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Supplementary Tables and Figures from A Phase Ib/II Study of Ivosidenib with Venetoclax ± Azacitidine in <i>IDH1</i>-Mutated Myeloid Malignancies
<p>Table S1: Pharmacokinetics of IVO+VEN and IVO+VEN+AZATable S2: Treatment characteristics across the four dose levels in the phase 1b study population.Table S3: Study medication adherence: (A), Adherence to protocol administered medications during DLT evaluation period (cycles 1 and 2) of protocol directed therapy. (B), Adherence to protocol administered medications during the first 12 months of protocol directed therapy.Table S4: Dose modifications in patients experiencing hematologic adverse events during the entire study period until data cut-off on March 15th, 2022.Table S5: Regions covered by institutional next-generation sequencing (NGS) interrogating the entire exonic or hotspot regions of 81-genes frequently mutated in myeloid malignancies.Table S6: Variants identified using targeted 81-gene myeloid NGS panelTable S7: CyTOF antibodies utilized.Figure S1: Molecular, cytogenetic, and IDH1 variants across the P1b study population. (A), Oncoprint of molecular mutations identified at diagnosis in 31 patients enrolled demonstrated a diverse molecular landscape. (B-C), Neither median mutation burden nor IDH1 VAF was significantly different between included disease types. (D), IDH1 variants differed across disease types, with R132C mutations most frequent at diagnosis in ND and R/R-AML. IDH1 R132L and R132S variants were not identified in patients with MDS or MPN. (E), Clonal hierarchy of baseline mutations assessed using bulk myeloid NGS panel on baseline samples.Figure S2: Pharmacokinetics of IVO+VEN or IVO+VEN+AZA (continued): (A), AUC 24 and (B), Cmax of IVO+VEN or IVO+VEN+AZA within each respective dose level demonstrated a decrease in the presence of IVO when assessed on C2D14 compared to sampling on C1D14 in the absence of co- occurring IVO administration.Figure S3: CONSORT diagram of study participantsFigure S4: Bone marrow response and recovery following IVO+VEN or IVO+VEN+AZA: (A), Bone marrow blast reduction following one cycle of therapy with IVO+AZA, or IVO+VEN+AZA among all patients with an adequate bone marrow samples (N=28). Three patients had inadequate/hypocellular EOC1 bone marrow aspirations and were excluded. One patient enrolled with MRD+ AML only. (B) Cycle lengths during the first four cycles of treatment. Patients treated with IVO+VEN had significantly shorter cycle lengths for cycle 1 compared to patients treated with IVO+VEN+AZA.Figure S5: Adverse events in patients treated with IVO+VEN or IVO+VEN+AZA: (A), Common adverse events occurring in four or more patients on study during the entire phase 1b study period demonstrated by grade, (B), by receipt of IVO+VEN vs. IVO+VEN+AZA, (C), and by dose level.Figure S6: Morphologic and MRD response to IVO+VEN in ND-AML. Morphologic response, MRD-MFC, and IDH1 ddPCR status by treatment cycle in patients with ND-AML treated with the doublet combination of IVO+VEN 400 or VEN 800Figure S7: Morphologic and MRD response to IVO+VEN+AZA in ND-AML. Morphologic response, MRD-MFC, and IDH1 ddPCR status by treatment cycle in patients with ND-AML treated with the triplet combination of IVO+VEN 400 or VEN 800 +AZAFigure S8: Morphologic and MRD response to IVO+VEN or IVO+VEN+AZA in R/R-AML. Morphologic response, MRD-MFC, and IDH1 ddPCR status by treatment cycle in patients with R/R-AML treated with IVO+VEN with or without AZAFigure S9: Response and outcome of patients treated with IVO+VEN or IVO+VEN+AZA. (A), Swimmer's plot of patients on study with IVO+VEN +/- AZA by dose level.Figure S10: Landmark overall survival analyses based on IDH1 mutation detection in CRc using ddPCR as though performed on patients at baseline. (A), Overall survival from treatment start. (B), Including patients surviving at least 3-months (correlating with end of cycle 3). (C), Including patients surviving at least 5- months (correlating with end of cycle 5). (D), Including patients surviving at least 7-months (correlating with end of cycle 7).Figure S11: Influence of biological pathways on survival following IVO+VEN or IVO+VEN+AZA treatment. (A), Overall survival by methylation