Expert Review of Hematology最新文献

Introduction: Transfusion-related acute lung injury (TRALI) remains a leading cause of blood transfusion associated mortality, particularly in the intensive care unit. TRALI is underrecognized, underreported and lacks specific biomarkers and clinical therapies.

Areas covered: In this review, the focus will be on the key pathophysiological features of TRALI. This will include the latest insights into the critical importance of complement (in contrast to Fcγ-receptors; FcγRs) as a driver of TRALI, and the role of recipient immune cells such as neutrophils and macrophages, and also the contribution of the pulmonary endothelium.

Expert opinion: Increased efforts are needed to stimulate active reporting of TRALI cases. More research into the immuno-cellular pathophysiology of TRALI is required, including the role of the pulmonary endothelium. Heterogeneity in the underlying clinical condition and the different transfusion triggers should be taken into consideration. This will aid in the search for novel biomarkers and therapeutic modalities. At the moment, the most promising potential therapeutic strategies appear to be administration of interleukin (IL)-10, inhibition of complement activation and blockade of Osteopontin (OPN). Follow-up investigations are, however, highly warranted which should pave the way for multicenter international clinical trials, in order to battle the mortality due to TRALI.

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder of hematopoietic stem cells, characterized by somatic mutations of the Phosphatidylinositol Glycan Class A Gene, resulting in increased hemolysis. The advent of complement inhibitors has since changed the way clinicians approach treating PNH. Pegcetacoplan is a C3 inhibitor that has shown promise in this field and improved outcomes for patients who have been diagnosed with PNH.

Areas covered: This review article will aim to examine the pathophysiology of PNH and the current treatments available, with a focus on pegcetacoplan. It will focus on the pharmacodynamics, pharmocokinetics and evidence in the use of pegcetacoplan in PNH. Electronic sources including PubMed, MEDLINE, were utilized with studies in the last 5 years prioritized, especially the phase 3 Prince and Pegasus studies.

Expert opinion: The results from phase 3 studies for pegcetacoplan have been promising, showing good efficacy and improvements in patients' conditions. More research is required to evaluate the use of pegcetacoplan, especially in combination with existing treatment in patients who are having suboptimal results. Nonetheless, with more results on the way and new agents to treat PNH in the vicinity, this remains a very exciting time for both clinicians and patients.

Introduction: Chronic myeloid leukemia (CML) represents one of the first neoplasms whose molecular pathogenesis was successfully unraveled, with tyrosine kinase inhibitors (TKIs) representing one of the first-targeted therapies. TKIs have revolutionized long-term outcomes of CML patients and their life expectancy. Nonetheless, a minority of patients will develop TKI resistance due to a complex and multifactorial process that ultimately leads to the emergence of an unresponsive cancer clone. Overcoming TKI resistance is considered one of the major challenges in CML management.

Areas covered: In this review, the main findings extrapolated from published research, guidelines, and clinical trials regarding TKI resistance (published before October 2024) are discussed. Data have been obtained through broad research on Medline, Embase, Pubmed, and archives from EHA and ASH congresses.

Expert opinion: Nowadays, asciminib and ponatinib have expanded the therapeutic arsenal for resistant-CML management and allogenic transplant still represents an important alternative in the context of multiple TKI failures. Off-label use of TKIs combination therapies, although theoretically appealing, lacks robust clinical evidence and regulatory approval. Looking ahead, the introduction of novel technologies such as digital PCR (dPCR) and next generation sequencing (NGS) holds great potential to revolutionize the management of TKI-resistant CML cases.

Background: Understanding the disease-specific risks and patient-related barriers of children with bleeding disorders is necessary for primary oral health promotion. Our goal was to assess the oral health status and the impact of oral health promotion among patients with bleeding disorders.

Research design and methods: At baseline, 70 patients with inherited and acquired bleeding disorders had a complete intraoral examination, completed the oral health-related quality of life (OHRQoL) questionnaires, and an oral health education was given. After 6 months, the effectiveness of the oral hygiene promotion was evaluated clinically and through the OHRQoL questionnaires.

Results: Our cohort included 33 patients with chronic immune thrombocytopenia (cITP), 27 hemophilia A patients, and 10 with inherited thrombasthenia. Forty patients (57.1%) had dental caries, 90.0% showed fair oral hygiene status with variable degrees of gingivitis. The baseline self-image score was significantly inferior among patients with inherited bleeding disorders, while the psychological domain for family was greatly affected among cITP patients. After 6 months, there was a significant reduction in the oral debris, the modified gingival indexes, the percentages of cases with oral bleeding, and a significantly improved mean OHRQoL total score.

Conclusions: After the oral health education, the OHRQoL scores had significantly improved, and oral hygiene status were acceptable among patients with bleeding disorders.

Introduction: Hairy cell leukemia accounts for less than 2% of leukemias. The hairy cells express CD11c, CD25, CD103, and CD123 markers. The BRAF^V600E mutation was detected in 95% of HCL cases. Patients achieve high complete response rate with purine analogues with or without rituximab, but relapses are inevitable. HCL-like disorders including HCL variant, splenic diffuse red pulp lymphoma, and splenic marginal zone lymphoma are BRAF^V600E negative. The CD25 expression is negative. The absence of BRAF^V600E mutation in HCL variant contrasts with the presence of mitogen-activated protein kinase kinase 1 (MAP2K1) mutations in 50% of cases.

