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Frontiers in Endocrinology 2023
Topics: Humans; Bone Neoplasms; Bone and Bones; Bone Marrow Diseases
PubMed: 37564977
DOI: 10.3389/fendo.2023.1256406 -
Journal of Clinical Oncology : Official... Oct 2023Allogeneic hematopoietic cell transplantation (HCT) in patients with myelodysplastic syndrome (MDS) improves overall survival (OS). We evaluated the impact of MDS...
Allogeneic Hematopoietic Cell Transplantation Improves Outcome in Myelodysplastic Syndrome Across High-Risk Genetic Subgroups: Genetic Analysis of the Blood and Marrow Transplant Clinical Trials Network 1102 Study.
PURPOSE
Allogeneic hematopoietic cell transplantation (HCT) in patients with myelodysplastic syndrome (MDS) improves overall survival (OS). We evaluated the impact of MDS genetics on the benefit of HCT in a biological assignment (donor no donor) study.
METHODS
We performed targeted sequencing in 309 patients age 50-75 years with International Prognostic Scoring System (IPSS) intermediate-2 or high-risk MDS, enrolled in the Blood and Marrow Transplant Clinical Trials Network 1102 study and assessed the association of gene mutations with OS. Patients with mutations were classified as if two alleles were altered (via point mutation, deletion, or copy-neutral loss of heterozygosity).
RESULTS
The distribution of gene mutations was similar in the donor and no donor arms, with (28% 29%; = .89), (23% 29%; = .37), and (16% 16%; = .99) being most common. OS in patients with a mutation was worse compared with patients without mutation (21% ± 5% [SE] 52% ± 4% at 3 years; < .001). Among those with a mutation, OS was similar between versus (22% ± 8% 20% ± 6% at 3 years; = .31). Considering HCT as a time-dependent covariate, patients with a mutation who underwent HCT had improved OS compared with non-HCT treatment (OS at 3 years: 23% ± 7% 11% ± 7%; = .04), associated with a hazard ratio of 3.89; 95% CI, 1.87 to 8.12; < .001 after adjustment for covariates. OS among patients with molecular IPSS (IPSS-M) very high risk without a mutation was significantly improved if they had a donor (68% ± 10% 0% ± 12% at 3 years; = .001).
CONCLUSION
HCT improved OS compared with non-HCT treatment in patients with mutations irrespective of allelic status. Patients with IPSS-M very high risk without a mutation had favorable outcomes when a donor was available.
Topics: Humans; Middle Aged; Aged; Bone Marrow; Hematopoietic Stem Cell Transplantation; Myelodysplastic Syndromes; Mutation; Transplantation, Homologous; Prognosis
PubMed: 37607457
DOI: 10.1200/JCO.23.00866 -
Blood Reviews Nov 2023Despite recent advancements, treatment of cytopenia due to bone marrow failures (BMF) and myeloid neoplasms remains challenging. Androgens promote renewal and maturation... (Review)
Review
Despite recent advancements, treatment of cytopenia due to bone marrow failures (BMF) and myeloid neoplasms remains challenging. Androgens promote renewal and maturation of blood cells and may be beneficial in these forms. Here we report a systematic review of androgens use as single agent in hematologic conditions. Forty-six studies, mainly retrospective with various androgen types and doses, were included: 12 on acquired aplastic anemia (AA), 11 on inherited BMF, 17 on myelodysplastic syndromes (MDS), and 7 on myelofibrosis. Responses ranged from 50 to 70% in inherited BMF, 40-50% in acquired AA and MDS, while very limited evidence emerged for myelofibrosis. In acquired AA, response was associated with presence of non-severe disease; in MDS androgens were more effective on thrombocytopenia or mild to moderate anemia, whilst limited benefit was observed for transfusion dependent anemia. Toxicity profile mainly consisted of virilization and liver enzyme elevation, whilst the risk of leukemic evolution remains controversial.
Topics: Humans; Androgens; Primary Myelofibrosis; Retrospective Studies; Neoplasms; Anemia, Aplastic; Myelodysplastic Syndromes; Bone Marrow Failure Disorders; Pancytopenia; Myeloproliferative Disorders; Thrombocytopenia
PubMed: 37709654
DOI: 10.1016/j.blre.2023.101132 -
Leukemia Jan 2024Diamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure disorder characterized by erythroid hypoplasia. It primarily affects infants and is often caused... (Review)
Review
Diamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure disorder characterized by erythroid hypoplasia. It primarily affects infants and is often caused by heterozygous allelic variations in ribosomal protein (RP) genes. Recent studies also indicated that non-RP genes like GATA1, TSR2, are associated with DBA. P53 activation, translational dysfunction, inflammation, imbalanced globin/heme synthesis, and autophagy dysregulation were shown to contribute to disrupted erythropoiesis and impaired red blood cell production. The main therapeutic option for DBA patients is corticosteroids. However, half of these patients become non-responsive to corticosteroid therapy over prolonged treatment and have to be given blood transfusions. Hematopoietic stem cell transplantation is currently the sole curative option, however, the treatment is limited by the availability of suitable donors and the potential for serious immunological complications. Recent advances in gene therapy using lentiviral vectors have shown promise in treating RPS19-deficient DBA by promoting normal hematopoiesis. With deepening insights into the molecular framework of DBA, emerging therapies like gene therapy hold promise for providing curative solutions and advancing comprehension of the underlying disease mechanisms.
