Hematological Malignancies Clinical Trial
Official title:
Molecular Disease Profile of Haematological Malignancies. A Prospective Registry Study by the Rete Ematologica Lombarda (REL) Clinical Network
In this prospective multicentric study, the University of Pavia together with the Fondazione IRCCS Policlinico San Matteo, Pavia and the IRCCS Fondazione Maugeri, Pavia, Italy will provide a systematic analysis of gene mutations in hematological malignancies by using NGS techniques. Patients with a conclusive diagnosis of haematological malignancies according to WHO criteria referred to the Rete Ematologica Lombarda clinical network (REL, www.rel-lombardia.net) will be enrolled. The investigators will analyse genomic DNA extracted from hematopoietic cells at different time points of patient disease. The study contemplates the use of molecular platforms (Next Generation Sequencing, NGS) aimed at the identification of recurrent mutations in myeloid and lymphoid neoplasms, respectively. Screening of gene mutations by NGS will be prospectively implemented in the context of REL clinical network. Patient samples will be analyzed at diagnosis and sequentially during the course of the disease at specific timepoints. The researchers will analyze the correlations between somatic mutations, specific clinical phenotypes (according to the WHO classification) and disease evolution. This will allow to: 1) identify new recurrent genetic mutations involved in the molecular pathogenesis of hematological malignancies; 2) define the role of mutated genes, distinguishing between genes which induce a clonal proliferation of hematopoietic stem cells, and genes which determine the clinical phenotype of the disease; 3) identify mutations which are responsible for disease evolution; 4) define the diagnostic/prognostic role of the identified mutations, and update the current disease classifications and prognostic scores by including molecular parameters. A systematic biobanking of biological material will be provided.
1. BACKGROUND
Molecular medicine is the branch of knowledge whose purpose is to elucidate the genetic
basis of the diseases, to improve the diagnostic definition and prognostic assessment
of patients and to contribute to the development of innovative treatments. Genomic
information is increasingly being used in the treatment decision making process for
individual patients. The clinical implementation of molecular medicine requires
systematic approaches based on the integration of scientific, medical and technological
expertises.
Hematological malignancies include leukemia, lymphoma, and multiple myeloma. The
molecular basis of many hematological neoplasms are still unknown. At the present of
researchers' knowledge, scientists know that hematological malignancies are mostly
dynamic diseases that arise from a large series of primary and secondary biological and
genetic events (i.e. driver and passenger mutations). The Identification of key
molecular changes that drive tumour development and progression is essential for the
development of new targeted and personalized therapies.
Hematological malignancies typically occur in elderly people and, as a result of
population aging, represent a growing critical issue for health policies. Hematological
malignancies are an ideal context for the implementation of molecular medicine. The
paradigmatic example of this is chronic myeloid leukemia, in which the discovery of the
molecular basis (the fusion gene BCR/ABL1) has been translated into major clinical
advances in diagnosis, treatment and disease monitoring.
The World Health Organization (WHO) classification of myeloid and lymphoid neoplasm
published in 2008 introduced many genetic changes in the diagnostic definition of blood
cancers. Since 2008 plenty of genetic lesions have been identified in many
hematological malignancies and the next WHO classification will include many of them.
Next generation sequencing (NGS) techniques gave the best contribute to these findings.
NGS use high-technology tools that can sequence, in a short time and with relatively
low costs, the whole genome or a specific part of it (e.g. exome or targeted genes).
The advantage of NGS compared to standard sequencing consists in higher efficiency (a
large amount of genes rapidly analysed in a large amount of samples) and higher
sensitivity (capacity of detecting mutations in very small clones of neoplastic cells).
In last years the availability of new technologies for genomic has enabled the
high-throughput screening of somatic mutations in hematological malignancies. It is
expected that the results of these studies will significantly improve the management of
individual patients through the implementation of innovative diagnostic/prognostic
systems and the development of therapeutic strategies based on individual genomic
profile.
The Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo and
University of Pavia has significantly contributed to the definition of molecular basis
of hematological malignancies. In 2005 the University of Pavia described the diagnostic
and prognostic significance of the JAK2 V617F mutation in myeloproliferative neoplasms
(MPN): this mutation was included into the WHO classification of MPN and innovative
anti-JAK2 drugs were developed. In 2010, the University of Pavia joined the Cancer
Genome Project, a consortium of international research Centers coordinated by the
Wellcome Trust Sanger Institute of Cambridge with the aim to elucidate the molecular
basis of cancer. In this context, by using massive genome sequencing, recurrent
mutations in SF3B1 gene - that encode for a core component of RNA splicing machinery -
were described in myelodysplastic syndromes.
Moreover in last years, researchers from the University of Pavia gave a significant
contribution in the definition of the molecular basis of lymphoid neoplasms (i.e., BRAF
V600E mutation in Hairy cell Leukemia, MYD88 L265P mutation in Waldenstrom disease, and
SF3B1 mutations in Chronic Lymphocytic Leukemia). Finally, in the very last months the
Universisty of Pavia had a key role in the identification of CALR mutations in
JAK2-negative MPN. This is again an important finding in the comprehension of the
genetic basis of this groups of diseases.
