Blood Reviews最新文献

Chronic myeloid leukaemia (CML) is caused by BCR::ABL1. Tyrosine kinase-inhibitors (TKIs) are the initial therapy. Several organizations have reported milestones to evaluate response to initial TKI-therapy and suggest when a change of TKI should be considered. Achieving treatment-free remission (TFR) is increasingly recognized as the optimal therapy goal. Which TKI is the best initial therapy for which persons and what depth and duration of molecular remission is needed to achieve TFR are controversial. In this review we discuss these issues and suggest future research directions.

B-cell lymphoma-2 (BCL-2) family proteins are fundamental regulators of the intrinsic apoptotic pathway which modulate cellular fate. In many haematological malignancies, overexpression of anti-apoptotic factors (BCL-2, BCL-XL and MCL-1) circumvent apoptosis. To address this cancer hallmark, a concerted effort has been made to induce apoptosis by inhibiting BCL-2 family proteins. A series of highly selective BCL-2 homology 3 (BH3) domain mimetics are in clinical use and in ongoing clinical trials for acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL), and multiple myeloma (MM). These inhibitors serve as promising candidates, both as single agents or in combination therapy to improve patient outcomes. In other diseases such as follicular lymphoma, efficacy has been notably limited. There are also clinical problems with BCL-2 family inhibition, including drug resistance, disease relapse, tumour lysis syndrome, and clinically relevant cytopenias. Here, we provide a balanced view on both the clinical benefits of BCL-2 inhibition as well as the associated challenges.

The acute pain crisis (APC) is the commonest complication of sickle cell disease (SCD). Severe episodes may require treatment in hospital with strong opioid analgesic drugs, combined with additional supportive care measures. Guidelines for APC management have been produced over the past two decades gathering evidence from published studies, expert opinion, and patient perspective. Unfortunately, reports from multiple sources indicate that guidelines are often not followed, and that acute care in emergency departments and on acute medical wards is suboptimal. It is important to understand what leads to this breakdown in health care, and to identify evidence-based interventions which could be implemented to improve care. This review focuses on recently published articles as well as information about on-going clinical trials.

Aspects of care which could potentially make a difference to patient experience include availability and accessibility of individual care plans agreed between patient and treating specialist, innovative means of delivering initial opioids to reduce time to first analgesia, and availability of a specialist unit away from the ED, where expert care can be delivered in a more compassionate environment. The current evidence of improved outcomes and health economic advantage with these interventions is inadequate, and this is hampering their implementation into health care systems.

Recent advancements in gene editing illuminate new potential therapeutic approaches for Sickle Cell Disease (SCD), a debilitating monogenic disorder caused by a point mutation in the β-globin gene. Despite the availability of several FDA-approved medications for symptomatic relief, allogeneic hematopoietic stem cell transplantation (HSCT) remains the sole curative option, underscoring a persistent need for novel treatments. This review delves into the growing field of gene editing, particularly the extensive research focused on curing haemoglobinopathies like SCD. We examine the use of techniques such as CRISPR-Cas9 and homology-directed repair, base editing, and prime editing to either correct the pathogenic variant into a non-pathogenic or wild-type one or augment fetal haemoglobin (HbF) production. The article elucidates ways to optimize these tools for efficacious gene editing with minimal off-target effects and offers insights into their effective delivery into cells. Furthermore, we explore clinical trials involving alternative SCD treatment strategies, such as LentiGlobin therapy and autologous HSCT, distilling the current findings. This review consolidates vital information for the clinical translation of gene editing for SCD, providing strategic insights for investigators eager to further the development of gene editing for SCD.

