Severe B12 Deficiency Causing a Maturation Defect Mimicking Myelodysplastic Syndrome With Excess Blasts.

Vitamin B12 deficiency is a common condition that is often asymptomatic, though in severe cases may cause megaloblastic anemia and even neurologic symptoms. Occasionally, the clinical presentation can include pancytopenia and thus mimic a more concerning myelodysplastic syndrome (MDS) until corrected by B12 supplementation. In this unusual case, we present a patient with B12 deficiency who presents with severe macrocytic anemia, neutropenia, lymphocytosis, and a bone marrow morphology consistent with MDS.

VEXAS syndrome: A 2-case series report.

VEXAS syndrome is a rare entity secondary to UBA1 gene mutations, located on the X chromosome. This mutation generates, as a consequence, a characteristic vacuolation on haematopoietic stem-cells. It is characterized by multiple autoinflammatory and haematologic manifestations, which respond and end up being dependent on corticosteroid treatment. In this publication we present a 2-case series diagnosed at our hospital and make a brief literature review of the published evidence so far.

Abstracts of the Cell Therapy Transplant Canada 2023 Annual Conference.

On behalf of Cell Therapy Transplant Canada (CTTC), we are pleased to present the Abstracts of the CTTC 2023 Annual Conference. The conference was held in-person, 31 May-2 June 2023, in Halifax, Nova Scotia at the Westin Nova Scotian hotel. Poster authors presented their work during a lively and engaging welcome reception on Thursday, 1 June, and oral abstract authors were featured during the oral abstract session in the afternoon of Friday, 2 June 2023. Twenty-three (23) abstracts were selected for presentation as posters and four (4) as oral presentations. Abstracts were submitted within four categories: (1) Basic/Translational Sciences, (2) Clinical Trials/Observations, (3) Laboratory/Quality, and (4) Pharmacy/Nursing/Other Transplant Support. The top four (4) oral abstracts and top four (4) poster abstracts were selected to receive an award. All of these were marked as "Award Recipient" within the relevant category. We congratulate all the presenters on their research and contributions to the field.

Clinicians' Perspectives on the Telehealth Serious Illness Care Program for Older Adults With Myeloid Malignancies: Single-Arm Pilot Study.

BACKGROUND: Serious illness conversations may help patients avoid unwanted treatments. We previously piloted the telehealth Serious Illness Care Program (SICP) for older adults with acute myeloid leukemia and myelodysplastic syndrome. OBJECTIVE: In this study, we aimed to understand the experience of the telehealth SICP from the clinician's perspective. METHODS: We studied 10 clinicians who delivered the telehealth SICP to 20 older adults with acute myeloid leukemia or myelodysplastic syndrome. Quantitative outcomes included confidence and acceptability. Confidence was measured using a 22-item survey (range 1-7; a higher score is better). Acceptability was measured using an 11-item survey (5-point Likert scale). Hypothesis testing was performed at α=.10 (2-tailed) due to the pilot nature and small sample size. Clinicians participated in audio-recorded qualitative interviews at the end of the study to discuss their experience. RESULTS: A total of 8 clinicians completed the confidence measure and 7 clinicians completed the acceptability measure. We found a statistically significant increase in overall confidence (mean increase of 0.5, SD 0.6; P=.03). The largest increase in confidence was in helping families with reconciliation and goodbye (mean 1.4, SD 1.5; P=.04). The majority of clinicians agreed that the format was simple (6/7, 86%) and easy to use (6/7, 86%). Clinicians felt that the telehealth SICP was effective in understanding their patients' values about end-of-life care (7/7, 100%). A total of three qualitative themes emerged: (1) the telehealth SICP deepened relationships and renewed trust; (2) each telehealth SICP visit felt unique and personal in a positive way; and (3) uninterrupted, unrushed time optimized the visit experience. CONCLUSIONS: The telehealth SICP increased confidence in having serious illness conversations while deepening patient-clinician relationships. TRIAL REGISTRATION: ClinicalTrials.gov NCT04745676; https://www.clinicaltrials.gov/study/NCT04745676.

Inflamma-miRs Profile in Myelodysplastic Syndrome Patients.

