DELIBERAZIONE N. 602/2015 ADOTTATA IN DATA 16/04/2015
OGGETTO: Autorizzazione allo svolgimento presso l’USC Ematologia del progetto di
ricerca “High Throughput Sequencing efficacy in clonality and MRD evaluation
in ALL patients lacking molecular probes by ASOQPCR” approvato e
finanziato dall’Associazione italiana per la ricerca sul cancro (AIRC).
IL DIRETTORE GENERALE
Assistito dal Direttore sanitario e dal Direttore amministrativo, che svolge le funzioni di
verbalizzante;
Premesso che:
 in data 18 marzo 2014 è stata inoltrata all’Associazione italiana per la ricerca sul cancro
(AIRC), nell’ambito della Call for Proposal 2014, la richiesta di finanziamento del progetto
“High Throughput Sequencing efficacy in clonality and MRD evaluation in ALL patients
lacking molecular probes by ASOQPCR” proposto dall’USC Ematologia - Laboratorio di
diagnostica ematologica “Paolo Belli”;
 con nota del 18 novembre 2014, AIRC ha reso noto che il Consiglio direttivo, avendo
valutato positivamente il progetto, lo ha approvato chiedendo nel contempo la
rimodulazione delle voci di budget, atteso che a fronte di una spesa prevista di € 245.718,00
è stata messa a disposizione dell’azienda la somma complessiva vincolata di € 240.000,00
per il triennio 2015 - 2017;
 in data 12 gennaio 2015 è stato quindi dato riscontro alla richiesta di AIRC, trasmettendo la
scheda di rimodulazione del budget triennale;
Premesso, altresì, che con scritto in data 10 marzo 2015, prot. n. 9973, il direttore
dell’USC Ematologia ha chiesto l’autorizzazione a condurre presso il Laboratorio di
diagnostica ematologica “Paolo Belli” il citato progetto di ricerca e ha trasmesso,
contestualmente, la relativa documentazione, dalla quale si rilevano le caratteristiche del
progetto di ricerca, documentazione alla quale si rinvia per gli eventuali approfondimenti;
Sottolineato l’interesse di questa azienda alla conduzione del citato progetto, atteso che
rientra tra le proprie finalità lo svolgimento di attività di ricerca;
Accertato che il progetto rientra tra le collaborazioni scientifiche che prevedono lo
svolgimento di attività di studio in ambito laboratoristico, con l’utilizzo di campioni
provenienti da pazienti che già hanno fornito il consenso alla raccolta, stoccaggio e impiego di
campioni biologici per finalità di ricerca, nel rispetto delle prescrizioni del Comitato di
bioetica;
Responsabile del procedimento dr.ssa Mariagiulia Vitalini
FIRMATA DIGITALMENTE dal Direttore generale / Direttore sanitario / Direttore amministrativo
U.S.C. Affari Generali MGV
Accertato, altresì, che la tipologia della collaborazione non richiede l’acquisizione di una
preventiva autorizzazione da parte del Comitato di bioetica ma la sola notifica allo stesso
Comitato ai fini della presa d’atto del progetto di ricerca;
Ritenuto, pertanto, di poter accogliere la richiesta del direttore dell’USC Ematologia;
Ritenuto, altresì, al fine di semplificare le fasi di riscossione e di utilizzo del
finanziamento AIRC vincolato alla realizzazione del progetto di ricerca “High Throughput
Sequencing efficacy in clonality and MRD evaluation in ALL patients lacking molecular
probes by ASOQPCR”, di autorizzare i competenti uffici a introitare le somme che AIRC
assegnerà annualmente al progetto di ricerca, destinandole al fondo di struttura dell’USC
Ematologia al netto della quota destinata alla copertura dei costi indiretti e dei costi generali,
nella misura prevista dalla scheda di “Rimodulazione budget”;
Ritenuto, inoltre, per le medesime finalità, di porre in capo al direttore dell’USC
Ematologia la responsabilità di utilizzare la quota di finanziamento che alimenterà il fondo di
struttura nel rispetto del budget rimodulato di progetto e delle eventuali istruzioni di AIRC per
la gestione amministrativa del grant assegnato nonché del regolamento per la gestione dei fondi
di struttura, approvato con deliberazione n. 453 del 13 aprile 2010;
DELIBERA
1. di autorizzare l’USC Ematologia a condurre il progetto di ricerca “High Throughput
Sequencing efficacy in clonality and MRD evaluation in ALL patients lacking molecular
probes by ASOQPCR” approvato e finanziato dall’Associazione Italiana per la Ricerca sul
Cancro (AIRC) (allegato A);
2. di prendere atto della scheda “Rimodulazione budget”, dalla quale si rileva che all’azienda
è destinato un finanziamento complessivo triennale di € 240.000,00, suddiviso in annualità
di ammontare pari a € 80.000,00 (allegato B);
3. di autorizzare i competenti uffici ad introitare annualmente il finanziamento AIRC
destinandolo al fondo di struttura dell’USC Ematologia, al netto della quota relativa alla
copertura dei costi indiretti e dei costi generali, nella misura indicata dalla scheda di
“Rimodulazione budget”;
4. di porre in capo al direttore dell’USC Ematologia la responsabilità di utilizzare tale somma
nel pieno rispetto del budget rimodulato di progetto e delle eventuali istruzioni di AIRC per
la gestione amministrativa del grant assegnato nonché del regolamento sulla gestione dei
fondi di struttura, approvato con deliberazione n. 453 del 13 aprile 2010.
