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Blood Cancer Discovery Jul 2023The safety and efficacy of combining the isocitrate dehydrogenase-1 (IDH1) inhibitor ivosidenib (IVO) with the BCL2 inhibitor venetoclax (VEN; IVO + VEN) ± azacitidine...
UNLABELLED
The safety and efficacy of combining the isocitrate dehydrogenase-1 (IDH1) inhibitor ivosidenib (IVO) with the BCL2 inhibitor venetoclax (VEN; IVO + VEN) ± azacitidine (AZA; IVO + VEN + AZA) were evaluated in four cohorts of patients with IDH1-mutated myeloid malignancies (n = 31). Most (91%) adverse events were grade 1 or 2. The maximal tolerated dose was not reached. Composite complete remission with IVO + VEN + AZA versus IVO + VEN was 90% versus 83%. Among measurable residual disease (MRD)-evaluable patients (N = 16), 63% attained MRD--negative remissions; IDH1 mutation clearance occurred in 64% of patients receiving ≥5 treatment cycles (N = 14). Median event-free survival and overall survival were 36 [94% CI, 23-not reached (NR)] and 42 (95% CI, 42-NR) months. Patients with signaling gene mutations appeared to particularly benefit from the triplet regimen. Longitudinal single-cell proteogenomic analyses linked cooccurring mutations, antiapoptotic protein expression, and cell maturation to therapeutic sensitivity of IDH1-mutated clones. No IDH isoform switching or second-site IDH1 mutations were observed, indicating combination therapy may overcome established resistance pathways to single-agent IVO.
SIGNIFICANCE
IVO + VEN + AZA is safe and active in patients with IDH1-mutated myeloid malignancies. Combination therapy appears to overcome resistance mechanisms observed with single-agent IDH-inhibitor use, with high MRD-negative remission rates. Single-cell DNA ± protein and time-of-flight mass-cytometry analysis revealed complex resistance mechanisms at relapse, highlighting key pathways for future therapeutic intervention. This article is highlighted in the In This Issue feature, p. 247.
Topics: Humans; Neoplasm Recurrence, Local; Antineoplastic Agents; Azacitidine; Isocitrate Dehydrogenase
PubMed: 37102976
DOI: 10.1158/2643-3230.BCD-22-0205 -
Journal of Hematology & Oncology Jul 2023Pevonedistat is a first-in-class, small molecular inhibitor of NEDD8-activating enzyme that has clinical activity in acute myeloid leukemia (AML) and myelodysplastic...
BACKGROUND
Pevonedistat is a first-in-class, small molecular inhibitor of NEDD8-activating enzyme that has clinical activity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Preclinical data suggest synergy of pevonedistat with azacitidine and venetoclax.
METHODS
This single-center, phase 1/2 study evaluated the combination of azacitidine, venetoclax and pevonedistat in older adults with newly diagnosed secondary AML or with MDS or chronic myelomonocytic leukemia (CMML) after failure of hypomethylating agents. Patients received azacitidine 75 mg/m IV on days 1-7, venetoclax at maximum dose of 200-400 mg orally on days 1-21 (AML cohort) or days 1-14 (MDS/CMML cohort) and pevonedistat 20 mg/m IV on days 1, 3 and 5 for up to 24 cycles. The primary endpoints for the phase 2 portion of the study were the CR/CRi rate in the AML cohort and the overall response rate (CR + mCR + PR + HI) in the MDS/CMML cohort.
FINDINGS
Forty patients were enrolled (32 with AML and 8 with MDS/CMML). In the AML cohort, the median age was 74 years (range 61-86 years), and 27 patients (84%) had at least one adverse risk cyto-molecular feature, including 15 (47%) with a TP53 mutation or MECOM rearrangement; seventeen patients (53%) had received prior therapy for a preceding myeloid disorder. The CR/CRi rate was 66% (CR 50%; CRi 16%), and the median overall survival (OS) was 8.1 months. In the MDS/CMML cohort, 7 patients (87%) were high or very high risk by the IPSS-R. The overall response rate was 75% (CR 13%; mCR with or without HI 50%; HI 13%). The most common grade 3-4 adverse events were infection in 16 patients (35%), febrile neutropenia in 10 patients (25%) and hypophosphatemia in 9 patients (23%). In an exploratory analysis, early upregulation of NOXA expression was observed, with subsequent decrease in MCL-1 and FLIP, findings consistent with preclinical mechanistic studies of pevonedistat. Upregulation of CD36 was observed, which may have contributed to therapeutic resistance.
