|
| Status |
Public on Mar 01, 2023 |
| Title |
The menin inhibitor SNDX-5613 for KMT2A rearranged or NPM1 mutant leukemia |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Targeting critical epigenetic regulators reverses aberrant transcription in cancer,
thereby restoring normal tissue function. The interaction of menin with lysine
methyltransferase 2A (KMT2A), an epigenetic regulator, is a dependency in acute
leukaemia caused by either rearrangement of KMT2A or mutation in Nucleophosmin 1(NPM1). KMT2A rearrangements occur in up to 10% of acute leukaemias and have an adverse prognosis whereas NPM1 mutations occur in up to 30%, forming the most common genetic alteration in acute myeloid leukaemia7,8. Here, we describe the results of the first-in-human phase 1 clinical trial investigating revumenib (SNDX-5613), a potent and selective oral inhibitor of the menin–KMT2A interaction, in patients with relapsed or refractory acute leukaemia (ClinicalTrials.gov, NCT04065399). We show that therapy with revumenib was associated with a low frequency of grade 3 or higher treatment-related adverse events and a 30% rate of complete remission or complete remission with partial haematologic recovery (CR/CRh) in the efficacy analysis population. Asymptomatic prolongation of the QT interval on electrocardiography was identified as the only dose-limiting toxicity. Remissions occurred in leukaemias refractory to multiple previous lines of therapy. We demonstrate clearance of residual disease using sensitive clinical assays and identify hallmarks of differentiation into normal haematopoietic cells, including differentiation syndrome. These data establish menin inhibition as a therapeutic strategy for susceptible acute leukaemia subtypes.
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| |
|
| Overall design |
RNA-sequencing of human leukemia cells from bone marrow on patient derived xenografts (PDX) treated with SNDX-5613 for 1 week.
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| |
|
| Contributor(s) |
Perner F, Hatton C |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Oct 27, 2022 |
| Last update date |
Mar 04, 2023 |
| Contact name |
Florian Perner |
| E-mail(s) |
f.perner@googlemail.com
|
| Phone |
+49 1515 9980628
|
| Organization name |
Dana Farber Cancer Institute
|
| Department |
Pediatric oncology
|
| Lab |
Armstrong
|
| Street address |
360 Longwood Ave, LC8210
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02215 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
|
| Samples (12)
|
|
| Relations |
| BioProject |
PRJNA895062 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE216730_CBAM68552_rlog_counts_z-scores.txt.gz |
1.2 Mb |
(ftp)(http) |
TXT |
| GSE216730_DFAM22359_rlog_counts_z-scores.txt.gz |
1.2 Mb |
(ftp)(http) |
TXT |
| GSE216730_PDX_SNDX_CBAM68552_vs_vehicle_DESeq2_DiffExp_allGenes_CBAM68552Samples_rmdup-20210116.csv.gz |
1.9 Mb |
(ftp)(http) |
CSV |
| GSE216730_PDX_SNDX_DFAM22359_vs_vehicle_DESeq2_DiffExp_allGenes_DFAM22359Samples_rmdup-20210116.csv.gz |
1.9 Mb |
(ftp)(http) |
CSV |
| GSE216730_PDX_SNDX_rlog_expression_rmdup_counts_DESeq2_CBAM68552Samples_blindFalse-20210116.csv.gz |
1.6 Mb |
(ftp)(http) |
CSV |
| GSE216730_PDX_SNDX_rlog_expression_rmdup_counts_DESeq2_DFAM22359Samples_blindFalse-20210116.csv.gz |
1.5 Mb |
(ftp)(http) |
CSV |
| GSE216730_RAW.tar |
596.0 Mb |
(http)(custom) |
TAR (of TDF) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
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