Cancer survivors are at significant risk of cardiovascular (CV) morbidity and mortality; patients with hematologic malignancies have a higher rate of death due to heart failure compared to all other cancer subtypes. The majority of conventional hematologic cancer treatments is associated with increased risk of acute and long-term CV toxicity. The incidence of cancer therapy induced CV toxicity depends on the combination of patient characteristics and on the type, dose, and duration of the therapy. Early diagnosis of CV toxicity, appropriate referral, more specific cardiac monitoring follow-up and timely interventions in target patients can decrease the risk of CV adverse events, the interruption of oncological therapy, and improve the patient's prognosis. Herein, we summarize the CV effects of conventional treatments used in hematologic malignancies with a focus on definitions and incidence of the most common CV toxicities, guideline recommended early detection approaches, and preventive strategies before and during cancer treatments.

Platelet factor 4 (PF4) combines with heparin to form an antigen that could produce IgG antibodies and participate in heparin-induced thrombocytopenia (HIT). PF4 has attracted wide attention due to its role in novel coronavirus vaccine-19 (COVID-9)-induced immune thrombotic thrombocytopenia (VITT) and cognitive impairments. The electrostatic interaction between PF4 and negatively charged molecules is vital in the progression of VITT, which is similar to HIT. Emerging evidence suggests its multiple roles in hematopoietic and angiogenic inhibition, platelet coagulation interference, host inflammatory response promotion, vascular inhibition, and antitumor properties. The emerging pharmacological effects of PF4 may help deepen the exploration of its mechanism, thus accelerating the development of targeted therapies. However, due to its pleiotropic properties, the development of drugs targeting PF4 is at an early stage and faces many challenges. Herein, we discussed the characteristics and biological functions of PF4, summarized PF4-mediated signaling pathways, and discussed its multiple roles in diseases to inform novel approaches for successful clinical translational research.

The updated WHO 5th edition and ICC 2022 classification systems for AML aim to refine our diagnostic criteria and definitions of AML with deeper incorporation of cytogenetic and molecular aberrations. The two classification systems diverge, however, in numerous AML defining criteria and subclassifications, including the incorporation of blast enumeration and the integration of specific genomic mutations. These differences often create challenges for clinicians in not only establishing a diagnosis of AML, but also in determining the best treatment plan for patients. In this review, we highlight the literature surrounding the contrasting areas between the WHO and ICC guidelines and offer guidance in the clinical application of these guidelines in the management of patients with AML.

Children with Down syndrome (DS) have a 10- to 20-fold greater predisposition to develop acute leukemia compared to the general population, with a skew towards myeloid leukemia (ML-DS). While ML-DS is known to be a subtype with good outcome, patients who relapse face a dismal prognosis. Acute lymphocytic leukemia in DS (DS-ALL) is considered to have poor prognosis. The relapse rate is high in DS-ALL compared to their non-DS counterparts. We have a better understanding about the mutational spectrum of DS leukemia. Studies using animal, embryonic stem cell- and induced pluripotent stem cell-based models have shed light on the mechanism by which these mutations contribute to disease initiation and progression. In this review, we list the currently available treatment strategies for DS-leukemias along with their outcome with emphasis on challenges with chemotherapy-related toxicities in children with DS. We focus on the mechanisms of initiation and progression of leukemia in children with DS and highlight the novel molecular targets with greater success in preclinical trials that have the potential to progress to the clinic.

Melphalan, has been a major component of myeloma therapy since the 1950s. In the context of hematopoietic cell transplantation (HCT), high dose melphalan (HDM) is the most common conditioning regimen used due to its potent anti-myeloma effects and manageable toxicities. Common toxicities associated with HDM include myelosuppression, gastrointestinal issues, and mucositis. Established approaches to reduce these toxicities encompass dose modification, nausea prophylaxis with 5HT3 receptor antagonists, cryotherapy, amifostine use, and growth factors. Optimization of melphalan exposure through personalized dosing and its combination with other agents like busulfan, or bendamustine show promise. Propylene glycol-free melphalan (Evomela) represents a novel formulation aiming to enhance drug stability and reduce adverse effects. This review explores strategies to enhance the efficacy and mitigate the toxicity of HDM in multiple myeloma. Future directions involve exploring these strategies in clinical trials to improve the safety and efficacy of HDM, thereby enhancing outcomes for multiple myeloma patients undergoing autologous HCT.