Neoplasms

Symptoms and General Pathology

All Conditions

Blood and Lymph Conditions

Diseases and Abnormalities at or Before Birth

Rare Diseases

Neoplasm Metastasis

Leukemia

Congenital Abnormalities

Leukemia, Myeloid

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Chromosome Aberrations

Chromosomal Instability

Chromosome Disorders

Neoplasms by Histologic Type

Hematologic Diseases

Myeloproliferative Disorders

Bone Marrow Diseases

Chronic Disease

Disease Attributes

Genetic Diseases, Inborn

Myeloid Leukemia

Chronic Graft Versus Host Disease

Chronic Myeloid Leukemia

Chronic Myeloproliferative Disorders

Antineoplastic Agents

All Drugs and Chemicals

Imatinib Mesylate

bone marrow aspiration

Jeff Lipton, MD

Martin Blackstein, MD

In order to distinguish between clonal instability driven by imatinib in CML and actual changes with secondary clones induced by imatinib we would like to investigate the karyotype of non-CML patients treated with imatinib such as GIST patients.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence of the Philadelphia (Ph) chromosome - a t(9:22) translocation that results in the production of a BCR/ABL fusion protein with Abl kinase activity.

Imatinib mesylate (Gleevec) specifically targets a limited set of protein tyrosine kinases - ABL, Arg (Abl-related gene), c-Kit, platelet-derived growth factor receptor (PDGF-R) - and their oncogenic forms, most notably BCR/ABL Imatinib is also a potent inhibitor of a receptor-type c-Kit tyrosine kinase. Therefore imatinib was examined for therapeutic efficacy against malignant gastro-intestinal stromal tumors (GIST) Recent articles have drawn attention to the development of new Ph-negative, cytogenetically unrelated clones after therapy of Ph-positive CML with imatinib. Trisomy 8 and monosomy 7 are the most frequent defects, but other aberrations have also been reported. Some of these cytogenetic abnormalities are associated with acute myeloid leukemia and MDS.

Chromosome Abnormalities in Chronic Myeloid Leukemia (CML) on Imatinib. GIST Patients on Imatinib

Are the Secondary Chromosome Abnormalities Seen in Chronic Myeloid Leukemia (CML) Cells Induced to Ph-Chromosome Negativity by Imatinib a Result of Chromosome Instability or a Side Effect of the Therapy - a Study in GIST (Gastrointestinal Stromal Cell Tumors) Patients Treated With Imatinib.

Princess Margaret Hospital, Canada

Mount Sinai Hospital, Canada

Novartis

University Health Network, Toronto

Dr. Jeff Lipton

Syndrome

Leukemia, Myeloid, Acute

Preleukemia

Myelodysplastic Syndromes

Anemia

Precancerous Conditions

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

AML With Myelodysplasia-related Features

Chromosome 5q Deletion

description of MDS pzatient cohort

Nathalie Douet-Guilbert, MD, PhD

Marie-Bérengère Troadec, PhD

Nathalie DOUET-GUILBERT

Nathalie Douet-Guilbert, MD,PhD

Myelodysplastic syndromes (MDS) are chronic myeloid hemopathies characterized by ineffective hematopoiesis (with peripheral cytopenias) and which contrast with a marrow of normal richness. MDS is considered one of the four most common blood diseases. The incidence is estimated at 4,059 cases / year in 2012 with an average age of 78 years in men and 81 years in women (INCA report, Cancers in France in 2015). The incidence increases with lengthening of the lifespan. The main risk of MDS is transformation to acute leukemia in 30 to 40% of cases. Treatment options depend on clinical, hematologic and chromosomal abnormalities. The prognosis is considered to be at low or high risk of developing acute leukemia. This distinction will therefore have an impact on the therapeutic solution (s). MDS exhibit clinical, morphological and genetic heterogeneity. It is therefore necessary to form subgroups of patients to better understand the physiopathogenesis of this pathology. The constitution of a biocollection will make it possible to search for clinical and biological prognostic markers in order to identify patients progressing to acute myeloid leukemia.

