ABSTRACT
Here we report efficacy, pharmacokinetics, and safety data obtained in treatment-naive, pediatric patients with newly diagnosed advanced MDS receiving azacitidine in the AZA-JMML-001 study. The primary endpoint was response rate (proportion of patients with complete response [CR], partial response [PR], or marrow CR, sustained for ≥4 weeks). Of the 10 patients enrolled, one had an unconfirmed marrow CR and none had confirmed responses after three cycles; the study was therefore closed after stage 1. Azacitidine was well tolerated. The lack of efficacy of azacitidine in pediatric patients with newly diagnosed advanced MDS highlights the need for effective new treatments in these patients.
Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Humans , Child , Azacitidine/adverse effects , Leukemia, Myeloid, Acute/drug therapy , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/diagnosis , Treatment Outcome , Hematopoietic Stem Cell Transplantation/adverse effectsSubject(s)
Neoplasms , Humans , Child , Ireland/epidemiology , Neoplasms/epidemiology , Neoplasms/therapy , Socioeconomic Factors , Social ClassSubject(s)
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Child , Humans , Chromosomes, Human, Pair 21 , Chromosome Aberrations , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Prognosis , Risk Assessment , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/geneticsABSTRACT
OBJECTIVE: A high platelet turnover rate may produce a population of platelets that confers an inadequate response to aspirin. We aimed to investigate the relationship between residual platelet aggregation and platelet turnover in paediatric cardiology patients on aspirin monotherapy by evaluating the fraction of immature platelets as a marker for turnover and secondly to test the predictive value of the immature platelet fraction (IPF) to classify patients as responsive or non-responsive to aspirin. METHODS: Sixty patients divided into two age categories (≤90 days, >90 days of age) were included in this prospective observational study. Patients were then stratified into tertiles using their IPF level. Platelet studies included thromboelastography with platelet mapping (TEGPM). RESULTS: The overall incidence of 'inadequate response to aspirin' was 38 % in our patient cohort recently post-cardiac surgery a consequence that warrants further study. The frequency of inadequate response to aspirin was higher in the upper tertile of IPF when compared to the lower tertile, (88 %) versus (4 %) respectively (p < 0.05). The 'cut off' for IPF was determined to be 3.9 % with a sensitivity of 95.7 %, and a specificity of 92.9 % (area under the curve of 0.955 [CI 0.896-1.014, p < 0.05]). CONCLUSION: This study demonstrates that inadequate response to aspirin occurs in approximately 38 % of patients undergoing specific high-risk congenital cardiac procedures using the dosing practice of a national centre. This study supports the hypothesis that an elevated platelet turnover may result in aspirin being less effective in patients who are recently post cardiac surgery. These data are of direct translational relevance.
Subject(s)
Cardiac Surgical Procedures , Heart Defects, Congenital , Child , Humans , Infant , Aspirin/therapeutic use , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation Inhibitors/therapeutic use , Blood Platelets/physiology , Cardiac Surgical Procedures/adverse effects , Heart Defects, Congenital/surgerySubject(s)
Heterozygote , Mutation, Missense , Phenotype , Shwachman-Diamond Syndrome/diagnosis , Shwachman-Diamond Syndrome/genetics , Signal Recognition Particle/genetics , Biomarkers , Biopsy , DNA Mutational Analysis , Disease Management , Genetic Association Studies , Genetic Predisposition to Disease , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Humans , Infant, Newborn , Male , Radiography , Treatment OutcomeABSTRACT
Germline SAMD9 and SAMD9L mutations (SAMD9/9Lmut) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9Lmut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9Lmut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9Lmut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9Lmut suppressed HEK293 cell growth, and mutations expressed in CD34+ cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9Lmut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 ± cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9Lmut). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9Lmut MDS and exemplify the exceptional plasticity of hematopoiesis in children.
