☆ 4.6 Review

Molecularly Targeted Therapy in Acute Myeloid Leukemia: Current Treatment Landscape and Mechanisms of Response and Resistance

CANCERS (2023)

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Article Hematology

Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial

Justin M. Watts et al.

Summary: This study evaluated the safety, pharmacokinetics, pharmacodynamics, and clinical activity of Olutasidenib in patients with acute myeloid leukemia or myelodysplastic syndrome with mutant IDH1. The results showed that Olutasidenib, as monotherapy or in combination with azacitidine, was well tolerated and exhibited meaningful clinical activity. These findings provide a rationale for further evaluation of Olutasidenib in different populations of patients with myeloid malignancies.

LANCET HAEMATOLOGY (2023)

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Article Oncology

Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naive Acute Myeloid Leukemia

Marina Konopleva et al.

Summary: The efficacy and safety of venetoclax + azacitidine in patients with FLT3-mutant acute myeloid leukemia were evaluated. The results showed significant differences in composite complete remission rates and overall survival between patients treated with venetoclax + azacitidine and those treated with azacitidine alone. These findings suggest that venetoclax + azacitidine may be of importance in the treatment of patients with FLT3 mutations.

CLINICAL CANCER RESEARCH (2022)

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Article Oncology

Efficacy and safety of enasidenib and azacitidine combination in patients with IDH2 mutated acute myeloid leukemia and not eligible for intensive chemotherapy

Sangeetha Venugopal et al.

Summary: Enasidenib and azacitidine synergistically enhance cell differentiation, and the addition of venetoclax appears to improve outcomes in IDH2 mutated acute myeloid leukemia. This study showed that ENA+AZA was effective and well-tolerated in elderly patients with newly diagnosed IDH2(mut) AML, as well as in patients with relapsed/refractory AML.

BLOOD CANCER JOURNAL (2022)

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Article Hematology

Differential impact of IDH1/2 mutational subclasses on outcome in adult AML: results from a large multicenter study

Jan M. Middeke et al.

Summary: Mutations in the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are common in acute myeloid leukemia (AML), affecting about 20% of patients. While these mutations do not impact treatment response rates or overall survival, different subtypes of IDH1/2 mutations may have an association with outcomes.

BLOOD ADVANCES (2022)

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Article Medicine, General & Internal

Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia

Pau Montesinos et al.

Summary: This study demonstrated that the combination therapy of oral ivosidenib and azacitidine showed better event-free survival and longer overall survival in patients with newly diagnosed IDH1-mutated acute myeloid leukemia.

NEW ENGLAND JOURNAL OF MEDICINE (2022)

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Article Oncology

Hypomethylating agent and venetoclax with FLT3 inhibitor triplet therapy in older/unfit patients with FLT3 mutated AML

Musa Yilmaz et al.

Summary: In older/unfit newly diagnosed patients with FLT3 mutated AML, lower intensity chemotherapy in combination with either a FLT3 inhibitor or with venetoclax results in improved overall survival rates.

BLOOD CANCER JOURNAL (2022)

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Article Oncology

Venetoclax Plus Gilteritinib for FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia

Naval Daver et al.

Summary: Combining gilteritinib with venetoclax has shown promising results in treating relapsed/refractory FLT3-mutated AML, with high rates of response and molecular remission regardless of prior FLT3 inhibitor therapy.

JOURNAL OF CLINICAL ONCOLOGY (2022)

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Article Oncology

Long-term results of a phase 2 trial of crenolanib combined with 7+3 chemotherapy in adults with newly diagnosed FLT3 mutant AML.

Eunice S. Wang et al.

JOURNAL OF CLINICAL ONCOLOGY (2022)

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Article Oncology

A phase Ib/II study of ivosidenib with venetoclax +/- azacitidine in IDH1-mutated hematologic malignancies.

Curtis Andrew Lachowiez et al.

JOURNAL OF CLINICAL ONCOLOGY (2022)

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Article Oncology

Eprenetapopt Plus Azacitidine After Allogeneic Hematopoietic Stem-Cell Transplantation for TP53-Mutant Acute Myeloid Leukemia and Myelodysplastic Syndromes

Asmita Mishra et al.