mutations. (B), Overall survival by signaling mutations. (C), Overall survival in all patients with signaling mutations based upon receipt of IVO+VEN or IVO+VEN+AZA. (D), Overall survival in patients with AML and signaling mutations based upon receipt of IVO+VEN or IVO+VEN+AZA.Figure S12: Persistent mutations in a long-term responder with ND-AML identifies mutations within a CD16+ monocytic population. (A and B), DAb-seq analysis at diagnosis and in remission in a patient with ND-AML (accession #18) and co-occurring RUNX1 p. L204Q and IDH1 p.R132H mutations treated with IVO+VEN+AZA demonstrated treatment eliminated the majority of IDH1 and RUNX1 co-mutated cells. (C and D), The predominant population of CD34+ myeloblasts was eliminated with therapy, however residual cells containing IDH1 and RUNX1 in remission were clustered with a monocytic cell population with increased CD16 expression (C and D).Figure S13: Immunophenotypic shift occurring under treatment selection with targeted therapy. Multiparameter flow cytometry in a patient with ND-AML (accession #20) demonstrating an alternative CD34+ population expanding at relapse compared to baseline, consistent with a phenotypic shift at disease.Figure S14: Increased alternative antiapoptotic protein expression levels correlate with resistance to IVO+VEN+AZA. CyTOF analysis in a patient with ND-AML (accession #11) treated with IVO+VEN+AZA who initially attained CRc followed by disease progression. Increased alternative anti-apoptotic protein levels (BCL-xL and MCL1) were observed, in addition to increased CD44 levels.Figure S15: Increased BCL2 levels relative to alternative anti-apoptotic proteins is associated with ongoing response to IVO+VEN+AZA. CyTOF analysis in a patient with ND-AML (accession #26) treated with IVO+VEN+AZA with a durable response to treatment following 18 cycles of therapy. The patient had multiple CD34+ cell populations at diagnosis, with higher BCL2 levels relative to BCL-xL or MCL-1. Following 3 cycles of therapy, marked reduction in these blast populations were observed.Figure S16: Increased alternative anti-apoptotic protein expression is observed in maturing myeloid populations with monocytic differentiation. CyTOF analysis in a patient with R/R-AML (accession #10) treated with IVO+VEN with a durable response to treatment following 41 cycles of therapy. Following cycle 3 of treatment, an expanding CD34+ cell populations with increased BCL-xL and MCL-1 levels was observed with an associated maturing CD14+ monocytic immunophenotype.</p>
Supplementary Protocol from A Phase Ib/II Study of Ivosidenib with Venetoclax ± Azacitidine in <i>IDH1</i>-Mutated Myeloid Malignancies
<p>Supplementary protocol for "Phase Ib/II Investigator Initiated Study of the IDH1-mutant inhibitor ivosidenib (AG120) with the BCL2 inhibitor venetoclax +/- azacitidine in IDH1-mutated hematologic malignancies"</p>
Absolute quantitation of individual SARS-CoV-2 RNA molecules provides a new paradigm for infection dynamics and variant differences.
Despite an unprecedented global research effort on SARS-CoV-2, early replication events remain poorly understood. Given the clinical importance of emergent viral variants with increased transmission, there is an urgent need to understand the early stages of viral replication and transcription. We used single-molecule fluorescence in situ hybridisation (smFISH) to quantify positive sense RNA genomes with 95% detection efficiency, while simultaneously visualising negative sense genomes, subgenomic RNAs, and viral proteins. Our absolute quantification of viral RNAs and replication factories revealed that SARS-CoV-2 genomic RNA is long-lived after entry, suggesting that it avoids degradation by cellular nucleases. Moreover, we observed that SARS-CoV-2 replication is highly variable between cells, with only a small cell population displaying high burden of viral RNA. Unexpectedly, the B.1.1.7 variant, first identified in the UK, exhibits significantly slower replication kinetics than the Victoria strain, suggesting a novel mechanism contributing to its higher transmissibility with important clinical implications.
The dual ubiquitin binding mode of SPRTN secures rapid spatiotemporal proteolysis of DNA-protein crosslinks.
