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Association details:
| Biomarker: | FLT3-ITD mutation |
|---|---|
| Cancer: | Acute Myelogenous Leukemia |
| Drug: | Vanflyta (quizartinib) (FLT3 inhibitor) |
| Direction: | Sensitive |
Evidence:
Source:
Title:
VANFLYTA Approved in the EU as the First FLT3 Inhibitor Specifically for Patients with Newly Diagnosed FLT3-ITD Positive AML
Published date:
11/09/2023
Excerpt:
Daiichi Sankyo’s...VANFLYTA®(quizartinib) has been approved in the European Union (EU) for use in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, followed by VANFLYTA single-agent maintenance therapy for adult patients with newly diagnosed acute myeloid leukemia (AML) that is FLT3-ITD positive.
Secondary therapy:
cytarabine
Source:
Published date:
07/20/2023
Excerpt:
VANFLYTA is a kinase inhibitor indicated in combination with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) that is FLT3 internal tandem duplication (ITD)-positive as detected by an FDA-approved test.
Secondary therapy:
cytarabine; Chemotherapy
Source:
Published date:
10/03/2023
Excerpt:
Acute Myeloid Leukemia: PRINCIPLES OF SYSTEMIC THERAPY...Standard 7 + 3 (daunorubicin or idarubicin) + quizartinib (FLT3-ITD only)…
Secondary therapy:
idarubicin hydrochloride; daunorubicin
Source:
Title:
832 Quantum-First Trial: FMS-like Tyrosine Kinase 3-Internal Tandem Duplication (FLT3-ITD)–Specific Measurable Residual Disease (MRD) Clearance Assessed through Induction (IND) and Consolidation (CONS) Is Associated with Improved Overall Survival (OS) in Newly Diagnosed (nd) FLT3-ITD+ AML Patients (pts)
Published date:
11/02/2023
Excerpt:
In QuANTUM-First, 539 nd FLT3-ITD+ AML pts were randomized to Quiz (n=268) or placebo (PBO; n=271)…Our data suggest that long-term OS benefits conferred by Quiz in part derive from a deep and sustained reduction of the FLT3-ITD+ leukemia burden.
Trial ID:
Source:
Title:
Quizartinib Recommended for Approval in EU by CHMP for Patients with Newly Diagnosed FLT3-ITD Positive AML
Published date:
09/15/2023
Excerpt:
Daiichi Sankyo...announced that quizartinib has been recommended for approval in the European Union (EU) in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, followed by quizartinib single agent maintenance therapy, for adult patients with newly diagnosed acute myeloid leukemia (AML) that is FLT3-ITD positive...The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) based its positive opinion on results from the phase 3 QuANTUM-First trial, which were published in The Lancet.
Secondary therapy:
cytarabine
Source:
Title:
IMPACT OF ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN FIRST COMPLETE REMISSION PLUS FLT3 INHIBITION WITH QUIZARTINIB IN ACUTE MYELOID LEUKEMIA WITH FLT3-ITD: RESULTS FROM QUANTUM-FIRST
Published date:
05/11/2023
Excerpt:
...study evaluated the novel, highly potent, and selective type II FLT3 inhibitor quizartinib (Quiz) with standard chemotherapy in pts with FLT3-ITD+ newly diagnosed AML...Kaplan-Meier plot of OS in pts undergoing allo-HCT in CR1 by latest pre–allo-HCTFLT3-ITD MRD status (cutoff 10−4), showed longer OS with Quiz...Pts on Quiz had longer OS than pts on PBO, irrespective of allo-HCT in CR1. Pts on Quiz who underwent allo-HCTin CR1 had longer OS than pts on PBO, irrespective of pre–allo-HCT MRD status.
Secondary therapy:
Chemotherapy
Trial ID:
Source:
Title:
Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial
Published date:
04/25/2023
Excerpt:
At a median follow-up of 39·2 months (IQR 31·9–45·8), median overall survival was 31·9 months (95% CI 21·0–not estimable) for quizartinib versus 15·1 months...The addition of quizartinib to standard chemotherapy with or without allo-HCT, followed by continuation monotherapy for up to 3 years, resulted in improved overall survival in adults aged 18–75 years with FLT3-ITD-positive newly diagnosed AML.
