Mutations of the CCAAT/enhancer binding protein alpha (CEBPA) gene have been associated with a favorable outcome in patients with acute myeloid leukemia (AML), but mainly in those with a normal karyotype. Here, we analyzed the impact of associated cytogenetic abnormalities or bad-prognosis fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) in 53 patients with CEBPA ؉ de novo AML treated in the Acute Leukemia French Association trials. We found that only those with a normal karyotype and no FLT3-ITD displayed the expected favorable outcome. In this context, relapsefree, disease-free, and overall survival were significantly longer than in corresponding patients without the CEBPA mutation (P ؍ .035, .016, and .047, respectively). This was not observed in the context of an abnormal karyotype or associated FLT3-ITD. Furthermore, after adjustment on age, trial, and mutation type, these features were independently predictive of shorter overall survival in the subset of patients with CEBPA ؉ AML (multivariate hazard ratio ؍ 2.7; 95% confidence interval, 1.08-6.7; and 2.9; 95% confidence interval, 1. IntroductionThe prognosis of patients with acute myeloid leukemia (AML) has been deeply refined because of the impact of new molecular markers. If standard cytogenetics remains a strong factor for both complete remission (CR) achievement and relapse, several gene mutations have been described and demonstrated as significantly influencing the outcome of these patients. 1 In this new context, most cooperative groups recommend to screen for some gene mutations at diagnosis, including the fms-like tyrosine kinase 3 (FLT3), the nucleophosmine (NPM1), and the CCAAT/enhancer binding protein alpha (CEBPA) genes. 2 We have previously reported that CEBPA mutations are associated with a favorable outcome in younger patients with newly diagnosed AML. 3 This was confirmed by other groups, but mainly in patients with cytogenetically normal (CN) AML. [4][5][6][7] The issue of whether this favorable impact is still observed in patients with AML carrying cytogenetic abnormalities remains open. Another open issue is to determine whether cooperating bad-prognosis FLT3 internal tandem duplication (FLT3-ITD) may alter the prognosis of CEBPA mutated (CEBPA ϩ ) AML. 3,5,7 Finally, it has been recently reported that only CEBPA double mutations, but not single, might be associated with a good outcome. 8 In the present study, we thus analyzed the role of these factors in 53 patients with CEBPA ϩ AML treated in Acute Leukemia French Association (ALFA) trials. MethodsA total of 1529 patients (15-70 years of age) with newly diagnosed AML entered the ALFA-9000, ALFA-9801, and ALFA-9802 trials between 1990 and 2006. Trial designs have been already reported. [9][10][11] Briefly, the first ALFA-9000 trial demonstrated the superiority of an intensified timedsequential over a standard (3 ϩ 7) induction in terms of relapse incidence in the subgroup of patients 50 years of age or younger. 9 From 1998, these younger patients were thus treated...
FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia (F/P+ MN-eo) is a rare disease: robust epidemiological data are lacking and reported issues are scarce, of low sample-size and limited follow-up. Imatinib mesylate (IM) is highly efficient but no predictive factor of relapse after discontinuation has yet been identified. One hundred and fifty-one patients with F/P+ MN-eo (143 males; mean age at diagnosis 49 years; mean annual incidence: 0.18 case per million population) were included in this retrospective nationwide study involving all French laboratories who perform the search of F/P fusion gene (study period: 2003-2019). The main organs involved included the spleen (44%), skin (32%), lungs (30%), heart (19%) and central nervous system (9%). Serum vitamin
Classical hairy cell leukemia (HCL-c) is a rare lymphoid neoplasm. BRAFV600E mutation, detected in more than 80% of the cases, is described as a driver mutation, but additional genetic abnormalities appear to be necessary for the disease progression. For cases of HCL-c harboring a wild-type BRAF gene, the differential diagnosis of the variant form of HCL (HCL-v) or splenic diffuse red pulp lymphoma (SDRPL) is complex. We selected a panel of 21 relevant genes based on a literature review of whole exome sequencing studies (BRAF, MAP2K1, DUSP2, MAPK15, ARID1A, ARID1B, EZH2, KDM6A, CREBBP, TP53, CDKN1B, XPO1, KLF2, CXCR4, NOTH1, NOTCH2, MYD88, ANXA1, U2AF1, BCOR, and ABCA8). We analyzed 20 HCL-c and 4 HCL-v patients. The analysis of diagnostic samples mutations in BRAF (n = 18), KLF2 (n = 4), MAP2K1 (n = 3), KDM6A (n = 2), CDKN1B (n = 2), ARID1A (n = 2), CREBBP (n = 2) NOTCH1 (n = 1) and ARID1B (n = 1). BRAFV600E was found in 90% (18/20) of HCL-c patients. In HCL-c patients with BRAFV600E, other mutations were found in 33% (6/18) of cases. All 4 HCL-v patients had mutations in epigenetic regulatory genes: KDM6A (n = 2), CREBBP (n = 1) or ARID1A (n = 1). The analysis of sequential samples (at diagnosis and relapse) from 5 patients (2 HCL-c and 3 HCL-v), showed the presence of 2 new subclonal mutations (BCORE1430X and XPO1E571K) in one patient and variations of the mutated allele frequency in 2 other cases. In the HCL-v disease, we described new mutations targeting KDM6A that encode a lysine demethylase protein. This opens new perspectives for personalized medicine for this group of patients.
