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Blood Jun 2023The European LeukemiaNet recently revised both the clinical (2022) and measurable residual disease testing (2021) guidelines for acute myeloid leukemia (AML). The...
The European LeukemiaNet recently revised both the clinical (2022) and measurable residual disease testing (2021) guidelines for acute myeloid leukemia (AML). The updated World Health Organization and International Consensus Classification for myeloid neoplasms were also published in 2022. Together, these documents update the classification, risk stratification, prognostication, monitoring recommendations, and response assessment of patients with AML. Increased appreciation of the genetic drivers of AML over the past decade and our increasingly sophisticated understanding of AML biology have been translated into novel therapies and more complex clinical treatment guidelines. Somatic genetic abnormalities and germ line predispositions now define and guide treatment and counseling for the subtypes of this hematologic malignancy. In this How I Treat article, we discuss how we approach AML in daily clinical practice, considering the recent updates in the context of new treatments and discoveries over the past decade.
Topics: Humans; Leukemia, Myeloid, Acute; Neoplasm, Residual; Consensus; Genotype; Hematologic Neoplasms
PubMed: 36758209
DOI: 10.1182/blood.2022017808 -
Annual Review of Pathology Jan 2024Somatic or acquired mutations are postzygotic genetic variations that can occur within any tissue. These mutations accumulate during aging and have classically been... (Review)
Review
Somatic or acquired mutations are postzygotic genetic variations that can occur within any tissue. These mutations accumulate during aging and have classically been linked to malignant processes. Tremendous advancements over the past years have led to a deeper understanding of the role of somatic mutations in benign and malignant age-related diseases. Here, we review the somatic mutations that accumulate in the blood and their connection to disease states, with a particular focus on inflammatory diseases and myelodysplastic syndrome. We include a definition of clonal hematopoiesis (CH) and an overview of the origins and implications of these mutations. In addition, we emphasize somatic disorders with overlapping inflammation and hematologic disease beyond CH, including paroxysmal nocturnal hemoglobinuria and aplastic anemia, focusing on VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Finally, we provide a practical view of the implications of somatic mutations in clinical hematology, pathology, and beyond.
Topics: Humans; Clonal Hematopoiesis; Hematologic Neoplasms; Myelodysplastic Syndromes; Aging; Inflammation; Hematopoiesis
PubMed: 37832948
DOI: 10.1146/annurev-pathmechdis-051222-122724 -
Science Translational Medicine Sep 2023In the absence of cell surface cancer-specific antigens, immunotherapies such as chimeric antigen receptor (CAR) T cells, monoclonal antibodies, or bispecific T cell...
In the absence of cell surface cancer-specific antigens, immunotherapies such as chimeric antigen receptor (CAR) T cells, monoclonal antibodies, or bispecific T cell engagers typically target lineage antigens. Currently, such immunotherapies are individually designed and tested for each disease. This approach is inefficient and limited to a few lineage antigens for which the on-target/off-tumor toxicities are clinically tolerated. Here, we sought to develop a universal CAR T cell therapy for blood cancers directed against the pan-leukocyte marker CD45. To protect healthy hematopoietic cells, including CAR T cells, from CD45-directed on-target/off-tumor toxicity while preserving the essential functions of CD45, we mapped the epitope on CD45 that is targeted by the CAR and used CRISPR adenine base editing to install a function-preserving mutation sufficient to evade CAR T cell recognition. Epitope-edited CD45 CAR T cells were fratricide resistant and effective against patient-derived acute myeloid leukemia, B cell lymphoma, and acute T cell leukemia. Epitope-edited hematopoietic stem cells (HSCs) were protected from CAR T cells and, unlike CD45 knockout cells, could engraft, persist, and differentiate in vivo. Ex vivo epitope editing in HSCs and T cells enables the safe and effective use of CD45-directed CAR T cells and bispecific T cell engagers for the universal treatment of hematologic malignancies and might be exploited for other diseases requiring intensive hematopoietic ablation.
