Best Practice & Research Clinical Haematology最新文献

The tumor microenvironment (TMicroE) and tumor macroenvironment (TMacroE) are defining features of classical Hodgkin lymphoma (cHL). They are of critical importance to clinicians since they explain the common signs and symptoms, allow us to classify these neoplasms, develop prognostic and predictive biomarkers, bioimaging and novel treatments. The TMicroE is defined by effects of cancer cells to their immediate surrounding and within the tumor. Effects of cancer cells at a distance or outside of the tumor define the TMacroE. Paraneoplastic syndromes are signs and symptoms due to effects of cancer at a distance or the TMacroE, which are not due to direct cancer cell infiltration. The most common paraneoplastic symptoms are B-symptoms, which manifest as fevers, chills, drenching night sweats, and/or weight loss. Less common paraneoplastic syndromes include those that affect the central nervous system, skin, kidney, and hematological autoimmune phenomena including hemophagocytic lymphohistiocytosis (HLH). Paraneoplastic signs such as leukocytosis, lymphopenia, anemia, and hypoalbuminemia are prognostic biomarkers. The neoplastic cells in cHL are the Hodgkin and Reed Sternberg (HRS) cells, which are preapoptotic germinal center B cells with a high mutational burden and almost universal genetic alterations at the 9p24.1 locus primarily through copy gain and amplification with strong activation of signaling via PD-L1, JAK-STAT, NFkB, and c-MYC. In the majority of cases of cHL over 95% of the tumor cells are non-neoplastic. In the TMicroE, HRS cells recruit and mold non-neoplastic cells vigorously via extracellular vesicles, chemokines, cytokines and growth factors such as CCL5, CCL17, IL6, and TGF-β to promote a feed-forward inflammatory loop, which drives cancer aggressiveness and anti-cancer immune evasion. Novel single cell profiling techniques provide critical information on the role in cHL of monocytes-macrophages, neutrophils, T helper, Tregs, cytotoxic CD8⁺ T cells, eosinophils, mast cells and fibroblasts. Here, we summarize the effects of EBV on the TMicroE and TMacroE. In addition, how the metabolism of the TMicroE of cHL affects bioimaging and contributes to cancer aggressiveness is reviewed. Finally, we discuss how the TMicroE is being leveraged for risk adapted treatment strategies based on bioimaging results and novel immune therapies. In sum, it is clear that we cannot effectively manage patients with cHL without understanding the TMicroE and TMacroE and its clinical importance is expected to continue to grow rapidly.

Much of the modern focus of Hodgkin's Lymphoma (HL) treatment involves the prevention of secondary organ injury. Despite rationalisations of radiotherapy fields, many patients still develop late radiation-related cardiotoxicity that is severe and requires interventional management. No guidelines exist to direct management of these complex patients who often present with multiple concurrent cardiac pathologies. Despite possessing a greater mortality risk than in the general population, cardiac surgery has an important role in treating radiation-associated heart disease. This review summarises the body of literature surrounding cardiac surgery in HL survivors post-radiotherapy, highlighting the benefits and risks unique to this cohort. The pathophysiology and presentation of radiation-associated heart disease is also explored in relation to HL patients.

Donor lymphocyte infusion (DLI) is an important treatment modality in the management of relapsed hematological malignancies after allogeneic hematopoietic cell transplantation (allo-HCT). Donor T lymphocytes can be used in a therapeutic, pre-emptive or prophylactic manner in an attempt to stimulate a graft versus leukemia (GVL) effect and eradicate residual disease or even prevent relapse in a high-risk setting. DLIs are not without complications, however, graft versus host disease (GVHD) in particular. Data to date is limited to retrospective and small prospective studies. This review summarizes the available literature on approaches to managing relapse, dosing and timing of DLI, complications and potential future therapies.

Observational studies and clinical trials in hematology aim to examine treatments for blood disorders. The outcomes being studied must address the goals of the study and provide meaningful information about treatment course, disease progression, describe patients’ survival experience and quality of life. Endpoints are the specific measures of these outcomes, and much consideration should be given to their selection. In this review, we describe the outcomes and endpoints frequently used in studying hematologic diseases and provide general guidelines for their statistical analysis. The main focus is on clinical outcomes which are commonly used in establishing treatment safety and efficacy. We also briefly discuss the role surrogate and composite endpoints play in hematology studies. The importance of patient reported outcomes to comprehensive assessment of the treatment effectiveness is highlighted. Provided practical considerations for choosing primary and secondary endpoints may be helpful in designing hematology clinical trials.