Etiological factors involved in myelodysplastic syndrome (MDS) include immunologic, oxidative stress and inflammatory factors, among others, and these are targets for microRNAs (miRNs). Here, we evaluated whether some miRNs may affect tumor development comparing untreated and 5-azacitidine (5-AZA) MDS-treated patients. Peripheral blood samples were collected from 20 controls and 24 MDS patients, and selected miRNs related to redox balance and inflammation (inflamma-miRs), including miR-18a, miR-21, miR-34a and miR-146a, were isolated and measured by quantitative real-time polymerase chain reaction (qRTPCR). A differential expression profile of miRNs was detected in untreated MDS patients and the 5-AZA group. Inflammation increases miRNs and, specifically, miR-18a, miR-21 and miR-34a were significantly overexpressed in untreated MDS, compared to controls. However, we did not observe any miRN profile alteration during the progression of the disease. On the other hand, 5-AZA treatment tends to restore miRN expression levels. Relating to prognostic risk factors, high-risk MDS groups (high Revised International Prognostic Scoring System (IPSS-R), high cytogenetic risk, high molecular risk (HMR) mutations) tended to be related with higher expression levels of miR-18a and miR-34a. Higher miRN expression is correlated with lower glutathione peroxidase activity, while they are related with a higher profile of pro-inflammatory cytokines (IL-2, IL-6, IL-8, TNF-α). Although our study was limited by the low number of MDS patients included, we identified miRN deregulation involved in MDS development that could regulate redox sensors and inflammatory responses. Finally, 5-AZA treatment is related with lower miRN expression levels in MDS patients.

HALP score as a novel prognostic factor for patients with myelodysplastic syndromes.

Myelodysplastic syndrome (MDS) is a heterogeneous spectrum of clonal hematopoietic disorders with varying degrees of cytopenia and morphologic dysplasia. The hemoglobin, albumin, lymphocyte, and platelet (HALP) score is a prognostic marker in several types of malignant tumors. Prognostic value of HALP score remains unclear for MDS. To determine the prognostic value of baseline HALP score in MDS. We retrospectively analyzed data from 130 newly diagnosed MDS patients evaluated and classified under HALP score. By the receiver operating characteristic (ROC) analysis, the optimal cut-off value of HALP was > 67.5 in predicting mortality. Patients were divided into two groups: with low and high HALP scores, and the characteristics were compared between both groups. Patients' median age was 68 (19-84) years, and 79 (60.8%) were male. Higher HALP score was detected in MDS patients with intermediate-risk under IPSS score, and at high and very high risks under IPSS-R score, and those receiving azacitidine (AZA) treatment. The survival rates of those with a HALP score > 67.5 were significantly lower than those with low HALP score at 17.77 ± 3.98 (median ± SE) (p < 0.001). The 3-, 5- and 10-years survival rates of individuals with HALP scores > 67.5 were found as 25, 18, and 11%, respectively. Median overall survival (OS) was also determined as 33.10 (95% CI 16.34-49.88) months by the Kaplan-Meier method. HALP score has shown an ability to be a useful prognostic biomarker in various cancers, including MDS. The meaningful cut-off value of HALP is disease-specific and largely study-specific. High HALP score is associated with unfavorable clinicopathological characteristics. Also, it may be useful in predicting OS and mortality of MDS.

[Effect of TP53 Allelic State on Clinical Performance and Prognosis of Patients with Myelodysplastic Syndrome].

OBJECTIVE: To investigate the clinical significance of TP53 allelic state in patients with myelodysplastic syndromes (MDS). METHODS: The clinical data of 858 MDS patients who underwent second-generation sequencing (NGS) testing in the First Affiliated Hospital of Soochow University from January 2019 to December 2021 were retrospectively analyzed. RESULTS: The median age of the patients was 52 years old, and median follow-up time was 23.8 (0.4-109.6) months. Four hundred and one patients (46.7%) had at least one chromosomal abnormality, including 106 complex karyotypes and 78 monosomal karyotypes. A total of 103 cases of TP53 mutations were identified, with a mutation rate of 12%. Compared with TP53 wild-type, various types of chromosomal abnormalities were significantly more common in patients with TP53 mutations (all P < 0.001). Patients with TP53 mutations had lower hemoglobin levels, lower platelet counts and higher percentage of bone marrow primitive cell compared with TP53 wild type (all P < 0.05), and significantly shorter overall survival (OS). Among 97 evaluable patients, 33 cases (34%) were mono-allelic TP53 mutation, while 64 cases were bi-allelic TP53 mutation. Patients in bi-allelic TP53 mutation subgroup had a higher proportion of chromosomal abnormalities and a lower number of co-mutations compared with mono-allelic TP53 mutation. The median OS was 33.6 months in patients with mono-allelic state and only 11.4 months in patients with bi-allelic state (HR=2.138, 95%CI : 1.053-4.343, P >0.05). Median OS was not reached in TP53 wild-type patients, and there was a significant difference in OS among TP53 wild-type, mono-allelic and bi-allelic TP53 mutation patients (P < 0.001). Multivariable Cox regression analysis showed that bi-allelic TP53 was an independent predictor of poor outcomes (HR=2.808, 95%CI : 1.487-5.003, P =0.001), while mono-allelic TP53 mutation and wild-type TP53 were not. CONCLUSION: Patients with TP53 mutations have a poor prognosis, and bi-allelic TP53 mutations have a worse prognosis compared with mono-allelic TP53 mutations and independently affect the prognosis of MDS patients.