In addition to the implementation of next-generation techniques (NGS) for genomic
analysis, there is clearly a need to develop effective solutions to analyze and
integrate molecular and clinical data of large patient populations, in order to fully
understand the relationship between genotype and the clinical expression of a disease.
The implementation of molecular medicine requires systematic approaches based on the
integration of scientific, clinical and technological expertise. In Italy, the ideal
context for the development of molecular medicine programs is represented by
hematological regional networks. They represent an innovative model of organization and
collaboration, based on the networking of health care facilities. The Rete Ematologica
Lombarda (REL, www.rel-lombardia.net) brings together 11 hematological referral centres
and has recently provided the basis for a systematic study of these diseases. The
strategic objective of REL clinical network is to ensure the better access to the
health care facilities, the high quality of services and the continuity of care for all
the hematological patients.
REL clinical network can give a crucial contribute on the translational research on
hematological malignancies and recently, with this purpose, the Regione Lombardia in
January 2014 financed a biotechnology cluster for the implementation of genomic
analysis and the development of new treatments for hematological diseases. The REL
biotechnology cluster (www.relab-lombardia.net) involves the Department of Hematology
Oncology, Fondazione IRCCS Policlinico S. Matteo, the University of Pavia, the biotech
company Clonit (www.clonit.it) and the pharmaceutical company Novartis. This cluster
aims to investigate the molecular basis of hematological malignancies and to develop
personalized treatments.
2. GENERAL POURPOSE of the STUDY
In this study, the Department of Hematology Oncology, Fondazione IRCCS Policlinico San
Matteo, Pavia in collaboration with the University of Pavia and the IRCCS Fondazione
Maugeri, Pavia will provide a systematic analysis of gene mutations in hematological
malignancies by using NGS techniques.
Patients with a conclusive diagnosis of haematological malignancies according to WHO
criteria referred to the REL clinical network will be enrolled. The researchers will
analyse genomic DNA and RNA extracted from hematopoietic cells at different time points
of patient disease. The study contemplates the use of two optimized molecular platforms
aimed at the identification of recurrent mutations in myeloid and lymphoid neoplasms,
respectively.
Screening of gene mutations by NGS will be prospectively implemented in the context of
REL clinical network. Patient samples will be analyzed at diagnosis and sequentially
during the course of the disease at specific timepoints.
The investigators will analyze the correlations between somatic mutations, specific
clinical phenotypes (according to the WHO classification) and disease evolution. This
will allow to: 1) identify new recurrent genetic mutations involved in the molecular
pathogenesis of hematological malignancies; 2) define the role of mutated genes,
distinguishing between genes which induce a clonal proliferation of hematopoietic stem
cells, and genes which determine the clinical phenotype of the disease; 3) identify
mutations which are responsible for disease evolution; 4) define the
diagnostic/prognostic role of the identified mutations, and update the current disease
classifications and prognostic scores by including molecular parameters.
A systematic biobanking of biological material will be provided.
3. OBJECTIVES
The general objective of the study is to perform a systematic analysis of gene
mutations associated to hematological malignancies by using a NGS targeted sequencing
approach.
4. ENDPOINTS:
- Cumulative incidence (%) of gene mutations in principal clone and subclones in
each hematological malignancy
- Genotype - phenotype correlations between clinical characteristics and mutational
status, evaluated by the Fisher's exact test (for categorical variables) or by the
Mann-Whitney or the Kruskall-Wallis tests (for quantitative variables compared in
two or more groups of patients, respectively) with p-value
- Overall survival and disease free survival according to clinical and biological
risk factors at diagnosis and during disease evolution, evaluated by the
Kaplan-Meier product limit method and the Cox proportional hazard model both for
time-dependent and not time-dependent covariates
5. PATIENTS SELECTION:
Inclusion criteria:
- Conclusive diagnosis of myeloid or lymphoid neoplasm according to 2008 WHO criteria
- age ≥ 18 years. There is no upper age limit
- signed written informed consent
Exclusion criteria:
- severe neurological or psychiatric disorder interfering with ability to give an
informed consent
- no written informed consent
- no consent for biobanking
7. STUDY DESIGN :
This is a multicentric, prospective, observational study. All patients with a diagnosis of
hematological malignancy according to WHO classification performed within REL clinical
network are intended to be enrolled.
8. ASPECTS OF GOOD CLINICAL PRACTICE, DATA PRIVACY
Biobanking is governed under the general regulatory framework for biomedical research. This
is a mosaic of formal legal instruments and regulatory bodies put in place at national and
European levels, as well as more informal types of governance tools and instruments such as
professional guidelines and best practice. Regulation of biomedical research consists of
binding and non-binding legal instruments at both national and European levels. This is in
the form of specific law for medical research - for example the Council of Europe Oviedo
Convention 1997 - and more general legal instruments - such as human rights and data
protection law - some of which have relevance for biobanking. Responsibility for the
oversight of research and ensuring compliance with the legal requirements has largely been
delegated to national bodies, such as research ethics committees.
