4.4 Review

Which FLT3 Inhibitor for Treatment of AML?

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Article Hematology

Venetoclax combines synergistically with FLT3 inhibition to effectively target leukemic cells in FLT3-ITD+ acute myeloid leukemia models

Raghuveer Singh Mali et al.

Summary: The combination of FLT3-ITD inhibition with venetoclax demonstrates impressive anti-tumor activity in FLT3-ITD+ AML preclinical models, highlighting the strong mechanistic rationale for clinical studies.

HAEMATOLOGICA (2021)

Review Hematology

Hematopoietic Cell Transplantation in the Treatment of Newly Diagnosed Adult Acute Myeloid Leukemia: An Evidence-Based Review from the American Society of Transplantation and Cellular Therapy

Bhagirathbhai Dholaria et al.

Summary: This evidence-based review examines the role of hematopoietic cell transplantation (HCT) in the management of newly diagnosed adult acute myeloid leukemia (AML) and recommends the preferential use of allogeneic HCT with myeloablative conditioning in eligible patients. Allogeneic HCT offers a survival benefit in intermediate- and high-risk AML patients and is now considered part of standard clinical care.

TRANSPLANTATION AND CELLULAR THERAPY (2021)

Article Hematology

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

Siddhartha Ganguly et al.

Summary: Quizartinib significantly prolonged overall survival in patients with R/R FLT3-ITD AML, with transplant recipients showing longer median overall survival compared to those treated without allo-HSCT. Continuation of quizartinib after HSCT was found to be tolerable and may be associated with prolonged survival, highlighting its potential value in managing FLT3-ITD R/R AML patients.

TRANSPLANTATION AND CELLULAR THERAPY (2021)

Article Hematology

Midostaurin in combination with chemotherapy is most effective in patients with acute myeloid leukemia presenting with high FLT3-ITD allelic ratio who proceed to allogeneic stem cell transplantation while in first complete remission

Yishai Ofran et al.

Summary: The study demonstrates the benefits of incorporating midostaurin into intensive chemotherapy regimens, particularly for high-AR AML patients, to whom it should be offered along with allo-SCT in CR1.

EUROPEAN JOURNAL OF HAEMATOLOGY (2021)

Article Biophysics

Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia

Richard T. Maziarz et al.

Summary: The study evaluated the efficacy of adding midostaurin to standard-of-care treatment in preventing relapse following alloHSCT in FLT3-ITD AML patients. Results showed an 18-month RFS rate of 89% in the midostaurin maintenance therapy group compared to 76% in the SOC group. The inhibition of FLT3 phosphorylation to <70% of baseline was associated with improved RFS, indicating potential clinical benefit in some patients.

BONE MARROW TRANSPLANTATION (2021)

Review Hematology

Maintenance therapy for FLT3-ITD-mutated acute myeloid leukemia

Andreas Burchert

Summary: FLT3-ITD, a constitutively activated variant of FLT3 tyrosine kinase receptor, is associated with poor prognosis in AML. Development of FLT3-specific TKI has shown promising results in improving outcomes, especially in the context of maintenance therapy post-HCT. Recent trials with sorafenib have demonstrated the potential of targeted maintenance therapy in changing the treatment paradigm for FLT3-ITD mutated AML.

HAEMATOLOGICA (2021)

Article Hematology

Clonal evolution of acute myeloid leukemia with FLT3-ITD mutation under treatment with midostaurin

Laura K. Schmalbrock et al.

Summary: This study investigated clonal evolution and resistance mechanisms in FLT3-ITD-mutated AML patients treated with midostaurin, revealing that some patients acquired mutations in signaling pathways, such as MAPK, after becoming FLT3-ITD negative, while others showed no FLT3-ITD mutational changes, suggesting alternative resistance mechanisms or loss of midostaurin inhibitory activity due to inadequate drug levels.
Correction Oncology

Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML (vol 13, 132, 2020)

Musa Yilmaz et al.

JOURNAL OF HEMATOLOGY & ONCOLOGY (2021)

Article Oncology

Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial

Christoph Roellig et al.

Summary: The addition of sorafenib to standard chemotherapy in newly diagnosed AML patients led to a significant improvement in event-free and relapse-free survival, although the overall survival benefit did not reach statistical significance. The results confirm the anti-leukemic activity of sorafenib.

LEUKEMIA (2021)

Article Oncology

Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial

Richard A. Larson et al.

Summary: The addition of midostaurin to standard chemotherapy in FLT3-mutant AML patients has shown significant benefits in reducing the risk of death and relapse. However, the impact of maintenance therapy on overall outcomes remains inconclusive.

LEUKEMIA (2021)

Review Oncology

Acute myeloid leukemia: Treatment and research outlook for 2021 and the MD Anderson approach

Hagop M. Kantarjian et al.

Summary: Research on acute myeloid leukemia (AML) has progressed rapidly, with the US FDA approving 10 drugs for various AML indications since 2017. Different subsets of AML require tailored treatment strategies, including young patients fit for chemotherapy and older patients not suitable for intensive treatment, with combination therapy showing promising results.

CANCER (2021)

Article Hematology

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 or myelodysplastic syndrome

Mahesh Swaminathan et al.

Summary: In this trial, the combination of quizartinib with AZA or LDAC showed promising results in improving overall survival and relapse-free survival in both frontline and first salvage therapy for patients with FLT3-ITD-mutated AML, with good tolerability.

HAEMATOLOGICA (2021)

Article Hematology

Randomized evaluation of quizartinib and low-dose ara-C vs low-dose ara-C in older acute myeloid leukemia patients

Mike Dennis et al.

Summary: For older AML patients not suitable for intensive chemotherapy, the addition of quizartinib to low-dose ara-C (LDAC) therapy improved response rates and overall survival, particularly in FLT3-ITD positive patients. This study suggests that quizartinib may be considered for future triplet-based treatment approaches.