Topics: Humans; Epitopes; Gene Editing; Hematologic Neoplasms; Immunotherapy; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 37651540
DOI: 10.1126/scitranslmed.adi1145 -
European Journal of Pediatrics Jun 2023Hemoglobinopathies, including thalassemias and sickle cell disease, are the most common monogenic diseases worldwide, with estimated annual births of more than 330,000... (Review)
Review
Hemoglobinopathies, including thalassemias and sickle cell disease, are the most common monogenic diseases worldwide, with estimated annual births of more than 330,000 affected infants. Hemoglobin disorders account for about 3.4% of deaths in children under 5 years of age. The distribution of these diseases is historically linked to current or previously malaria-endemic regions; however, immigration has led to a worldwide distribution of these diseases, making them a global health problem. During the last decade, new treatment approaches and novel therapies have been proposed, some of which have the potential to change the natural history of these disorders. Indeed, the first erythroid maturation agent, luspatercept, and gene therapy have been approved for beta-thalassemia adult patients. For sickle cell disease, molecules targeting vaso-occlusion and hemoglobin S polymerization include crizanlizumab, which has been approved for patients ≥ 16 years, voxelotor approved for patients ≥ 12 years, and L-glutamine for patients older than 5 years. Conclusion: We herein present the most recent advances and future perspectives in thalassemia and sickle cell disease treatment, including new drugs, gene therapy, and gene editing, and the current clinical trial status in the pediatric populations. What is Known: • Red blood cell transfusions, iron chelation therapy and hematopoietic stem cell transplantation have been the mainstay of treatment of thalassemia patients for decades. • For sickle cell disease, until 2005, treatment strategies were mostly the same as those for thalassemia, with the option of simple transfusion or exchange transfusion. In 2007, hydroxyurea was approved for patients ≥ 2 years old. What is New: • In 2019, gene therapy with betibeglogene autotemcel (LentiGlobin BB305) was approved for TDT patients ≥ 12 years old non β0/β0 without matched sibling donor. • Starting from 2017 several new drugs, such as L-glutamine (approved only by FDA), crizanlizumab (approved by FDA and EMA for patients ≥ 16 years), and lastly voxelotor (approved by FDA and EMA for patients ≥ 12 years old).
Topics: Infant; Child; Humans; Young Adult; Child, Preschool; Glutamine; Anemia, Sickle Cell; Hemoglobinopathies; Thalassemia
PubMed: 36997768
DOI: 10.1007/s00431-023-04900-w -
Frontiers in Immunology 2023Sepsis is accompanied by thrombocytopenia and the severity of the thrombocytopenia is associated with mortality. This thrombocytopenia is characteristic of disseminated... (Review)
Review
Sepsis is accompanied by thrombocytopenia and the severity of the thrombocytopenia is associated with mortality. This thrombocytopenia is characteristic of disseminated intravascular coagulation (DIC), the sepsis-associated coagulopathy. Many of the pathogens, both bacterial and viral, that cause sepsis also directly activate platelets, which suggests that pathogen-induced platelet activation leads to systemic thrombosis and drives the multi-organ failure of DIC. In this paper we review the mechanisms of platelet activation by pathogens and the evidence for a role for anti-platelet agents in the management of sepsis.
Topics: Humans; Blood Platelets; Disseminated Intravascular Coagulation; Thrombocytopenia; Blood Coagulation Disorders; Sepsis; Anemia
PubMed: 37350961
DOI: 10.3389/fimmu.2023.1210219 -
Current Opinion in Anaesthesiology Jun 2023The purpose of this article is to provide an overview of currently recommended treatment approaches for anemia during pregnancy, with a special focus on iron deficiency... (Review)
Review
PURPOSE OF REVIEW
The purpose of this article is to provide an overview of currently recommended treatment approaches for anemia during pregnancy, with a special focus on iron deficiency and iron deficiency anemia (IDA).
RECENT FINDINGS
As consistent patient blood management (PBM) guidelines in obstetrics are still lacking, recommendations regarding the timing of anemia screening and the treatment recommendations for iron deficiency and IDA during pregnancy are still controversial. Based on increasing evidence, early screening for anemia and iron deficiency should be recommended at the beginning of each pregnancy. To reduce maternal and fetal burden, any iron deficiency, even without anemia, should be treated as early as possible during pregnancy. While oral iron supplements administered every other day are the standard treatment in the first trimester, the use of intravenous iron supplements is increasingly suggested from the second trimester onwards.