Allogeneic hematopoietic stem cell transplantation (HSCT) is commonly utilized in the management of leukemia across multiple subtypes. Graft versus leukemia (GVL) is a critical component of successful transplantation and involves donor cells eradicating residual leukemia within the recipient. Graft versus host disease (GVHD) by contrast is a common complication of the transplantation process in which donor cells identify the recipient's various organ systems as foreign, thereby leading to a multitude of organ toxicities that can be described as autoimmune in nature. As both GVL and GVHD are mediated by a similar mechanism, these processes are felt to occur in tandem with one another. Here, we review the allogeneic HCT process in the context of GVL.

While the mainstay of treatment for high-risk or relapsed, refractory leukemia has historically revolved around allogeneic hematopoietic stem cell transplant (allo-HSCT), targeted immunotherapies have emerged as a promising therapeutic option, especially given the poor prognosis of patients who relapse after allo-HSCT. Novel cellular immunotherapies that harness the cytotoxic abilities of the immune system in a targeted manner (often called “adoptive” cell therapy), have changed the way we treat r/r hematologic malignancies and continue to change the treatment landscape given the rapid evolution of these powerful, yet sophisticated precision therapies that often offer a less toxic alternative to conventional salvage therapies. Importantly, adoptive cell therapy can be allo-HSCT-enabling or a therapeutic option for patients in whom transplantation has failed or is contraindicated. A solid understanding of the core concepts of adoptive cell therapy is necessary for stem cell transplant physicians, nurses and ancillary staff given its proximity to the transplant field as well as its inherent complexities that require specific expertise in compliant manufacturing, clinical application, and risk mitigation. Here we will review use of targeted cellular therapy for the treatment of r/r leukemia, focusing on chimeric antigen receptor T-cells (CAR T-cells) given the remarkable sustained clinical responses leading to commercial approval for several hematologic indications including leukemia, with brief discussion of other promising investigational cellular immunotherapies and special considerations for sustainability and scalability.

Blood-related diseases are complex diseases with diverse origins, treatments and prognosis. In haematology studies, investigators are interested in multiple outcomes and multiple prognostic variables that may change value over the course of follow-up. These time-dependent variables can be of different nature. Time-dependent events such as treatment with haematopoeitic stem cell transplant (HCT) and acute or chronic graft-versus-host disease (GVHD) typically interact with outcomes respectively after diagnosis or HCT. Longitudinal measurement such as immune response do influence survival after HCT. Effect of these time-dependent variables on outcomes can be investigated using different approaches, such as time-dependent Cox regression, landmark analysis, multi-state models or joint modelisation. In this paper we review basic principles of these different approaches using examples from haematological studies.

One of the consistent features in development of hematopoietic stem cell transplant (HCT) for Acute Lymphoblastic Leukemia (ALL) is the rapidity with which discoveries in the laboratory are translated into innovations in clinical care. Just a few years after murine studies demonstrated that rescue from radiation induced marrow failure is mediated by cellular not humoral factors, E. Donnall Thomas reported on the transfer of bone marrow cells into irradiated leukemia patients. This was followed quickly by the first descriptions of Graft versus Leukemia (GvL) effect and Graft versus Host Disease (GvHD). Despite the pivotal nature of these findings, early human transplants were uniformly unsuccessful and identified the challenges that continue to thwart transplanters today – leukemic relapse, regimen related toxicity, and GvHD. While originally only an option for young, fit patients with a matched family donor, expansion of the donor pool to include unrelated donors, umbilical cord blood units, and more recently the growing use of haploidentical donors have all made transplant a more accessible therapy for patients with ALL. Novel agents for conditioning, prevention and treatment of GvHD have improved outcomes and investigators continue to develop novel treatment strategies that balance regimen related toxicity with disease control. Our evolving understanding of how to prevent and treat GvHD and how to prevent relapse are incorporated into novel clinical trials that are expected to further improve outcomes.

Here we review current considerations and future directions for both adult and pediatric patients undergoing HCT for ALL, including indication for transplant, donor selection, cytoreductive regimens, and outcomes.