The objective of the biocollection is to respond to 3 scientific projects in MDS :

Project 1: splicing anomalies in MDS with SF3B1 mutations : About 95% of the coding genes in humans are subjected to alternative splicing, a complex, highly regulated mechanism that diversifies the proteome by defining multiple proteins from a single gene. Deregulation of splicing is observed in many cancers and hemopathies (review Yoshida et al., 2014), especially in myelodysplastic syndromes More than half of MDS patients present an acquired mutation in a gene involved in the splicing of pre -RNA messengers. The SF3B1 gene (splice factor 3B subunit 1), which encodes a protein involved in the recognition of 3 'splice sites is the most frequently mutated gene in SMDs, at a frequency of 20-28% MDS, and up to 85% of myelodysplastic syndromes with crowned sideroblasts (Yoshida et al., 2011, Papaemmanuil et al., 2011). The functional consequences of the splicing abnormalities thus generated on the pathophysiology of MDS are far from clear. The transcriptome analyzes (by RNA-seq) carried out recently in various acquired pathologies that the most frequent variants of the SF3B1 gene lead to the formation of aberrant transcripts by the use of a 3 ' cryptic splicing site. The investigators seek to study the functional implications of SF3B1 mutations found in MDS patients in particular on the formation of sideroblasts in the crown. The investigators want to identify, by RNAseq, the aberrant junctions specifically expressed in the cells of MDS patients with mutated SF3B1, and which would affect transcripts of genes involved in iron metabolism or its regulation. For this, the investigators will use the cells obtained from the marrow of SMD SF3B1WT patients versus SF3B1K700E and collected in the Chromosomal Genetics laboratory, site of the CRB of the CHRU of Brest. The investigators will then analyze the functional repercussions associated with the presence of these aberrant junctions on the cells in culture of these same patients (detection of certain proteins, enzymatic analyzes, etc.). The collection of biological and clinical data from these patients of interest is essential for the interpretation of the results. This project is part of a more global approach to the study of the various splicing anomalies in this pathology.

Project 2: splicing abnormalities in MDS with chromosomal abnormalities as 5q deletion : Chromosome 5 deletions are the most frequent structural abnormalities in MDS and constitute a good prognostic entity if isolated or associated with an anomaly and poor prognosis if associated with more than 3 chromosomal abnormalities. Two genes located on chromosomes 5 encode proteins of a complex involved in the splicing of pre-messenger RNAs: the RBM22 gene (RNA Binding Motif Protein 22) and the SLU7 gene (SLU7 Homolog Splicing Factor).

The investigators want to identify subgroups of patients with loss of these 2 genes or loss of RBM22 and conservation of SLU7. Does the loss of one or both genes play a role in the pathophysiogenesis of MDS with chromosome deletions and is it associated with worsening of the disease? Understanding these mechanisms could also have an impact on the therapeutic management of this pathology.

The study of these chromosomal abnormalities associated with splicing abnormalities in MDS for the chromosomal genetics laboratory both from a diagnostic and research perspective. Several works carried out have given rise to numerous scientific publications with an international reading committee for several years.

Project 3: Evolution of MDS in acute myeloid leukemia (AML) More than one third of patients with MDS progress to AML. The investigators want to focus on this group of patients and understand the clonal architecture of their malignant cells to detect new predictive markers of indolent or rapid disease progression.

Health services research and follow up DMS

Biocollection in MyeloDysplastic Syndrome (P-MDS)

Biocollection in Patients With Myelodysplastic Syndrome (P-MDS)

All collected data that underlie results in a publication

University Hospital, Brest

Immune System Diseases

Infections

Respiratory Tract (Lung and Bronchial) Diseases

Nervous System Diseases

Skin and Connective Tissue Diseases

Leukemia, Myelomonocytic, Juvenile

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Influenza, Human

Hematologic Neoplasms

Neoplasm, Residual

Neurofibromatoses

Neurofibromatosis 1

Neurofibroma

Monosomy

Lymphoma

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Nerve Sheath Neoplasms

Neoplasms, Nerve Tissue

Neoplastic Syndromes, Hereditary

Neurocutaneous Syndromes

Heredodegenerative Disorders, Nervous System

Neurodegenerative Diseases

Peripheral Nervous System Diseases

Neuromuscular Diseases

Neoplastic Processes

Myelodysplastic-Myeloproliferative Diseases

Aneuploidy

Chronic Myelomonocytic Leukemia

Juvenile Myelomonocytic Leukemia

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Neurofibromatosis

Neurofibromatosis Type 1

Lymphosarcoma

Myelodysplastic/myeloproliferative Disease

Antirheumatic Agents

Anticonvulsants

Nootropic Agents

Fludarabine

Fludarabine phosphate

Rituximab

Melphalan

Levetiracetam

Busulfan

Antineoplastic Agents, Immunological

Immunologic Factors

Immunosuppressive Agents

Antineoplastic Agents, Alkylating

Alkylating Agents

Patients will be treated on the most medically appropriate regimen with a preference for Flu/TBI Arm followed by an infusion at Day 0 of Alpha/Beta T Cell-Depleted Hematopoietic Stem Cells.

