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Blood Nov 2023Intratumor heterogeneity as a clinical challenge becomes most evident after several treatment lines, when multidrug-resistant subclones accumulate. To address this...
Intratumor heterogeneity as a clinical challenge becomes most evident after several treatment lines, when multidrug-resistant subclones accumulate. To address this challenge, the characterization of resistance mechanisms at the subclonal level is key to identify common vulnerabilities. In this study, we integrate whole-genome sequencing, single-cell (sc) transcriptomics (scRNA sequencing), and chromatin accessibility (scATAC sequencing) together with mitochondrial DNA mutations to define subclonal architecture and evolution for longitudinal samples from 15 patients with relapsed or refractory multiple myeloma. We assess transcriptomic and epigenomic changes to resolve the multifactorial nature of therapy resistance and relate it to the parallel occurrence of different mechanisms: (1) preexisting epigenetic profiles of subclones associated with survival advantages, (2) converging phenotypic adaptation of genetically distinct subclones, and (3) subclone-specific interactions of myeloma and bone marrow microenvironment cells. Our study showcases how an integrative multiomics analysis can be applied to track and characterize distinct multidrug-resistant subclones over time for the identification of molecular targets against them.
Topics: Humans; Multiple Myeloma; Multiomics; Mutation; Transcriptome; Tumor Microenvironment
PubMed: 37390336
DOI: 10.1182/blood.2023019758 -
Journal of Thrombosis and Haemostasis :... Sep 2023The introduction of adeno-associated virus-mediated, liver-directed gene therapy into the hemophilia treatment landscape brings not only great promise but also... (Review)
Review
The introduction of adeno-associated virus-mediated, liver-directed gene therapy into the hemophilia treatment landscape brings not only great promise but also considerable uncertainty to a community that has a history punctuated by the devastating effects of HIV and hepatitis C virus. These infections were introduced into people with hemophilia through the innovation of factor concentrates in the 1970s and 1980s. Concentrates, heralded as a major advance in treatment at the time, brought devastation and death to the community already challenged by the complications of bleeding into joints, vital organs, and the brain. Over the past 5 decades, considerable advances in hemophilia treatment have improved the survival, quality of life, and participation of people with hemophilia, although challenges remain and health equity with their unaffected peers has not yet been achieved. The decision to take a gene therapy product is one in which an informed, holistic, and shared decision-making approach must be employed. Bias on the part of health care professionals and people with hemophilia must be addressed and minimized. Here, we review data leading to the regulatory authorization of valoctocogene roxaparvovec, an adeno-associated virus 5 gene therapy, in Europe to treat hemophilia A and etranacogene dezaparvovec-drlb in the United States and Europe to treat hemophilia B. We also provide an overview of the decision-making process and recommend steps that should be taken by the hemophilia community to ensure the safety of and optimal outcomes for people with hemophilia who choose to receive a gene therapy product.
Topics: Humans; Hemophilia A; Quality of Life; Hemophilia B; Genetic Therapy
PubMed: 37353081
DOI: 10.1016/j.jtha.2023.06.016 -
Blood Transfusion = Trasfusione Del... Nov 2023Emicizumab, a monoclonal bispecific antibody that mimics the function of activated factor VIII (FVIII), is currently licensed for prophylactic use in patients with... (Review)
Review
Emicizumab, a monoclonal bispecific antibody that mimics the function of activated factor VIII (FVIII), is currently licensed for prophylactic use in patients with congenital hemophilia A with and without inhibitors. Acquired hemophilia A (AHA) is a very rare bleeding disorder caused by the development of autoantibodies that inhibit FVIII activity in plasma; males and females are equally affected. Therapeutic options for patients with AHA currently include eradication of the inhibitor with immunosuppressive treatments and management of acute bleeding with bypassing agents or recombinant porcine FVIII. More recently, several reports described the off-label use of emicizumab in patients with AHA and a phase III study is ongoing in Japan. The aims of this review are to describe the 73 reported cases, and to highlight the advantages and disadvantages of this novel approach to the prevention and treatment of bleeding in AHA.
