Sylvie D Freeman's research while affiliated with University of Birmingham and other places
What is this page?
This page lists the scientific contributions of an author, who either does not have a ResearchGate profile, or has not yet added these contributions to their profile.
It was automatically created by ResearchGate to create a record of this author's body of work. We create such pages to advance our goal of creating and maintaining the most comprehensive scientific repository possible. In doing so, we process publicly available (personal) data relating to the author as a member of the scientific community.
If you're a ResearchGate member, you can follow this page to keep up with this author's work.
If you are this author, and you don't want us to display this page anymore, please let us know.
It was automatically created by ResearchGate to create a record of this author's body of work. We create such pages to advance our goal of creating and maintaining the most comprehensive scientific repository possible. In doing so, we process publicly available (personal) data relating to the author as a member of the scientific community.
If you're a ResearchGate member, you can follow this page to keep up with this author's work.
If you are this author, and you don't want us to display this page anymore, please let us know.
Publications (134)
Measurable residual disease (MRD) surveillance in acute myeloid leukemia (AML) may identify patients destined for relapse and thus provide the option of pre-emptive therapy to improve their outcome. Whilst flow cytometric MRD (Flow-MRD) can be applied to high-risk AML/ myelodysplasia patients, its diagnostic performance for detecting impending rela...
Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings integral to disease progression. While molecular inclusions into prognostic models have substantively advanced risk stratification, recent revelations have emphasized the pivotal rol...
Although NPM1-mutated acute myeloid leukemia (AML) carries a generally favorable prognosis, many patients still relapse and die. Previous studies identified several molecular and clinical features associated with poor outcome, however only FLT3-ITD mutation and adverse karyotype are currently used for risk stratification due to inconsistent results...
Measurable residual disease (MRD) surveillance in acute myeloid leukemia (AML) may identify patients destined for relapse and thus provide the option of pre-emptive therapy to improve their outcome. Whilst ow cytometric MRD (Flow-MRD) can be applied to high-risk AML/ myelodysplasia patients, its diagnostic performance for detecting impending relaps...
Measurable residual disease (MRD) surveillance in acute myeloid leukemia (AML) may identify patients destined for relapse and thus provide the option of pre-emptive therapy to improve their outcome. Whilst flow cytometric MRD (Flow-MRD) can be applied to high-risk AML/ myelodysplasia patients, its diagnostic performance for detecting impending rela...
Selection of patients with NPM1 mutated AML for allogeneic transplant in 1st complete remission (CR1-allo) remains controversial due to a lack of robust data. Consequently, some centres consider baseline FLT3-ITD an indication for transplant and others rely on measurable residual disease (MRD) status. Using prospective data from the UK NCRI AML17 a...
PURPOSE
To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics.
PATIENTS AND METHODS
One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (d...
Background
While there is accumulating evidence that measurable residual disease (MRD) negative patients with intermediate risk AML may not benefit from allogeneic transplantation in 1 st complete remission (CR1-allo), many consider the presence of a FLT3 Internal Tandem Duplication (ITD) an indication for this procedure. However, the studies suppo...
Background
NPM1 mutated (mut) AML is considered favourable risk unless associated with FLT3 internal tandem duplication (ITD) or adverse karyotype. However many other genetic and clinical risk factors have been identified, including high white cell count (WCC), secondary disease, co-mutations and presence of a “triple hit” genotype ( NPM1mut, FLT3...
Introduction: t(6;9)(p23;q34.1)/DEK-NUP214 patients represent a discrete group of younger AML patients recognised as a separate disease entity in the World Health Organization classification of myeloid neoplasms. They typically display a dismal prognosis, higher relapse rate and a striking co-occurrence with FLT3-ITD mutations in > 70% of cases. DE...
Background
Following intensive chemotherapy in acute myeloid leukemia (AML), residual disease, assessed by failure to achieve a remission (CR/CRi) or the presence of measurable residual disease (MRD) in remission identifies a poor risk group of patients. In the NCRI AML16 trial for older adults (>60yrs), patients who were MRD+ve by flow cytometry i...
