Best Practice & Research Clinical Haematology最新文献

Approaches to comparing safety and efficacy of interventions include analyzing data from randomized controlled trials (RCTs), registries and observational databases (ODBs). RCTs are regarded as the gold standard but data from such trials are sometimes unavailable because a disease is uncommon, because the intervention is uncommon, because of structural limitations or because randomization cannot be done for practical or (seemingly) ethical reasons. There are many examples of an unproved intervention being so widely-believed to be effective that clinical trialists and potential subjects decline randomization. Often, when a RCT is finally done the intervention is proved ineffective or even harmful. These situations are termed medical reversals and are not uncommon [1,2]. There is also the dilemma of when seemingly similar RCTs report discordant conclisions

Data from high-quality registries, especially ODBs can be used when data from RCTs are unavailable but also have limitations. Biases and confounding co-variates may be unknown, difficult or impossible to identify and/or difficult to adjust for adequately. However, ODBs sometimes have large numbers of diverse subjects and often give answers more useful to clinicians than RCTs. Side-by-side comparisons suggest analyses from high-quality ODBs often give similar conclusions from high quality RCTs. Meta-analyses combining data from RCTs, registries and ODBs are sometimes appropriate. We suggest increased use of registries and ODBs to compare efficacy of interventions.

Gaucher disease GD), is a rare lysosomal storage disorder caused by deficient acid β-glucosylceramidase activity and accumulation of glucosylceramide in tissue macrophages. With the 1991 advent of alglucerase enzyme replenishment therapy (ERT), the manufacturer (Genzyme Corporation) created the ICGG Gaucher Registry to collect longitudinal observational “real word” information about GD world-wide in heterogeneous patient populations, to annotate phenotypes and genotypes that define the natural history of GD in untreated patients, and to document and analyze treatment outcomes for alglucerase and any other future treatments. For 32 years, the ICGG Gaucher Registry has functioned as an educational tool for patients, clinicians, and other stakeholders to increase scientific knowledge of GD, to provide practical management guidance, and to positively impact patient care. This paper illustrates how an industry sponsored registry guided by a company independent scientific advisory board has successfully addressed its mission and evolved in step with technologic and scientific advances.

The bone marrow failure syndromes (BMFS) are a diverse group of acquired and inherited diseases which may manifest in cytopenias, haematological malignancy and/or syndromic multisystem disease. Patients with BMFS frequently experience poor outcomes, and improved treatment strategies are needed. Collation of clinical characteristics and patient outcomes in a national disease-specific registry represents a powerful tool to identify areas of need and support clinical and research collaboration. Novel treatment strategies such as gene therapy, particularly in rare diseases, will depend on the ability to identify eligible patients alongside the molecular genetic features of their disease that may be amenable to novel therapy. The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry (AAR) aims to improve outcomes for all paediatric and adult patients with BMFS in Australia by describing the demographics, treatments (including supportive care) and outcomes, and serving as a resource for research and practice improvement.

The goal of a disease classification system is (or should be) to provide a tool for researchers and clinicians to study and treat the disease. The last decade has seen a markedly improved understanding of the pathophysiology of acute myeloid leukemia (AML), the development of new methods to measure the disease, and approval by the Food and Drug Administration (FDA) of at least ten new therapies targeted to its treatment. In response, in 2022 one updated and one new AML classification system were published. In the same year, the European LeukemiaNet updated their recommendations about how to incorporate the advances in diagnosis and treatment into the risk stratification of AML and its treatment. The following discussion summarizes the highlights of these changes and offers an opinion of how well these changes meet the goal of aiding researchers and clinicians in the study and treatment of AML.

Options for GVHD prophylaxis after allogeneic hematopoietic cell transplantation can best be chosen by understanding the pathophysiology of GVHD. Interventions to limit T cell activation, expansion and subsequent tissue injury can each be utilized in designing successful GVHD prevention strategies Depleting, tolerizing or blunting T cells or host antigen presenting cells (APCs), blocking co-stimulation or more broadly suppressing inflammation have all been used. Interventions which spare regulatory T cells (Tregs) may prevent GVHD and facilitate controlled allo-responses and not compromise subsequent relapse risks. Graft manipulations and pharmacologic interventions each have potential to limit the morbidity of GVHD while permitting the immunocompetence to prevent infection or relapse.