CONCLUSIONS
The triplet combination of azacitidine, venetoclax and pevonedistat shows encouraging activity in this very poor-risk population of patients with AML, MDS or CMML. Trial registration ClinicalTrials.gov (NCT03862157).
Topics: Humans; Aged; Middle Aged; Aged, 80 and over; Azacitidine; Leukemia, Myelomonocytic, Chronic; Treatment Outcome; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37422688
DOI: 10.1186/s13045-023-01476-8 -
Cancer Discovery Jun 2023The BCL2 inhibitor venetoclax (VEN) in combination with azacitidine (5-AZA) is currently transforming acute myeloid leukemia (AML) therapy. However, there is a lack of...
UNLABELLED
The BCL2 inhibitor venetoclax (VEN) in combination with azacitidine (5-AZA) is currently transforming acute myeloid leukemia (AML) therapy. However, there is a lack of clinically relevant biomarkers that predict response to 5-AZA/VEN. Here, we integrated transcriptomic, proteomic, functional, and clinical data to identify predictors of 5-AZA/VEN response. Although cultured monocytic AML cells displayed upfront resistance, monocytic differentiation was not clinically predictive in our patient cohort. We identified leukemic stem cells (LSC) as primary targets of 5-AZA/VEN whose elimination determined the therapy outcome. LSCs of 5-AZA/VEN-refractory patients displayed perturbed apoptotic dependencies. We developed and validated a flow cytometry-based "Mediators of apoptosis combinatorial score" (MAC-Score) linking the ratio of protein expression of BCL2, BCL-xL, and MCL1 in LSCs. MAC scoring predicts initial response with a positive predictive value of more than 97% associated with increased event-free survival. In summary, combinatorial levels of BCL2 family members in AML-LSCs are a key denominator of response, and MAC scoring reliably predicts patient response to 5-AZA/VEN.
SIGNIFICANCE
Venetoclax/azacitidine treatment has become an alternative to standard chemotherapy for patients with AML. However, prediction of response to treatment is hampered by the lack of clinically useful biomarkers. Here, we present easy-to-implement MAC scoring in LSCs as a novel strategy to predict treatment response and facilitate clinical decision-making. This article is highlighted in the In This Issue feature, p. 1275.
Topics: Humans; Proteomics; Proto-Oncogene Proteins c-bcl-2; Leukemia, Myeloid, Acute; Bridged Bicyclo Compounds, Heterocyclic; Azacitidine; Stem Cells; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36892565
DOI: 10.1158/2159-8290.CD-22-0939 -
Proceedings of the National Academy of... Jul 2023Aberrant alternative splicing of mRNAs results in dysregulated gene expression in multiple neurological disorders. Here, we show that hundreds of mRNAs are incorrectly...
Aberrant alternative splicing of mRNAs results in dysregulated gene expression in multiple neurological disorders. Here, we show that hundreds of mRNAs are incorrectly expressed and spliced in white blood cells and brain tissues of individuals with fragile X syndrome (FXS). Surprisingly, the gene is transcribed in >70% of the FXS tissues. In all -expressing FXS tissues, RNA itself is mis-spliced in a CGG expansion-dependent manner to generate the little-known -217 RNA isoform, which is comprised of exon 1 and a pseudo-exon in intron 1. -217 is also expressed in FXS premutation carrier-derived skin fibroblasts and brain tissues. We show that in cells aberrantly expressing mis-spliced , antisense oligonucleotide (ASO) treatment reduces -217, rescues full-length RNA, and restores FMRP (Fragile X Messenger RibonucleoProtein) to normal levels. Notably, gene reactivation in transcriptionally silent FXS cells using 5-aza-2'-deoxycytidine (5-AzadC), which prevents DNA methylation, increases -217 RNA levels but not FMRP. ASO treatment of cells prior to 5-AzadC application rescues full-length expression and restores FMRP. These findings indicate that misregulated RNA-processing events in blood could serve as potent biomarkers for FXS and that in those individuals expressing , ASO treatment may offer a therapeutic approach to mitigate the disorder.