IL DIRETTORE GENERALE
dott. Carlo Nicora
IL DIRETTORE SANITARIO
dott.ssa Laura Chiappa
Responsabile del procedimento dr.ssa Mariagiulia Vitalini
FIRMATA DIGITALMENTE dal Direttore generale / Direttore sanitario / Direttore amministrativo
IL DIRETTORE AMMINISTRATIVO
dott. Peter Assembergs
U.S.C. Affari Generali MGV
AIRC
Associazione Italiana per la Ricerca sul Cancro
Investigator Grant - IG 2014
YEAR 2014
Current address: Via San Vito, 7 - 20123 Milan, Italy
Legal address: Via Corridoni, 7 - 20122 Milan, Italy
Tel: +39-02-7797-374/350/222
Fax: +39-02-7797259
E-mail: [email protected]
Table of Contents
TITLE PAGE
3
ABSTRACT
4
PROPOSAL MAIN BODY
5
PERSONNEL INVOLVED IN THE RESEARCH
14
DESCRIPTION OF THE WORK FOR EVERY UNIT OF PERSONNEL
15
BUDGET FORM AND JUSTIFICATIONS
16
BIOGRAPHICAL SKETCH
18
NARRATIVE BIOSKETCH
19
PI TRACK RECORD SUMMARY
20
PUBLICATIONS OF THE PI
21
BIO-ETHICAL REQUIREMENTS
28
Addendum A - PERSONNEL INVOLVED IN THE RESEARCH - CURRICULUM VITAE
29
Addendum B - BUDGET FORM AND JUSTIFICATIONS
31
Addendum C - PUBLICATIONS OF THE PI
32
Addendum D - BIO-ETHICAL REQUIREMENTS
33
TITLE PAGE
Rambaldi Alessandro [PI]
TITLE PAGE
Principal Investigator
Surname
Rambaldi
Name
Alessandro
Position
Head
Proposal Title
High Throughput Sequencing efficacy in clonality and MRD evaluation in ALL patients lacking molecular probes by ASOQPCR
Type of grant
IG 2014
Area
Cancer Genetics
Keywords
ALL; Minimal Residual Disease (MRD); Next generation sequencing
Budget 2014 (euro): € 81.906,00
Estimated budget 2014 - 2016 (euro): € 245.718,00
Hosting Institution
Department/Laboratory
Azienda Ospedaliera Papa Giovanni XXIII
- "Paolo Belli" Laboratory
Address
Piazza OMS - Organizzazione Mondiale della Sanità, 1
Phone
Fax
0352674649
Zipcode and City
24127 Bergamo (Bergamo)
E-mail
[email protected]
Legal Representative
Nicora Carlo
Address
Piazza OMS - Organizzazione Mondiale della Sanità, 1
Phone
Fax
Proponent's signature
_____________________
Rambaldi Alessandro
Codice Riferimento: 16105
Zipcode and City
24127 Bergamo (BG)
E-mail
[email protected]
Legal Representative's signature
_____________________
Nicora Carlo
Date
18 mar 2014
ABSTRACT
Rambaldi Alessandro [PI]
ABSTRACT
Background
Residual leukemia levels (Minimal Residual Disease, MRD) has been demonstrated as the most important predictor of outcome
of Acute Lymphoblastic Leukemia (ALL) patients (1, 2). From year 2000 two multicenter clinical trials (NILG-09/00,
ClinicalTrials.gov Id: NCT00358072 and NILG-10/07 ClinicalTrials.gov Id: NCT00795756) have been conducted to test
prospectively the predictive value of MRD in adult ALL patients (3). Patients with undetectable MRD (MRDneg) at the end of
induction/consolidation received maintenance chemotherapy while patients with persistence of disease (MRDpos) received
allogeneic transplantation or high-dose chemotherapy supported by autologous transplant. The MRDneg cohort had a DFS of
72% while MRDpos cohort had a DFS of 14% at 5 years (3). A proportion of patients (MRDunk) could not benefit of MRD
based treatment allocation due to the lack of a molecular probe with a suitable sensitivity, as reported for adult (4) and pediatric
(5) ALL patients. In our studies MRD evaluation was performed with allele-specific oligonucleotide quantitative PCR (ASOQPCR) which is considered the gold standard method (6). This approach requires the development of reagents and assay