Topics: Infant; Humans; Anemia, Diamond-Blackfan; Ribosomal Proteins; Hematopoietic Stem Cell Transplantation; Genetic Therapy; Erythropoiesis; Bone Marrow Failure Disorders
PubMed: 37973818
DOI: 10.1038/s41375-023-02082-w -
Haematologica Feb 2024
Topics: Humans; Primary Myelofibrosis; Pyrimidines; Nitriles; Janus Kinase 2; Benzamides; Pyrazoles
PubMed: 37259556
DOI: 10.3324/haematol.2023.283106 -
Blood Advances Aug 2023Liposomal daunorubicin and cytarabine (CPX-351) improved overall survival (OS) compared with 7+3 chemotherapy in older patients with secondary acute myeloid leukemia... (Randomized Controlled Trial)
Randomized Controlled Trial
Liposomal daunorubicin and cytarabine (CPX-351) improved overall survival (OS) compared with 7+3 chemotherapy in older patients with secondary acute myeloid leukemia (AML); to date, there have been no randomized studies in younger patients. The high-risk cohort of the UK NCRI AML19 trial (ISRCTN78449203) compared CPX-351 with FLAG-Ida in younger adults with newly diagnosed adverse cytogenetic AML or high-risk myelodysplastic syndromes (MDS). A total of 189 patients were randomized (median age, 56 years). Per clinical criteria, 49% of patients had de novo AML, 20% had secondary AML, and 30% had high-risk MDS. MDS-related cytogenetics were present in 73% of the patients, with a complex karyotype in 49%. TP53 was the most common mutated gene, in 43%. Myelodysplasia-related gene mutations were present in 75 (44%) patients. The overall response rate (CR + CRi) after course 2 was 64% and 76% for CPX-351 and FLAG-Ida, respectively. There was no difference in OS (13.3 months vs 11.4 months) or event-free survival in multivariable analysis. However, relapse-free survival was significantly longer with CPX-351 (median 22.1 vs 8.35 months). There was no difference between the treatment arms in patients with clinically defined secondary AML or those with MDS-related cytogenetic abnormalities; however, an exploratory subgroup of patients with MDS-related gene mutations had significantly longer OS with CPX-351 (median 38.4 vs 16.3 months). In conclusion, the OS of younger patients with adverse risk AML/MDS was not significantly different between CPX-351 and FLAG-Ida.
Topics: Adult; Humans; Aged; Middle Aged; Daunorubicin; Cytarabine; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Karyotype; United Kingdom
PubMed: 37171402
DOI: 10.1182/bloodadvances.2023010276 -
RMD Open Aug 2023The VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an adult-onset systemic autoinflammatory condition that is caused by an acquired...
The VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an adult-onset systemic autoinflammatory condition that is caused by an acquired deficiency of the UBA1 gene in hematopoietic progenitor cells. The clinical spectrum of the VEXAS syndrome currently comprises a broad range of phenotypes such as vasculitis, relapsing polychondritis and Sweet's syndrome. In the past, VEXAS patients have left clinicians puzzled and the true nature of this disease has not been captured until late 2020. This viewpoint describes the relevant clinical features of the VEXAS syndrome and reviews different approaches to establish the diagnosis. Finally, future directions within the field of systemic inflammatory diseases caused by somatic mutations are being discussed.
Topics: Humans; Myelodysplastic Syndromes; Phenotype
PubMed: 37532466
DOI: 10.1136/rmdopen-2023-003332 -
Journal of Visualized Experiments : JoVE Nov 2023The bone marrow microenvironment consists of distinct cell populations, such as mesenchymal stromal cells, endothelial cells, osteolineage cells, and fibroblasts, which...
The bone marrow microenvironment consists of distinct cell populations, such as mesenchymal stromal cells, endothelial cells, osteolineage cells, and fibroblasts, which provide support for hematopoietic stem cells (HSCs). In addition to supporting normal HSCs, the bone marrow microenvironment also plays a role in the development of hematopoietic stem cell disorders, such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). MDS-associated mutations in HSCs lead to a block in differentiation and progressive bone marrow failure, especially in the elderly. MDS can often progress to therapy-resistant AML, a disease characterized by a rapid accumulation of immature myeloid blasts. The bone marrow microenvironment is known to be altered in patients with these myeloid neoplasms. Here, a comprehensive protocol to isolate and phenotypically characterize bone marrow microenvironmental cells from murine models of myelodysplastic syndrome and acute myeloid leukemia is described. Isolating and characterizing changes in the bone marrow niche populations can help determine their role in disease initiation and progression and may lead to the development of novel therapeutics targeting cancer-promoting alterations in the bone marrow stromal populations.