Bacterial Pericarditis With Underlying Severe Aortic Stenosis and Myelodysplastic Syndrome.

We herein describe a case of a 79-year-old male who presented with severe aortic stenosis with myelodysplastic syndrome. He was hospitalized to undergo presurgical evaluation and puncture of pericardiocentesis. After the placement of pericardial drainage, he developed bacterial pericarditis. His heart failure had worsened due to new onset of atrial fibrillation and pericardial constriction. Methicillin-sensitive Staphylococcus aureus was identified as the pathogen from the puncture. A pericardial windowing was performed so that his circulatory status was stabilized. An aortic valve replacement as well as resection of pericardial fibrosis was finally performed, and he was discharged without any sequela.

A Brief Overview of the Molecular Landscape of Myelodysplastic Neoplasms.

Myelodysplastic neoplasm (MDS) is a heterogeneous group of clonal hematological disorders that originate from the hematopoietic and progenitor cells and present with cytopenias and morphologic dysplasia with a propensity to progress to bone marrow failure or acute myeloid leukemia (AML). Genetic evolution plays a critical role in the pathogenesis, progression, and clinical outcomes of MDS. This process involves the acquisition of genetic mutations in stem cells that confer a selective growth advantage, leading to clonal expansion and the eventual development of MDS. With the advent of next-generation sequencing (NGS) assays, an increasing number of molecular aberrations have been discovered in recent years. The knowledge of molecular events in MDS has led to an improved understanding of the disease process, including the evolution of the disease and prognosis, and has paved the way for targeted therapy. The 2022 World Health Organization (WHO) Classification and the International Consensus Classification (ICC) have incorporated the molecular signature into the classification system for MDS. In addition, specific germline mutations are associated with MDS development, especially in pediatrics and young adults. This article reviews the genetic abnormalities of MDS in adults with a brief review of germline predisposition syndromes.

Multiplex imaging reveals spatially resolved DNA-damage response neighborhoods in TP53-mutated myelodysplastic neoplasms.

While increased DNA damage is a well-described feature of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), it is unclear whether all lineages and all regions of the marrow are homogeneously affected. In this study, we performed immunohistochemistry on formalin-fixed, paraffin-embedded whole-section bone marrow biopsies using a well-established antibody to detect pH2A.X (phosphorylated histone variant H2A.X) that recognizes DNA double-strand breaks. Focusing on TP53-mutated and complex karyotype MDS/AML, we find a greater pH2A.X+ DNA damage burden compared to TP53 wild-type neoplastic cases and non-neoplastic controls. To understand how double-strand breaks vary between lineages and spatially in TP53-mutated specimens, we applied a low-multiplex immunofluorescence staining and spatial analysis protocol to visualize pH2A.X+ cells with p53 protein staining and lineage markers. pH2A.X marked predominantly mid- to late-stage erythroids, whereas early erythroids and CD34+ blasts were relatively spared. In a prototypical example, these pH2A.X+ erythroids were organized locally as distinct colonies, and each colony displayed pH2A.X+ puncta at a synchronous level. This highly coordinated immunophenotypic expression was also seen for p53 protein staining and among presumed early myeloid colonies. Neighborhood clustering analysis showed distinct marrow regions differentially enriched in pH2A.X+/p53+ erythroid or myeloid colonies, indicating spatial heterogeneity of DNA-damage response and p53 protein expression. The lineage and architectural context within which DNA damage phenotype and oncogenic protein are expressed is relevant to current therapeutic developments that leverage macrophage phagocytosis to remove leukemic cells in part due to irreparable DNA damage. © 2024 The Pathological Society of Great Britain and Ireland.

Donor Lymphocyte Infusion (DLI) post allogeneic stem cell transplant (allo-SCT) in Acute Myeloid Leukemia (AML) and High-Grade Myelodysplastic Syndrome (MDS). A longitudinal retrospective study using peripheral blood (PB) CD34+ and CD3+ donor chimerism (DC) monitoring.