DNA-protein crosslinks (DPCs) are endogenous and chemotherapy-induced genotoxic DNA lesions and, if not repaired, lead to embryonic lethality, neurodegeneration, premature ageing, and cancer. DPCs are heavily polyubiquitinated, and the SPRTN protease and 26S proteasome emerged as two central enzymes for DPC proteolysis. The proteasome recognizes its substrates by their ubiquitination status. How SPRTN protease, an essential enzyme for DPC proteolysis, achieves specificity for DPCs is still not entirely clear. We found that the N-terminal SPRTN catalytic region (SprT) possesses a ubiquitin-binding domain that we named the Ubiquitin Interface of SprT Domain (USD). Using multiple biochemical, biophysical, and structural approaches, we reveal that USD binds ubiquitin chains in an avidity manner. SPRTN binding to ubiquitin chains via USD leads to ∼67-fold higher activation of SPRTN proteolysis towards polyubiquitinated DPCs than the unmodified DPCs. In contrast, the constitutive components of the replisome during unperturbed or translesional DNA synthesis, namely proliferating cell nuclear antigen (PCNA) or monoUb-PCNA, respectively, were poorly degraded, if at all, by SPRTN. This study reveals that the poly-ubiquitination of DPCs serves as the key signal for SPRTN's rapid proteolysis and determines its substrate specificity towards DPCs, rather than the replisome.
Making it Personal - play script
Play script created as part of Making it Personal - an engagement with research project funded by the PCER Fund, University of Oxford and the Centre for Personalised Medicine, University of Oxford.
Erythropoiesis in the human
Erythropoiesis is the production of haemoglobin-containing red blood cells for oxygen delivery to the tissues. Approximately 1-2 Ã- 1012red cells are produced each day, and this remarkable productivity under stable conditions is also complemented by the capacity for rapid and substantial expansion when required. This chapter describes the developmental origins of primitive and definitive erythropoiesis in the yolk sac, the fetal liver and the bone marrow. Our current understanding of the mechanisms of erythroid lineage specification from multipotent haemopoietic stem cells remains incomplete, but key erythroid-specific transcription factors are known to be critical in directing erythroid-specific transcription. Characteristic changes in morphology, gene expression and cell surface markers allow the identification of erythroid cells at different stages of their differentiation and maturation. At a system level, the hormone erythropoietin is the principal regulator of erythroid activity. Following upregulation of its transcription by Hypoxia-Inducible Factor, erythropoietin directs an expansion of the pool of erythroid precursors and accelerated red cell maturation. This, together with coordinated iron absorption and delivery, provides an appropriate response to hypoxia caused by reduced numbers of circulating red blood cells associated with a very wide spectrum of causes.
From pioneer to repressor: Bimodal foxd3 activity dynamically remodels neural crest regulatory landscapein vivo
The neural crest (NC) is a transient embryonic stem cell population characterised by its multipotency and broad developmental potential. Here, we perform NC-specific transcriptional and epigenomic profiling of foxd3 -mutant versus wild type cells in vivo to define the gene regulatory circuits controlling NC specification. Together with global binding analysis obtained by foxd3 biotin-ChIP and single cell profiles of foxd3 -expressing premigratory NC, our analysis shows that during early steps of NC formation, foxd3 acts globally as a pioneer factor to prime the onset of genes regulating NC specification and migration by re-arranging the chromatin landscape, opening cis -regulatory elements and reshuffing nucleosomes. Strikingly, foxd3 then switches from an activator to its canonical role as a transcriptional repressor. Taken together, these results demonstrate that foxd3 acts bimodally in the neural crest as a switch from permissive to repressive nucleosome/chromatin organisation to maintain stemness and define cell fates.
The spatiotemporal distribution of human pathogens in ancient Eurasia.
Infectious diseases have had devastating effects on human populations throughout history, but important questions about their origins and past dynamics remain1. To create an archaeogenetic-based spatiotemporal map of human pathogens, we screened shotgun-sequencing data from 1,313 ancient humans covering 37,000 years of Eurasian history. We demonstrate the widespread presence of ancient bacterial, viral and parasite DNA, identifying 5,486 individual hits against 492 species from 136 genera. Among those hits, 3,384 involve known human pathogens2, many of which had not previously been identified in ancient human remains. Grouping the ancient microbial species according to their likely reservoir and type of transmission, we find that most groups are identified throughout the entire sampling period. Zoonotic pathogens are only detected from around 6,500 years ago, peaking roughly 5,000 years ago, coinciding with the widespread domestication of livestock3. Our findings provide direct evidence that this lifestyle change resulted in an increased infectious disease burden. They also indicate that the spread of these pathogens increased substantially during subsequent millennia, coinciding with the pastoralist migrations from the Eurasian Steppe4,5.
