Evidence map›Paper›PMID 32414851›Full record

ArticleHaematologica2021

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

Raghuveer Singh Mali, Qi Zhang, Rosa Anna DeFilippis, Antonio Cavazos, Vinitha Mary Kuruvilla, Jayant Raman, Vidhi Mody, Edna F Choo, Monique Dail, Neil P Shah and 3 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Haematologica, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
89citing papers in PubMed, 1 pooled it
10.6field-weighted citation impact, top 1% of its field
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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

89 citing papers in PubMed, 1 synthesis or guideline pooled it, 138 citations in OpenAlex.

  1. Pooled it
  2. Trial
  3. Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed and Relapsed or RefractoryJournal of clinical oncology : official journal of the American Society of Clinical Oncology · 2024
    Trial
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  18. Triplet regimens for all: genomically agnostic approaches to improve on HMA + VEN in AML?Hematology. American Society of Hematology. Education Program · 2025
    Review
  19. Review
  20. Article

29 more citing papers are in PubMed but not listed here.

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

13 authors at 3 institutions in 1 country.

Raghuveer Singh MaliDepartment of Translational Oncology, Genentech, Inc., South San Francisco, CA, USA.
Qi ZhangDepartment of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
Rosa Anna DeFilippisDivision of Hematology and Oncology, University of California at San Francisco, San Francisco, USA.
Antonio CavazosDepartment of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
Vinitha Mary KuruvillaDepartment of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
Jayant RamanDivision of Hematology and Oncology, University of California at San Francisco, San Francisco, USA.
Vidhi ModyDepartment of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA.
Edna F ChooDepartment of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA.
Monique DailOncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA.
Neil P ShahHelen Diller Comprehensive Cancer Center, University of California at San Francisco, USA.
Marina KonoplevaDepartment of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
Deepak SampathDepartment of Translational Oncology, Genentech, Inc., South San Francisco, CA, USA.
Elisabeth A LasaterDepartment of Translational Oncology, Genentech, Inc., South San Francisco, CA, USA.
The University of Texas MD Anderson Cancer Center · USUniversity of California, San Francisco · USUCSF Helen Diller Family Comprehensive Cancer Center · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

FLT3 internal tandem duplication (FLT3-ITD) mutations account for ~25% of adult acute myeloid leukemia cases and are associated with poor prognosis. Venetoclax, a selective BCL-2 inhibitor, has limited monotherapy activity in relapsed/refractory acute myeloid leukemia with no responses observed in a small subset of FLT3-ITD+ patients. Further, FLT3-ITD mutations emerged at relapse following venetoclax monotherapy and combination therapy suggesting a potential mechanism of resistance. Therefore, we investigated the convergence of FLT3-ITD signaling on the BCL-2 family proteins and determined combination activity of venetoclax and FLT3-ITD inhibition in preclinical models. In vivo, venetoclax combined with quizartinib, a potent FLT3 inhibitor, showed greater anti-tumor efficacy and prolonged survival compared to monotherapies. In a patient-derived FLT3-ITD+ xenograft model, cotreatment with venetoclax and quizartinib at clinically relevant doses had greater anti-tumor activity in the tumor microenvironment compared to quizartinib or venetoclax alone. Use of selective BCL-2 family inhibitors further identified a role for BCL-2, BCL-XL and MCL-1 in mediating survival in FLT3-ITD+ cells in vivo and highlighted the need to target all three proteins for greatest anti-tumor activity. Assessment of these combinations in vitro revealed synergistic combination activity for quizartinib and venetoclax but not for quizartinib combined with BCL-XL or MCL-1 inhibition. FLT3-ITD inhibition was shown to indirectly target both BCL-XL and MCL-1 through modulation of protein expression, thereby priming cells toward BCL-2 dependence for survival. These data demonstrate that FLT3-ITD inhibition combined with venetoclax has impressive anti-tumor activity in FLT3-ITD+ acute myeloid leukemia preclinical models and provides strong mechanistic rational for clinical studies.

Indexed as

Leukemia, Myeloid, AcuteAdultBridged Bicyclo Compounds, HeterocyclicCell Line, Tumorfms-Like Tyrosine Kinase 3HumansProtein Kinase InhibitorsSulfonamidesTumor MicroenvironmentBridged Bicyclo Compounds, HeterocyclicFLT3 protein, humanfms-Like Tyrosine Kinase 3Protein Kinase InhibitorsSulfonamidesvenetoclax

Identifiers

PMID32414851
PMCPMC8017817
OpenAlexW3024508217

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC
Read underepoch 390

Registered trials

None linked

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.