INTRODUCTION: This longitudinal study was based on the outcomes of Donor Lymphocyte Infusion (DLI) for falling peripheral blood (PB) CD34+ and CD3+ donor chimerism (DC). METHODS: From 2012 to 2018, data was collected from the BMT database and electronic medical records (EMR). The primary objective was to compare the indication for DLI based on falling PB CD34+ or CD3+ DC in patients post allo-SCT for AML and MDS and their overall survival (OS). RESULTS: 18/70 patients met the inclusion criteria. Indications for DLI were i) falling PB CD34+ DC ≤ 80 % with morphological relapse, ii) falling PB CD34+ DC ≤ 80 % without morphological relapse and iii) falling PB CD3+ DC ≤ 80 % without falling PB CD34+ DC. Log rank analysis showed falling PB CD34+ DC and morphological relapse had significantly lower OS. Linear regression demonstrated better OS post DLI if there was PB CD34+ and CD3+ chimerism response at 30 days (p = 0.029), GVHD (p = 0.032) and tapering immunosuppression at the time of falling DC (p = 0.042). CONCLUSION: DLI for PB CD34+ DC values ≤ 80 % and morphological relapse had the lowest OS. In this study, full DC was achieved after DLI even with a PB CD3+DC value as low as 13 %, provided the PB CD34+ DC remained > 80 %. Further research is vital in CD34+ DC as a biomarker for disease relapse and loss of engraftment.

Treatment of Anemia in Lower-Risk Myelodysplastic Syndrome.

OPINION STATEMENT: A majority of patients with lower-risk myelodysplastic syndrome (MDS) will present with or develop anemia. Anemia in MDS is associated with decreased quality of life and may correlate with decreased progression-free survival and overall survival. In this state of the art review we summarize current risk stratification approaches to identify lower-risk MDS (LR-MDS), the natural history of the disease, and meaningful clinical endpoints. The treatment landscape of LR-MDS with anemia is also rapidly evolving; we review the role of supportive care, erythropoietin stimulating agents, lenalidomide, luspatercept, hypomethylating agents (HMAs), and immunosuppressive therapy (IST) in the management of LR-MDS with anemia. In patients with deletion 5q (del5q) syndrome lenalidomide has both efficacy and durability of response. For patients without del5q who need treatment, the management approach is impacted by serum erythropoietin (EPO) level, SF3B1 mutation status, and ring sideroblast status. Given the data from the Phase III COMMANDS trial, we utilize luspatercept in those with SF3B1 mutation or ring sideroblasts that have an EPO level < 500 U/L; in patients without an SF3B1 mutation or ring sideroblasts there is equipoise between luspatercept and use of an erythropoietin stimulating agent (ESA). For patients who have an EPO level ≥ 500 U/L or have been previously treated there is not a clear standard of care. For those without previous luspatercept exposure it can be considered particularly if there is an SF3B1 mutation or the presence of ring sideroblasts. Other options include HMAs or IST; the Phase III IMERGE trial supports the efficacy of the telomerase inhibitor imetelstat in this setting and this may become a standard option in the future as well.

Effects of immune cells in mediating the relationship between gut microbiota and myelodysplastic syndrome: a bidirectional two-sample, two-step Mendelian randomization study.

BACKGROUND: The definitive establishment of a causal relationship between gut microbiota and myelodysplastic syndrome (MDS) has not been achieved. Furthermore, the involvement of immune cells in mediating the connection between gut microbiota and MDS is presently unclear. METHODS: To elucidate the bidirectional correlation between gut microbiota and MDS, as well as to investigate the mediating role of immune cells, a bidirectional two-sample, two-step Mendelian randomization (MR) study was conducted. Summary statistics were obtained from genome-wide association studies (GWAS), including MDS (456,348 individuals), gut microbiota (18,340 individuals), and 731 immune cells signatures (3757 individuals). RESULTS: Genetically predicted eight gut microbiota traits were significantly associated with MDS risk, but not vice versa. Through biological annotation of host-microbiome shared genes, we found that immune regulation may mediate the impact of gut microbiota on MDS. Subsequently, twenty-three immunophenotypes that exhibited significant associations with MDS risk and five of these immunophenotypes were under the causal influence of gut microbiota. Importantly, the causal effects of gut microbiota on MDS were significantly mediated by five immunophenotypes, including CD4 +T cell %leukocyte, CD127 on CD45RA - CD4 not regulatory T cell, CD45 on CD33 + HLA DR + WHR, CD33 on basophil, and Monocyte AC. CONCLUSIONS: Gut microbiota was causally associated with MDS risk, and five specific immunophenotypes served as potential causal mediators of the effect of gut microbiota on MDS. Understanding the causality among gut microbiota, immune cells and MDS is critical in identifying potential targets for diagnosis and treatment.

BRAF mutation in myeloid neoplasm: incidences and clinical outcomes.