Subject(s)
Clonal Evolution/genetics , Clonal Hematopoiesis/genetics , Intracellular Signaling Peptides and Proteins/genetics , Myelodysplastic Syndromes/genetics , Tumor Suppressor Proteins/genetics , Adolescent , Bone Marrow Cells/metabolism , Child , Child, Preschool , Female , GATA2 Transcription Factor/genetics , Germ-Line Mutation/genetics , HEK293 Cells , High-Throughput Nucleotide Sequencing , Humans , Infant , Kaplan-Meier Estimate , Male , Myelodysplastic Syndromes/pathology , Single-Cell AnalysisSubject(s)
Dependovirus/genetics , Genetic Therapy/methods , Animals , Genetic Vectors/genetics , HumansABSTRACT
BACKGROUND: Acute megakaryoblastic leukaemia (AMKL) is a subtype of myeloid leukaemia and is the most common leukaemia type in children with Down syndrome (DS) under 4 years of age. AMKL is often preceded by a transient neonatal pre-leukaemic syndrome, transient myeloproliferative disorder (TMD). Although TMD often spontaneously resolves, 20-30% of these patients subsequently develop AMKL within the first 4 years of life. AIMS: To perform a retrospective consecutive national audit of all documented cases of childhood TMD and AMKL-DS from 1990 to 2018 at Our Lady's Children's Hospital, Crumlin (OLCHC), Ireland. METHODS: All patients with a diagnosis of AMKL treated consecutively at (OLCHC) between 1990 and 2018 were reviewed. Kaplan-Meier survival curves were constructed. RESULTS: Twenty-seven patients with AMKL-DS were identified. A prior neonatal diagnosis of TMD was described in 10 patients (37%). Nineteen patients (70%) are alive and well, in complete remission, at a median follow-up of 11.4 years. Overall survival (OS) of this cohort has risen from 54% from those treated between the years 1990 and 2004 (n = 13) to 93% for those treated between the years 2005 and 2018 (n = 14). CONCLUSION: High cure rates are observed in AMKL-DS using current polychemotherapy protocols. The finding of a low platelet count at time of diagnosis is in keeping with the knowledge that AMKL-DS is a malignancy of platelet progenitor cells.
Subject(s)
Down Syndrome/complications , Leukemia, Myeloid/etiology , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Ireland , Male , Retrospective StudiesABSTRACT
Sickle cell anaemia (SCA) is the consequence of abnormal haemoglobin production due to an inherited point mutation in the ß-globin gene. The resulting haemoglobin tetramer is poorly soluble when deoxygenated, and when this is prolonged, intracellular gelation of sickle haemoglobin occurs, followed by haemoglobin polymerisation. If many cycles of sickling and unsickling occur, the red cell membrane will be disrupted leading to haemolysis and vaso-occlusive events. Recent studies have also shown that leucocyte adhesion molecules and nitric oxide (NO) depletion are involved in endothelial damage. New insights in SCA pathophysiology and vascular biology have shown that cell-derived microparticle (MP) generation is also involved in the vaso-occlusion. Endothelial damage is perpetuated by impaired production or increased consumption of protective modulators such as protein C, protein S and NO. New therapeutic interventions should address these aspects of SCA pathogenesis. To date, the only US-FDA-approved therapy to prevent painful vaso-occulsive episodes is hydroxyurea that reduces haemoglobin polymerisation in sickle cells by increasing the production of foetal haemoglobin and L-glutamine. However, several new drugs have been tested in the last years in randomised clinical trials. We here report an update on the current status of knowledge on SCA.
Subject(s)
Anemia, Sickle Cell/etiology , Anemia, Sickle Cell/therapy , Anemia, Sickle Cell/diagnosis , Anemia, Sickle Cell/metabolism , Animals , Antisickling Agents/pharmacology , Antisickling Agents/therapeutic use , Biomarkers , Blood Coagulation , Cell Adhesion Molecules/metabolism , Cell-Derived Microparticles/metabolism , Clinical Trials as Topic , Disease Models, Animal , Erythrocyte Membrane/metabolism , Erythrocytes, Abnormal/metabolism , Genotype , Hemoglobin, Sickle/genetics , Hemolysis , Humans , Hydroxyurea/pharmacology , Hydroxyurea/therapeutic use , Intermediate-Conductance Calcium-Activated Potassium Channels/antagonists & inhibitors , Intermediate-Conductance Calcium-Activated Potassium Channels/metabolism , Mutation , Nitric Oxide/metabolism , beta-Globins/geneticsABSTRACT
Biallelic variants in the ERCC excision repair 6 like 2 gene (ERCC6L2) are known to cause bone marrow failure (BMF) due to defects in DNA repair and mitochondrial function. Here, we report on eight cases of BMF from five families harboring biallelic variants in ERCC6L2, two of whom present with myelodysplasia. We confirm that ERCC6L2 patients' lymphoblastoid cell lines (LCLs) are hypersensitive to DNA-damaging agents that specifically activate the transcription coupled nucleotide excision repair (TCNER) pathway. Interestingly, patients' LCLs are also hypersensitive to transcription inhibitors that interfere with RNA polymerase II (RNA Pol II) and display an abnormal delay in transcription recovery. Using affinity-based mass spectrometry we found that ERCC6L2 interacts with DNA-dependent protein kinase (DNA-PK), a regulatory component of the RNA Pol II transcription complex. Chromatin immunoprecipitation PCR studies revealed ERCC6L2 occupancy on gene bodies along with RNA Pol II and DNA-PK. Patients' LCLs fail to terminate transcript elongation accurately upon DNA damage and display a significant increase in nuclear DNA-RNA hybrids (R loops). Collectively, we conclude that ERCC6L2 is involved in regulating RNA Pol II-mediated transcription via its interaction with DNA-PK to resolve R loops and minimize transcription-associated genome instability. The inherited BMF syndrome caused by biallelic variants in ERCC6L2 can be considered as a primary transcription deficiency rather than a DNA repair defect.