With the availability of effective targeted agents, significant changes have occurred in the management of patients with acute myeloid leukemia (AML) over the past several years, particularly for those considered unfit for intensive chemotherapy. While testing for measurable residual disease (MRD) is now routinely performed in patients treated with...
Addition of gemtuzumab ozogamicin (GO) to induction chemotherapy improves outcomes in older patients with acute myeloid leukemia (AML) but it is uncertain whether a fractionated schedule provides additional benefit to a single dose. We randomised 852 older adults (median age 68yrs) with AML/high risk myelodysplasia to GO on day 1 (GO1), or on days...
Patients with FLT3-mutated AML have a high relapse rate and suboptimal outcomes. Many have co-mutations suitable for measurable residual disease (MRD) monitoring by RT-qPCR and those destined to relapse can be identified by high or rising levels of MRD, called molecular failure. This provides a window for pre-emptive intervention, but there is litt...
The existence of two acute myeloid leukaemia classification systems-one put forth by WHO and one by the International Consensus Classification in 2022-is concerning. Although both systems appropriately move towards genomic disease definitions and reduced emphasis on blast enumeration, there are consequential disagreements between the two systems on...
Approximately 90% of patients with myelodysplastic syndromes (MDS) have somatic mutations in the malignant cells that are known or suspected to be oncogenic. The genetic risk-stratification of MDS has evolved substantially by the introduction of the clinical-molecular International Prognostic Scoring System (IPSS-M) that establishes next-generation...
Liposomal daunorubicin and cytarabine (CPX-351) improves overall survival (OS) compared to 7+3 chemotherapy in older patients with secondary acute myeloid leukaemia (AML); to date there have been no randomized studies in younger patients. The high-risk cohort of the UK NCRI AML19 trial (ISRCTN78449203) compared CPX-351 with FLAG-Ida in younger adul...
Allogeneic stem-cell transplantation allows the delivery of curative graft-versus-leukemia (GVL) in patients with acute myeloid leukemia/myelodysplasia (AML/MDS). Surveillance of T-cell chimerism, measurable residual disease (MRD) and blast HLA-DR expression may inform whether GVL effectiveness is reduced. We report the prognostic impact of these b...
Progress in acute myeloid leukaemia treatment is occurring at an unprecedented pace. The past decade has witnessed an increasingly improved scientific understanding of the underlying biology of acute myeloid leukaemia, leading to enhanced prognostication tools and refined risk assessments, and most especially incorporating measurable residual disea...
Background
For patients with acute myeloid leukaemia (AML), the only potentially curative treatment is intensive chemotherapy (IC). This is highly toxic, particularly for patients > 60 years, potentially leading to prolonged hospitalisations requiring intensive supportive care, and sometimes treatment-related death. This also results in extensive h...
Measurable residual disease (MRD) is associated with relapse and survival in acute myeloid leukemia (AML). We aimed to quantify the impact of MRD on outcomes across clinical contexts, including its association with hematologic response and MRD assay sensitivity. We performed systematic literature review and meta-analysis of 48 studies that reported...
Clinical recommendations for Acute Myeloid Leukemia (AML) classification and risk-stratification remain heavily reliant on cytogenetic findings at diagnosis , which are present in <50% of patients. Using comprehensive molecular profiling data from 3,653 patients we characterize and validate 16 molecular classes describing 100% of AML patients. Each...
Measurable residual disease (MRD) detected by multiparametric flow cytometry (MFC) is associated with unfavorable outcome in patients with AML. A simple, broadly applicable eight-color panel was implemented and analyzed utilizing a hierarchical gating strategy with fixed gates to develop a clear-cut LAIP-based DfN approach. In total, 32 subpopulati...
Clinical recommendations for AML classification and risk-stratification remain heavily reliant on cytogenetic findings at diagnosis, which are present in <50% of patients. Using comprehensive molecular profiling data from 3,653 patients we characterize and validate 16 molecular classes describing 100% of AML patients. Each class represents diverse...
