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dbGaP phs000922 Genetic Aberrations and Subclonal Structure Impact Chronic Lymphocytic Leukemia - pht004924.v2.p1

- 18/04/24 - 4 moduli, 1 ItemGroup, 3 elementi, 1 linguaggio
ItemGroup: pht004924
Principal Investigator: Catherine Wu, MD, Dana-Farber Cancer Institute, Boston, MA, USA MeSH: Leukemia, Lymphocytic, Chronic, B-Cell https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000922 Large-scale whole-exome sequencing (WES) of primary tumor samples enables the unbiased discovery of recurrent putative driver events and patterns of clonal evolution. We report the identification of 44 recurrently mutated genes and 11 recurrent CNVs through the WES of 538 chronic lymphocytic leukemia (CLL) and matched germline DNAs. These include previously unrecognized cancer drivers (e.g., RPS15, IKZF3), and collectively identify nuclear export, MYC activity and MAPK signaling as central pathways affected by somatic mutation in CLL. A clonality analysis of this large dataset further enabled the reconstruction of temporal relationships between these driver events. Several drivers were associated with shorter progression-free survival (PFS) in 280 samples that were collected prior to uniform treatment with front line chemo-immunotherapy, with mature follow up of greater than 10 years. Direct comparison between matched pretreatment and relapse CLL from 59 samples demonstrated marked clonal evolution occurring in more than 95% of these patients. Distinct patterns of clonal evolution in relationship to specific gene alteration were observed, suggesting a hierarchy of fitness amongst mutations. Thus, large WES datasets of clinically informative samples enable the discovery of novel driver genes as well as the network of relationships between the drivers and their impact on disease relapse and clinical outcome. Additionally, we performed RNA-seq for 268 CLL samples (including 26 follow-up samples) and used them to identify expression subtypes of CLL. RRBS for 30 of these samples was also generated. In an integrative analysis of genetic, transcriptomic, and epigenetic data, incorporating known and newly identified subtypes of CLL, we built new models to improve patient prognostication.

pht004925.v2.p1

1 ItemGroup 2 elementi

pht004926.v2.p1

1 ItemGroup 2 elementi

pht004927.v2.p1

1 ItemGroup 7 elementi

dbGaP phs000879 DFCI Brown Lab CLL Sequencing Study - pht005032.v1.p1

- 26/03/24 - 4 moduli, 1 ItemGroup, 2 elementi, 1 linguaggio
ItemGroup: pht005032
Principal Investigator: Jennifer R. Brown, Dana-Farber Cancer Institute, Broad Institute, Boston, MA, USA MeSH: Leukemia, Lymphocytic, Chronic, B-Cell https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000879 Chronic Lymphocytic Leukemia (CLL) is a hematological malignancy characterized by accumulation of CD5+CD19+ B cells in peripheral lymphoid organs, bone marrow and blood. In this study we analyze matched whole genome sequencing and RNA-seq data from CLL patients to characterize the mutational processes operative throughout tumor evolution. Source of tumor and normal DNA used is patient PBMC or B cells and saliva respectively.

pht005033.v1.p1

1 ItemGroup 3 elementi

pht005034.v1.p1

1 ItemGroup 2 elementi

pht005035.v1.p1

1 ItemGroup 3 elementi

dbGaP phs001091 Clonal Evolution in Patients with Chronic Lymphocytic Leukemia - pht006063.v1.p1

- 21/06/23 - 4 moduli, 1 ItemGroup, 2 elementi, 1 linguaggio
ItemGroup: pht006063
Principal Investigator: Catherine Wu, MD, Dana Farber Cancer Institute, Boston, MA, USA MeSH: Leukemia, Lymphocytic, Chronic, B-Cell https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001091 We analyzed clonal evolution in serial samples from five CLL patients who became resistant to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, using whole-exome and deep targeted sequencing. We observe a BTK-C481S mutation in one of five patients, and multiple PLCG2 mutations in a second patient. The other patients had an expansion of clones harboring del(8p) carrying additional driver mutations (EP300, MLL2, EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. We calculated the growth kinetics of ibrutinib-resistant subclones and estimated the size of the resistant clones at treatment initiation, which we validated by droplet-microfluidic technology. Haplo-insufficiency of TRAIL-R, a consequence of del(8p), led to TRAIL insensitivity which may contribute to development of ibrutinib resistance. These findings demonstrate that ibrutinib therapy has the potential to lead to clonal selection and expansion of rare cell populations already present at the time of treatment initiation. They also provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance, previously attributed solely to mutations in BTK and related pathway molecules.