Summary: This study evaluated the efficacy and safety of Eprenetapopt combined with azacitidine as maintenance therapy after HCT in patients with mTP53 AML and MDS. The results showed that this treatment regimen was well tolerated and achieved encouraging RFS and OS outcomes in this high-risk population.

JOURNAL OF CLINICAL ONCOLOGY (2022)

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Meeting Abstract Hematology

Update on a Phase 1/2 First-in-Human Study of the Menin-KMT2A (MLL) Inhibitor Ziftomenib (KO-539) in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Harry P. Erba et al.

BLOOD (2022)

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Meeting Abstract Hematology

The Menin Inhibitor SNDX-5613 (revumenib) Leads to Durable Responses in Patients (Pts) with KMT2A-Rearranged or NPM1 Mutant AML: Updated Results of a Phase (Ph) 1 Study

Ghayas C. Issa et al.

BLOOD (2022)

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Article Hematology

Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study

Eytan M. Stein et al.

Summary: Ivosidenib and enasidenib, as targeted oral inhibitors, demonstrated good safety and efficacy when combined with intensive chemotherapy in newly diagnosed mIDH1/2 AML patients, achieving end-of-induction complete remission rates of 55% and 47% respectively.

BLOOD (2021)

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Meeting Abstract Hematology

Quizartinib (Quiz) with Decitabine (DAC) and Venetoclax (VEN) Is Highly Active in Patients (pts) with FLT3-ITD Mutated Acute Myeloid Leukemia (AML) - RAS/MAPK Mutations Continue to Drive Primary and Secondary Resistance

Musa Yilmaz et al.

BLOOD (2021)

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Meeting Abstract Hematology

Long-Term Overall Survival (OS) with Oral Azacitidine (Oral-AZA) in Patients with Acute Myeloid Leukemia (AML) in First Remission after Intensive Chemotherapy (IC): Updated Results from the Phase 3 QUAZAR AML-001 Trial

Andrew H. Wei et al.

BLOOD (2021)

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Meeting Abstract Hematology

Phase II Study of Cladribine, Idarubicin, Cytarabine (CLIA) Plus Gilteritinib in Patients with FLT3 Mutated Acute Myeloid Leukemia (AML)

Tareq Abuasab et al.

BLOOD (2021)

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Meeting Abstract Hematology

A Triplet Combination of Azacitidine, Venetoclax and Gilteritinib for Patients with FLT3-Mutated Acute Myeloid Leukemia: Results from a Phase I/II Study

Nicholas J. Short et al.

BLOOD (2021)

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Meeting Abstract Hematology

Phase I/II Study of Azacitidine (AZA) with Venetoclax (VEN) and Magrolimab (Magro) in Patients (pts) with Newly Diagnosed Older/Unfit or High-Risk Acute Myeloid Leukemia (AML) and Relapsed/Refractory (R/R) AML

Naval Daver et al.

BLOOD (2021)

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Article Oncology

Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes

David A. Sallman et al.

Summary: The combination treatment with eprenetapopt and azacitidine is well-tolerated and results in high rates of clinical response and molecular remissions in patients with TP53-mutant MDS and oligoblastic AML.

JOURNAL OF CLINICAL ONCOLOGY (2021)

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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.

BLOOD (2021)

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Article Oncology

Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial

Courtney D. DiNardo et al.

Summary: The study evaluated the safety and activity of enasidenib plus azacitidine in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia, showing that the combination therapy significantly improved overall response rates compared to azacitidine monotherapy, which may lead to improved outcomes for these patients.

LANCET ONCOLOGY (2021)

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Article Oncology

Eprenetapopt Plus Azacitidine in TP53-Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia: A Phase II Study by the Groupe Francophone des Myelodysplasies (GFM)

Thomas Cluzeau et al.

Summary: The combination of Eprenetapopt with AZA showed potentially higher overall response rate (ORR) and complete remission (CR) rate, as well as longer overall survival (OS) in untreated high-risk TP53m MDS and AML patients, with main treatment-related adverse events being febrile neutropenia and neurologic adverse events.