Myeloid malignancies such as myelodysplastic syndrome (MDS) & acute myeloid leukemia (AML) are clonal diseases that emerge and progress due to the expansion of disease-initiating aberrant hematopoietic stem cells, that are not eliminated by conventional cytotoxic therapies. Hypomethylating agents(HMA), azacytidine and decitabine are the first line agents for treatment of MDS and a combination with BCL-2 inhibitor, venetoclax, is approved for AML induction in patients above 75 years and is also actively being investigated for use in high risk MDS. Resistance to these drugs has become a significant clinical challenge in treatment of myeloid malignancies. In this review, we discuss molecular mechanisms underlying the development of resistance to HMA and venetoclax. Insights into these mechanisms can help identify potential biomarkers for resistance prediction, aid in the development of combination therapies and strategies to prevent resistance and advance the field of cancer therapeutics.

Myelodysplastic syndromes/neoplasms (MDS) are a heterogeneous group of hematopoietic cancers characterized by recurrent molecular alterations driving the disease pathogenesis with a variable propensity for progression to acute myeloid leukemia (AML). Clinical decision making for MDS relies on appropriate risk stratification at diagnosis, with higher-risk patients requiring more intensive therapy. The conventional clinical prognostic systems including the International Prognostic Scoring System (IPSS) and its revised version (IPSS-R) have dominated the risk stratification of MDS from 1997 until 2022. Concurrently, the use of next-generation sequencing has revolutionized the field by revealing multiple recurrent genetic mutations, which correlate with phenotype and prognosis. Significant efforts have been made to formally incorporate molecular data into prognostic tools to improve proper risk identification and personalize treatment strategies. In this review, we will critically compare the available molecular scoring systems for MDS focusing on areas of progress and potential limitations that can be improved in subsequent revisions of these tools.

Asparaginase in various forms is a standard part of the treatment of acute lymphoblastic leukemia (ALL) in children and adolescents. However, its use is more selective in adults. One of the key reasons is the toxicity observed from this class of agents. In a series of recent post hoc analyses of large prospective studies, obesity has emerged as a key factor that contributes to the challenges with administering regimens that include asparaginase. In this review, the most salient findings are highlighted from these latest publications, both from the pediatric and adult literature. These data are consolidated into recommendations for clinicians who treat adults with ALL, including proposals for how treatment may be modified to try to account for these complications. Lastly, avenues for future investigation are proposed in an attempt to narrow our knowledge gaps in this field, with the goal of safer and more effective treatment for adults with obesity who develop ALL.

For the routine diagnosis of haematological neoplasms an integrative approach is used considering the morphology, and the immunophenotypic, and molecular features of the tumor sample, along with clinical information. The identification and characterization of recurrent chromosomal aberrations mainly detected by conventional and molecular cytogenetics in the tumor cells has a major impact on the classification of lymphoid neoplasms. Some of the B-cell non-Hodgkin lymphomas are characterized by particular chromosomal aberrations, highlighting the relevance of conventional and molecular cytogenetic studies in their diagnosis and prognosis. In the current genomics era, next generation sequencing provides relevant information as the mutational profiles of haematological malignancies, improving their classification and also the clinical management of the patients. In addition, other new technologies have emerged recently, such as the optical genome mapping, which can overcome some of the limitations of conventional and molecular cytogenetics and may become more widely used in the cytogenetic laboratories in the upcoming years. Moreover, epigenetic alterations may complement genetic changes for a deeper understanding of the pathogenesis underlying B-cell neoplasms and a more precise risk-based patient stratification. Overall, here we describe the current state of the genomic data integrating chromosomal rearrangements, copy number alterations, and somatic variants, as well as a succinct overview of epigenomic changes, which altogether constitute a comprehensive diagnostic approach in B-cell non-Hodgkin lymphomas.