Fedratinib combined with ropeginterferon alfa-2b in patients with myelofibrosis (FEDORA): study protocol for a multicentre, open-label, Bayesian phase II trial.
BACKGROUND: Myelofibrosis (MF) is a clonal haematopoietic disease, with median overall survival for patients with primary MF only 6.5 years. The most frequent gene mutation found in patients is JAK2V617F, causing constitutive activation of the kinase and activation of downstream signalling. Fedratinib is an oral selective JAK2 inhibitor. It has shown activity in MF and is well-tolerated, but combination with other therapies is likely needed to achieve clonal remission. Combining a JAK2 inhibitor with an interferon may be synergistic, as haematopoietic cells are activated from quiescence (a typical kinase resistance mechanism) rendering them more sensitive to inhibition. Ropeginterferon alfa-2b is a next generation pegylated interferon-α-2b with high tolerability and clinical activity in patients with MF, however, evidence of tolerability and activity in combination with fedratinib is lacking in this setting. The aim of the FEDORA trial is to assess tolerability, safety, and activity of fedratinib with ropeginterferon alfa-2b in patients with MF who require treatment to justify further investigation in a phase III trial. METHODS: FEDORA is a single arm, multicentre, open-label, Bayesian phase II trial to assess tolerability, safety, and activity of fedratinib with ropeginterferon alfa-2b aiming to recruit 30 patients. Patients with JAK2V617F positive primary or secondary MF, who are aged ≥ 18 years, have intermediate-1 with palpable splenomegaly of > 5cm, intermediate-2, or high-risk disease according to the Dynamic International Prognostic Scoring System (DIPSS), and who require treatment are eligible. The primary outcome is tolerability, whereby the combination is deemed intolerable in a patient if drug-related toxicities in the first four months of treatment lead to: either drug being discontinued; delays in treatment exceeding 28 consecutive days; or death. FEDORA uses a within-patient dose escalation regimen to ensure each patient reaches a personalised dose combination that is acceptable. DISCUSSION: FEDORA is using a Bayesian trial design and aims to provide evidence of the tolerability, safety, and activity of combining fedratinib with ropeginterferon alfa-2b upon which the decision as to whether a phase III trial is warranted will be based. TRIAL REGISTRATION: EudraCT number: 2021-004056-42. ISRCTN: 88,102,629.
SFX-01 is therapeutic against myeloproliferative disorders caused by activating mutations in Shp2.
Activating mutations of Src homology-2 domain-containing protein tyrosine phosphatase-2 (Shp2) cause multiple childhood conditions for which there is an unmet therapeutic need, including juvenile myelomonocytic leukemia (JMML) and Noonan syndrome. SFX-01, an α-cyclodextrin-stabilized sulforaphane complex currently in clinical development, covalently adducts cysteine residues. Using unbiased proteomics, its protein targets were identified, including Shp2. SFX-01 induced an inhibitory dithiolethione modification at the Shp2 active site cysteine. Importantly, in a transgenic mouse model of human Noonan syndrome with hyperactive D61G Shp2, SFX-01 concomitantly normalized their phosphatase activity and myeloid cell count. Furthermore, SFX-01 also attenuated JMML human patient-derived hematopoietic stem cell proliferation that was linked to STAT1 signaling and decreased cyclin D1 expression, resulting in cell-cycle arrest. We conclude that SFX-01 is an activating mutant Shp2 inhibitor and may offer beneficial effects in patients with JMML or Noonan syndrome.