Flu/Bu/Mel will the preference for patients with JMML or infants with leukemia.

Fludarabine 25mg/m2 IV on days -8 to -6 or days -4 to -2. 40mg/m2 IV on days -5 to -2.

Busulfan 82.1 mg\*hr/L IV on days -5 to -2 or days -8 to -5

200 mg/m2 intravenous given once on day-1

As seizures have occurred following high dose busulfan, all patients will be treated with Keppra beginning day -6 and continuing until day -1 per institutional guidelines.

Margaret MacMillan

This is a phase II, open-label, prospective study of T cell receptor alpha/beta depletion (α/β TCD) peripheral blood stem cell (PBSC) transplantation for children and adults with hematological malignancies

MT2021-08T Cell Receptor Alpha/Beta Depletion PBSC Transplantation for Heme Malignancies

Phase II, Open-Label, Prospective Study of T Cell Receptor Alpha/Beta Depletion (A/B TCD) Peripheral Blood Stem Cell (PBSC) Transplantation for Children and Adults With Hematological Malignancies

For the purposes of data and safety monitoring, this study is classified as high risk (investigator initiated under an IND). Therefore the following requirements will be fulfilled:

* The Masonic Cancer Center Data and Safety Monitoring Council (DSMC) will review the study's progress at least quarterly.
* The PI will comply with at least twice yearly monitoring of the project by the Masonic Cancer Center monitoring services.
* The PI will oversee the submission of all reportable adverse events per the definition of reportable in Section 11.5 to the Masonic Cancer Center's SAE Coordinator, the University of Minnesota IRB, and the FDA.

Monitor median rate of engraftment by 42 days.

Determine the rate of graft failure by day 100 (defined as lack of achievement of an ANC \>=500/mL with associated pancytopenia)

Determine the incidence of non-relapse mortality (NRM) at 100 days and 1 year

Number of participants experiencing progression free survival at one year follow up

Masonic Cancer Center, University of Minnesota

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Chromosome Abnormalities in Chronic Myeloid Leukemia (CML) on Imatinib. GIST Patients on Imatinib	NCT00461929	Chronic Myeloid... Gastrointestina... Chromosome Abno...	bone marrow asp...	18 Years -	University Health Network, Toronto
Chromosome Abnormalities in Chronic Myeloid Leukemia (CML) on Imatinib. GIST Patients on Imatinib	NCT00461929	Chronic Myeloid... Gastrointestina... Chromosome Abno...	bone marrow asp...	18 Years -	University Health Network, Toronto
Biocollection in MyeloDysplastic Syndrome (P-MDS)	NCT04869683	Myelodysplastic... Myelodysplastic... Myelodysplastic... Myelodysplastic... Acute Myeloid L... Chromosome Abno...	description of ...	18 Years -	University Hospital, Brest
Chromosome Abnormalities in Chronic Myeloid Leukemia (CML) on Imatinib. GIST Patients on Imatinib	NCT00461929	Chronic Myeloid... Gastrointestina... Chromosome Abno...	bone marrow asp...	18 Years -	University Health Network, Toronto
MT2021-08T Cell Receptor Alpha/Beta Depletion PBSC Transplantation for Heme Malignancies	NCT05735717	Hematologic Mal... Acute Leukemia Remission Acute Myeloid L... Acute Lymphobla... AML TP53 Intrachromosoma... Cytogenetic Abn... CNS Leukemia Minimal Residua... Myelodysplasia Juvenile Myelom... Somatic Mutatio... PTPN11 Gene Mut... N-RAS Gene Ampl... Neurofibromatos... NF1 Mutation CBL Gene Mutati... Monosomy 7 Chromosome Abno... Fetal Hemoglobi...	Fludarabine Busulfan Melphalan Rituximab Levetiracetam	- 60 Years	Masonic Cancer Center, University of Minnesota

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