conditions for each patient and is laborious and time consuming. Recently, it has been described a new approach based on High
Throughput Sequencing (HTS) to identify clonal rearrangements and to monitor MRD in ALL and lymphoid malignancies (7,
8). This approach does not need the development of patient specific reagents, applies the same strategy at diagnosis and
monitoring and can release molecular information suitable for clinical decision in as few as 7 days.
Hypothesis
The new HTS based method could be useful to identify clonality and to monitor MRD in patients in which gold standard ASOPCR failed.
Aims
Aim of this study is to apply the HTS technology to patients enrolled into our clinical trials that could not benefit of MRD
categorization due to the lack of a molecular marker suitable for MRD evaluation. The new categorization as MRDpos or
MRDneg derived from this study will be correlated to patients’ outcome.
Experimental Design
HTS technology validation will be performed on ten diagnostic and ten post induction/consolidation samples completely and
successfully characterized for clonality and MRD evaluation with conventional ASO-QPCR. Subsequently, HTS technology
will be applied to samples of patients who failed MRD characterization (MRDunk) with conventional method. MRD recategorization in MRDpos or MRDneg will then be correlated to patients’ outcome. Finally the HTS technology will be
prospectively applied to the MRDunk cohort of patients identified in the new, national treatment protocol (ClinicalTrials.gov Id:
NCT02067143).
Expected Results
We expect that HTS technique applied to the validation set will obtain results substantially concordant with those previously
obtained with a possible increase in identified clonal marker at diagnosis. MRD evaluation should also be concordant with some
exceptions: low positive reclassified as background and negative reclassifies as low positive due to the HTS higher specificity
and sensitivity. We also expect to be able to find clonal rearrangements and to monitor MRD in the MRDunk cohort of patients
of the previous as well as new prospective clinical trials.
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PROPOSAL MAIN BODY
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Background
Acute Lymphoblastic Leukemia (ALL) is a rare lymphoid malignancy characterized by an
aggressive clinical course in adults patients. Treatment of ALL consists of remission induction,
consolidation and maintenance chemotherapy with or without allogeneic stem cell transplantation.
Complete remission (CR) can now be achieved in the majority of adults with ALL but only 40-50%
is cured, the proportion varying according to well-described clinical and biological risk factors. The
main adverse risk factors are: older age (>35-55 years), hyper leukocytosis (>25-100x109/L), time
to complete remission (> 4 weeks), and adverse cytogenetic abnormalities such as t(9;22) and
t(4;11). It has been demonstrated that the measurement of residual leukemia levels (Minimal
residual disease, MRD) represent the most important predictor of outcome as the persistence of
MRD is the strongest adverse prognostic factor in this disease (1, 2).