pht006064.v1.p1

1 ItemGroup 3 elementi

pht006065.v1.p1

1 ItemGroup 6 elementi

pht006066.v1.p1

1 ItemGroup 4 elementi

dbGaP phs001181 Single-Cell DNA and RNA Sequencing over A 29-Year Period of A CLL Patient - pht005769.v1.p1

- 02/06/23 - 4 moduli, 1 ItemGroup, 3 elementi, 1 linguaggio
ItemGroup: pht005769
Principal Investigator: Michael Dean, PhD, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA MeSH: Leukemia, Lymphocytic, Chronic, B-Cell https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001181 Chronic lymphocytic leukemia (CLL) is a frequent B-cell malignancy characterized by recurrent somatic chromosome alterations and a low level of point mutations. Here we present single nucleotide polymorphism (SNP) microarray analyses of a single CLL patient over 29-years of observation and treatment, and transcriptome and whole genome sequencing at selected timepoints. We identified chromosome alterations of 13q14-, 6q- and 12q+ in early cell clones, elimination of clonal populations following therapy, and subsequent appearance of a clone containing trisomy 12 and a chromosome 10 copy neutral loss of heterogeneity (LOH) that marks a major population dominant at death. Serial single cell RNA sequencing revealed elevated mRNA expression of the FOS, JUN and KLF4 genes just before the appearance of acute disease requiring therapy. This gene expression pattern became undetectable following therapy, but reoccurred following relapse. Transcriptome evolution indicates that complex expression changes occur over time. In conclusion, CLL can evolve gradually during indolent phases, and undergo rapid changes following therapy.

pht005770.v1.p1

1 ItemGroup 3 elementi

pht005771.v1.p1

1 ItemGroup 3 elementi

pht005772.v1.p1

1 ItemGroup 6 elementi

dbGaP phs001219 Detection of Genes Predisposing to Hematologic Malignancies - pht007857.v1.p1

- 26/04/23 - 6 moduli, 1 ItemGroup, 2 elementi, 1 linguaggio
ItemGroup: pht007857
Principal Investigator: Neil E. Caporaso, MD, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA MeSH: Leukemia, Lymphocytic, Chronic, B-Cell,Hodgkin Disease,Lymphoma, Non-Hodgkin,Waldenstrom Macroglobulinemia,Leukemia, Hairy Cell,Leukemia, Myeloid, Acute,Leukemia, Myelomonocytic, Juvenile https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001219 We have been conducting genetic studies on families at high risk of different hematologic malignancies, in order to define the related tumors in the families, define precursor and other related conditions, and map and identify susceptibility genes. We have focused mainly on four types of lymphoid malignancies: chronic lymphocytic leukemia (CLL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and Waldenström macroglobulinemia (WM). A few families with a rare lymphoma subtype, hairy cell leukemia (HCL) are included. In addition, single large pedigrees with acute myeloid leukemia (AML), and juvenile myelomocytic leukemia (JMML) are included. Families are ascertained for having at least two patients with the same hematologic malignancy and are classified by the type of malignancy that predominates in the family. Multiple types of lymphoid malignancies are often found in the same family. Other data has shown that these conditions aggregate together in families. Verification of cancer diagnoses is obtained through medical records, pathology reports, and flow cytometry. Family members with precursor traits are also included, monoclonal B-cell lymphocytosis (MBL) in CLL families and IgM monoclonal gammopathy of undetermined significance (MGUS) in WM families.

pht007858.v1.p1

1 ItemGroup 6 elementi

Eligibility

1 ItemGroup 1 elemento

pht007859.v1.p1

1 ItemGroup 3 elementi

pht007860.v1.p1

1 ItemGroup 10 elementi

pht007861.v1.p1

1 ItemGroup 5 elementi

dbGaP phs000435 Whole Exome Sequencing of Chronic Lymphocytic Leukemia - pht002524.v3.p1