Measurable residual disease (MRD) quantified by multiparameter flow cytometry (MFC) is a strong and independent prognostic factor in acute myeloid leukemia (AML). However, several technical factors may affect the final read-out of the assay. Experts from the MRD Working Party of the European LeukemiaNet evaluated which aspects are crucial for accur...
Allogeneic stem-cell transplantation is an important curative strategy in acute myeloid leukaemia (AML) consequent upon the development of a graft-versus-leukaemia (GVL) effect. Disease relapse is the major cause of transplant failure and novel therapeutic strategies are required in patients with measurable residual disease (MRD) post-transplant. R...
Background
Early data suggest that patients undergoing salvage chemotherapy for relapsed or refractory (R/R) acute myeloid leukaemia (AML) have poor outcomes if infected with SARS-CoV-2, and nosocomial transmission has been a major problem worldwide. Gilteritinib is effective in R/R FLT3 mutated AML, is significantly less immunosuppressive and does...
Background
Based on early evidence of a high rate of coronavirus mortality in patients with acute myeloid leukaemia (AML) undergoing intensive chemotherapy (IC), the national health service (NHS) in the United Kingdom temporarily made venetoclax available as an alternative therapy, with the aim of reducing both mortality and healthcare resource use...
Measurable residual disease (MRD) is an important biomarker in acute myeloid leukemia (AML) that is used for prognostic, predictive, monitoring, and efficacy-response assessments. The European LeukemiaNet (ELN) MRD working party evaluates standardization and harmonization of MRD in an ongoing manner and has updated the 2018 ELN MRD recommendations...
Reduced Intensity Conditioning (RIC) transplantation is increasingly offered to older patients with acute myeloblastic leukemia (AML). We have previously shown that a RIC allograft, particularly from a sibling donor is beneficial in intermediate risk patients aged 35-65 years. We here present analyses from the NCRI AML16 trial extending this experi...
Introduction
Measurements of residual leukemia strongly correlate with survival, as well as relapse, in patients with acute myeloid leukemia (AML) and, therefore, when used appropriately with other prognostic variables, provide an opportunity to improve their treatment. However, the deployment and interpretation of measurable residual disease (MRD)...
Measurable (previously minimal) residual disease (MRD) detection in acute myeloid leukemia (AML) has progressed beyond being a recognized strong prognostic factor. MRD-risk stratification is now incorporated into many treatment schedules and there is ongoing evaluation of MRD-directed therapy. Evolving assay technology such as next-generation seque...
PURPOSE
Reduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demo...
PURPOSE
The optimum number of treatment courses for younger patients with acute myeloid leukemia (AML) is uncertain. The United Kingdom National Cancer Research Institute AML17 trial randomly assigned patients who were not high risk to a total of three versus four courses.
PATIENTS AND METHODS
Patients received two induction courses based on dauno...
Aims
In AML, several risk factors obtained at first diagnosis (FD) have been reported to be associated with shorter RFS and OS. The primary prognostic relevance of multicolour flow cytometry (MFC) has been a matter of debate for years. During follow-up (FU), the prognostic relevance of MRD as detected by MFC is less controversial and MFC is recomme...
Background:
The poor-risk cytogenetic subgroup of acute myeloid leukaemia (AML) includes various chromosomal aberrations and represents a heterogeneous population of patients with a dismal 10-year overall survival. While the success of genetic landscaping studies is encouraging, it is debatable whether genomics, or indeed any single-omics platform...
Background: The persistence of measurable residual disease (MRD) has been shown to correlate with higher rates of relapse and worse survival in several leukemias. Individual studies have similarly suggested that the detection of MRD is associated with inferior outcomes in patients with acute myeloid leukemia (AML) undergoing frontline therapy; howe...
In recent years there have been major advances in the use of molecular diagnostic and monitoring techniques for patients with acute myeloid leukaemia (AML). Coupled with the simultaneous explosion of new therapeutic agents, this has sown the seeds for significant improvements to treatment algorithms. Here we show, using a selection of real‐life exa...