Subject(s)
Alleles , Bone Marrow Diseases/metabolism , DNA Helicases/metabolism , DNA Repair , Genetic Diseases, Inborn/metabolism , Genomic Instability , Transcription, Genetic , A549 Cells , Bone Marrow Diseases/genetics , Bone Marrow Diseases/pathology , DNA Helicases/genetics , DNA-Activated Protein Kinase/genetics , DNA-Activated Protein Kinase/metabolism , Female , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/pathology , HeLa Cells , Humans , Male , RNA Polymerase II/genetics , RNA Polymerase II/metabolism , SyndromeSubject(s)
Down Syndrome/diagnosis , Down Syndrome/genetics , Leukemoid Reaction/diagnosis , Leukemoid Reaction/genetics , Mutation , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Blood Cells/pathology , Bone Marrow/pathology , DNA Mutational Analysis , Female , Humans , Infant , Infant, NewbornABSTRACT
G-CSF post-allogeneic HSCT accelerates neutrophil engraftment, but evidence that it impacts on cost-related outcomes is lacking. We performed a retrospective child and adolescent single-center cohort study examining G-CSF administration from Day +6 of allogeneic HSCT vs. ad hoc G-CSF use where clinically indicated. Forty consecutive children and adolescents undergoing allogeneic HSCT were included. End-points were as follows: time to engraftment; incidence of acute and chronic GvHD; number of patients alive at Day +100; 180-day TRM; post-transplant days in hospital; and cost of antimicrobials, TPN, and G-CSF usage. Neutrophil engraftment occurred earlier in the group that received G-CSF from Day +6. There was no difference between groups in any of the other end-points with the following exception: the cost of GCSF was significantly higher in the D + 6 G-CSF group. However, median G-CSF cost in this group amounted to only 280. There was a trend towards reduced cost of antimicrobials in the D + 6 G-CSF group, although this did not reach significance (p = 0.13). The median cost per patient of antimicrobial agents between groups differed by 1116. This study demonstrated the administration of G-CSF on Day +6 in pediatric HSCT to be safe. A further study using a larger cohort of patients is warranted to ascertain its true clinico-economic value.
Subject(s)
Granulocyte Colony-Stimulating Factor/administration & dosage , Health Care Costs , Hematopoietic Stem Cell Transplantation/methods , Neutrophils/cytology , Adolescent , Anti-Infective Agents/chemistry , Child , Child, Preschool , Female , Graft vs Host Disease , Granulocyte Colony-Stimulating Factor/economics , Hematopoietic Stem Cell Transplantation/economics , Humans , Infant , Male , Pediatrics/methods , Postoperative Complications , Retrospective Studies , Time Factors , Transplantation, Homologous/economics , Transplantation, Homologous/methodsABSTRACT
Low-dose azacitidine is efficient and safe in the therapy of malignant myeloid disorders in adults but data in children are lacking. We present a retrospective analysis of 24 children and young adults with myelodysplastic syndrome (MDS) who received azacitidine at the time of first diagnosis or relapse after allotransplant (2 children were treated with azacitidine both initially and for relapse). Diagnoses were refractory cytopenia of childhood (N = 4), advanced primary MDS (N = 9) and secondary MDS (N = 11). The median duration of treatment was four cycles. Azacitidine was well tolerated, but cytopenias led to dose reduction in five cases. Treatment was discontinued in one child because of impaired renal function. Sixteen MDS patients were treated with azacitidine at first diagnosis. One complete clinical remission was observed and one child showed complete marrow remission; six children experienced stable disease with haematological improvement. Ten children received azacitidine for relapsed MDS after transplant: of these, seven experienced stable disease for 2-30 cycles (median 3), including one patient with haematological improvement for seven cycles. In summary, azacitidine is effective in some children with MDS and appears to be a non-toxic option in palliative situations to prolong survival.