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1.
Blood ; 141(11): 1316-1321, 2023 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-36493342

RESUMO

Myelodysplastic neoplasms (MDSs) and chronic myelomonocytic leukemia (CMML) are clonal disorders driven by progressively acquired somatic mutations in hematopoietic stem cells (HSCs). Hypomethylating agents (HMAs) can modify the clinical course of MDS and CMML. Clinical improvement does not require eradication of mutated cells and may be related to improved differentiation capacity of mutated HSCs. However, in patients with established disease it is unclear whether (1) HSCs with multiple mutations progress through differentiation with comparable frequency to their less mutated counterparts or (2) improvements in peripheral blood counts following HMA therapy are driven by residual wild-type HSCs or by clones with particular combinations of mutations. To address these questions, the somatic mutations of individual stem cells, progenitors (common myeloid progenitors, granulocyte monocyte progenitors, and megakaryocyte erythroid progenitors), and matched circulating hematopoietic cells (monocytes, neutrophils, and naïve B cells) in MDS and CMML were characterized via high-throughput single-cell genotyping, followed by bulk analysis in immature and mature cells before and after AZA treatment. The mutational burden was similar throughout differentiation, with even the most mutated stem and progenitor clones maintaining their capacity to differentiate to mature cell types in vivo. Increased contributions from productive mutant progenitors appear to underlie improved hematopoiesis in MDS following HMA therapy.


Assuntos
Leucemia Mielomonocítica Crônica , Síndromes Mielodisplásicas , Humanos , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/metabolismo , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Células-Tronco Hematopoéticas/metabolismo , Monócitos , Células Clonais
2.
J Clin Immunol ; 44(5): 118, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38758417

RESUMO

Deficiency of Adenosine Deaminase 2 (DADA2) patients presenting with primary immunodeficiency are at risk of uncontrolled EBV infection and secondary malignancies including EBV-related lymphoproliferative disorders (LPD). This paper describes the first case of EBV related diffuse large B-cell lymphoma in a patient with DADA2 and uncontrolled EBV infection. Consideration should be given to monitoring for EBV viraemia and to preventative EBV specific therapy in DADA2 and patients with at risk primary immunodeficiencies. A type I interferon (IFN) gene signature is associated with DADA2 though its association with immune dysregulation is unclear.


Assuntos
Adenosina Desaminase , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/etiologia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/genética , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Feminino , Doenças Hereditárias Autoinflamatórias
3.
Pathology ; 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-39025727

RESUMO

Measurable residual disease (MRD) is useful for prognostication and for monitoring response to treatment in patients with acute leukaemia. MRD by multiparametric flow cytometry (MFC-MRD) utilises the leukaemia-associated immunophenotype (LAIP) and difference from normal (DfN) strategies to identify the leukaemic clone. Difficulties arise when the LAIP overlaps with normal regeneration, there is clonal evolution, or when the abnormal clone population is exceptionally small e.g., <0.01% of CD45+ cells. Such cases are reported as 'indeterminate'; however, there is little international consensus on this reporting. The relationship between clinical outcomes and indeterminate MFC-MRD is unknown. Here we determine the rate of indeterminate MFC-MRD reporting, its relationship to concurrent molecular MRD results when available, and to clinical outcomes to 12 months. We performed an internal audit of all adult testing for MFC-MRD between January and December 2021. A total of 153 consecutive patients with a diagnosis of acute leukaemia were included. Successive MFC-MRD results and clinical outcomes were recorded over a 12-month period from time of inclusion into the study. In total, 460 MFC-MRD tests from 153 patients were reviewed and 73 (16%) MFC-MRD tests from 54 (35%) patients were reported as indeterminate. The majority (70%) were at low levels between 0.01-0.1% of CD45+ cells. Compared to patients with a negative result, acute myeloid leukaemia (AML) was more frequent in patients who had an indeterminate MFC-MRD (70% vs 36%), and B-cell acute lymphoblastic leukaemia was less common (20% vs 55%). In patients with indeterminate MFC-MRD results, one-third had received either chemotherapy or allogeneic haemopoietic stem cell transplant (aHSCT) within the preceding 3 months. Agreement between MFC and molecular MRD testing was low. Patients with indeterminate MFC-MRD had leukaemia relapse rates below patients with a positive MFC-MRD, but greater than those with negative MFC-MRD (positive 33% vs indeterminate 21% vs negative 8%, p = 0.038). Overall, these findings indicate that indeterminate MFC-MRD results are more common in adults with AML and also in those who have received chemotherapy or aHSCT within the previous 3 months. We report for the first time that indeterminate MFC-MRD is a finding of potential clinical significance, which associates with a numerically higher median relapse rate within 12 months when compared to a negative MFC-MRD result.