SUMMARY
The treatment of anemia, and more specifically iron deficiency anemia during pregnancy, holds many possibilities for improvement. The fact that the period of risk is known well in advance and thus there is a long optimization phase is per se an ideal prerequisite for the best possible therapy of treatable causes of anemia. Standardization of recommendations and guidelines for screening and treatment of IDA in obstetrics is required for the future. In any case, a multidisciplinary consent is the precondition for a successfully implementation of anemia management in obstetrics to establish an approved algorithm easily enabling detection and treatment of IDA during pregnancy.
Topics: Pregnancy; Female; Humans; Anemia, Iron-Deficiency; Obstetrics; Iron; Anemia; Iron Deficiencies
PubMed: 36794901
DOI: 10.1097/ACO.0000000000001252 -
Annals of Hematology Aug 2023Myeloid sarcoma (MS) is a distinct entity among myeloid neoplasms defined as a tumour mass of myeloid blasts occurring at an anatomical site other than the bone marrow,... (Review)
Review
Myeloid sarcoma (MS) is a distinct entity among myeloid neoplasms defined as a tumour mass of myeloid blasts occurring at an anatomical site other than the bone marrow, in most cases concomitant with acute myeloid leukaemia (AML), rarely without bone marrow involvement. MS may also represent the blast phase of chronic myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS). However, the clinical and molecular heterogeneity of AML, as highlighted by the 2022 World Health Organization (WHO) and International Consensus (ICC) classifications, indirectly define MS more as a set of heterogeneous and proteiform diseases, rather than a homogeneous single entity. Diagnosis is challenging and relies mainly on histopathology, immunohistochemistry, and imaging. Molecular and cytogenetic analysis of MS tissue, particularly in isolated cases, should be performed to refine the diagnosis, and thus assign prognosis guiding treatment decisions. If feasible, systemic therapies used in AML remission induction should be employed, even in isolated MS. Role and type of consolidation therapy are not univocally acknowledged, and systemic therapies, radiotherapy, or allogeneic hematopoietic stem cell transplantation (allo-HSCT) should be considered. In the present review, we discuss recent information on MS, focusing on diagnosis, molecular findings, and treatments also considering targetable mutations by recently approved AML drugs.
Topics: Humans; Sarcoma, Myeloid; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Myeloproliferative Disorders; Hematopoietic Stem Cell Transplantation
PubMed: 37286874
DOI: 10.1007/s00277-023-05288-1 -
Cancer Research Sep 2023Identifying mechanisms underlying relapse is a major clinical issue for effective cancer treatment. The emerging understanding of the importance of metastasis in...
UNLABELLED
Identifying mechanisms underlying relapse is a major clinical issue for effective cancer treatment. The emerging understanding of the importance of metastasis in hematologic malignancies suggests that it could also play a role in drug resistance and relapse in acute myeloid leukemia (AML). In a cohort of 1,273 AML patients, we uncovered that the multifunctional scavenger receptor CD36 was positively associated with extramedullary dissemination of leukemic blasts, increased risk of relapse after intensive chemotherapy, and reduced event-free and overall survival. CD36 was dispensable for lipid uptake but fostered blast migration through its binding with thrombospondin-1. CD36-expressing blasts, which were largely enriched after chemotherapy, exhibited a senescent-like phenotype while maintaining their migratory ability. In xenograft mouse models, CD36 inhibition reduced metastasis of blasts and prolonged survival of chemotherapy-treated mice. These results pave the way for the development of CD36 as an independent marker of poor prognosis in AML patients and a promising actionable target to improve the outcome of patients.
SIGNIFICANCE
CD36 promotes blast migration and extramedullary disease in acute myeloid leukemia and represents a critical target that can be exploited for clinical prognosis and patient treatment.