Areas covered: We investigated the criteria used to distinguish HCL from HCL-like disorders. Recent discoveries in molecular biology have enabled the introduction of several new drugs in HCL patients. We explore the investigational agents: inhibitors of BRAF, MEK, and Bruton tyrosine kinase and potential future strategies we will use in the future in patients with relapsed/refractory HCL. We also discuss the clinical trials in progress.

Expert opinion: The association of Cladribine (CDA) with rituximab (R) is the standard first-line treatment in fit HCL and HCL variant patients. BRAF and BTK inhibitors are options in relapsed/refractory HCL patients. The optimal treatment sequences remain to be determined.

Introduction: Allogeneic hemopoietic stem cell transplantation (HSCT) is a curative therapy for sickle cell disease (SCD). Exposure to both SCD and HSCT conditioning regimens is associated with late health effects.

Areas covered: This review addresses post-HSCT outcomes and late health effects among individuals with SCD exposed to allogeneic HSCT regimens, summarizes recommendations for long-term care, and identifies future survivorship research needs.

Expert opinion: Individuals with SCD exposed to HSCT and gene therapy require multidisciplinary care to monitor late health effects. To optimize care, multi-disciplinary clinics that include experts in late effects of HSCT exposure, SCD, complex chronic pain, mental health, and social work are needed. Research defining the late effects of exposure is needed to inform patient management and build clinical care infrastructure.

Introduction: The introduction of venetoclax has revolutionized the treatment landscape of acute myeloid leukemia, offering new therapeutic opportunities. However, the clinical response to venetoclax varies significantly between patients, with many experiencing limited duration of response.

Areas covered: Identified resistance mechanisms include both intrinsic and acquired resistance to VEN. The former is associated with cell lineage and differentiation state. The latter includes dependency on alternative BCL-2 family anti-apoptotic protein(s) mediated by genetic, epigenetic, or post-translational mechanisms, mitochondrial and metabolic involvement, as well as microenvironment. Understanding these mechanisms is crucial for optimizing venetoclax-based therapies and enhancing treatment outcomes for patients with acute myeloid leukemia. This review aims to elucidate the primary mechanisms underlying resistance to venetoclax and explore current therapeutic strategies to overcome this challenge.

Expert opinion: In patients with venetoclax resistance, alternative options include targeted combination therapies tailored to individual cases based on cytogenetics and prior treatments. Many of these therapies require further clinical investigation to validate their safety and efficacy.

Introduction: Sickle cell disease is ameliorated and perhaps can be 'cured' if enough fetal hemoglobin is present in most erythrocytes. Hydroxyurea, which increases fetal hemoglobin levels, is widely available and effective, especially in children. Nevertheless, only cell-based gene therapy can achieve a 'curative' fetal hemoglobin threshold.

Areas covered: We cover the path to modulating fetal hemoglobin gene expression and the use of CRISPR/Cas9 gene editing as a viable clinical modality for treating severe sickle cell disease relying on references obtained from PubMed. Mobilized autologous hematopoietic stem and progenitor cells are engineered with vectors that derepress genes that regulate fetal hemoglobin gene expression. Following myeloablative conditioning, gene-edited cells are reinfused, engrafted, and make large amounts of fetal hemoglobin. Within months, fetal hemoglobin forms more than 40% of the total hemoglobin and hemoglobin levels normalize; symptoms of sickle cell disease disappear.

Expert opinion: Optimistically, these patients are 'cured,' but long term follow-up is needed. Although approved by regulatory agencies and highly efficacious, because of its technical imperatives and cost, this first gene editing therapeutic will be unavailable to most people with severe sickle cell disease. It is highly likely that improved methods of genomic editing will simplify gene therapy, reduce its costs, and lead to its wider applicability.

Introduction: Mantle cell lymphoma (MCL) is a non-Hodgkin B-cell lymphoma typically regarded as incurable with standard chemotherapy. Ibrutinib has become an accepted second-line treatment for relapsed or refractory MCL. Although venetoclax has shown activity against the disease, these results have not been consistently seen in the post-ibrutinib era. Therefore, there is growing evidence that supports using ibrutinib and venetoclax together in patients with chronic lymphocytic leukemia.

Areas covered: This article looks at the evidence for combining ibrutinib and venetoclax in treating relapsed or refractory MCL, particularly from the AIM and SYMPATICO studies. The phase II AIM study evaluated the ongoing combination of ibrutinib and venetoclax following a run-in period of ibrutinib. The phase III SYMPATICO study started both drugs without a run-in period and included a fixed two-year duration of venetoclax.

Expert opinion: The combination of ibrutinib and venetoclax has shown effectiveness in patients with relapsed/refractory MCL, indicating potential for fixed-duration therapy. The emerging use of measurable residual disease and molecular data may help identify which patients are suitable for stopping treatment. As new information becomes available on ibrutinib in first-line settings and chimeric T-cell therapy, the optimal timing for combining ibrutinib and venetoclax may require further refinement.