Hairy cell leukemia (cHCL) patients have, in most cases, a specific clinical and biological presentation with splenomegaly, anemia, leukopenia, neutropenia, monocytopenia and/or thrombocytopenia, identification of hairy cells that express CD103, CD123, CD25, CD11c and identification of the V600E mutation in the B-Raf proto-oncogene (BRAF) in 90% of cases. Monocytopenia is absent in vHCL and SDRPL patients and the abnormal cells do not express CD25 or CD123 and do not present the BRAFV600E mutation. Ten percent of cHCL patients are BRAFWT and the distinction between cHCL and HCL-like disorders including the variant form of HCL (vHCL) and splenic diffuse red pulp lymphoma (SDRPL) can be challenging. We performed deep sequencing in a large cohort of 84 cHCL and 16 HCL-like disorders to improve insights into the pathogenesis of the diseases. BRAF mutations were detected in 76/82 patients of cHCL (93%) and additional mutations were identified in Krüppel-like Factor 2 (KLF2) in 19 patients (23%) or CDKN1B in 6 patients (7.5%). Some KLF2 genetic alterations were localized on the cytidine deaminase (AID) consensus motif, suggesting AID-induced mutations. When analyzing sequential samples, a clonal evolution was identified in half of the cHCL patients (6/12 pts). Among the 16 patients with HCL-like disorders, we observed an enrichment of MAP2K1 mutations in vHCL/SDRPL (3/5 pts) and genes involved in the epigenetic regulation (KDM6A, EZH2, CREBBP, ARID1A) (3/5 pts). Furthermore, MAP2K1 mutations were associated with a bad prognosis and a shorter time to next treatment (TTNT) and progression-free survival (PFS), independently of the HCL classification.
Recent developments in the management of chronic lymphocytic leukemia (CLL) patients have made necessary the availability of dependable prognostic factors. We have developed a prognostic index derived from the multivariate analysis of 339 stage A patients at diagnosis, exhaustively studied for classical and recent predictive markers. Only 4 biologic parameters were found to be independent predictors of progression-free survival (PFS): serum thymidine kinase (sTK), lymphocytosis, 2-microglobulin, and CD38 expression. Two groups were distinguishable: cases with no or 1 risk factor (among whom 85% did not progress after 7 years), IntroductionWithin the past decade, treatment options in chronic lymphocytic leukemia (CLL) have moved from being palliative to potentially curative. The clinical staging systems developed by Rai et al 1 and Binet et al 2 define early-, intermediate-, and advanced-disease stages. Nonetheless, as substantial variability in the course of the disease is observed among patients at each stage, particularly stage A, 3 there has been a sustained effort to identify reliable prognostic factors in CLL. However, the identification of high-risk (or low-risk) patients remains challenging.Currently, up to 80% of newly diagnosed patients present with Binet stage A. 4 Among them, identifying patients at high risk of progression and precisely evaluating time to progression are fundamental needs for both patients and physicians. For patients with indolent disease, number of follow-up visits may be reduced. Therefore, clinicians in charge of CLL patients would benefit from a simple prognostic index similar to the International Prognostic Index 5 for aggressive non-Hodgkin lymphomas.We exhaustively studied a cohort of 339 stage A CLL patients at diagnosis and determined both typical and specialized prognostic factors. The multivariate analysis allowed us to propose a prognostic score for an easy, fast, and effective assessment of the risk of progression in Binet stage A patients. Methods PatientsOver a period of 8 years, 339 patients diagnosed with CLL in 3 university hospitals were enrolled in the study. All cases were CD5 ϩ CD23 ϩ and had an RMH-Matutes score Ն 4. Patients were followed up from diagnosis until progression to Binet stage B/C. This study was approved by the institutional review board of Hôpital Avicenne. IGHV gene mutational statusIGHV mutational status was evaluated in genomic DNA as previously described. 6 Data obtained after automated sequencer processing were analyzed using the IMGT 7 database. A sequence was considered unmutated when at least 98% identity to the closest germline VH gene was observed. Cytogenetics/targeted chromosome alterationsThe 4 relevant chromosomal abnormalities-del13q, trisomy12, del11q, and del17p-were investigated by interphasic fluorescence in situ hybridization (FISH) analysis. sTKSerum thymidine kinase (sTK) was investigated using a Profiligen TK-Rea kit (Diasorin). CD38 expression by flow cytometryCD38 expression was measured on fresh cells at diagnosis usi...
Mature lymphoid B‐cell proliferations with hairy cells represent heterogeneous entities where specific diagnosis is difficult but important since it impacts therapeutic management. The clinical cases of variant hairy cell leukemia reported herein illustrate the persistence of a clear interest in the use of splenectomy as a therapeutic alternative. Furthermore, ibrutinib appears to be a promising treatment in patients with relapsed/refractory disease.
External quality assurance (EQA) programs are vital to ensure high quality and standardized results in molecular diagnostics. It is important that EQA for quantitative analysis takes into account the variation in methodology. Results cannot be expected to be more accurate than limits of the technology used, and it is essential to recognize factors causing substantial outlier results. The present study aimed to identify parameters of specific importance for JAK2 V617F quantification by quantitative PCR, using different starting materials, assays, and technical platforms. Sixteen samples were issued to participating laboratories in two EQA rounds. In the first round, 19 laboratories from 11 European countries analyzing JAK2 V617F as part of their routine diagnostics returned results from in-house assays. In the second round, 25 laboratories from 17 countries participated. Despite variations in starting material, assay set-up and instrumentation the laboratories were generally well aligned in the EQA program. However, EQA based on a single technology appears to be a valuable tool to achieve standardization of the quantification of JAK2 V617F allelic burden.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.