Topics: Humans; Animals; Mice; Leukemia, Myeloid, Acute; Treatment Outcome; Prognosis; Recurrence; Blast Crisis; Chronic Disease
PubMed: 37327406
DOI: 10.1158/0008-5472.CAN-22-3682 -
Annals of Laboratory Medicine Sep 2023The fifth edition of the WHO classification (2022 WHO) and the International Consensus Classification (2022 ICC) of myeloid neoplasms have been recently published. We...
Implications of the 5 Edition of the World Health Organization Classification and International Consensus Classification of Myeloid Neoplasm in Myelodysplastic Syndrome With Excess Blasts and Acute Myeloid Leukemia.
The fifth edition of the WHO classification (2022 WHO) and the International Consensus Classification (2022 ICC) of myeloid neoplasms have been recently published. We reviewed the changes in the diagnosis distribution in patients with MDS with excess blasts (MDS-EB) or AML using both classifications. Forty-seven patients previously diagnosed as having AML or MDS-EB with available mutation analysis data, including targeted next-generation and RNA-sequencing data, were included. We reclassified 15 (31.9%) and 27 (57.4%) patients based on the 2022 WHO and 2022 ICC, respectively. One patient was reclassified as having a translocation categorized as a rare recurring translocation in both classifications. Reclassification was mostly due to the addition of mutation-based diagnostic criteria (i.e., AML, myelodysplasia-related) or a new entity associated with mutation. In both classifications, MDS diagnosis required the confirmation of multi-hit alterations. Among 14 patients with mutations, 11 harbored multi-hit alterations, including four with mutations and loss of heterozygosity. Adverse prognosis was associated with multi-hit alterations (=0.009) in patients with MDS-EB, emphasizing the importance of detecting the mutations at diagnosis. The implementation of these classifications may lead to the identification of different subtypes from previously heterogeneous diagnostic categories based on genetic characteristics.
Topics: Humans; Consensus; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Myeloproliferative Disorders; Mutation; World Health Organization
PubMed: 37080752
DOI: 10.3343/alm.2023.43.5.503 -
Blood Advances Jul 2023Acute myeloid leukemia (AML) with retinoic acid receptor γ (RARG) rearrangement has clinical, morphologic, and immunophenotypic features similar to classic acute...
Acute myeloid leukemia (AML) with retinoic acid receptor γ (RARG) rearrangement has clinical, morphologic, and immunophenotypic features similar to classic acute promyelocytic leukemia. However, AML with RARG rearrangement is insensitive to alltrans retinoic acid (ATRA) and arsenic trioxide (ATO) and carries a poor prognosis. We initiated a global cooperative study to define the clinicopathological features, genomic and transcriptomic landscape, and outcomes of AML with RARG rearrangements collected from 29 study groups/institutions worldwide. Thirty-four patients with AML with RARG rearrangements were identified. Bleeding or ecchymosis was present in 18 (54.5%) patients. Morphology diagnosed as M3 and M3v accounted for 73.5% and 26.5% of the cases, respectively. Immunophenotyping showed the following characteristics: positive for CD33, CD13, and MPO but negative for CD38, CD11b, CD34, and HLA-DR. Cytogenetics showed normal karyotype in 38% and t(11;12) in 26% of patients. The partner genes of RARG were diverse and included CPSF6, NUP98, HNRNPc, HNRNPm, PML, and NPM1. WT1- and NRAS/KRAS-mutations were common comutations. None of the 34 patients responded to ATRA and/or ATO. Death within 45 days from diagnosis occurred in 10 patients (∼29%). At the last follow-up, 23 patients had died, and the estimated 2-year cumulative incidence of relapse, event-free survival, and overall survival were 68.7%, 26.7%, and 33.5%, respectively. Unsupervised hierarchical clustering using RNA sequencing data from 201 patients with AML showed that 81.8% of the RARG fusion samples clustered together, suggesting a new molecular subtype. RARG rearrangement is a novel entity of AML that confers a poor prognosis. This study is registered with the Chinese Clinical Trial Registry (ChiCTR2200055810).
Topics: Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Tretinoin; HLA-DR Antigens; Arsenic Trioxide
PubMed: 36799929
DOI: 10.1182/bloodadvances.2022008364