Topics: Humans; Fragile X Syndrome; Trinucleotide Repeat Expansion; Oligonucleotides, Antisense; Decitabine; Fragile X Mental Retardation Protein; Oligonucleotides; RNA
PubMed: 37364131
DOI: 10.1073/pnas.2302534120 -
Blood Cancer Journal Sep 2023FLT3 is the most frequently mutated gene in acute myeloid leukemia (AML), with FLT3 internal tandem duplication (ITD) mutations being associated with a more aggressive... (Review)
Review
FLT3 is the most frequently mutated gene in acute myeloid leukemia (AML), with FLT3 internal tandem duplication (ITD) mutations being associated with a more aggressive clinical course. While two large, randomized clinical trials have shown a survival benefit with the frontline use of an oral FLT3 inhibitor (midostaurin or quizartinib) in patients with FLT3-mutated AML, the role of FLT3 inhibitors in older adults with newly diagnosed FLT3-mutated AML remains unclear. A definitive improvement in survival has not been observed in intensively treated patients over 60 years of age receiving frontline FLT3 inhibitors. Furthermore, many patients with FLT3-mutated AML are unsuitable for intensive chemotherapy due to age and/or comorbidities, and this population represents a particular unmet need. For these older patients who are unfit for intensive approaches, azacitidine + venetoclax is a new standard of care and is used by many clinicians irrespective of FLT3 mutation status. However, FLT3-ITD mutations confer resistance to venetoclax and are a well-established mechanism of relapse to lower-intensity venetoclax-based regimens, leading to short durations of remission and poor survival. Preclinical and clinical data suggest synergy between FLT3 inhibitors and venetoclax, providing rationale for their combination. Novel strategies to safely incorporate FLT3 inhibitors into the standard hypomethylating agent + venetoclax backbone are now being explored in this older, less fit population with newly diagnosed FLT3-mutated AML, with encouraging early results. Herein, we discuss the frontline use of FLT3 inhibitors in older adults with FLT3-mutated AML, including the potential role of FLT3 inhibitors in combination with intensive chemotherapy and as part of novel, lower-intensity doublet and triplet regimens in this older population.
Topics: Humans; Middle Aged; Aged; Sulfonamides; Protein Kinase Inhibitors; Leukemia, Myeloid, Acute; Mutation; fms-Like Tyrosine Kinase 3
PubMed: 37696819
DOI: 10.1038/s41408-023-00911-w -
Clinical and Translational Science Aug 2023Although DNA methyltransferase inhibitors (DNMTis), such as azacitidine and decitabine, are used extensively in the treatment of myelodysplastic syndromes and acute... (Review)
Review
Although DNA methyltransferase inhibitors (DNMTis), such as azacitidine and decitabine, are used extensively in the treatment of myelodysplastic syndromes and acute myeloid leukemia, there remain unanswered questions about DNMTi's mechanism of action and predictors of clinical response. Because patients often remain on single-agent DNMTis or DNMTi-containing regimens for several months before knowing whether clinical benefit can be achieved, the development and clinical validation of response-predictive biomarkers represents an important unmet need in oncology. In this review, we will summarize the clinical studies that led to the approval of azacitidine and decitabine, as well as the real-world experience with these drugs. We will then focus on biomarker development for DNMTis-specifically, efforts at determining exposure-response relationships and challenges that remain impacting the broader clinical translation of these methods. We will highlight recent progress in liquid-chromatography tandem mass spectrometry technology that has allowed for the simultaneous measurement of decitabine genomic incorporation and global DNA methylation, which has significant potential as a mechanism-of-action based biomarker in patients on DNMTis. Last, we will cover important research questions that need to be addressed in order to optimize this potential biomarker for clinical use.
Topics: Humans; Decitabine; Azacitidine; Enzyme Inhibitors; Leukemia, Myeloid, Acute; DNA Methylation; DNA; Methyltransferases
PubMed: 37345219
DOI: 10.1111/cts.13548 -
Science Translational Medicine Nov 2023Aberrant DNA methylation has been implicated as a key driver of prostate cancer lineage plasticity and histologic transformation to neuroendocrine prostate cancer...
