Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The role of FLT3 inhibitors as maintenance therapy following hematopoietic stem cell transplant.

ABSTRACT: Activating mutations in FLT3 in acute myeloid leukemia (AML) portend a poor prognosis, and targeting FLT3 with a tyrosine kinase inhibitor has been an area of intense research recently. Most FLT3 mutated AML patients undergo hematopoietic stem cell transplantation (HSCT) as standard of care but a significant proportion of patients relapse. Although the use of FLT3 inhibitors in the pre-HSCT perspective is more clearly defined, its use in the post-HSCT scenario, when most relapses occur, remains unclear. In this review, we comprehensively present the data on the recent and ongoing studies evaluating the role of various FLT3 inhibitors in AML with a particular focus in the post-HSCT setting.

SUBMITTER: Li GX

PROVIDER: S-EPMC6092446 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

The role of FLT3 inhibitors as maintenance therapy following hematopoietic stem cell transplant.

Li Grace Xiuqing GX Wang Lan L Yaghmour Bassam B Ramsingh Giridharan G Yaghmour George G

Leukemia research reports 20180719

Activating mutations in FLT3 in acute myeloid leukemia (AML) portend a poor prognosis, and targeting FLT3 with a tyrosine kinase inhibitor has been an area of intense research recently. Most FLT3 mutated AML patients undergo hematopoietic stem cell transplantation (HSCT) as standard of care but a significant proportion of patients relapse. Although the use of FLT3 inhibitors in the pre-HSCT perspective is more clearly defined, its use in the post-HSCT scenario, when most relapses occur, remains ...[more]

PMID: 30112274

Similar Datasets

FLT3 Inhibitors as Maintenance Therapy after Allogeneic Stem-Cell Transplantation.

Project description:Mutations in the FLT3 gene are associated with poor prognosis in patients with AML, even after consolidation with allogeneic hematopoietic cell transplantation (alloHCT) in first remission. Treatment failure in FLT3-mutated AML is largely driven by excessive risk of relapse compared to other genetic subtypes, including in patients post-alloHCT. As a result, there is substantial interest in studying posttransplant maintenance therapy in FLT3-mutated AML as an approach to optimize disease control and improve long-term outcomes. Clinical trials utilizing posttransplant FLT3 inhibitors, such as sorafenib and midostaurin, have shown feasibility, safety, and encouraging posttransplant outcomes, and there are ongoing studies using newer-generation tyrosine-kinase inhibitors as posttransplant maintenance therapy. Here, we review the toxicities and efficacy of FLT3 inhibitors as posttransplant maintenance, recommendations on the use of FLT3 inhibitors by international consensus guidelines, and highlight key remaining questions.

| S-EPMC9464008 | biostudies-literature

FLT3 inhibitors as maintenance therapy post allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia patients with FLT3 mutations: A meta-analysis.

Project description:BackgroundAcute myeloid leukemia (AML) patients with a Fms-like tyrosine kinase 3 (FLT3) mutation have a high incidence of relapse despite allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a subsequent poor prognosis. FLT3 inhibitors (FLT3i) have been suggested to reduce the post-transplant relapse risk in recent studies. As more evidence is accumulated, we perform the present meta-analysis to assess the efficacy and safety of FLT3i as post-transplant maintenance therapy in AML patients.MethodsLiterature search was performed in public databases from inception to December 31, 2021. Overall survival (OS), relapse-free survival (RFS), cumulative incidence of relapse (CIR), non-relapse mortality (NRM), graft-versus-host disease (GVHD) and adverse events were compared between FLT3i and control groups. Pooled hazard ratio (HR) or relative risk (RR) with corresponding 95% confidence interval (CI) were calculated.ResultsWe identified 12 eligible studies with 2282 FLT3-mutated AML patients who had received HSCT. There was no between-study heterogeneity and a fix-effect model was used. Post-transplant FLT3i maintenance significantly prolonged OS (HR = 0.41, 95%CI: 0.32-0.52, p < 0.001) and RFS (HR = 0.39, 95%CI 0.31-0.50, p < 0.001), and reduced CIR (HR = 0.31, 95%CI 0.20-0.46, p < 0.001) as compared with control. There were no significant risk differences in NRM (RR = 0.69, 95%CI 0.41-1.17, p = 0.169), acute GVHD (RR = 1.17, 95%CI 0.93-1.47, p = 0.175), chronic GVHD (RR = 1.31, 95%CI 0.91-1.39, p = 0.276) and grade ≥3 adverse events between both groups, except for skin toxicity (RR = 5.86, 95%CI 1.34-25.57, p = 0.019).ConclusionPost-transplant FLT3i maintenance can improve survival and reduce relapse in FLT3-mutated AML patients and is tolerable.