Current methodologies for MRD monitoring include flow cytometry detection of aberrant
immunophenotype
and
allele-specific
oligonucleotides
quantitative
PCR
(ASO-QPCR)
amplification of immunoglobulin (Ig) and T-cell Receptor (TCR) genes. Flow cytometry can detect
1 leukemic cell among 10.000 normal cells (i.e. 1x10-4 detection limit) and requires a high level of
operator expertise to interpret results. ASO-QPCR approach is usually more sensitive and can reach
reproducible detection limit of up to 1x10-5 (i.e. 1 leukemic cell among 10.000 normal cells) (9).
This technique is based on the amplification of the most commonly used TCR and Ig
rearrangements followed by Sanger sequencing. The obtained sequences are used to design allele
specific oligonucleotides (ASO) on junctional regions that are unique for each lymphocyte
rearrangement. These oligonucleotides are then used for MRD evaluation by quantitative PCR in
combination with primers and probes recognizing constant regions of the identified rearrangement.
ASO-QPCR conditions have to be optimized for each found rearrangement in each patient to find at
least two molecular markers with sufficient (10-4) sensitivity. This procedure requires time, efforts
and specialized personnel and its applicability is restricted to patients with Ig/TCR gene
rearrangements with junctional regions suited to reach sufficient sensitivity. Another important
limitation of the above mentioned techniques is the limited or absent capability to identify the
presence of oligoclonality at diagnosis or to monitor the clonal evolution of the leukemic clone that
can generate potential false negative MRD evaluation during the follow-up of the patients (10).
Recently, it has been described a new approach to identify clonal rearrangements and to monitor
minimal residual disease in Acute lymphoblastic leukemia and lymphoid malignancies (7, 8). This
method is based on the amplification of all the known genes of Ig and TCR loci and the sequencing
of the amplification products on a High Throughput Sequencing (HTS) platform. With this
technique it was possible to identify 1-6 clonal markers per patient and monitor the MRD with a
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PROPOSAL MAIN BODY
Rambaldi Alessandro [PI]
sensitivity of 1x10-6. Furthermore, a good correlation was seen between the standard clonal
rearrangement identification (6) and the new technique. The same correlation was seen between the
MRD results obtained with the patient specific approach (6) and the new method; discrepancies was
mostly due to the higher sensitivity of the HTS based technique and on its capacity to identify
clonal evolution of leukemic cell (8). The advantage of this approach is that it does not need the
development of patient specific reagent but it applies the same strategy to all patients in all the
disease phases, i.e. diagnosis and monitoring and can release molecular information suitable for
clinical decision in as few as 7 days. Furthermore, due to the possibility to obtain many individual
sequences even in follow-up samples, this methodology can well discriminate between leukemia
rearrangements and similar normal rearrangements which can generate background amplification in
ASO-QPCR and cause difficult results interpretation.
However this promising technology has been applied to selected cases of B precursor ALL and B
lymphoid malignancies and the authors suggest the usefulness to apply this method in prospective
studies to evaluate predictive value of HTS in MRD detection (8). Furthermore, other similar HTS
based
approaches
are
under
development
within
international
cooperative
groups
(EuroClonality/EuroMRD). This new technology, upon validation by scientific community, could
easily represent the future for minimal residual disease detection for patients affected by acute
lymphoblastic leukemia. In addition, it could represent a valid alternative from now for patients in
which no appropriate probe can be generated with standard procedure (6).
In our hospital starting from 2000 year a multicenter treatment study for ALL (NILG trial 09/00,
ClinicalTrials.gov Id: NCT00358072) was initiated to test prospectively the predictive value of
minimal residual disease (MRD) in adult ALL patients (n=280) (3). Our laboratory centralized
samples for all the participating institutions and developed a molecular probe based on clonespecific T cell Receptor (TCR) or Immunoglobulin (Ig) rearrangements. With this approach we
were able to categorize patients in two distinct groups after the consolidation therapy: one in which
the minimal residual disease was undetectable (MRDneg) and one with detectable residual disease
(MRDpos); the first group of patient received only chemotherapy whether the second group was
switched to an allogeneic stem cell transplantation, when possible or an high dose chemotherapy
course supported by an autologous stem cell transplantation. The MRDneg group had a DFS of
72% weather the MRDpos had a DFS of 14% at 5 years (3). A proportion of patients (30 out of 142
patients concluding the consolidation phase in our cohort) could not benefit of MRD categorization
for subsequent treatment allocation. This was mainly due to the lack of a molecular probe with a
suitable sensitivity. This condition is common to adult ALL patients (3) (4) as well as pediatric
ALL patients (5). Due to the 09/2000 as well as the 10/07 (ClinicalTrials.gov Id: NCT00795756)
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PROPOSAL MAIN BODY
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clinical trial a high number of well characterized samples are present in our Institution suitable for
the verification of the performance of the HTS based technologies in identifying clonal
rearrangements and monitor MRD especially in patients with no molecular probes identified by
conventional approach (6). All the patients signed an informed consent for samples collection,
clonal rearrangements identification and for the MRD evaluation. Clinical and biological features
are also registered into databases.