Making it Personal - play script
Making it Personal is an innovative public and community engagement with research project at the University of Oxford. Theatre offers a unique platform to “set the scene” on an emotional and personal level, highlighting how individuals process risk and medical information—often in ways that differ significantly from clinical perspectives. Making it Personal utilises theatre to engage the public with genetics research (the iPREGCARE study) and to spark conversations around how a couple might receive and process a de novo (new) genetic diagnosis in their child and approach the question could it happen again? This play script was developed over several months (January – April 2025) by Dr Alison Kay and Dr Minna Jeffery and a co-production panel of genetics practitioners and people with lived experience of genetic diagnosis. A staged reading took place on 17 May 2025 at the MOLT Theatre, St Anne’s College. The recording of the staged reading is available to view on the YouTube channel of the Centre for Personalised Medicine, Oxford.
Tumor-Infiltrating Clonal Hematopoiesis.
BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with increased mortality among patients with cancer. CHIP mutations with high variant-allele frequencies can be detected in tumors, a phenomenon we term tumor-infiltrating clonal hematopoiesis (TI-CH). The frequency of TI-CH and its effect on tumor evolution are unclear. METHODS: We characterized CHIP and TI-CH in 421 patients with early-stage non-small-cell lung cancer (NSCLC) from the TRACERx study and in 49,351 patients from the MSK-IMPACT pan-cancer cohort. We studied the association of TI-CH with survival and disease recurrence and evaluated the functional effect of TET2-mutant CHIP on the biologic features of lung tumors. RESULTS: Among patients with NSCLC, 42% of those with CHIP had TI-CH. TI-CH independently predicted an increased risk of death or recurrence, with an adjusted hazard ratio of 1.80 (95% confidence interval [CI], 1.23 to 2.63) as compared with the absence of CHIP and an adjusted hazard ratio of 1.62 (95% CI, 1.02 to 2.56) as compared with CHIP in the absence of TI-CH. Among patients with solid tumors, 26% of those with CHIP had TI-CH. TI-CH conferred a risk of death from any cause that was 1.17 times (95% CI, 1.06 to 1.29) as high as the risk with CHIP in the absence of TI-CH. TET2 mutations were the strongest genetic predictor of TI-CH; such mutations enhanced monocyte migration to lung tumor cells, fueled a myeloid-rich tumor microenvironment in mice, and resulted in the promotion of tumor organoid growth. CONCLUSIONS: TI-CH increased the risk of disease recurrence or death among patients with NSCLC and the risk of death from any cause among patients with solid tumors. TI-CH remodeled the tumor immune microenvironment and accelerated tumor organoid growth, findings that support a role for an aging-related hematologic clonal proliferation in cancer evolution. (Funded by the Royal Society and others.).
Predictive Performance of Cardiovascular Risk Scores in Cancer Survivors From the UK Biobank.
BACKGROUND: Cardiovascular preventive strategies are guided by risk scores with unknown validity in cancer cohorts. OBJECTIVES: This study aimed to evaluate the predictive performance of 7 established cardiovascular risk scores in cancer survivors from the UK Biobank. METHODS: The predictive performance of QRISK3, Systematic Coronary Risk Evaluation 2 (SCORE2)/Systematic Coronary Risk Evaluation for Older Persons (SCORE-OP), Framingham Risk Score, Pooled Cohort equations to Prevent Heart Failure (PCP-HF), CHARGE-AF, QStroke, and CHA2DS2-VASc was calculated in participants with and without a history of cancer. Participants were propensity matched on age, sex, deprivation, health behaviors, family history, and metabolic conditions. Analyses were stratified into any cancer, breast, lung, prostate, brain/central nervous system, hematologic malignancies, Hodgkin lymphoma, and non-Hodgkin lymphoma. Incident cardiovascular events were tracked through health record linkage over 10 years of follow-up. The area under the receiver operating curve, balanced accuracy, and sensitivity were reported. RESULTS: The analysis included 31,534 cancer survivors and 126,136 covariate-matched controls. Risk score distributions were near identical in cases and controls. Participants with any cancer had a significantly higher incidence of all cardiovascular outcomes than matched controls. Performance metrics were significantly worse for all risk scores in cancer cases than in matched controls. The most notable differences were among participants with a history of hematologic malignancies who had significantly higher outcome rates and poorer risk score performance than their matched controls. The performance of risk scores for predicting stroke in participants with brain/central nervous system cancer was very poor, with predictive accuracy more than 30% lower than noncancer controls. CONCLUSIONS: Existing cardiovascular risk scores have significantly worse predictive accuracy in cancer survivors compared with noncancer comparators, leading to an underestimation of risk in this cohort.