| S-EPMC10067110 | biostudies-literature

Role of stem cell transplant and maintenance therapy in plasma cell disorders.

Project description:Autologous stem cell transplant (ASCT) has been an important component of therapy for myeloma patients eligible for high-dose chemotherapy. Recent studies comparing early transplant to low-dose chemotherapy support the continued use of ASCT as consolidation following induction therapy, even in the era of immunomodulatory drugs, proteasome inhibitors, and other novel agents. Despite the marked improvements in outcomes with this approach, most patients will eventually experience disease progression. Thus, inclusion of post-ASCT consolidation/maintenance strategies is used to improve long-term disease control. Multiple randomized studies support the use of lenalidomide maintenance therapy following ASCT. The next generation of clinical trials will incorporate novel agents such as monoclonal antibodies, proteasome inhibitors, and other novel pathway modulatory agents into post-ASCT treatment strategies with the goal of achieving even deeper responses and longer durations of disease control.

| S-EPMC6142442 | biostudies-literature

Post-allogeneic stem cell transplant <i>FLT3</i>- targeted maintenance therapy: updates and considerations for clinical practice.

Project description:Acute myeloid leukemia (AML) is characterized by multiple molecular and cytogenetic abnormalities, with increasing data to support clinical and prognostic implications to guide clinical decision making. One of the most well described mutations involves fms-like tyrosine kinase 3 (FLT3) that results in a constitutively active tyrosine kinase and is generally associated with poor prognosis involving shorter overall survival and higher rates of relapse. Advancements in targeted therapies have greatly influenced available treatment options in a landscape that has remained largely unchanged for the past five decades. Tyrosine kinase inhibitors (TKI), specifically FLT3-targeted therapies, are now integral treatment options for patients with this targetable mutation. As allogeneic hematopoietic cell transplant (alloHCT) remains the primary curative therapy for most adult AML patients, the goal is for eligible patients to proceed to transplant. However, post-alloHCT relapse remains exceedingly high even in patients achieving deep responses to therapy. Limited evaluation of FLT3-targeted TKIs as post-alloHCT maintenance therapy in FLT3-positive patients suggest improved outcomes and tolerable safety profiles, with ongoing studies further investigating second-generation agents. Thus, this commentary aims to review the role of post-alloHCT FLT3-targeted maintenance therapy and considerations for clinical practice.

| S-EPMC9802584 | biostudies-literature

Maintenance Tyrosine Kinase Inhibitors Following Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Myelogenous Leukemia: A Center for International Blood and Marrow Transplant Research Study.