Topics: Male; Female; Humans; Animals; Swine; Hemophilia A; Factor VIII; Hemorrhage; Antibodies, Monoclonal, Humanized
PubMed: 36795341
DOI: 10.2450/2023.0247-22 -
Nature Medicine Sep 2023B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T...
B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging data report that downregulation of G-protein-coupled receptor family C group 5 member D (GPRC5D) protein often occurs at relapse after anti-GPRC5D CAR T therapy. To examine the tumor-intrinsic factors that promote MM antigen escape, we performed combined bulk and single-cell whole-genome sequencing and copy number variation analysis of 30 patients treated with anti-BCMA and/or anti-GPRC5D CAR T/TCE therapy. In two cases, MM relapse post-TCE/CAR T therapy was driven by BCMA-negative clones harboring focal biallelic deletions at the TNFRSF17 locus at relapse or by selective expansion of pre-existing subclones with biallelic TNFRSF17 loss. In another five cases of relapse, newly detected, nontruncating, missense mutations or in-frame deletions in the extracellular domain of BCMA negated the efficacies of anti-BCMA TCE therapies, despite detectable surface BCMA protein expression. In the present study, we also report four cases of MM relapse with biallelic mutations of GPRC5D after anti-GPRC5D TCE therapy, including two cases with convergent evolution where multiple subclones lost GPRC5D through somatic events. Immunoselection of BCMA- or GPRC5D-negative or mutant clones is an important tumor-intrinsic driver of relapse post-targeted therapies. Mutational events on BCMA confer distinct sensitivities toward different anti-BCMA therapies, underscoring the importance of considering the tumor antigen landscape for optimal design and selection of targeted immunotherapies in MM.
Topics: Humans; Multiple Myeloma; Antigenic Drift and Shift; DNA Copy Number Variations; Receptors, Chimeric Antigen; Neoplasm Recurrence, Local; Immunotherapy; Antibodies; Membrane Proteins
PubMed: 37653344
DOI: 10.1038/s41591-023-02491-5 -
Seminars in Thrombosis and Hemostasis Jul 2023
Topics: Humans; Factor XIII; Factor XIII Deficiency
PubMed: 36781152
DOI: 10.1055/s-0043-1762576 -
Internal Medicine (Tokyo, Japan) Feb 2024
Topics: Humans; Liver Diseases; Amyloidosis; Multiple Myeloma; Hepatomegaly
PubMed: 37344422
DOI: 10.2169/internalmedicine.2186-23 -
Hamostaseologie Aug 2023
Topics: Humans; Hemophilia A; Germany; Plasma
PubMed: 37652075
DOI: 10.1055/a-2031-7804 -
Hamostaseologie Dec 2023
Topics: Humans; Hemophilia A; Acute-Phase Reaction; Hemorrhage
PubMed: 38096833
DOI: 10.1055/s-0043-1777817 -
Haematologica Apr 2024D-dimer, a soluble fibrin degradation product that originates from plasmin-induced degradation of cross-linked fibrin, is an important biomarker of coagulation... (Review)
Review
D-dimer, a soluble fibrin degradation product that originates from plasmin-induced degradation of cross-linked fibrin, is an important biomarker of coagulation activation and secondary fibrinolysis that is routinely used to rule out venous thromboembolism (VTE), and to evaluate the risk of VTE recurrence, as well as the optimal duration of anticoagulant therapy. Besides VTE, D-dimer may be high due to physiologic conditions, including aging, pregnancy, and strenuous physical activity. In addition, several disorders have been associated with increased D-dimer levels, ranging from disseminated intravascular coagulation to infectious diseases and cancers. Thus, it is far from unusual for hematologists to have to deal with ambulatory individuals with increased D-dimer without signs or symptoms of thrombus formation. This narrative review is dedicated to the management of these cases by the hematologist.
Topics: Female; Pregnancy; Humans; Venous Thromboembolism; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Disseminated Intravascular Coagulation
PubMed: 37881856
DOI: 10.3324/haematol.2023.283966