EZH2 modulates mRNA splicing and exerts part of its oncogenic function through repression of splicing factors in CML.

The polycomb protein EZH2 is up-regulated in Chronic Myeloid Leukaemia (CML) and associated with transcriptional reprogramming. Here we tested whether EZH2 might also act as a modulator of the mRNA splicing landscape to elicit its oncogenic function in CML. We treated CML cell lines with EZH2 inhibitors and detected differential splicing of several hundreds of events, potentially caused by the transcriptional regulation of splicing factors.

A phase I/II study of adoptive SARS-CoV-2-specific T cells in immunocompromised hosts with or at risk of severe COVID-19 infection.

Background: Post-transplant or hematological cancer patients have a higher risk of mortality after infection with ancestral and early variants of severe acute respiratory syndrome (SARS)-CoV-2. Adoptive cell therapy (ACT) with virus-specific T cells (VSTs) could augment endogenous T cell immunity to avoid disease deterioration before viral clearance.

Methods: We established a third-party SARS-CoV-2-specific T cell (COVID-T) bank in 2020 (NCT04351659) using convalescent and/or vaccinated donors.

Core-binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis.

Adenosine-to-inosine RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes, ADAR1 and ADAR2, has been shown to contribute to multiple cancers. However, other than the chronic myeloid leukemia blast crisis, relatively little is known about its role in other types of hematological malignancies. Here, we found that ADAR2, but not ADAR1 and ADAR3, was specifically downregulated in the core-binding factor (CBF) acute myeloid leukemia (AML) with t(8;21) or inv(16) translocations.

Phase I study of expanded natural killer cells in combination with cetuximab for recurrent/metastatic nasopharyngeal carcinoma.

Background: Nasopharyngeal carcinoma (NPC) cells express high levels of epidermal growth factor receptor (EGFR). Cetuximab is an anti-EGFR monoclonal antibody that promotes natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) via engagement of CD16. We studied safety and efficacy of combining cetuximab with autologous expanded NK cells in patients with recurrent and/or metastatic NPC who had failed at least two prior lines of chemotherapy.

Dendritic cell therapy with CD137L-DC-EBV-VAX in locally recurrent or metastatic nasopharyngeal carcinoma is safe and confers clinical benefit.

Introduction: Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), and provides a target for a dendritic cell (DC) vaccine. CD137 ligand (CD137L) expressed on antigen presenting cells, costimulates CD137-expressing T cells, and reverse CD137L signaling differentiates monocytes to CD137L-DC, a type of DC, which is more potent than classical DC in stimulating T cells.

Methods: In this phase I study, patients with locally recurrent or metastatic NPC were administered CD137L-DC pulsed with EBV antigens (CD137L-DC-EBV-VAX).

Effective Killing of Acute Myeloid Leukemia by TIM-3 Targeted Chimeric Antigen Receptor T Cells.

Acute myeloid leukemia (AML) is an aggressive disease with poor outcomes, overwhelmingly due to relapse. Minimal residual disease (MRD), defined as the persistence of leukemic cells after chemotherapy treatment, is thought to be the major cause of relapse. The origins of relapse in AML have been traced to rare therapy-resistant leukemic stem cells (LSCs) that are already present at diagnosis.

Rapid production of clinical-grade SARS-CoV-2 specific T cells.

Objectives: To determine whether the frequencies of SARS-CoV-2-specific T cells are sufficiently high in the blood of convalescent donors and whether it is technically feasible to manufacture clinical-grade products overnight for T-cell therapy and assessment of COVID-19 immunity.

Methods: One unit of whole blood or leukapheresis was collected from each donor following standard blood bank practices. The leukocytes were stimulated using overlapping peptides of SARS-CoV-2, covering the immunodominant sequence domains of the S protein and the complete sequence of the N and M proteins.

Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers.

Purpose: Natural killer (NK) cells exert antibody-dependent cell cytotoxicity (ADCC). We infused expanded, activated autologous NK cells to potentiate trastuzumab-mediated ADCC in patients with HER2-positive malignancies.

Patients And Methods: In a phase I trial, patients with treatment-refractory HER2-positive solid tumors received trastuzumab, with or without bevacizumab, and autologous NK cells expanded by 10-day coculture with K562-mb15-41BBL cells.

A roundtable on responsible innovation with autologous stem cells in Australia, Japan and Singapore.

We report on a roundtable event hosted in Singapore that sought to identify some of the ethical and regulatory challenges in translating autologous cell-based interventions, particularly those claiming to involve stem cells, into safe and effective therapies and to propose some solutions to encourage responsible innovation with these products. Challenges are identified in the three areas of cell manufacturing and processing, innovative uses of autologous cells in clinical practice and standards of evidence. Proposed solutions are discussed within a co-operative model of statutory laws and regulations that can enable product development with autologous cells and professional codes and standards that can encourage ethical conduct in clinical practice.

Preleukemic and second-hit mutational events in an acute myeloid leukemia patient with a novel germline mutation.