Importance:
Measurable residual disease (MRD) refers to neoplastic cells that cannot be detected by standard cytomorphologic analysis. In patients with acute myeloid leukemia (AML), determining the association of MRD with survival may improve prognostication and inform selection of efficient clinical trial end points.
Objective:
To examine the a...
Leukaemic stem cells (LSC) have been experimentally defined as the leukaemia‐propagating population and are thought to be the cellular reservoir of relapse in acute myeloid leukaemia (AML). Therefore, LSC measurements are warranted to facilitate accurate risk stratification. Previously, we published the composition of a one‐tube flow cytometric ass...
Relapse remains the most common cause of treatment failure for patients with acute myeloid leukaemia (AML) who undergo allogeneic stem cell transplantation (alloSCT) and carries a grave prognosis. Multiple studies have identified the presence of measurable residual disease (MRD) assessed by flow cytometry (FCM) prior to alloSCT as a strong predicto...
MRD technologies increase our ability to measure response in acute myeloid leukemia (AML) beyond the limitations of morphology. When applied in clinical trials, molecular and immunophenotypic MRD assays have improved prognostic precision, providing a strong rationale for their use to guide treatment, as well as to measure its effectiveness. Initiat...
INTRODUCTION:
Allogeneic stem cell transplantation (allo-SCT) is an important curative strategy in adults with high risk acute myeloid leukemia (AML) and myelodysplasia (MDS). Disease relapse represents the major cause of treatment failure and whilst retrospective analyses have identified that pre-transplant measurable residual disease (MRD) is an...
Key Points
Flt3L is a biomarker of progenitor cell mass in AML. Measurement of Flt3L during induction chemotherapy and follow-up provides prognostic information.
Background
Relapse remains the primary cause of treatment failure for patients with acute myeloid leukaemia (AML) who undergo allogeneic stem cell transplantation (alloSCT) and carries a grave prognosis. Multiple studies have identified the presence of minimal residual disease (MRD) assessed by flow cytometry or next‐generation sequencing prior to...
Epigenetic regulators, such as EZH2, are frequently mutated in cancer, and loss-of-function EZH2 mutations are common in myeloid malignancies. We have examined the importance of cellular context for Ezh2 loss during the evolution of acute myeloid leukemia (AML), where we observed stage-specific and diametrically opposite functions for Ezh2 at the e...
Introduction
Relapse remains the most common cause of treatment failure for patients with acute myeloid leukaemia (AML) who undergo allogeneic stem cell transplantation (SCT) and carries a grave prognosis. Multiple studies have identified the presence of minimal residual disease (MRD) prior to SCT assessed by flow cytometry (FCM) as a strong predic...
Minimal (or measurable) residual (MRD) disease provides a biomarker of response quality for which there is robust validation in the context of modern intensive treatment for younger patients with Acute Myeloid Leukemia (AML). Nevertheless, it remains a relatively unexplored area in older patients with AML. The lack of progress in this field can be...
Mounting evidence indicates that the presence of measurable ("minimal") residual disease (MRD), defined as posttherapy persistence of leukemic cells at levels below morphologic detection, is a strong, independent prognostic marker of increased risk of relapse and shorter survival in patients with acute myeloid leukemia (AML) and can be used to refi...
Purpose
We investigated the effect on outcome of measurable or minimal residual disease (MRD) status after each induction course to evaluate the extent of its predictive value for acute myeloid leukemia (AML) risk groups, including NPM1 wild-type (wt) standard risk, when incorporated with other induction response criteria.
Methods
As part of the N...
Measurable residual disease (MRD, previously termed minimal residual disease) is an independent, post-diagnosis, prognostic indicator in acute myeloid leukemia (AML) that is important for risk stratification and treatment planning, in conjunction with other well-established clinical, cytogenetic, and molecular data assessed at diagnosis. MRD can be...