8.1 DATA COLLECTION
The study contemplate the collection of clinical and biological indispensable data for a
precise diagnostic and prognostic standard definition in a ad-hoc electronic CRF and the
analysis of specific genes that can be involved in the molecular basis of the diseases
through a NGS techniques.
8.2 CLINICAL DATA WAREHOUSE (Informatics for Integrating Biology and the Bedside, I2B2)
Informatics for Integrating Biology and the Bedside (i2b2, www.i2b2.org) is an open source
clinical data warehouse, which is efficiently interrogated to find sets of interesting
patients preserving their privacy through a query tool interface. Within this architecture,
interoperable server-side software objects, called "cells", are able to exchange information
with each other, relying on web services technology.
In order to support and improve the efficiency of clinical research in oncology, the
University of Pavia and the IRCCS Fondazione Salvatore Maugeri of Pavia developed and
implemented a novel ICT platform, called Onco-i2b2, grounded on the i2b2 software and
installed in the IRCCS Fondazione S. Maugeri, Pavia. Onco-i2b2 is able to integrate data
from different sources inside the i2b2 data warehouse through the implementation of a
complex IT architecture, which includes development of new i2b2-cells for data analysis.
As result of this project, hospital researchers have been enabled to obtain information from
the pathology database, from a biobank management system and to merge them with the clinical
information present in the hospital information system, in order to select interesting
patients with a specific phenotype of interest.
8.3 TECHNICAL DESCRIPTION OF PSEUDONYMIZATION PROCESS AND USED TOOLS
Actually a specific regulation at national level for technical aspects relate to biobank
does not exist, but some workgroups of experts (e.g. AIOM e SIAPEC-IAP) have raised up
initiatives for defining and harmonizing the existing national general procedures. A brief
list of structural and technological requirements can be identified in:
1. Definition of a programmatic documentation with objective of the biobank, a functional
specifications to be performed, the type of the preserved material, number of expected
specimens, methods of drawdown, processing and conservation, management of information,
specimens transport and reception from the receiving unit, management of the possible
biological risk and an economic plan for medium-large period
2. Logical definition of the dedicated locals, conditioning systems and access control. In
addiction temperature of the cryo-containers have to be monitored continuously.
3. Disaster recovery plan for equipment and cryo containers has to be defined (e.g. use of
systems for electrical continuity or list of competent staff that should intervene when
special events occur)
4. Use of a certified quality system for each step of the different procedures is
recommended, keeping track of data quality from the acquisition of the informed consent
to the storage of the specimen
5. Definition of a dedicated information system for managing the biobank samples , related
to clinical information stored in the hospital information system, to track the
specimen movements and update the follow-up data deriving by the scientific research
performed.
6. Disaster recovery plan also for the IT architecture has to be implemented. It consists
in an incremental backup of all biobank data that allows the IT system managers to
restore all the information in any period of time In the "Bruno Boerci" oncologic
biobank each biological specimen is identified by a specific code, printed on the tube
using a data matrix barcode (a bi-dimensional bar code readable through the use of a
laser scanner), and stored in the biobank database and managed by the biobank
management software, that allows also to view its position inside the biobank cryo
container. Clinical data for each follow up are collected automatically retrieving data
from the hospital information system. Clinical data and biobank information are
constantly and continually inserted in clinical data warehouse by an automatic update
procedure. Clinical and pathological data are codified using SNOMED, TNM and ICD9-CM
standards. The use of the BRISQ system for data standardization (Biospecimen Reporting
for Improved Study Quality, Biopreservation and Biobanking, 2011) is recommended, but
not implemented yet.
8.4 TRANSFER OF PATIENTS SAMPLES AND BIOBANK SAMPLES ENTRANCE
Bio specimens anonymisation (or better, de-identification) has to be performed in to assure
high levels of data privacy. The terminology used in the European documents identifies the
term 'anonymized' when biological material is stored alongside associated information, such
as the type of tumour, medical treatment, donor's age and so forth, but all information that
would allow identification of the research participant or patient is stripped, either
irreversibly (unlinked anonymized) or reversibly (linked anonymized). In the case of linked
anonymized samples, identification is possible by a code, to which researchers or other
users of the material—as part of the definition of the term 'reversibly/linked
anonymized'—do not have access. Coded samples have the same characteristics as linked
(reversibly) anonymized samples, the only difference being that researchers and users have
access to the code.
In this project the use of coded-anonymisation is preferred in order to have an adequate
level of privacy security and feasibility of research activities.
The proposed architecture that will implement this type of de -identification requires the
definition of a code that identifies the bio specimen from the beginning and a second code
that will be generated before the specimen will be stored in the biobank. A third code will
automatically generated during the acceptance phase of the specimen and will be stored in a
separate location. In this way the information related to the first code and those related
to the final one are totally decoupled, unless the third code is known: this happens only
when researchers need to access to both data concurrently.
9 MOLECOLAR ANALYSIS
The molecular analysis is performed by using 2 different NGS platforms for the
target-resequencing. The platforms are outlined on the basis of the most recent literature
on the molecular biology of myeloid and lymphoid neoplasm. It is noteworthy that the efforts
of the scientific community in this area are huge, and this contributes to a continuous flow
of new information and discoveries, with the consequent possibility of modifying the
platforms.
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