- 12/10/22 - 4 moduli, 1 ItemGroup, 4 elementi, 1 linguaggio
ItemGroup: pht002524
Principal Investigator: Catherine Wu, Broad Institute, Cambridge, MA, Dana Farber Cancer Institute, Boston MA, USA MeSH: Chronic Lymphocytic Leukemia,Leukemia, Lymphocytic, Chronic, B-Cell https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000435 The somatic genetic basis of chronic lymphocytic leukemia (CLL), a common and clinically heterogenous adult leukemia, remains poorly understood. Massively parallel sequencing technology now provides a method for systematic discovery of genetic alterations that underlie disease, and for uncovering new therapeutic targets and biomarkers. In study version 2 we presented a dataset consisting of DNA sequencing from 169 CLL samples (with matched germline controls). Samples were collected from patients displaying a wide range of characteristics representing the broad clinical spectrum of CLL. Understanding the mutational landscape of CLL provides a starting point for systematic analyses to address fundamental questions in CLL, including how mutated genes alter cellular networks and phenotypes, and thereby contribute to disease heterogeneity. Intratumoral heterogeneity plays a critical role in tumor evolution. To define the contribution of DNA methylation to heterogeneity within tumors, we performed genome-scale bisulfite sequencing of 100 primary chronic lymphocytic leukemias (CLLs; data presented in study version 3). Compared with 26 normal B cell samples, CLLs consistently displayed higher intrasample variability of DNA methylation patterns across the genome, which appears to arise from stochastically disordered methylation in malignant cells. Transcriptome analysis of bulk and single CLL cells revealed that methylationdisorder was linked to low-level expression. Disordered methylation was further associated with adverse clinical outcome. We therefore propose that disordered methylation plays a similar role to that of genetic instability, enhancing the ability of cancer cells to search for superior evolutionary trajectories.

pht002521.v3.p1

1 ItemGroup 6 elementi

pht002522.v3.p1

1 ItemGroup 3 elementi

pht002523.v3.p1

1 ItemGroup 11 elementi

dbGaP phs000364 Genome-Wide Analysis of Chronic Lymphocytic Leukemia - Eligibility

- 12/10/22 - 5 moduli, 1 ItemGroup, 1 elemento, 1 linguaggio
ItemGroup: IG.elig
Principal Investigator: Riccardo Dalla-Favera, Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA MeSH: Chronic Lymphocytic Leukemia,Richter Syndrome https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000364 *Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation* The pathogenesis of chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is still largely unknown since the full spectrum of genetic lesions that are present in the CLL genome, and therefore the number and identity of dysregulated cellular pathways, have not been identified. By combining next-generation sequencing and copy number analysis, we show here that the typical CLL coding genome contains less than 20 clonally represented gene alterations/case, including predominantly non-silent mutations and fewer copy number aberrations. These analyses led to the discovery of several genes not previously known to be altered in CLL. While most of these genes were affected at low frequency in an expanded CLL screening cohort, mutational activation of NOTCH1, observed in 8.3% of CLL at diagnosis, was detected at significantly higher frequency during disease progression toward Richter transformation (31.0%) as well as in chemorefractory CLL (20.8%). Consistent with the association of NOTCH1 mutations with clinically aggressive forms of the disease, NOTCH1 activation at CLL diagnosis emerged as an independent predictor of poor survival. These results provide initial data on the complexity of the CLL coding genome and identify a dysregulated pathway of diagnostic and therapeutic relevance. *Genetic Lesions associated with Chronic Lymphocytic Leukemia transformation to Richter Syndrome* Richter syndrome (RS) derives from the rare transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly of the diffuse large B cell type (DLBCL). The molecular pathogenesis of RS is only partially understood. By combining whole-exome sequencing and copy-number analysis of 9 CLL-RS pairs and of an extended panel of 43 RS cases, we show that this aggressive disease typically arises from the predominant CLL clone by acquiring an average of ~20 genetic lesions/case. RS lesions are heterogeneous in terms of load and spectrum among patients, and include those involved in CLL progression and chemorefractoriness (TP53 disruption and NOTCH1 activation) as well as some not previously implicated in CLL or RS pathogenesis. In particular, disruption of the CDKN2A/B cell cycle regulator locus is associated with ~30% of RS cases. Finally, we report that the genomic landscape of RS is significantly different from that of de novo DLBCL, suggesting that they represent distinct disease entities. These results provide insights into RS pathogenesis, and identify dysregulated pathways of potential diagnostic and therapeutic relevance.