JOURNAL OF CLINICAL ONCOLOGY (2021)

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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)

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Letter Oncology

Triplet therapy with venetoclax, FLT3 inhibitor and decitabine for FLT3-mutated acute myeloid leukemia

Abhishek Maiti et al.

BLOOD CANCER JOURNAL (2021)

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Article Hematology

Prognostic significance of concurrent gene mutations i n intensively treated patients with IDH-mutated AML: an ALFA study

Matthieu Duchmann et al.

Summary: This study analyzed the prognostic impact of co-occurring genetic alterations and HSCT in AML patients with IDH mutations treated with IC. NPM1 mutations were found to be associated with improved overall survival in different IDH subgroups. HSCT was shown to have a positive impact on the outcomes of nonfavorable IDH1/2-mutated AML patients.

BLOOD (2021)

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Article Multidisciplinary Sciences

Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia

Feng Wang et al.

Summary: The authors found that stemness features are the major drivers of primary resistance to IDH inhibitors, while high-risk mutations are the main drivers of acquired resistance. Targeting stemness and certain high-risk co-occurring mutations may help overcome resistance to IDH inhibitors in AML.

NATURE COMMUNICATIONS (2021)

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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)

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Review Oncology

Therapeutic implications of menin inhibition in acute leukemias

Ghayas C. Issa et al.

Summary: Menin inhibitors are novel targeted agents currently being developed for the treatment of genetically defined subsets of acute leukemia, showing promising early results in specific leukemia types, such as NPM1 mutations. These inhibitors target various gene regulatory roles of menin in leukemogenesis and are being investigated in clinical studies for relapsed acute leukemias.

LEUKEMIA (2021)

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Article Hematology

CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial

Jeffrey E Lancet et al.

Lancet Haematology (2021)

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Meeting Abstract Hematology

Safety and Efficacy of Menin Inhibition in Patients (Pts) with MLL-Rearranged and NPM1 Mutant Acute Leukemia: A Phase (Ph) 1, First-in-Human Study of SNDX-5613 (AUGMENT 101)

Eytan M. Stein et al.

BLOOD (2021)

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Article Oncology

Patterns of Resistance Differ in Patients with Acute Myeloid Leukemia Treated with Type I versus Type II FLT3 Inhibitors

Ahmad S. Alotaibi et al.

Summary: The study revealed distinct emergent mutations in FLT3-mutated AML patients treated with FLT3 inhibitors, indicating different pathways of secondary resistance. Furthermore, pretreatment RAS/MAPK mutations may be associated with primary resistance in patients.

BLOOD CANCER DISCOVERY (2021)

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Review Oncology

Therapeutic Targeting of the Macrophage Immune Checkpoint CD47 in Myeloid Malignancies

Mark P. Chao et al.

FRONTIERS IN ONCOLOGY (2020)

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Article Oncology

Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With FLT3-Internal Tandem Duplication Mutation (SORMAIN)

Andreas Burchert et al.

JOURNAL OF CLINICAL ONCOLOGY (2020)

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Article Hematology

Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML

Sung Choe et al.

BLOOD ADVANCES (2020)

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Letter Oncology

Clonal evolution with acquisition of BCR-ABL1 in refractory acute myeloid leukemia post therapy with FLT3-inhibitor

Beenu Thakral et al.

LEUKEMIA & LYMPHOMA (2020)

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Article Medicine, General & Internal

Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia

C. D. DiNardo et al.

NEW ENGLAND JOURNAL OF MEDICINE (2020)

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Article Oncology

Emergence of BCR-ABL1 Fusion in AML Post-FLT3 Inhibitor-Based Therapy: A Potentially Targetable Mechanism of Resistance - A Case Series

Ahmad S. Alotaibi et al.

FRONTIERS IN ONCOLOGY (2020)

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Article Oncology

Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia

Daniel A. Pollyea et al.

LEUKEMIA (2019)

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Article Oncology

Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in Acute Myeloid Leukemia

Christine M. McMahon et al.