Secondary therapy:
Chemotherapy
DOI:
10.1016/S0140-6736(23)00464-6
Trial ID:
Source:
Title:
Quizartinib Granted Priority Review in the U.S. for Patients with Newly Diagnosed FLT3-ITD Positive Acute Myeloid Leukemia
Published date:
10/24/2022
Excerpt:
Daiichi Sankyo (TSE: 4568) received notification of acceptance by the U.S. Food and Drug Administration (FDA) of the New Drug Application (NDA) of quizartinib in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, and as continuation monotherapy following consolidation, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) that is FLT3-ITD positive. The application has been granted Priority Review.
Secondary therapy:
cytarabine; Chemotherapy
Source:
Title:
Open Label Study to Evaluate Safety and Efficacy of 2 Doses of Quizartinib in Patients With Relapsed or Refractory Acute Myeloid Leukemia
Excerpt:
...- Subject is positive for FLT3-ITD activating mutation in bone marrow or peripheral blood (>10% allelic ratio)...
Trial ID:
Source:
Title:
Safety and Efficacy of Quizartinib in Children and Young Adults With Acute Myeloid Leukemia (AML), a Cancer of the Blood
Excerpt:
...- Has presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood as defined in the protocol...
Trial ID:
More C2 evidence
Source:
Title:
(QuANTUM-R): An Open-label Study of Quizartinib Monotherapy vs. Salvage Chemotherapy in Acute Myeloid Leukemia (AML) Subjects Who Are FLT3-ITD Positive
Excerpt:
...Presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood (allelic ratio as determined by a central laboratory with a cutoff of ≥3% FLT3-ITD/total FLT3)....
Trial ID:
Source:
Title:
Phase 2 Study of Quizartinib in Participants With Acute Myeloid Leukemia (AML) FLT3 Internal Tandem Duplication (FLT3/ITD) Mutation
Excerpt:
...- Presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood...
Trial ID:
Source:
Title:
A Study to Assess AC220 Given in Combination With Induction and Consolidation Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML)
Excerpt:
...- internal tandem duplication (FLT3-ITD) mutation status are eligible....
Trial ID:
Source:
Title:
Quizartinib With Standard of Care Chemotherapy and as Continuation Therapy in Patients With Newly Diagnosed FLT3-ITD (+) Acute Myeloid Leukemia (AML)
Excerpt:
...Presence of FLT3-ITD activating mutation in bone marrow (allelic ratio of ≥3% FLT3-ITD/total FLT3); 6....
Trial ID:
Source:
Title:
Quizartinib and High-dose Ara-C Plus Mitoxantrone in Relapsed/Refractory AML With FLT3-ITD
Excerpt:
...- Positive for FLT3-ITD (defined as a ratio of mutant to wild-type alleles of at least 0.05; measured within 2 weeks before inclusion)...
Trial ID:
Source:
Title:
Daunorubicin or Idarubicin With Cytarabine Plus Quizartinib vs Physician's Choice in Newly Diagnosed FLT3-ITD+ AML
Excerpt:
...- Positive for FLT3-ITD (defined as a ratio of mutant to wild-type alleles of at least 0.05; measured within 4 weeks before randomization)...
Trial ID:
Source:
Title:
Expanded Treatment Protocol for Adults With FLT3-ITD Mutated Relapsed or Refractory Acute Myeloid Leukemia (AML) to Receive Quizartinib
Excerpt:
...Has documented FLT3-ITD mutation in bone marrow or peripheral blood in relation R/R disease 6....
Trial ID:
Less C2 evidence
Source:
Title:
QuANTUM‑First Trial: FLT3–Internal Tandem Duplication (FLT3‑ITD)–Specific Measurable Residual Disease (MRD) Clearance Is Associated With Improved Overall Survival (OS)
Published date:
09/01/2023
Excerpt:
To determine whether detection of MRD using FLT3-ITD in QuANTUM-First (NCT02668653) impacted clinical outcomes or the benefits provided by the FLT3 inhibitor quizartinib in patients with newly diagnosed FLT3-ITD+ AML….A best response of CRc with MRD <10-4 correlated with improved OS (HR=0.562)….Long-term OS benefits conferred by quizartinib in QuANTUM-First may, in part, derive from an early and deep reduction of the FLT3-ITD+ leukemia burden.
