Sorafenib Therapy Is Associated with Improved Outcomes for FMS-like Tyrosine Kinase 3 Internal Tandem Duplication Acute Myeloid Leukemia Relapsing after Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

The optimal therapy for patients with acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) who relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. In this study we retrospectively evaluated the efficacy of sorafenib combined with other therapeutic strategies as salvage therapy for these patients. Eighty-three AML patients with FLT3-ITD relapsing after allo-HSCT were enrolled in this study. Fifty-three patients received salvage therapy containing sorafenib and 30 patients did not. Salvage therapy containing sorafenib was superior to that without sorafenib with respect to complete remission rates, overall survival (OS), and progression-free survival (PFS) (66.0% versus 30.0%, 46.8% versus 20.0%, and 44.9% versus 16.7%, respectively; P = .002, P = .003, and P = .001). Further subgroup analysis revealed that the OS and PFS of patients who received sorafenib combined with chemotherapy followed by donor lymphocyte infusion (DLI) were superior to those receiving other therapeutic regimens, including sorafenib combined with chemotherapy, chemotherapy followed by DLI, and monochemotherapy (P = .003, P < .001). Multivariate analysis revealed that salvage therapy including sorafenib was the only protective factor for longer OS (P = .035; hazard ratio [HR], .526); salvage therapy including sorafenib and DLI were the protective factors for longer PFS (P = .011, HR, .423; P = .019, HR, .508). Our data suggest that sorafenib therapy is associated with improved outcomes for FLT3-ITD AML relapsing after allo-HSCT, and whether sorafenib combined with chemotherapy followed by DLI reveals an optimal efficacy merits further study.

Clinical Outcomes in Patients with FLT3-ITD-Mutated Relapsed/Refractory Acute Myelogenous Leukemia Undergoing Hematopoietic Stem Cell Transplantation after Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial

“…Of note, many patients with R/R FLT3-ITD AML in QuAN-TUM-R and other studies mentioned above [10,16,28,30] did not receive FLT3 inhibitor therapy as a first-line therapy, which mD 3 1 7 X Xight not reflect the current population of patients who may be undergoing receiving an allo-HSCT as a part of consolidation after initial therapy with an FLT3 inhibitor [8]. Preclinical data show that quizartinib has antitumor activity in FLT3-ITD-D 3 1 8 X Xmutated AML models that are resistant to the FLT3 inhibitor midostaurin, potentially due to a more complete and sustained inhibition of the FLT3 signaling pathway [34].…”

“…In a landmark analysis from day 60 after HSCT, the median OS was 16.2 months in patients who continued gilteritinib after allo-HSCT versus 8.4 months in those who did not [28]. Several retrospective and observational analyses have also demonstrated that treatment with FLT3 inhibitors is associated with improved outcomes in patients with FLT3-ITD AML who have relapsed after HSCT [10,29,30]. Preclinical data and a recent case study suggest that treatment with FLT3 inhibitors after allo-HSCT could enhance graft-versus-leukemia effects in addition to having direct effects on FLT3 mutation-positive leukemia cells [31,32], lending further support for their potential use in this setting.…”

“…Traditional cytotoxic salvage chemotherapy has been largely ineffective in controlling FLT3-ITD R/R disease, enabling only D 3 3 X X20% of patients to proceed to HSCT [5,6]. In aD 3 4 X XdditionD 3 5 X X, despite improved outcomes with HSCT, the risk of relapse in patients with FLT3-ITD AML is higher than that seenD 3 6 X X in patients without FLT3 mutation [7][8][9][10]. The presence of FLT3-ITD has been shown to be independently associated with increased risk of relapse and reduced disease-free survival in patients who underwent HSCT [7,11], with poorer outcomes observed in patients with a higher FLT3-ITD allelic burden [7].…”

Clinical implications of recurrent gene mutations in acute myeloid leukemia

“…Targeting mutant FLT3 by small molecule inhibitors has rapidly emerged as a new therapeutic approach in patients with AML. Different FLT3 inhibitor therapeutic agents have been developed and are summarized in Tables 1, 2 [9,[37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53].…”

Clinical Benefits and Safety of FMS-Like Tyrosine Kinase 3 Inhibitors in Various Treatment Stages of Acute Myeloid Leukemia: A Systematic Review, Meta-Analysis, and Network Meta-Analysis

“…( 30 ) and Xuan et al. ( 31 ) also revealed enhanced OS comparing sorafenib with salvage chemotherapy in FLT3 (+) rrAML, which should be further confirmed in RCT. Finally, midostaurin might be specifically effective in the untreated AML rather than rrAML, since in vitro studies, midostaurin had broader activity and might achieve greater clinical utility in newly diagnosed AML with blasts tending to be less addicted to FLT3 -mediated signaling than rrAML ( 32 ).…”