Project description:It remains unknown whether the administration of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 after allogeneic hematopoietic cell transplantation (HCT) is associated with improved outcomes for patients with chronic myelogenous leukemia (CML). In this registry study, we analyzed clinical outcomes of 390 adult patients with CML who underwent transplantation between 2007 and 2014 and received maintenance TKI following HCT (n?=?89) compared with no TKI maintenance (n?=?301), as reported to the Center for International Blood and Marrow Transplant Research. All patients received TKI therapy before HCT. The majority of patients had a disease status of first chronic phase at HCT (n?=?240; 62%). The study was conducted as a landmark analysis, excluding patients who died, relapsed, had chronic graft-versus-host disease, or were censored before day +100 following HCT. Of the 89 patients who received TKI maintenance, 77 (87%) received a single TKI and the other 12 (13%) received multiple sequential TKIs. The most common TKIs used for maintenance were dasatinib (n?=?50), imatinib (n?=?27), and nilotinib (n?=?27). As measured from day +100, the adjusted estimates for 5-year relapse (maintenance, 35% versus no maintenance, 26%; P?=?.11), leukemia-free survival (maintenance, 42% versus no maintenance, 44%; P?=?.65), or overall survival (maintenance, 61% versus no maintenance, 57%; P?=?.61) did not differ significantly between patients receiving TKI maintenance or no maintenance. These results remained unchanged in multivariate analysis and were not modified by disease status before transplantation. In conclusion, our data from this day +100 landmark analysis do not demonstrate a significant impact of maintenance TKI therapy on clinical outcomes. The optimal approach to TKI administration in the post-transplantation setting in patients with CML remains undetermined.

| S-EPMC7358778 | biostudies-literature

Back to the future! The evolving role of maintenance therapy after hematopoietic stem cell transplantation.

Project description:Relapse is a devastating event for patients with hematologic cancers treated with hematopoietic stem cell transplantation. In most situations, relapse treatment options are limited. Maintenance therapy offers the possibility of delaying or avoiding disease recurrence, but its role remains unclear in most conditions that we treat with transplantation. Here, Dr. Hourigan presents an overview of minimal residual disease (MRD) measurement in hematologic malignancies and the applicability of MRD-based post-transplantation interventions. Dr. McCarthy reviews current knowledge of maintenance therapy in the autologous transplantation context, with emphasis on immunologic interventions and immune modulation strategies designed to prevent relapse. Dr. de Lima discusses current lines of investigation in disease recurrence prevention after allogeneic transplantation, focusing on acute myeloid leukemia and myelodysplastic syndrome.

| S-EPMC4205045 | biostudies-literature

Results of a phase 1 study of quizartinib as maintenance therapy in subjects with acute myeloid leukemia in remission following allogeneic hematopoietic stem cell transplant.

Project description:FLT3-ITD-mutated acute myeloid leukemia (AML) has very high risk of relapse and is associated with poor outcome following allogeneic hematopoietic-cell transplant (allo-HCT). This two-part, phase 1, multicenter, open-label, sequential-group, dose-escalation study aimed to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and safety/tolerability of quizartinib, a selective and highly potent FLT3 inhibitor, when administered as maintenance therapy after allo-HCT. Thirteen subjects with documented FLT3-ITD-mutated AML in morphological remission following allo-HCT received one of two quizartinib dihydrochloride dose levels (DL): 40 mg/d (DL1; n = 7) and 60 mg/d (DL2; n = 6), administered orally in 28-day cycles for up to 24 cycles. Median age of participants was 43 years. All subjects received human leukocyte antigen (HLA)-matched allo-HCT. One subject treated at DL1 and 1 treated at DL2 had DLTs that required drug interruption (grade 3 gastric hemorrhage and grade 3 anemia, respectively). Ten subjects (77%) received quizartinib for >1 year; 5 (38%) completed 24 cycles. Four subjects (31%) discontinued quizartinib due to adverse events. One subject (8%) experienced relapse during cycle 1 and discontinued treatment. Most common grade 3/4 adverse events were neutropenia (23%), anemia (15%), leukopenia (15%), lymphopenia (15%), and thrombocytopenia (15%). This study demonstrated acceptable tolerability and early evidence of reduced relapse rate following allo-HCT with quizartinib maintenance compared to historical cohorts. No MTD was identified, but 60 mg daily was selected as highest dose for continuous daily administration based on randomized comparison of daily 30 and 60 mg doses in relapsed/refractory AML.

| S-EPMC6585789 | biostudies-literature

Adoptive T Cell Therapy Following Haploidentical Hematopoietic Stem Cell Transplantation.