It remains unclear in adult acute myeloid leukemia (AML) whether leukemic expression of CD33, the target antigen for Gemtuzumab Ozogamicin (GO), add prognostic information on GO effectiveness at different doses. CD33 expression quantified in 1583 patients recruited to UK-NCRI-AML17 (younger adults) and UK-NCRI-AML16 (older adults) trials was correl...
BCL2 inhibition induces toxicity in AML blasts from CD34+ and CD34− AMLs.
(PDF)
AML patient /sample characteristics.
(DOCX)
ki67 and BCL2 expression in immunophenotypic subsets.
(PDF)
In acute myeloid leukemia (AML) quiescence and low oxidative state, linked to BCL2 mitochondrial regulation, endow leukemic stem cells (LSC) with treatment-resistance. LSC in CD34? and more mature CD34? AML have heterogeneous immunophenotypes overlapping with normal stem/progenitor cells (SPC) but may be differentiated by functional markers. We the...
Comparing ROS levels between AML marrow and blood diagnosis specimens.
(PDF)
Immunophenotypic characterisation of stem/progenitor cell populations.
(PDF)
Heat maps of ki67, BCL2 and ROS levels in AML and control progenitors.
(PDF)
Supplementary Information & Methods.
(DOCX)
Stem/progenitor cell (SPC) composition of ROS-separated AML, MDS and control blasts.
(PDF)
Citations
... It has now been demonstrated that attainment of undetectable MRD with the use of a highsensitivity NPM1 real-time quantitative polymerase chain reaction assay is highly prognostic in NPM1 mut AML 146 and that the benefit of SCT, even in patients with co-occurring FLT3-ITD, appears to be limited to patients who were NPM1 MRD positive after induction. 146,147 CONCLUSION Progress in AML treatment is being made at an unprecedented pace. A deepened understanding of the pathophysiology and drivers of AML has led to the approval of several targeted agents. ...
![[object Object]](https://i1.rgstatic.net/ii/profile.image/11431281103908369-1669884505354_Q64/Jad-Othman.jpg)
![[object Object]](https://i1.rgstatic.net/ii/profile.image/651387952193536-1532314398255_Q64/Adam-Ivey.jpg)
... Further recommendations for the implementation of MRD in clinical practice include the use of myeloablative conditioning regimens before alloSCT for MRD-positive patients [111,112], as well as considering consolidation chemotherapy over alloSCT for MRD-negative intermediate-risk patients [102,103]. In contrast, NPM1-mutated patients with positive MRD after two induction cycles should receive alloSCT irrespective of their initial ELN risk to improve their outcome [118]. ...
![[object Object]](https://i1.rgstatic.net/ii/profile.image/11431281183513230-1692901439048_Q64/Yanis-Tazi.jpg)
... P = 0.02) in patients with NPM1 and FLT3 -ITD mutations where about one-half managed to receive preemptive therapy in a pre-specified subgroup analysis. 26 In this SOHO review article, we outline our general approach to implement pre-emptive therapy for molecular MRD failure in AML, followed by synthesis of the current literature in the various AML subgroups (APML, NPM1, FLT3 -ITD, CBF-AML) and a preview of the future of this highly promising strategy. ...
![[object Object]](https://i1.rgstatic.net/ii/profile.image/868215672553472-1584010155012_Q64/Abin-Thomas.jpg)
![[object Object]](https://i1.rgstatic.net/ii/profile.image/668929341014025-1536496591528_Q64/Richard-Dillon-5.jpg)
... Stringent MRD monitoring based on recent ELN-DAVID recommendations for further research appear to be essential in this context. 24 However, these data are retrospective with a limited number of patients, and we need to be cautious before proposing treatment discontinuation more widely. The FILO group will be prospectively evaluating treatment discontinuation in a cohort of patients in sustained complete remission with MRD neg and at least 12 months of therapy. ...