Furthermore a new, national MRD based study (ClinicalTrials.gov Id: NCT02067143) will be
started at our institution in which our laboratory will be one of the three reference laboratory for
rearrangement probe identification and MRD evaluation. In this context it will be possible to apply
prospectively the HTS technology patients in which conventional methodology failed to identify
molecular probes suitable for MRD evaluation.
Experimental Design
Since year 2000 all the patients affected by acute leukemia and suitable for enrolment into a clinical
trial were included and treated accordingly. In 09/2000 clinical trial (ClinicalTrials.gov Id:
NCT00358072) treatment options for ALL were decided based on MRD analysis performed on
bone marrow samples collected during the induction and consolidation phase. Patients with
persistence of MRD (MRDpos) underwent allogeneic transplantation, when possible, or high dose
chemotherapy supported by autologous stem cells transplant. Patients with no detectable MRD
(MRDneg) were consolidated with two year chemotherapy (3). Two hundred and thirty six patients
out of 280 enrolled patients reached the hematological remission and 146 completed the induction
and consolidation therapy. For 112 of the latter group the MRD evaluation was possible with MRD
positivity found in 54 patients and MRD negativity in 58 patients who were treated accordingly.
Thirty patients had no suitable molecular probe (3).
To validate the HTS method 10 diagnostic samples will be used. These samples will be selected
between the MRDpos patients (n=5) and MRDneg patients (n=5) in which at least two sensitive
probes (10-4) were obtained. The number and the type of clonal TCR and Ig rearrangements
obtained by HTS will be compared to the rearrangements found with conventional techniques (6).
Subsequently, the MRD time points collected at the end of consolidation and used to categorize
these patients as MRDneg or MRDpos for treatment allocation will also be evaluated with HTS
techniques to measure residual disease and to compare qualitative (pos/neg) and quantitative (MRD
levels) results with those obtained with conventional ASO-QPCR. These follow-up samples will be
selected with different MRD levels (from neg to pos) including a case in which, after the MRDneg
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PROPOSAL MAIN BODY
Rambaldi Alessandro [PI]
classification, a relapse was registered due to a subsequent, documented clonal evolution. We
expect to substantially confirm results obtained with conventional technique with possibly an
increased number of molecular markers found. We also expect to confirm MRD positive results on
follow-up samples with some exceptions in low ASO-QPCR positivity where some of them could
be re-defined as background amplification from normal leucocytes. Conversely, MRD negative
sample re-evaluation could lead to much more different results. In fact the new HTS method,
claimed to be more sensitive (down to 1x10-6) than traditional (1x10-5), could identify patients with
persistence of residual disease that could give rise of some relapse occurred in the MRD negative
cohort.
Upon technology validation on well characterized samples, the cohort of MRD unknown
patients (n=30) will be subjected to HTS study. Diagnostic samples will be used to identify clonal
rearrangements and stored follow-up samples will be used for MRD evaluation. Additional samples
from MRDunk patients of the subsequent 10/07 trial could be used to enlarge the study cohort, if
needed. We expect to be able to identify one or more clonal rearrangements in these patients and to
re-classify patients as MRDpos or MRDneg; the outcome of these patients will be correlated to this
new classification. The percentage of success of the technique in MRDunk patients will also
contribute to clarify if the failure in identifying a suitable clonal rearrangement relies on the
limitations of the conventional method firstly applied (6) or if it identifies a group of genetically
immature ALL with low rearranged receptors. This latter hypothesis seems not to be supported by
immunophenotypic features of this cohort, but nevertheless it need to be formally demonstrated.