CANCER DISCOVERY (2019)

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Article Oncology

Inhibition of Bcl-2 Synergistically Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Preclinical Models of FLT3-Mutated Acute Myeloid Leukemia

Jun Ma et al.

CLINICAL CANCER RESEARCH (2019)

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Article Oncology

Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial

Jorge E. Cortes et al.

LANCET ONCOLOGY (2019)

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Article Oncology

CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia

Jeffrey E. Lancet et al.

JOURNAL OF CLINICAL ONCOLOGY (2018)

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Article Medicine, General & Internal

Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML

C. D. DiNardo et al.

NEW ENGLAND JOURNAL OF MEDICINE (2018)

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Article Multidisciplinary Sciences

Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations

Andrew M. Intlekofer et al.

NATURE (2018)

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Article Multidisciplinary Sciences

Functional genomic landscape of acute myeloid leukaemia

Jeffrey W. Tyner et al.

NATURE (2018)

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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)

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Article Hematology

Co-occurrence of FLT3-TKD and NPM1 mutations defines a highly favorable prognostic AML group

Prajwal Boddu et al.

BLOOD ADVANCES (2017)

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Article Medicine, General & Internal

Genomic Classification and Prognosis in Acute Myeloid Leukemia

Elli Papaemmanuil et al.

NEW ENGLAND JOURNAL OF MEDICINE (2016)

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Article Oncology

Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia

Marina Konopleva et al.

CANCER DISCOVERY (2016)

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Article Hematology

Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML

Courtney D. DiNardo et al.

AMERICAN JOURNAL OF HEMATOLOGY (2015)

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Article Oncology

Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial

Christoph Rollig et al.

LANCET ONCOLOGY (2015)

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Article Biochemistry & Molecular Biology

Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia

Steven M. Chan et al.

NATURE MEDICINE (2015)

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Article Oncology

Clinical features of De Novo acute myeloid leukemia with concurrent DNMT3A, FLT3 and NPM1 mutations

Sanam Loghavi et al.

JOURNAL OF HEMATOLOGY & ONCOLOGY (2014)

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Editorial Material Oncology

R-2-Hydroxyglutarate as the Key Effector of IDH Mutations Promoting Oncogenesis

Dan Ye et al.

CANCER CELL (2013)

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Article Multidisciplinary Sciences

(R)-2-Hydroxyglutarate Is Sufficient to Promote Leukemogenesis and Its Effects Are Reversible

Julie-Aurore Losman et al.

SCIENCE (2013)

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Article Oncology

Prognostic significance of alterations in IDH enzyme isoforms in patients with AML treated with high-dose cytarabine and idarubicin

Farhad Ravandi et al.

CANCER (2012)

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Article Oncology

The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate

Patrick S. Ward et al.

CANCER CELL (2010)

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Article Oncology

Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation

Maria E. Figueroa et al.

CANCER CELL (2010)

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Article Oncology

Prognostic Impact of Isocitrate Dehydrogenase Enzyme Isoforms 1 and 2 Mutations in Acute Myeloid Leukemia: A Study by the Acute Leukemia French Association Group

Nicolas Boissel et al.

JOURNAL OF CLINICAL ONCOLOGY (2010)

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Article Oncology

IDH1 and IDH2 Mutations Are Frequent Genetic Alterations in Acute Myeloid Leukemia and Confer Adverse Prognosis in Cytogenetically Normal Acute Myeloid Leukemia With NPM1 Mutation Without FLT3 Internal Tandem Duplication

Peter Paschka et al.

JOURNAL OF CLINICAL ONCOLOGY (2010)

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Article Immunology

Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations

Stefan Gross et al.

JOURNAL OF EXPERIMENTAL MEDICINE (2010)

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Article Medicine, General & Internal

Anthracycline Dose Intensification in Acute Myeloid Leukemia

Hugo F. Fernandez et al.

NEW ENGLAND JOURNAL OF MEDICINE (2009)

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Article Medicine, General & Internal

Recurring Mutations Found by Sequencing an Acute Myeloid Leukemia Genome

Elaine R. Mardis et al.

NEW ENGLAND JOURNAL OF MEDICINE (2009)

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