Project description:Delayed immune reconstitution and the consequently high rates of leukemia relapse and infectious complications are the main limitations of haploidentical hematopoietic stem cell transplantation. Donor T cell addback can accelerate immune reconstitution but the therapeutic window between graft-vs.-host disease and protective immunity is very narrow in the haploidentical transplant setting. Hence, strategies to improve the safety and efficacy of adoptive T cell transfer are particularly relevant in this setting. Adoptive T cell transfer strategies in haploidentical transplantation include the use of antigen-specific T cells, allodepletion and alloanergy induction, immune modulation by the co-infusion of regulatory cell populations, and the use of safety switch gene-modified T cells. Whilst common principles apply, there are features that are unique to haploidentical transplantation, where HLA-mismatching directly impacts on immune reconstitution, and shared vs. non-shared HLA-allele can be an important consideration in antigen-specific T cell therapy. This review will also present an update on safety switch gene-modified T cells, which can be conditionally deleted in the event of severe graft- vs.-host disease or other adverse events. Herpes Virus Simplex Thymidine Kinase (HSVtk) and inducible caspase-9 (iCasp9) are safety switches that have undergone multicenter studies in haploidentical transplantation with encouraging results. These gene-modified cells, which are trackable long-term, have also provided important insights on the fate of adoptively transferred T cells. In this review, we will discuss the biology of post-transplant T cell immune reconstitution and the impact of HLA-mismatching, and the different cellular therapy strategies that can help accelerate T cell immune reconstitution after haploidentical transplantation.

| S-EPMC6691120 | biostudies-literature

Eltrombopag: Role in Cytopenias Following Hematopoietic Stem Cell Transplantation.

Project description:Eltrombopag is a small molecule oral agonist of the thrombopoietin receptor. Initially used for improving thrombocytopenia in chronic immune thrombocytopenia (ITP), it was later found to be efficacious in various other etiologies of thrombocytopenia as well as inherited marrow failure syndromes. Lately, it has been used for thrombocytopenia and poor graft function after allogeneic hematopoietic stem cell transplantation (HSCT) without any severe adverse events. Although prospective evidence of the efficacy is limited, there are increasing reports on the safety and efficacy with Eltrombopag in post HSCT thrombocytopenia and poor graft function. This provides an exciting opportunity for further research to evaluate both efficacy and cost-effectiveness of the use of Eltrombopag in this scenario. Here we review the current evidence on the indications for the use of Eltrombopag in the post allogeneic hematopoietic stem cell transplant setting.

| S-EPMC7229069 | biostudies-literature

Measurable residual disease status and FLT3 inhibitor therapy in patients with FLT3-ITD mutated AML following allogeneic hematopoietic cell transplantation.

Project description:Measurable residual disease (MRD) is associated with poor prognosis in acute myeloid leukemia (AML), even after allogeneic hematopoietic cell transplantation (HCT). New next-generation sequencing (NGS) methods have emerged as a highly sensitive and specific method to detect MRD. In addition to defining the role of post-HCT MRD monitoring in FLT3-ITD mutated AML, there is great interest in the optimal use of oral FLT3 tyrosine kinase inhibitors (FLT3 inhibitors) to maintain remission following HCT. In this study, we evaluated the clinical impact of sensitive FLT3 MRD testing early after HCT and maintenance FLT3 inhibitor use at our transplant center. We found that there was a trend towards inferior progression-free survival (PFS) for patients with early post-HCT MRD, but that overall survival (OS) was not significantly impacted by MRD. The use of maintenance FLT3 inhibitors led to a significantly superior PFS and OS in our cohort, and improved PFS and OS in both MRD-negative and MRD-positive patients. Altogether, our results demonstrate the prognostic significance of NGS-based MRD monitoring for FLT3-ITD and the ability of post-HCT maintenance therapy to prevent relapse and death in FLT3-ITD mutated AML.

| S-EPMC10324980 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data