Finally, we will prospectively use this new HTS based technology on patients enrolled into the new,
national MRD based study (ClinicalTrials.gov Id: NCT02067143) for ALL treatment. In this
clinical trial all the patients will be studied with conventional techniques and only patients with no
identification of molecular probe suitable for MRD analysis will be analyzed with HTS based
technologies. Subsequently, one decisional time point follow-up sample per patient (end of
consolidation) will be studied with the new technique to categorize patients into the MRDneg or
MRDpos cohort and to be later correlated to clinical outcome. This latter point could demonstrate
the feasibility of such approach in a prospective way where rearrangement identification and MRD
results should be available as soon as possible to drive clinical decisions.
Tasks:
Task 1-Analysis with HTS technique of the residual diagnostic material of a small cohort of 10
patients enrolled into the ALL 09-2000 and categorized as MRDpos or MRDneg.
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1.1 Sequencing of the diagnostic material of 5 MRDpos and 5 MRDneg patients on the HTS
platform
1.2 Analysis of the output sequences to identify Ig/TCR gene rearrangements
1.3 Comparison between Ig/TCR gene rearrangements identified by the new HTS platform and by
the conventional EuroMRD approach.
1.4 HTS sequencing of the end of consolidation samples of the same10 patients and comparison of
MRD results with those obtained with conventional AOS-QPCR.
Task 2- HTS analysis of the available diagnostic material of the MRD unknown cohort of patients
enrolled into the ALL 09-2000 study and treated following the clinical risk score because of a lack
of a molecular marker.
2.1 Sequencing of the diagnostic material of MRDunk cohort of patients on the HTS platform
2.2 Analysis of the output sequences to identify Ig/TCR gene rearrangements
2.3 Outcome analysis of MRDunk cohort newly re-classified as MRDpos or MRDneg.
Task 3- Prospective application of the HTS technique in parallel with conventional method on
newly diagnosed ALL patients which failed clonal rearrangement identification with conventional
approach.
3.1 Prospective Ig/TCR gene rearrangements identification with new HTS technique.
3.3 Analysis of MRD on samples collected at the end of consolidation therapy with the new HTS
method.
3.4 Evaluation of feasibility and applicability of this analysis in a prospective clinical trial in which
treatment are decided based on MRD results.
Feasibility
Material availability
During the 09-2000 and 10/07 clinical studies diagnostic and follow-up samples were collected,
studied and cryopreserved upon informed consent sign. This material is available for the proposed
study. All the biological features and significant clinical information were also collected into a data
file, which is accessible for the study. All newly ALL diagnosed patients will sign an informed
consent before enrollment into the new, prospective national trial (ClinicalTrials.gov Id:
NCT02067143).
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Experience of the lab
Our laboratory is experienced in cytomorphologic and immunophenotypic diagnosis of hematologic
diseases from 1987. Molecular diagnosis was introduced since 1994 for qualitative PCR and since
2004 for quantitative PCR. It is composed by a Senior PhD, two technicians, three senior fellows
and five younger fellows. Our laboratory was involved in the standardization of the qualitative (11)
and quantitative (12) analysis of the most common translocations in Acute Leukemia (LA) within
the BIOMED-1 international cooperative group for diagnostics in hematology. It represented the
laboratory for molecular analysis centralization for the multicentric treatment protocols LAL
09/2000 and LAL 10/07 and performed the clonality assay and the MRD evaluation of all the
enrolled patients.
Our laboratory is part of the following international and national organizations:
-EuroMRD Consortium (http://www.euromrd.org/usr/pub/participants.php) that was established in
2001 (formerly known as European Study Group on MRD detection in ALL; ESG-MRD-ALL) and
consists of 43 MRD-PCR laboratories across 18 countries in Europe, Israel, Singapore, Japan and
Australia. This consortium collects only experienced laboratory in the field of TCR-Ig
rearrangements study for lymphomas and lymphoblastic leukemia (9) and produced protocols and
guidelines for MRD detection and data interpretation (6). It also organizes quality control rounds
every 6 month to monitor the performance of each laboratory and discuss the results in meetings
organized every year. This study group belongs to the ESLHO (European Scientific foundation for
Laboratory HematoOncology, http://www.eslho.org/usr/index.php ) and in collaboration with the
EuroClonality division (also belonging to ESLHO) is promoting a project for the validation of new
HTS based procedures for clonatity assessment and MRD evaluation.