pht002260.v2.p1

1 ItemGroup 2 elementi

pht002261.v2.p1

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pht002262.v2.p1

1 ItemGroup 3 elementi

pht002263.v2.p1

1 ItemGroup 5 elementi

CLL Eligibility BO17072 NCT00090051 - Eligibility Chronic Lymphocytic Leukemia NCT00090051

- 18/11/21 - 1 modulo, 3 itemgroups, 37 elementi, 1 linguaggio
Itemgroups: Inclusion Criteria, Exclusion Criteria, Eligibility summary
An open-label, multicenter, randomized, comparative, phase III study to evaluate the efficacy and safety of rituximab plus fludarabine and cyclophosphamide (FCR) versus fludarabine and cyclophosphamide alone (FC) in previously treated patients with CD20 positive B-cell chronic lymphocytic leukemia (CLL). FCR Versus FC Alone in the Treatment of Chronic Lymphocytic Leukemia (CLL) in Relapsed Patients NCT00090051 Roche BO17072

CLL Completion BO17072 NCT00090051 - Treatment phase completion Chronic Lymphocytic Leukemia BO17072 NCT00090051

- 27/09/21 - 1 modulo, 3 itemgroups, 14 elementi, 1 linguaggio
Itemgroups: Death of Patient, Treatment phase completion, Additional observations
An open-label, multicenter, randomized, comparative, phase III study to evaluate the efficacy and safety of rituximab plus fludarabine and cyclophosphamide (FCR) versus fludarabine and cyclophosphamide alone (FC) in previously treated patients with CD20 positive B-cell chronic lymphocytic leukemia (CLL). NCT00090051

CLL History BO17072 NCT00090051 - History of Chronic lymphocytic leukemia NCT0090051

- 27/09/21 - 1 modulo, 5 itemgroups, 13 elementi, 1 linguaggio
Itemgroups: Vital signs and physical measurements, Sitting measurements, "B" symptoms, General physical examination, ECG
An open-label, multicenter, randomized, comparative, phase III study to evaluate the efficacy and safety of rituximab plus fludarabine and cyclophosphamide (FCR) versus fludarabine and cyclophosphamide alone (FC) in previously treated patients with CD20 positive B-cell chronic lymphocytic leukemia (CLL). FCR Versus FC Alone in the Treatment of Chronic Lymphocytic Leukemia (CLL) in Relapsed Patients NCT00090051 Roche BO17072

CLL Cycle 1 FCR vs FC BO17072 NCT00090051 - Chemotherapy Cycle 1 of Chronic Lymphocytic Leukemia NCT00090051 BO17072

- 27/09/21 - 1 modulo, 16 itemgroups, 80 elementi, 1 linguaggio
Itemgroups: Randomization, Pharmacokinetic assessments, Vital signs and physical measurements, Sitting measurements after al least 5 minutes rest, "B" symptoms, General physical examination, ECG, Laboratory analysis, Hematology, Blood chemistry, Electrocytes, Administration of Rituximab, Administration of Fludarabine, Fludarabine Medication, Administration of Cyclophosphamide, Cyclophosphamide Medication
An open-label, multicenter, randomized, comparative, phase III study to evaluate the efficacy and safety of rituximab plus fludarabine and cyclophosphamide (FCR) versus fludarabine and cyclophosphamide alone (FC) in previously treated patients with CD20 positive B-cell chronic lymphocytic leukemia (CLL). FCR Versus FC Alone in the Treatment of Chronic Lymphocytic Leukemia (CLL) in Relapsed Patients NCT00090051 Roche BO17072

Eligibility Leukemia NCT00004857

- 20/09/21 - 1 modulo, 1 ItemGroup, 20 elementi, 1 linguaggio
ItemGroup: Criteria
Fludarabine Followed by Alemtuzumab in Treating Patients With Chronic Lymphocytic Leukemia; ODM derived from: https://clinicaltrials.gov/show/NCT00004857

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