Search

In this special issue of Bone Marrow Transplantation, investigators report the impact of IDH1 [1], IDH2 [2], and FLT3-TKD [3] measurable residual disease (MRD) pre-hematopoietic cell transplantation (HCT) in predicting relapse of acute myeloid leukemia (AML) in adults receiving allogeneic HCT. The patient population for these retrospective cohorts, reflecting clinical transplant practice patterns and research biobank participation, was 84-86% non-Hispanic White (NHW) in each study. In this commentary, we explore the implications of racial and ethnic disparities in access to both HCT and HCT-related research and propose strategies to promote representation in precision medicine, given the emerging impact of the field on HCT outcomes., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The application of CD19-directed chimeric antigen receptor T (CAR T) cell therapy has improved outcomes for thousands of patients with non-Hodgkin B cell lymphoma (NHL). The toxicities associated with various CAR T cell products, however, can be severe and difficult to anticipate., Methods: In this systematic review and meta-analysis, we set out to determine whether there are measurable differences in common toxicities, including cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), cytopenias, and infections, between CAR T products that are commercially available for the treatment of NHL., Results: After a stringent study selection process, we used a cohort of 1364 patients enrolled in 15 prospective clinical trials investigating the use of axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), and tisagenlecleucel (tisa-cel). We found that the rates of CRS and ICANS were significantly higher with axi-cel as compared to both liso-cel and tisa-cel. Conversely, we demonstrated that rates of all-grade and severe neutropenia were significantly greater with liso-cel. Febrile neutropenia and all-grade infection rates did not differ significantly between products though rates of severe infection were increased with axi-cel., Conclusions: Overall, this study serves as the first to delineate toxicity profiles associated with various available CAR T products. By better understanding associated toxicities, it may become possible to tailor therapies towards individual patients and anticipate the development of toxicities at earlier stages., Competing Interests: Disclosure JL has received Consulting fees from Abbvie, Astellas, AstraZeneca, Bayer, Beigene, BMS, Calithera, Constellation, Caribou Biosciences, Eisai, Lilly, Epizyme, Genmab, Grail, Incyte, Jansssen, MEI Pharma, Merck, Mustang Bio, Novartis, Pfizer, Roche/Genentech, Seagen, Second Genome, Sutro. PM has received Consulting fees from Abbvie, AstraZeneca, Beigene, BMS, Daiichi Sankyo, Epizyme, Genentech, Janssen, Merck, Pepromene. SY has received Consulting fees from Bristol Myers Squibb. All other authors have no conflict of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