- EuroMRD for Ph+ ALL which is working on guidelines for the quantitation of the BCR-ABL
minor transcript in B-cell acute lymphoblastic leukemia (13).
- LabNet, a National network for the molecular quantitation of the BCR-ABL major transcript in
Chronic Myeloid Leukemia according to LeukemiaNet recommendations (14) with an International
Scale Conversion Factor (CF) that is validated every year with quality control rounds.
Our laboratory is also a part of the international IRONII project aimed to evaluate the HTS utility in
the oncohaematologic field (15, 16). This working group is developing tools to identify the most
significant molecular alteration at diagnosis of the most common hematologic disease based on the
454 HTS technology. In particular, we belongs to the ALL working group in which a number of
significant molecular markers have been explored, among them p53 mutations were searched at
disease onset and the results are under evaluation.
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PROPOSAL MAIN BODY
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Access to the instrumentations and facilities
Sequenta is a Company that provides clonality study and MRD evaluation on clinical samples with
HTS technology upon request. Furthermore, in our Institution are present two HTS platforms: the
MiSeq platform (Illumina) and the 454 Junior platform (Roche). A second MiSeq platform will be
available at later at the end of the year. All the instruments are accessible to research units and
bioinformatics support is guarantee.
Support
As above mentioned, our laboratory is part of the EuroMRD study which collects all the
experienced laboratory all around the Europe in the field of TCR-Ig rearrangements study for
lymphomas and lymphoblastic leukemia (9). The EuroMRD and EuroClonality working group have
already started collaborative efforts to validate the HTS in clonal rearrangements identification and
MRD evaluation.
Preliminary data
In 2000 in our hospital a multicenter treatment study for ALL (NILG trial 09/00, ClinicalTrials.gov
Id: NCT00358072) started to test prospectively the predictive value of minimal residual disease
(MRD) in adult ALL patients (n=280) (3). Our laboratory studied all the enrolled patients to
develop a molecular probe based on clone-specific T cell Receptor (TCR) or Immunoglobulin (Ig)
rearrangements. With this approach we were able to categorize patients in two distinct groups after
the consolidation therapy: one in which the minimal residual disease was undetectable (MRDneg,
n=58) and one with detectable residual disease (MRDpos, n=54); the first group of patient received
only chemotherapy whether the second group (n=54) was switched to an allogeneic stem cell
transplantation, when possible or an high dose chemotherapy course supported by an autologous
stem cell transplantation. The MRDneg group, treated with a two year chemotherapy, had a DFS of
72% weather the MRDpos group, treated with allogeneic transplantation or with high dose
chemotherapy and autologous transplantation, based on donor availability, had a DFS of 14% at 5
years (3). Patients in which it was not possible to generate a suitable molecular probe for MRD
monitoring (n=30) could not benefit of MRD categorization for subsequent treatment allocation.
These patients were treated according to clinical risk class and showed a DFS at 5 years of 40%.
This latter group would clearly benefit from a technology able to identify patients with no residual
disease already cured by chemotherapy and patients with persistence of disease in which therapy
intensification is recommended.
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References
1.
Bassan R, Hoelzer D. Modern therapy of acute lymphoblastic leukemia. J Clin Oncol
2011;29(5):532-43.
2.
Pui CH, Carroll WL, Meshinchi S, Arceci RJ. Biology, risk stratification, and therapy of
pediatric acute leukemias: an update. J Clin Oncol 2011;29(5):551-65.
3.
Bassan R, Spinelli O, Oldani E, Intermesoli T, Tosi M, Peruta B, et al. Improved risk
classification for risk-specific therapy based on the molecular study of minimal residual disease
(MRD) in adult acute lymphoblastic leukemia (ALL). Blood 2009;113(18):4153-62.
4.
Bruggemann M, Raff T, Flohr T, Gokbuget N, Nakao M, Droese J, et al. Clinical
significance of minimal residual disease quantification in adult patients with standard-risk acute
lymphoblastic leukemia. Blood 2006;107(3):1116-23.
5.
Flohr T, Schrauder A, Cazzaniga G, Panzer-Grumayer R, van der Velden V, Fischer S, et al.
Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of
immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial
AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia 2008;22(4):77182.