4.
Cancers (Basel) ; 15(20)2023 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-37894431

RESUMO

Measurable residual disease (MRD) detected by flow cytometry (FC) is well established in paediatric B- lymphoblastic leukaemia (B-ALL) and adult chronic lymphocytic leukaemia (CLL), but its utility in adult B-ALL and adult acute myeloid leukaemia (AML) is less clear. In this prospective MRD study, one of the largest in Australia to date, we examined consecutive bone marrow aspirates from adult participants with B-ALL (n = 47) and AML (n = 87) sent for FC-MRD testing at a quaternary referral hospital in Sydney. FC-MRD results were correlated to corresponding Mol-MRD testing where available and clinical outcomes at three-month intervals over 1 year. B-ALL showed a moderate positive correlation (rs = 0.401, p < 0.001), while there was no correlation between FC-MRD and Mol-MRD for AML (rs = 0.13, p = 0.237). Five FC-MRD patterns were identified which had significant associations with relapse (X2(4) = 31.17(4), p > 0.001) and survival (X2(4) = 13.67, p = 0.008) in AML, but not in B-ALL. The three-month MRD results were also strongly associated with survival in AML, while the association in B-ALL was less evident. There was a moderate correlation between FC-MRD and Mol-MRD in B-ALL but not AML. The association of FC-MRD with relapse and survival was stronger in AML than in B-ALL. Overall, these findings suggest divergent utilities of FC-MRD in AML and B-ALL.

5.
Clin Neurol Neurosurg ; 170: 165-169, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29803727

RESUMO

In the management of glioblastoma (GBM), there is a considerable predisposition to hyperglycemia due to significant integration of corticosteroid therapy to treat predictable clinical sequelae following diagnosis and treatment. The aim of this study was to quantify effect of hyperglycemia during the management of GBM on overall survival (OS). Searches of seven electronic databases from inception to January 2018 were conducted following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. There were 1475 articles identified for screening. Prognostic hazard ratios (HRs) derived from multivariate regression analysis were extracted, and analyzed using meta-analysis of proportions and linear regression. Six observational studies reporting prognostic HRs in 10 cohorts were included. They described 1481 GBM diagnoses, all surveyed for hyperglycemia during management. Hyperglycemia was found to confer a statistically significant poorer OS outcome (HR, 1.671; p < 0.001). This trend and its significance was not modified by study year, size or proportion of pre-diagnostic diabetes mellitus. Hyperglycemia in GBM is an independent poor prognostic factor for OS. Heterogeneity in clinical course limits inter-study comparability. Future, prospective, randomized studies will validate the findings of this study, and ascertain the potential benefit of more rigorous monitoring for hyperglycemia and glycemic control.


Assuntos
Neoplasias Encefálicas/mortalidade , Glioblastoma/mortalidade , Hiperglicemia/mortalidade , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/diagnóstico , Glioblastoma/sangue , Glioblastoma/diagnóstico , Humanos , Hiperglicemia/sangue , Hiperglicemia/diagnóstico , Estudos Observacionais como Assunto/métodos , Estudos Retrospectivos , Taxa de Sobrevida/tendências
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