As the prevalence of pediatric diabetes grows and new technologies to manage diabetes emerge, there is increasing concern about consistency in health management across institutional settings, particularly in schools. While much is known about barriers at school, there are still gaps in understanding the institutional dynamics that shape health management in this setting. Using focus groups with 19 youth with type 1 diabetes (T1D) and applying institutional role theory, we find healthcare providers' recommendations conflict with school rules and norms, making it difficult to enact both the "sick role" and the "student role." These conflicts elicit negative responses from teachers and peers and stigmatize youth with T1D in school. Caregiver involvement often heightens rather than ameliorates conflict and teachers do not intervene in effective ways. Ultimately, youth must manage conflicts and stigma. By reframing challenges in health management as institutional role conflict, this paper contributes to sociological research by highlighting the importance of institutional roles, especially beyond healthcare. More broadly, the study suggests health research and policy should investigate how to better align institutional roles-rather than relying on youth and their families-to support health management of chronic illnesses across institutional settings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Pulmonary complications constitute a major cause of morbidity and mortality in the post-allogenic hematopoietic stem cell transplantation (alloHSCT) period. Although chest X-ray (CXR) is customarily used for screening, we have used chest computed tomography (CT) scans. To characterize the prevalence of abnormalities and explore their impact on alloHSCT eligibility and outcomes post-transplantation, we conducted a retrospective analysis using real-world data collected at our center for adult patients who were evaluated for alloHSCT between January 2013 and December 2020 and identified 511 eligible patients. The most common primary disease was acute myeloid leukemia, in 49% of patients, followed by myelodysplastic syndrome (23%), lymphoma (11%), and acute lymphocytic leukemia (10%). Abnormal screening chest CT results were found in 199 patients (39%). The most frequent detected abnormality was pulmonary nodule, in 78 patients (35%), followed by consolidation in 42 (19%), ground-glass opacification in 33 (15%), bronchitis and bronchiolitis in 25 (11%), pleural effusions in 14 (6%), and new primary cancer in 7 (2%). CXR detected abnormalities in only approximately one-half of the patients (48%) with an abnormal chest CT scan. Among the 199 patients with an abnormal chest CT scan, 98 (49%) underwent further assessment and/or intervention before transplantation. The most common workup was pulmonary consultation in 32%, followed by infectious diseases consultation in 24%. Lung biopsy was obtained in 20%, and antimicrobial therapy was initiated after confirming an infection diagnosis in 20%. Patients with an abnormal chest CT scan demonstrated worse overall survival (P = .032), nonrelapse mortality (P = .015), and pulmonary-related mortality (P < .001) compared to those with a normal chest CT scan. Our study suggests that pretransplantation screening chest CT is beneficial in uncovering invasive infections and underlying malignancies and allows for appropriate interventions before alloHSCT to prevent potentially serious post-transplantation complications without causing a delay in alloHSCT. Nevertheless, abnormal CT findings prior to transplantation may be associated with overall worse prognosis., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Testing for measurable residual disease (MRD) provides important prognostic and predictive implications on survival and management of many hematologic diseases. Among the many clinical uses of MRD is post-therapy response assessment and risk stratification. With the integration of precision medicine in routine clinical care and the development of novel and innovative therapies resulting in deeper responses, it is necessary to refine the role of MRD, standardize available methodologies and define its role as a surrogate endpoint for relapse and time-to-next treatment in clinical studies. Chimeric Antigen Receptor (CAR) T-cell therapy is an approved treatment for various hematologic malignancies. Even though it produces high rates of remission, the durability of response is still a consideration as almost 40% to 50% of patients eventually relapse. MRD testing as a prognostic and surrogate marker is being explored in patients after CAR T-cell therapy to predict early relapse. In this chapter, we review the various tools available for MRD detection and monitoring post-CAR T-cell therapy. We later discuss disease-specific MRD assessment and its application in recent studies in the post-CAR T setting., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Next-generation sequencing (NGS) is increasingly employed for diagnosis, risk stratification, and management of patients with myelodysplastic syndrome (MDS). We aimed to describe beliefs and practice patterns among providers who treat MDS patients with respect to the utility of NGS in diagnosis, risk stratification, prognosis, and treatment decisions at various points along the disease trajectory, response assessment, and development of institutional guidelines for MDS-specific molecular profiling. Using a 23-question web-based survey in May-June 2018, we identified a widespread use of molecular profiling with MDS-specific panels ( N  = 53; 39%) and general panels including MDS-related genes ( N  = 63; 47%), with the majority done at diagnosis (92%). We found substantial variations in genes tested in assays, providers beliefs, practices, testing logistics, and interpretation of results, and recognized multiple challenges limiting a wider utilization of molecular profiling. High-quality data are needed to develop evidence-based guidelines for the role of NGS in the care of MDS patients.

Introduction: Commonly used scoring systems rely on blood counts, histological and cytological examination of bone marrow and peripheral blood as well as cytogenetic assessments to estimate prognosis of patients with myelodysplastic syndromes (MDS) and guide therapy decisions. Next-generation sequencing (NGS) has identified recurrent genetic abnormalities in up to 90% of patients with MDS and may provide important information regarding the pathogenesis of the disease, diagnostic and prognostic evaluation, and therapy selection. Areas covered: Herein, the authors review the role of NGS in diagnosis, treatment, and prognosis of MDS at various disease stages, and discuss advantages and caveats of incorporating molecular genetics in routine management of MDS. While a vast majority of patients harbor recurrent mutations implicated in MDS pathogenesis, similar mutations can be detected in otherwise healthy individuals with other hematologic malignancies. Besides establishing a diagnosis, NGS may be used to monitor minimal residual disease following treatment. Expert opinion: As more targeted therapies become available, assessment of genetic mutations will become central to individualized therapy selection and may improve diagnostic accuracy and further guide management for each patient. However, multiple challenges remain before NGS can be incorporated into routine clinical practice.

Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases characterized by ineffective hematopoiesis and a wide spectrum of manifestations ranging from indolent and asymptomatic cytopenias to acute myeloid leukemia (AML). MDS result from genetic and epigenetic derangements in clonal cells and their surrounding microenvironments. Studies have shown associations between MDS and other autoimmune diseases. Several immune mechanisms have been identified in MDS, suggesting that immune dysregulation might be at least partially implicated in its pathogenesis. This has led to rigorous investigations on the role of immunomodulatory drugs as potential treatment options. Epigenetic modification via immune check point inhibition, while well established as a treatment method for advanced solid tumors, is a new approach being considered in hematologic malignancies including high risk MDS. Several trials are looking at the efficacy of these agents in MDS, as frontline therapy and in relapse, both as monotherapy and in combination with other drugs. In this review, we explore the utility of immune checkpoint inhibitors in MDS and current research evaluating their efficacy.

Introduction: Myelodysplastic syndromes (MDS) encompass a heterogenous collection of clonal hematopoietic stem cell disorders defined by dysregulated hematopoiesis, peripheral cytopenias, and a risk of leukemic progression. Increasing data support the role of innate and adaptive immune pathways in the pathogenesis and disease course of MDS. The role of immunosuppressive therapy has an established role in the treatment of other hematologic diseases, such as aplastic anemia whose pathogenesis is postulated to reflect that of MDS with regards to many aspects of immune activation. Areas covered: This paper discusses the current understanding of immune dysregulation as it pertains to MDS, the clinical experience with immunosuppressive therapy in the management of MDS, as well as future prospects which will likely improve therapeutic options and outcomes for patients with MDS. Expert commentary: Though limited by paucity of high quality data, immunomodulatory and immunosuppressive therapies for the treatment of MDS have shown meaningful clinical activity in selected patients. Continued clarification of the immune pathways that are dysregulated in MDS and establishing predictors for clinical benefit of immunosuppressive therapy are vital to improve the use and outcomes with these therapies.

Background: A novel software application, Blip, was created to combine and display diabetes data from multiple devices in a uniform, user-friendly manner. The objective of this study was to test the usability of this application by adults and caregivers of children with type 1 diabetes (T1D)., Methods: Patients (n = 35) and caregivers of children with T1D (n = 30) using an insulin pump for >1 year ± CGM were given access to the software for 3 months. Diabetes management practices and the use of diabetes data were assessed at baseline and at study end, and feedback was gathered in a concluding questionnaire., Results: At baseline, 97% of participants agreed it was important for patients to know how to interpret glucose data. Most felt that clinicians and patients should share the tasks of reviewing data, finding patterns, and making changes to their insulin plans. However, despite valuing shared responsibility, at baseline, 43% of participants never downloaded pump data, and only 9% did so at least once per month. At study end, 72% downloaded data at least once during the 3-month study, and 38% downloaded at least once per month. Regarding the software application, participants liked the central repository of data and the user interface. Suggestions included providing tools for understanding and interpreting glucose patterns, an easier uploading process, and access with mobile devices., Conclusions: Collaboration between developers and researchers prompted iterative, rapid development of data visualization software and improvements in the uploading process and user interface, which facilitates clinical integration and future clinical studies.

Objective: It has been suggested that autoantibodies in systemic sclerosis (SSc) may induce the differentiation of cultured fibroblasts into myofibroblasts through platelet-derived growth factor receptor (PDGFR) activation. The present study aims to characterize the effects of SSc IgG on vascular smooth muscle cells (VSMCs) and to determine if stimulatory autoantibodies directed to the PDGFR can be detected, and whether they induce a profibrotic response in primary cultured VSMCs., Methods: Cultured VSMCs were exposed to IgG fractions purified from SSc-patient or control sera. VSMC responses were then analyzed for ERK1/2 and Akt phosphorylation, PDGFR immunoprecipitation, cellular proliferation, protein synthesis, and pro-fibrotic changes in mRNA expression., Results: Stimulatory activity in IgG fractions was more prevalent and intense in the SSc samples. SSc IgG immunoprecipitated the PDGFR with greater avidity than control IgG. Interestingly, activation of downstream signaling events (e.g. Akt, ERK1/2) was independent of PDGFR activity, but required functional EGFR. We also detected increased protein synthesis in response to SSc IgG (p<0.001) and pro-fibrotic changes in gene expression (Tgfb1 +200%; Tgfb2 -23%; p<0.001)) in VSMCs treated with SSc IgG., Conclusion: When compared to control IgG, SSc IgG have a higher stimulation index in VSMCs. Although SSc IgG interact with the PDGFR, the observed remodeling signaling events occur through the EGFR in VSMC. Our data thus favour a model of transactivation of the EGFR by SSc-derived PDGFR autoantibodies and suggest the use of EGFR inhibitors in future target identification studies in the field of SSc.