafenib group vs 24 [24%] of 102 in the control group), acute graft-versus-host-disease (GVHD; 23 [23%] of 100 vs 21 [21%] of 102), chronic GVHD (18 [18%] of 99 vs 17 [17%] of 99), and haematological toxicity (15 [15%] of 100 vs seven [7%] of 102). There were no treatment-related deaths.

INTERPRETATION:

Sorafenib maintenance post-transplantation can reduce relapse and is well tolerated in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation. This strategy could be a suitable therapeutic option for patients with FLT3-ITD acute myeloid leukaemia.

FUNDING:

None.

• Authors: Li Xuan, Yu Wang, Fen Huang, Zhiping Fan, Yajing Xu, Jing Sun, Na Xu, Lan Deng, Xudong Li, Xinquan Liang, Xiaodan Luo, Pengcheng Shi, Hui Liu, Zhixiang Wang, Ling Jiang, Chunzi Yu, Xuan Zhou, Ren Lin, Yan Chen, Sanfang Tu, Xiaojun Huang, Qifa Liu
• Journal: The Lancet. Oncology (Lancet Oncol) Vol. 21 Issue 9 Pg. 1201-1212 (09 2020) ISSN: 1474-5488 [Electronic] England
• PMID: 32791048 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• Sorafenib
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3

Topics

• Adolescent
• Adult
• China (epidemiology)
• Disease-Free Survival
• Drug-Related Side Effects and Adverse Reactions (drug therapy, pathology)
• Female
• Graft vs Host Disease (epidemiology, etiology, genetics, pathology)
• Hematopoietic Stem Cell Transplantation (adverse effects)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, epidemiology, genetics, pathology)
• Male
• Middle Aged
• Protein Kinase Inhibitors
• Remission Induction
• Sorafenib (administration & dosage, adverse effects)
• Tandem Repeat Sequences (genetics)
• Transplantation, Homologous (adverse effects)
• Young Adult
• fms-Like Tyrosine Kinase 3 (genetics)