The presence of BRAF mutation in hematological malignancies, excluding Hairy cell leukemia, and its significance as a driver mutation in myeloid neoplasms (MNs) remains largely understudied. This research aims to evaluate patient characteristics and outcomes of BRAF-mutated MNs. Among a cohort of 6667 patients, 48 (0.7%) had BRAF-mutated MNs. Notably, three patients exhibited sole BRAF mutation, providing evidence supporting the hypothesis of BRAF's role as a driver mutation in MNs. In acute myeloid leukemia, the majority of patients had secondary acute myeloid leukemia, accompanied by poor-risk cytogenic and RAS pathway mutations. Although the acquisition of BRAF mutation during disease progression did not correlate with unfavorable outcomes, its clearance through chemotherapy or stem cell transplant exhibited favorable outcomes (median overall survival of 34.8 months versus 10.4 months, p = 0.047). Furthermore, G469A was the most frequently observed BRAF mutation, differing from solid tumors and hairy cell leukemia, where V600E mutations were predominant.

Co-occurrence of High-Risk Myelodysplastic Syndrome With a Complex Karyotype/TP53 Mutation and IgG Lambda Monoclonal Gammopathy of Undetermined Significance.

Myelodysplastic syndrome (MDS) represents a group of hematologic disorders marked by abnormal cellular development in the bone marrow, while monoclonal gammopathy of undetermined significance (MGUS) involves abnormal plasma cells without symptomatic manifestations. This paper presents a compelling case of a 74-year-old Hispanic female diagnosed with a rare combination of high-risk MDS characterized by a complex karyotype and TP53 mutation, alongside IgG lambda MGUS. The patient's clinical presentation included a spectrum of symptoms such as body aches, rash, fever, dyspnea, and bloody watery diarrhea. Initial diagnostic evaluations yielded no significant findings, but subsequent investigations revealed abnormalities in both bone marrow and peripheral blood, indicative of coexisting MDS and MGUS. Chromosomal analysis further confirmed the presence of a complex karyotype with multiple aberrations, notably including 5q deletion. This case underscores the rarity of simultaneous high-risk MDS and MGUS, particularly with the additional complexity of a TP53 mutation and complex karyotype. It underscores the imperative for continued research efforts to elucidate the underlying mechanisms and optimal management strategies for such intricate cases. Moreover, it highlights the therapeutic challenges posed by concurrent MDS and plasma cell disorders, advocating for more aggressive interventions such as stem cell transplantation as potential avenues for improved patient outcomes.

A case report of secondary B-cell acute lymphoblastic leukemia treated with a combination of FLT3 inhibitor and decitabine.

Secondary acute lymphoblastic leukemia (s-ALL) refers to acute lymphoblastic leukemia that occurs after a previous malignant tumor, including therapy-related acute lymphoblastic leukemia (t-ALL) and prior malignant tumor acute lymphoblastic leukemia (pm-ALL). We report a case of a 51-year-old female patient who developed acute lymphoblastic leukemia 14 years after being diagnosed with diffuse large B-cell lymphoma (DLBCL). The patient was unresponsive to conventional chemotherapy for acute lymphoblastic leukemia (ALL) and achieved remission with a combination of sorafenib and decitabine based on the molecular biology characteristics of her B-ALL.

Evaluation of Posaconazole Serum Concentrations Achieved With Delayed-release Tablets and Oral Suspension in Patients Undergoing Intensive Chemotherapy for Acute Myeloid Leukemia and Myelodysplastic Syndrome.

Data on posaconazole serum levels of patients on prophylaxis with delayed-release tablets or oral suspension during intensive chemotherapy for acute myeloid leukemia and myelodysplastic syndrome are scarce. In this analysis, the proportion of patients with acute myeloid leukemia/myelodysplastic syndrome achieving posaconazole target concentrations with delayed-release tablets was higher than with oral suspension.

Myelodysplastic Syndrome: Clinical Characteristics and Significance of Preclinically Detecting Biallelic Mutations in the TET2 Gene.

Myelodysplastic syndrome (MDS) is a clonal disease derived from hematopoietic stem cells, characterized by ineffective hematopoiesis (resulting in peripheral blood cytopenia) and an increased risk of transformation into acute myeloid leukemia. MDS is caused by a complex combination of genetic mutations resulting in a heterogeneous genotype. Genetic studies have identified a set of aberrations that play a central role in the pathogenesis of MDS. In this article, we present a clinical case of MDS transformation into acute myeloid leukemia in the context of two cell lines exhibiting morphological, immunophenotypic, and dysmyelopoiesis markers and the presence of two heterozygous mutations in the TET2 gene.