Trial ID:
Source:
Title:
Randomised evaluation of quizartinib and low-dose ara-C vs low-dose ara-C in older acute myeloid leukemia patients
Published date:
10/01/2021
Excerpt:
...27 FLT3-ITD patients the addition of quizartinib to LDAC improved response (p=0.05) with CR/CRi for quizartinib + LDAC in 5/13 (38%) v 0/14 (0%) in patients receiving LDAC alone. Overall survival (OS) in these FLT3-ITD positive patients was also significantly improved at 2 years for quizartinib + LDAC...
Secondary therapy:
cytarabine
DOI:
https://doi.org/10.1182/bloodadvances.2021005038
Source:
Title:
A phase I/II study of the combination of quizartinib with azacitidine or low-dose cytarabine for the treatment of patients with acute myeloid leukemia and myelodysplastic syndrome
Published date:
04/15/2021
Excerpt:
...patients of any age receiving first-salvage treatment for FLT3-ITD AML or age >60 years with untreated myelodysplastic syndrome or AML were treated with quizartinib plus AZA or LDAC….The median OS for patients treated with quizartinib/AZA and quizartinib/LDAC was 12.8 vs. 4 months, respectively.
Secondary therapy:
azacitidine
DOI:
10.3324/haematol.2020.263392
Source:
Title:
A RANDOMISED EVALUATION OF LOW-DOSE ARA-C PLUS AC220 (QUIZARTINIB) VERSUS LOW DOSE ARA-C IN OLDER PATIENTS WITH ACUTE MYELOID LEUKAEMIA: RESULTS FROM THE LI-1 TRIAL
Published date:
06/12/2020
Excerpt:
Subgroup analyses stratified by FLT3-ITD (13 v 14) identified a benefit from AC220 in response (p=0.05) with CR/CRi for LDAC+AC220 in 5 (38%) v LDAC 0 (0%). OS was also significantly improved at 2 years for LDAC+AC220; HR 0.36 (0.16, 0.85), (p=0.04).
Source:
Title:
A Phase II Single-Arm Open-Labeled Study Evaluating Combination of Quizartinib and Omacetaxine Mepesuccinate (QUIZOM) in Newly Diagnosed or Relapsed/Refractory AML Carrying FlT3-ITD
Published date:
11/06/2019
Excerpt:
QUIZOM is effective and safe for newly diagnosed and R/R FLT3-ITD AML.
DOI:
https://doi.org/10.1182/blood-2019-126510
Source:
Title:
Effect of Co-Mutations and FLT3-ITD Variant Allele Frequency (VAF) on Response to Quizartinib or Salvage Chemotherapy (SC) in Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)
Published date:
11/06/2019
Excerpt:
Quizartinib treatment showed significantly longer median OS vs SC in patients with high FLT3-ITD VAF (23.9 vs 17 weeks respectively; HR, 0.689, P = 0.0148), while the median OS in patients with low FLT3-ITD VAF was similar (34.1 vs 26.6 weeks, respectively; HR, 0.857, P = 0.535)....quizartinib significantly improved survival of patients with high FLT3-ITD VAF relative to SC.
DOI:
https://doi.org/10.1182/blood-2019-121880
Source:
Title:
Clinical Outcomes and Characteristics of Patients (pts) with FLT3-Internal Tandem Duplication (FLT3-ITD)-Mutated Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) Undergoing Hematopoietic Stem Cell Transplant (HSCT) after Quizartinib (Q) or Salvage Chemotherapy (SC) in the Quantum-R Trial
Published date:
11/06/2019
Excerpt:
Independent of HSCT, Q improved survival vs SC in pts with FLT3-ITD R/R AML in QuANTUM-R. Q + SC pooled analyses showed longer survival in pts with HSCT vs pts w/o and in pts with CRc prior to allo-HSCT…Resumption of Q after HSCT was associated with better survival outcomes and was tolerable.
DOI:
https://doi.org/10.1182/blood-2019-124504
Trial ID:
Source:
Title:
Molecular targeted therapy in acute myeloid leukemia
Excerpt:
Quizartinib had significant clinical activity...Higher overall response rates and CR rates were observed in FLT3-ITD patients (56 and 28%, respectively) compared with those lacking the mutation (20 and 7%, respectively).
DOI:
https://doi.org/10.1179/102453312X13336169155619
Source:
Title:
Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial
Excerpt:
In cohort 1, 63 (56%) of 112 FLT3-ITD-positive patients and 16 (36%) of 44 FLT3-ITD-negative patients achieved composite complete remission, with three (3%) FLT3-ITD-positive patients and two (5%) FLT3-ITD-negative patients achieving complete remission....Single-agent quizartinib was shown to be highly active and generally well tolerated in patients with relapsed or refractory acute myeloid leukaemia, particularly those with FLT3-ITD mutations.
