Evidence map›Paper›PMID 40327322›Full record

ArticleClinical cancer research : an official journal of the American Association for Cancer Research2025

Synergistic Activity of Combined FLT3-ITD and MDM2 Inhibition with Quizartinib and Milademetan in FLT3-ITD Mutant/TP53 Wild-type Acute Myeloid Leukemias.

Weiguo Zhang, Li Li, Muharrem Muftuoglu, Mahesh Basyal, Noriko Togashi, Koichi Iwanaga, Fumie Tanzawa, Masashi Numata, Dale L Bixby, Harry P Erba and 8 more

Registry-linked trialAbstract readClinical Trial, Phase I
PubMed Full text at PMC Publisher
In one paragraph

Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03552029 (A Phase 1 Study of Milademetan in Combination With Quizartinib in Subjects With FLT3-ITD Mutant Acute Myeloid Leukemia That Are Relapsed/Refractory, or Newly Diagnosed and Unfit for Intensive Chemotherapy), which is not on this map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT03552029 phase1terminatednot on this map

A Phase 1 Study of Milademetan in Combination With Quizartinib in Subjects With FLT3-ITD Mutant Acute Myeloid Leukemia That Are Relapsed/Refractory, or Newly Diagnosed and Unfit for Intensive Chemotherapy

TypeinterventionalSponsorDaiichi SankyoRan2018 to 2021Enrolled10ConditionsAcute Myeloid LeukemiaArmsQuizartinib, Milademetan
3 · Its place in the literature

Who cites it

5 citing papers in PubMed.

  1. Review
  2. Article
  3. Article
  4. Review
  5. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors.

Weiguo Zhang *Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-3294-6322
Li Li *Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-6680-5886
Muharrem Muftuoglu *Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0001-8100-8554
Mahesh BasyalDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0009-0000-0190-9839
Noriko TogashiDaiichi Sankyo Co., Ltd., Tokyo, Japan.ORCID 0000-0003-2606-0231
Koichi IwanagaDaiichi Sankyo Co., Ltd., Tokyo, Japan.ORCID 0009-0005-7232-6485
Fumie TanzawaDaiichi Sankyo Co., Ltd., Tokyo, Japan.ORCID 0009-0007-2138-5359
Masashi NumataDaiichi Sankyo Co., Ltd., Tokyo, Japan.ORCID 0009-0004-6636-6272
Dale L BixbyHematologic Oncology, University of Michigan Medical School, Ann Arbor, Michigan.ORCID 0000-0001-6885-8239
Harry P ErbaHematologic Malignancies and Cellular Therapy, Duke University, Durham, North Carolina.ORCID 0000-0003-1093-2189
Nikolai PodoltsevHematology Section, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.ORCID 0000-0002-3657-778X
Gary J SchillerHematologic Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California.ORCID 0000-0002-7508-3467
Prasanna KumarDaiichi Sankyo, Inc., Basking Ridge, New Jersey.ORCID 0009-0007-1789-5057
Arnaud LesegretainDaiichi Sankyo, Inc., Basking Ridge, New Jersey.ORCID 0000-0003-3732-1273
Takeshi IsoyamaDaiichi Sankyo Co., Ltd., Tokyo, Japan.ORCID 0009-0001-1797-5205
Takahiko SekiDaiichi Sankyo, Inc., Basking Ridge, New Jersey.ORCID 0000-0002-1531-3291
Naval DaverDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0001-7103-373X
Michael AndreeffDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-1144-1958

Funding

Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Fabien Delerue · 1985 to 2026
$290.8M
Therapeutic targeting of p53 reactivation-induced OXPHOS dependency and stress responses to overcome resistance to venetoclax/HMA in AMLR21CA267401 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI ANDREEFF, MICHAEL · 2022 to 2023
$412k
Daiichi Sankyo Company ()NCI NIH HHS P30 CA016672NCI NIH HHS R21 CA267401Paul and Mary Haas Chair in Genetics
6 · The paper itself

Abstract

purposeAcute myeloid leukemia (AML) is characterized by frequent mutations in FMS-like tyrosine kinase 3 (FLT3), overexpression of murine double minute 2 (MDM2), and TP53 wild-type (WT). Monotherapies targeting FLT3 frequently result in the development of resistant disease. In this study, we investigated the antileukemic efficacy of co-targeting FLT3 and MDM2 with quizartinib and milademetan (Q/M) in FLT3 internal tandem duplication (FLT3-ITD) AML cell lines, xenograft and patient-derived xenograft (PDX) models, and a phase I clinical trial. EXPERIMENTAL

designPreclinical studies used human and murine cell lines carrying FLT3-ITD and/or tyrosine kinase domain mutations, TP53 WT/knockdown, leukemia cell xenograft models, and a PDX model. Assays were conducted using milademetan (DS-3032b) and murine-specific MDM2 inhibitor (DS-5272). An open-label, phase I, dose-escalation clinical trial (ClinicalTrials.gov NCT03552029) was conducted.

resultsDual inhibition of FLT3-ITD and MDM2 synergistically induced apoptosis in FLT3-ITD/TP53 WT AML and venetoclax-resistant cell lines, reduced tumor burden, and improved survival in xenograft and PDX models of FLT3-ITD AML. Phase I clinical data indicated favorable safety and tolerability for the Q/M combination treatment. Complete responses with incomplete hematologic recovery were achieved in 40% of patients with relapsed/refractory AML. Unsupervised single-cell proteomic analysis showed that Q/M treatment decreased the expression of prosurvival proteins (p-ERK, p-AKT, and Mcl-1) and activated protein signaling downstream of p53 including p53 upregulated modulator of apoptosis. YTHDF2 was increased after therapy in resistant cells. The Q/M combination demonstrated higher activity in CD34+ versus CD34- leukemia blasts.

conclusionsPreclinical and mechanistic rationale and preliminary clinical data support the future development of MDM2/FLT3-targeting strategies for FLT3-mutant AML.

Indexed as

Antineoplastic Combined Chemotherapy ProtocolsBenzothiazolesfms-Like Tyrosine Kinase 3Leukemia, Myeloid, AcuteMutationPhenylurea CompoundsProto-Oncogene Proteins c-mdm2Tumor Suppressor Protein p53AnimalsApoptosisCell Line, TumorDrug SynergismFemaleHumansMaleMiceBenzothiazolesFLT3 protein, humanfms-Like Tyrosine Kinase 3MDM2 protein, humanPhenylurea CompoundsProto-Oncogene Proteins c-mdm2quizartinibTP53 protein, humanTumor Suppressor Protein p53

Identifiers

PMID40327322
PMCPMC12260509

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.