Background: Germline mutations in the transcription factor give rise to a rare autosomal dominant genetic condition classified under the entity: Familial Platelet Disorders with predisposition to Acute Myeloid Leukaemia (FPD/AML). While several studies have identified a myriad of germline RUNX1 mutations implicated in this disorder, second-hit mutational events are necessary for patients with hereditary thrombocytopenia to develop full-blown AML. The molecular picture behind this process remains unclear.

Vinorelbine-Cyclophosphamide compared to cyclophosphamide in peripheral blood stem cell mobilization for multiple myeloma.

Background: High dose Cyclophosphamide (Cy) and Vinorelbine Cyclophosphamide (Vino-Cy) are stem cell (SC) mobilisation options for patients with multiple myeloma (MM). We present a comparison of mobilisation outcomes using these regimens.

Patients And Methods: Vino-Cy patients received Vinorelbine 25 mg/m on day 1, cyclophosphamide 1500 mg/m on day 2, and pegylated GCSF on day 4 or GCSF 10 mcg/kg/day from day 4 onwards.

Pegylated Filgrastim Versus Filgrastim for Stem Cell Mobilization in Multiple Myeloma After Novel Agent Induction.

Background: The current standard of care for transplant-eligible myeloma patients is novel agent-based induction, followed by high-dose chemotherapy and autologous stem cell rescue. Chemo-mobilization of peripheral blood CD34 stem cells (PBSCs) with pegylated filgrastim (pegfilgrastim), a sustained-duration formulation of filgrastim, has been used as an alternative to filgrastim in several studies involving heterogeneous cohorts of lymphoma and multiple myeloma (MM) patients and shown to be equivalent in PBSC yield and cost-effectiveness. The present study focused on the efficacy of pegfilgrastim in PBSC mobilization compared with filgrastim exclusively after novel agent-based induction in a homogeneous group of MM patients.

Successful Stem Cell Transplantation in a Patient with Pretransplant Hepatic Inflammatory Pseudotumour.

Inflammatory pseudotumours (IPT) are rare benign neoplasms of unknown aetiology. We present a case of hepatic IPT which was incidentally discovered in a patient with relapsed B-acute lymphoblastic leukaemia (B-ALL) undergoing pretransplant workup. After investigation to exclude an infective cause she underwent a reduced intensity conditioning stem cell transplant (SCT) successfully and currently remains well and in remission.

WPSS is a strong prognostic indicator for clinical outcome of allogeneic transplant for myelodysplastic syndrome in Southeast Asian patients.

To better understand the predictive factors and improve clinical outcome of allogeneic transplant for patients with myelodysplastic syndrome (MDS), we retrospectively analyzed the post-transplant outcome of 60 Southeast Asian patients with MDS. Multivariate analysis showed that WHO classification-based Prognostic Scoring System (WPSS) significantly affect overall survival (OS), progression-free survival (PFS), cumulative incidence of relapse (CIR), and cumulative incidence of non-relapse mortality (CINRM). Stratified by WPSS into very low/low, intermediate, high, and very high-risk categories, 3-year OS was 100, 61, 37, and 18% (p = 0.

Pre-transplant achievement of negativity in minimal residual disease and French-American-British L1 morphology predict superior outcome after allogeneic transplant for Philadelphia chromosome positive acute lymphoblastic leukemia: an analysis of Southeast Asian patients.

To better understand predictive factors and improve the clinical outcome of allogeneic transplant for patients with Philadelphia positive acute lymphoblastic leukemia, we analyzed 67 Southeast Asian patients transplanted in our institutions. Multivariate analysis showed that disease status before transplant, year of transplant and, interestingly, French-American-British (FAB) subtype had a significant impact on overall survival (OS) and non-relapse mortality. Patients who were minimal residual disease (MRD) negative at transplant had a 3-year OS of 73% compared to those who were MRD positive (45%) and refractory (0%).

Long term use of metformin leading to vitamin B 12 deficiency.

Metformin is a commonly used oral hypoglycaemic agent worldwide. Gastrointestinal side effects and lactic acidosis related to metformin usage are commonly recognized. However, the associated vitamin B12 deficiency is less well known.

Comparing peripheral blood stem cell collection using the COBE Spectra, Haemonetics MCS+, and Baxter Amicus.

Peripheral blood stem cells (PBSC) have become the most common source of hematopoietic cells for allogeneic or autologous blood and marrow transplantation (BMT). We performed an evaluation of PBSC collections using three different apheresis systems in two major transplantation centers in Singapore. Patients undergoing autologous BMT and donors collecting for allogeneic BMT were harvested using the COBE Spectra, Haemonetics MCS+, or Baxter Amicus.

Hereditary thrombophilia in an unselected cohort of venous thrombosis patients in Singapore.

Aim: Hereditary thrombophilic markers are commonly screened among patients diagnosed as having venous thromboembolism, but optimal patient selection and the goals of screening may differ between populations. Determining the patterns of hereditary thrombophilia may improve screening strategies.

Method: An unselected cohort of venous thromboembolism patients in three tertiary institutions in Singapore was prospectively tested for the prevalence of deficiencies of protein C, protein S, antithrombin III, factor V Leiden and prothrombin 20210 gene mutations.