DOI:
10.1016/S1470-2045(18)30240-7
Trial ID:
Source:
Title:
Outcomes of Relapsed or Refractory Acute Myeloid Leukemia after Frontline Hypomethylating Agent with Venetoclax Regimens
Published date:
11/06/2019
Excerpt:
Of the remaining 9 pts receiving other therapies, 1 pt with FLT3-ITD achieved a MLFS with quizartinib + low-dose ara-c.
DOI:
https://doi.org/10.1182/blood-2019-128909
Source:
Title:
TARGETING THE IRE1a-XBP1 PATHWAY INDUCES APOPTOSIS IN FLT3-ITD+ AML AND ENHANCES THE EFFECT OF TKI INDUCED FLT3-ITD INHIBITION
Published date:
05/12/2021
Excerpt:
While single treatment of human FLT3-ITD+ MV4-11 cells with either the IRE1α inhibitor or AC220 significantly induced apoptosis, the combinatorial treatment strongly enhanced this effect (by 3-fold p<0.001)…Likewise, the combination significantly decreased the clonogenic potential of FLT3-ITD+ AML cell lines and AML mononuclear patient cells, but not of healthy donor cells.
Source:
Title:
Homoharringtonine synergizes with quizartinib in FLT3-ITD acute myeloid leukemia by targeting FLT3-AKT-c-Myc pathway
Published date:
04/05/2021
Excerpt:
Here, we showed that HHT synergizes with a selective next-generation FLT3 inhibitor, quizartinib, to inhibit cell growth/viability and induce cell-cycle arrest and apoptosis in FLT3-ITD AML cells in vitro, significantly inhibit acute myeloid leukemia progression in vivo, and substantially prolong survival of mice-bearing human FLT3-ITD AML.
DOI:
10.1016/j.bcp.2021.114538
Source:
Title:
An Epigenetic Screen Identifies PRMT5 As a Target for Inhibition of FLT3-ITD AML Cell Growth in Combination with Tyrosine Kinase Inhibitors
Published date:
11/06/2019
Excerpt:
...exposed MOLM-13 and MV4-11 human FLT3-ITD positive AML cells to each inhibitor by itself and in combination with the TKI Quizartinib/AC220 (500pM, IC20)....Of a total of 38 epigenetic inhibitors, less than a third resulted in reduction in cell proliferation after 72 hours of treatment (greater than 10% decrease, 13 for MOLM13, 9 for MV4-11 cell line). When used in combination with TKI (AC220), several epigenetic inhibitors resulted in significantly increased inhibition of proliferation of FLT3-ITD positive AML cells compared to either agent alone (21 for MOLM13, 10 for MV4-11 cell line) (p<0.05).
DOI:
https://doi.org/10.1182/blood-2019-125178
Source:
Title:
Cxcr4 low FLT3/ITD+ Cells Exhibit Enhanced Resistance to the FLT3 Inhibitor Quizartinib Compared to Cxcr4 high FLT3/ITD+ Cells By Elevating Runx1 Expression
Published date:
11/06/2019
Excerpt:
...the number of viable cells incubated with quizartinib (2 or 5nM) was significantly higher in Cxcr4 dim cells compared to Cxcr4 intermediate and Cxcr4 high cells. Cxcl12 dose-dependently inhibited the reduction of viable cells induced by 5nM quizartinib in Cxcr4 dim FLT3/ITD+ Ba/F3 cells (N=5, P<0.05).
DOI:
https://doi.org/10.1182/blood-2019-129513
Source:
Title:
Exome sequencing identifies recurring FLT3 N676K mutations in core-binding factor leukemia
Excerpt:
Both compounds potently inhibited FLT3-ITD–expressing cells with a half maximal inhibitory concentration (IC50) of 13 nM for PKC412 and 2.5 nM for AC220, respectively. FLT3 N676K-expressing cells were also sensitive to FLT3 inhibitors with an IC50 of 7.5 nM for PKC412 and 3 nM for AC220. FLT3-ITD-N676K double mutants showed a strong resistance to both inhibitors (IC50 greater than 80 nM for PKC412 and greater than 16 nM for AC220).
DOI:
https://doi.org/10.1182/blood-2013-01-476473