Aberrant DNA methylation has been implicated as a key driver of prostate cancer lineage plasticity and histologic transformation to neuroendocrine prostate cancer (NEPC). DNA methyltransferases (DNMTs) are highly expressed, and global DNA methylation is dysregulated in NEPC. We identified that deletion of DNMT genes decreases expression of neuroendocrine lineage markers and substantially reduced NEPC tumor development and metastasis in vivo. Decitabine, a pan-DNMT inhibitor, attenuated tumor growth in NEPC patient-derived xenograft models, as well as retinoblastoma gene ()-deficient castration-resistant prostate adenocarcinoma (CRPC) models compared with -proficient CRPC. We further found that DNMT inhibition increased expression of B7 homolog 3 (B7-H3), an emerging druggable target, via demethylation of B7-H3. We tested DS-7300a (i-DXd), an antibody-drug conjugate targeting B7-H3, alone and in combination with decitabine in models of advanced prostate cancer. There was potent single-agent antitumor activity of DS-7300a in both CRPC and NEPC bearing high expression of B7-H3. In B7-H3-low models, combination therapy of decitabine plus DS-7300a resulted in enhanced response. DNMT inhibition may therefore be a promising therapeutic target for NEPC and RB1-deficient CRPC and may sensitize B7-H3-low prostate cancer to DS-7300a through increasing target expression. NEPC and RB1-deficient CRPC represent prostate cancer subgroups with poor prognosis, and the development of biomarker-driven therapeutic strategies for these populations may ultimately help improve patient outcomes.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; DNA Methylation; Decitabine; Cell Line, Tumor; Prostatic Neoplasms; Neuroendocrine Tumors; Transcription Factors; Antineoplastic Agents; Ubiquitin-Protein Ligases; Retinoblastoma Binding Proteins
PubMed: 37967200
DOI: 10.1126/scitranslmed.adf6732 -
Cancers Mar 2024Venetoclax is a BH3-mimetics agent interacting with the anti-apoptotic protein BCL2, facilitating cytochrome c release from mitochondria, subsequent caspases activation,... (Review)
Review
Venetoclax is a BH3-mimetics agent interacting with the anti-apoptotic protein BCL2, facilitating cytochrome c release from mitochondria, subsequent caspases activation, and cell death. Venetoclax combined with azacitidine (VEN-AZA) has become a new standard treatment for AML patients unfit for intensive chemotherapy. In the phase III VIALE-A study, VEN-AZA showed a 65% overall response rate and 14.7 months overall survival in comparison with 22% and 8 months in the azacitidine monotherapy control arm. Despite these promising results, relapses and primary resistance to venetoclax are frequent and remain an unmet clinical need. Clinical and preclinical studies have been conducted to identify factors driving resistance. Among them, the most documented are molecular alterations including , , , and the newly described mutations. Several non-genetic factors are also described such as metabolic plasticity, changes in anti-apoptotic protein expression, and dependencies, as well as monocytic differentiation status. Strategies to overcome venetoclax resistance are being developed in clinical trials, including triplet therapies with targeted agents targeting IDH, FLT3, as well as the recently developed menin inhibitors or immunotherapies such as antibody-drug conjugated or monoclonal antibodies. A better understanding of the molecular factors driving venetoclax resistance by single-cell analyses will help the discovery of new therapeutic strategies in the future.
PubMed: 38539426
DOI: 10.3390/cancers16061091 -
Leukemia Aug 2023Venetoclax/azacitidine combination therapy is effective in acute myeloid leukemia (AML) and tolerable for older, multimorbid patients. Despite promising response rates,...
Venetoclax/azacitidine combination therapy is effective in acute myeloid leukemia (AML) and tolerable for older, multimorbid patients. Despite promising response rates, many patients do not achieve sustained remission or are upfront refractory. Identification of resistance mechanisms and additional therapeutic targets represent unmet clinical needs. By using a genome-wide CRISPR/Cas9 library screen targeting 18,053 protein- coding genes in a human AML cell line, various genes conferring resistance to combined venetoclax/azacitidine treatment were identified. The ribosomal protein S6 kinase A1 (RPS6KA1) was among the most significantly depleted sgRNA-genes in venetoclax/azacitidine- treated AML cells. Addition of the RPS6KA1 inhibitor BI-D1870 to venetoclax/azacitidine decreased proliferation and colony forming potential compared to venetoclax/azacitidine alone. Furthermore, BI-D1870 was able to completely restore the sensitivity of OCI-AML2 cells with acquired resistance to venetoclax/azacitidine. Analysis of cell surface markers revealed that RPS6KA1 inhibition efficiently targeted monocytic blast subclones as a potential source of relapse upon venetoclax/azacitidine treatment. Taken together, our results suggest RPS6KA1 as mediator of resistance towards venetoclax/azacitidine and additional RPS6KA1 inhibition as strategy to prevent or overcome resistance.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Leukemia, Myeloid, Acute; Ribosomal Protein S6 Kinases; Ribosomal Protein S6 Kinases, 90-kDa; RNA, Guide, CRISPR-Cas Systems; Drug Resistance, Neoplasm
PubMed: 37414921
DOI: 10.1038/s41375-023-01951-8