![[object Object]](https://i1.rgstatic.net/ii/profile.image/277083952566272-1443073370104_Q64/Jacqueline-Cloos.jpg)
![[object Object]](https://i1.rgstatic.net/ii/profile.image/659526172815360-1534254701071_Q64/Francesco-Buccisano.jpg)
... Patient samples were from AML patients > 18 years old followed for flow cytometric measurable residual disease (MRD) detection using standard published methods [2,[12][13][14][15] by a single reference laboratory (Birmingham, UK) from April 2015 to September 2022. MRD bone marrow monitoring was conducted after completion of chemotherapy or post allogeneic hematopoietic stem cell transplantation (HSCT) in patients who had achieved a complete remission (CR) or CR with incomplete hematologic recovery (CRi). ...
... The World Health Organization (WHO) classification of hematolymphoid tumors has long served as an international diagnostic criterion. However, in 2022, the International Consensus Classification (ICC) and the 5 th edition of the WHO classification (WHO2022) offered similar but distinct diagnostic approaches, leading to confusion [1][2][3][4][5]. Since the French-American-British classification in 1976, subsequent updates like WHO2001, WHO2008, and WHO2016, have incorporated new diagnostic criteria that integrate molecular, pathological, and clinical variables into a morphological classification [6][7][8][9]. ...
![[object Object]](https://i1.rgstatic.net/ii/profile.image/590126023458822-1517708416112_Q64/Rory-Shallis.jpg)
![[object Object]](https://i1.rgstatic.net/ii/profile.image/288812237377537-1445869611764_Q64/Rami-Komrokji.jpg)
... These genetic and transcriptomic analyses revealed that the AML clone with KMT2A-AFDN and FLT3-ITD responded well to the chemotherapy, but then the PTPN11mutated subclone led to relapse. FLT3-ITD confers a high risk of AML relapse and dismal overall survival and can be targeted by FLT3 inhibitors as salvage therapy for patients with FLT3-mutated MRD [15] or as a frontline treatment for newly diagnosed patients [16]. While FLT3 inhibitors were not implemented in the treatment of this patient, the AML subclone with FLT3-ITD was not detected at relapse. ...
![[object Object]](https://i1.rgstatic.net/ii/profile.image/819601818521601-1572419709908_Q64/Katya-Mokretar.jpg)
... More recently, results from the UK NCRI AML19 in NPM1 mutated patients treated with 2 courses of FLAG-Ida-GO who were NPM1 MRD negative in the peripheral blood [28] had a similar OS and relapse free survival (RFS) independently of the number of consolidations (zero, one or two), in a non -randomised comparison [29]. ...
... Considering that SCS is principally shown to be capable of detecting low levels of residual disease (single cell-MRD) and providing additional information beyond the mere MRD usually assessed by traditional methods, this technology could be theoretically applied to MDS aiming to (1) assess the dynamics of low levels of disease and representative clones/subclones and dissect the genomic makeup of the disease at the single cell level, (2) couple the immunophenotypic and genetic information to elucidate the clonal hierarchy of affected lineages that could be patient specific, (3) monitor the dynamics of the neoplastic clones/subclones as altered by therapeutic modalities, (4) anticipate the emergence of resistant clones, and (5) identify proteogenomic patterns that may predict response or resistance to certain therapy and correlate with count recovery or transfusion independence via prospective clinical trials. As the assessment of MRD in MDS has not been standardized and there are no specific recommendations regarding limit of detection [12,65], sc-MRD with a reported sensitivity of 0.1% could be theoretically applicable, especially in patients with low-risk disease (blast count is usually <1-4%), as there is no available curative therapeutic modality outside alloHSCT. In contrast, for patients with higher-risk MDS with increased blasts (typically blast count is 5-19%), conventional MRD-assays could be utilized. ...
... To date, most CPX-351 clinical trials have been performed in the older AML population. The UK NCRI AML-19 trial examined the efficacy of the liposomal compound against conventional FLAG-IDA (fludarabine, high-dose cytarabine, idarubicin, and G-CSF) in younger adult patients (median age 56 years, range 18-70) [165]. Myelodysplasia-related chromosomal abnormalities and complex karyotypes were observed in 78% and 49% of these patients, respectively. ...