Topics: Humans; Animals; Mice; Aged; Bone Marrow; Endothelial Cells; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Hematopoietic Stem Cells; Tumor Microenvironment
PubMed: 38009736
DOI: 10.3791/66093 -
American Journal of Human Genetics Nov 2023Fanconi anemia (FA) is a clinically variable and genetically heterogeneous cancer-predisposing disorder representing the most common bone marrow failure syndrome. It is...
Fanconi anemia (FA) is a clinically variable and genetically heterogeneous cancer-predisposing disorder representing the most common bone marrow failure syndrome. It is caused by inactivating predominantly biallelic mutations involving >20 genes encoding proteins with roles in the FA/BRCA DNA repair pathway. Molecular diagnosis of FA is challenging due to the wide spectrum of the contributing gene mutations and structural rearrangements. The assessment of chromosomal fragility after exposure to DNA cross-linking agents is generally required to definitively confirm diagnosis. We assessed peripheral blood genome-wide DNA methylation (DNAm) profiles in 25 subjects with molecularly confirmed clinical diagnosis of FA (FANCA complementation group) using Illumina's Infinium EPIC array. We identified 82 differentially methylated CpG sites that allow to distinguish subjects with FA from healthy individuals and subjects with other genetic disorders, defining an FA-specific DNAm signature. The episignature was validated using a second cohort of subjects with FA involving different complementation groups, documenting broader genetic sensitivity and demonstrating its specificity using the EpiSign Knowledge Database. The episignature properly classified DNA samples obtained from bone marrow aspirates, demonstrating robustness. Using the selected probes, we trained a machine-learning model able to classify EPIC DNAm profiles in molecularly unsolved cases. Finally, we show that the generated episignature includes CpG sites that do not undergo functional selective pressure, allowing diagnosis of FA in individuals with reverted phenotype due to gene conversion. These findings provide a tool to accelerate diagnostic testing in FA and broaden the clinical utility of DNAm profiling in the diagnostic setting.
Topics: Humans; Fanconi Anemia; Fanconi Anemia Complementation Group Proteins; DNA Methylation; Proteins; DNA
PubMed: 37865086
DOI: 10.1016/j.ajhg.2023.09.014 -
Blood Advances Sep 2023Promising results have been reported for adult patients with high-risk hematologic malignancies undergoing haploidentical bone marrow transplant (haploBMT) with...
Promising results have been reported for adult patients with high-risk hematologic malignancies undergoing haploidentical bone marrow transplant (haploBMT) with posttransplant cyclophosphamide (PTCy). To our knowledge, we report results from the first multicenter trial for pediatric and young adult patients with high-risk acute leukemias and myelodysplastic syndrome (MDS) in the Pediatric Transplantation and Cellular Therapy Consortium. Nine centers performed transplants in 32 patients having acute leukemias or MDS, with myeloablative conditioning (MAC), haploBMT with PTCy, mycophenolate mofetil, and tacrolimus. The median patient age was 12 years. Diagnoses included AML (15), ALL (11), mixed-lineage leukemia (1), and MDS (5). Transplant-related mortality (TRM) at 180 days was 0%. The cumulative incidence (CuI) of grade 2 acute graft-versus-host disease (aGVHD) on day 100 was 13%. No patients developed grades 3-4 aGVHD. The CuI of moderate-to-severe chronic GVHD (cGVHD) at 1 year was 4%. Donor engraftment occurred in 27 patients (84%). Primary graft failures included 3 patients who received suboptimal bone marrow grafts; all successfully engrafted after second transplants. The CuI of relapse at 1 year was 32%, with more relapse among patients MRD positive pre-BMT vs MRD negative. Overall survival rates at 1 and 2 years were 77% and 73%, and event-free survival rate at 1 and 2 years were 68% and 64%. There was no TRM or severe aGVHD, low cGVHD, and favorable relapse and survival rates. This successful pilot trial has led to a phase 3 trial comparing MAC haploBMT vs HLA-matched unrelated donor BMT in the Children's Oncology Group. This trial was registered at www.clinicaltrials.gov as #NCT02120157.
Topics: Young Adult; Humans; Child; Prospective Studies; Cyclophosphamide; Bone Marrow Transplantation; Graft vs Host Disease; Leukemia; Acute Disease; Myelodysplastic Syndromes; Recurrence
PubMed: 37257193
DOI: 10.1182/bloodadvances.2023010281