BLOOD ADVANCES (2021)

Article Oncology

The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance

Sunil K. Joshi et al.

Summary: The study reveals that the bone marrow microenvironment protects residual AML cells and AML cells develop resistance mechanisms over time. By integrating multiple methods, early resistant cells were found to undergo metabolic reprogramming and depend on AURKB, while late resistant cells are characterized by expansion of pre-existing NRAS mutant subclones and metabolic reprogramming.

CANCER CELL (2021)

Article Hematology

Post-transplant maintenance therapy in patients with FLT3-mutated acute myeloid leukemia: Real-world treatment patterns and outcomes

James D. Griffin et al.

Summary: The study evaluated maintenance therapy patterns and outcomes in FLT3-mutated AML patients post-HSCT, showing that FLT3 inhibitor maintenance therapy can improve relapse-free survival and overall survival.

EUROPEAN JOURNAL OF HAEMATOLOGY (2021)

Meeting Abstract Oncology

Follow-up of patients with FLT3-mutated R/R AML in the phase 3 ADMIRAL trial.

Alexander E. Perl et al.

JOURNAL OF CLINICAL ONCOLOGY (2021)

Article Oncology

Acute cardiotoxicity after initiation of the novel tyrosine kinase inhibitor gilteritinib for acute myeloid leukemia

Lisa Kim et al.

Summary: Gilteritinib may be associated with early cardiotoxicities, including non-ischemic cardiomyopathy and myocarditis. Cardiac magnetic resonance imaging can be an important modality to help differentiate or diagnose early cardiotoxicities associated with novel targeted therapies.

CARDIO-ONCOLOGY (2021)

Article Oncology

FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

Naval Daver et al.

Summary: Approximately 30% of newly diagnosed AML patients have FLT3 gene mutations, with FLT3-ITDmut showing adverse prognostic impact. Guidelines recommend rapid molecular testing for FLT3(mut) and early use of targeted agents, but challenges remain in prolonged remission, limited options for refractory patients, and resistance mechanisms that call for multi-agent therapies.

BLOOD CANCER JOURNAL (2021)

Review Biochemistry & Molecular Biology

Mechanisms Underlying Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia

Motoki Eguchi et al.

BIOMEDICINES (2020)

Article Education, Scientific Disciplines

Management of toxicities associated with targeted therapies for acute myeloid leukemia: when to push through and when to stop

Eunice S. Wang et al.

HEMATOLOGY-AMERICAN SOCIETY OF HEMATOLOGY EDUCATION PROGRAM (2020)

Article Hematology

Gilteritinib: potent targeting of FLT3 mutations in AML

Mark Levis et al.

BLOOD ADVANCES (2020)

Review Oncology

Midostaurin In Acute Myeloid Leukemia: An Evidence-Based Review And Patient Selection

Hussein A. Abbas et al.

CANCER MANAGEMENT AND RESEARCH (2019)

Article Medicine, Research & Experimental

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure-FLT3 Relationship

Tao Liu et al.

CTS-CLINICAL AND TRANSLATIONAL SCIENCE (2018)

Review Oncology

FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions

Maria Larrosa-Garcia et al.

MOLECULAR CANCER THERAPEUTICS (2017)

Article Medicine, General & Internal

Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation

R. M. Stone et al.

NEW ENGLAND JOURNAL OF MEDICINE (2017)

Article Medicine, General & Internal

Genomic Classification and Prognosis in Acute Myeloid Leukemia

Elli Papaemmanuil et al.

NEW ENGLAND JOURNAL OF MEDICINE (2016)

Article Multidisciplinary Sciences

Crenolanib is a selective type I pan-FLT3 inhibitor

Catherine Choy Smith et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2014)

Review Hematology

Sorafenib Induced Hand Foot Skin Rash in FLT3 ITD Mutated Acute Myeloid Leukemia-A Case Report and Review of Literature

Jayastu Senapati et al.

MEDITERRANEAN JOURNAL OF HEMATOLOGY AND INFECTIOUS DISEASES (2014)

Article Multidisciplinary Sciences

Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia

Catherine C. Smith et al.

NATURE (2012)

Review Hematology

Molecular prognostic factors in cytogenetically normal acute myeloid leukemia

Alison Walker et al.

EXPERT REVIEW OF HEMATOLOGY (2012)

Article Hematology

Phase I study of sorafenib in patients with refractory or relapsed acute leukemias

Gautam Borthakur et al.

HAEMATOLOGICA-THE HEMATOLOGY JOURNAL (2011)

Article Oncology

Regulation of hematopoietic stem cells by the steel factor/KIT signaling pathway

David Kent et al.

CLINICAL CANCER RESEARCH (2008)

Article Oncology

Mutant FLT3:: A direct target of sorafenib in acute myelogenous leukemia

Weiguo Zhang et al.

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE (2008)

Article Medicine, General & Internal

Sorafenib in advanced hepatocellular carcinoma

Josep M. Llovet et al.

NEW ENGLAND JOURNAL OF MEDICINE (2008)

Article Oncology

The FLT3 inhibitor PKC412 in combination with cytostatic drugs in vitro in acute myeloid leukemia

Lars Mollgard et al.

CANCER CHEMOTHERAPY AND PHARMACOLOGY (2008)

Article Medicine, General & Internal

Sorafenib in advanced clear-cell renal-cell carcinoma

Bernard Escudier et al.

NEW ENGLAND JOURNAL OF MEDICINE (2007)

Review Biotechnology & Applied Microbiology

Discovery and development of sorafenib: a multikinase inhibitor for treating cancer

Scott Wilhelm et al.

NATURE REVIEWS DRUG DISCOVERY (2006)