6.
van der Velden VH, Cazzaniga G, Schrauder A, Hancock J, Bader P, Panzer-Grumayer ER,
et al. Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for
interpretation of real-time quantitative PCR data. Leukemia 2007;21(4):604-11.
7.
Faham M, Zheng J, Moorhead M, Carlton VE, Stow P, Coustan-Smith E, et al. Deepsequencing approach for minimal residual disease detection in acute lymphoblastic leukemia. Blood
2012;120(26):5173-80.
8.
Ladetto M, Bruggemann M, Monitillo L, Ferrero S, Pepin F, Drandi D, et al. Nextgeneration sequencing and real-time quantitative PCR for minimal residual disease detection in Bcell disorders. Leukemia 2013.
9.
Bruggemann M, Schrauder A, Raff T, Pfeifer H, Dworzak M, Ottmann OG, et al.
Standardized MRD quantification in European ALL trials: proceedings of the Second International
Symposium on MRD assessment in Kiel, Germany, 18-20 September 2008. Leukemia
2010;24(3):521-35.
10.
Szczepanski T, Willemse MJ, van Wering ER, van Weerden JF, Kamps WA, van Dongen
JJ. Precursor-B-ALL with D(H)-J(H) gene rearrangements have an immature immunogenotype with
a high frequency of oligoclonality and hyperdiploidy of chromosome 14. Leukemia
2001;15(9):1415-23.
11.
van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G, et al.
Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute
leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action:
investigation of minimal residual disease in acute leukemia. Leukemia 1999;13(12):1901-28.
12.
Gabert J, Beillard E, van der Velden VHJ, Bi W, Grimwade D, Pallisgaard N, et al.
Standardization and quality control studies of /`real-time/' quantitative reverse transcriptase
polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia - A
Europe Against Cancer Program. 2003;17(12):2318-2357.
13.
Pfeifer HM, Giovanni Cazzaniga, Orietta Spinelli, Jean-Michel Cayuela, Hélène Cavé, Peter
Vandenberghe, MD, Ph, Carmen Chillon*, Tomasz Sacha, MD, Sandrine Hayette, PhD, Silja
Roettgers, PhD, Thomas Lion, MD, PhD, Professor, Letizia Foroni, MD PhD, Vincent H.J. van der
Velden, PhD, Jan Zuna, Monica Hermanson, PhD, Martin Christian Mueller, MD, Thoralf Lange,
Miroslaw Majewski, MD, Israel Bendit, MD, Fabrizio Pane, Ilaria Iacobucci, PhD, Veli Kairisto,
MD, PhD, Christa Homburg, Smadar Avigad, Eng Juh Allen Yeoh, Beat Schäfer, Adele Fielding,
MB BS, PhD, Loredana Elia, Katarzyna Borg, Eric Delabesse, Susanne Schnittger, PhD, Sandra
Markovic, Volker Werner, Nicola Goekbuget, MD, Dieter Hoelzer, MD PhD, Jacques J.M. van
Dongen, PhDand Oliver G. Ottmann, MD, PhD. International Standardization of Minimal Residual
Codice Riferimento: 16105
Page 12 of 39
PROPOSAL MAIN BODY
Rambaldi Alessandro [PI]
Disease Assessment for in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
(Ph+ALL) Expressing m-BCR-ABL Transcripts: Updated Results of Quality Control Procedures by
the EWALL and ESG-MRD-ALL Consortia. Blood 2011.
14.
Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al.
European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.
Blood 2013;122(6):872-84.
15.
Kohlmann A, Martinelli G, Hofmann W-K, Kronnie G, Chiaretti S, Preudhomme C, et al.
The Interlaboratory Robustness of Next-Generation Sequencing (IRON) Study Phase II: DeepSequencing Analyses of Hematological Malignancies Performed by an International Network
Involving 26 Laboratories. ASH Annual Meeting Abstracts 2012;120(21):1399-.
16.
Kohlmann A, Klein HU, Weissmann S, Bresolin S, Chaplin T, Cuppens H, et al. The
Interlaboratory RObustness of Next-generation sequencing (IRON) study: a deep sequencing
investigation of TET2, CBL and KRAS mutations by an international consortium involving 10
laboratories. Leukemia 2011;25(12):1840-8.
Codice Riferimento: 16105
Page 13 of 39
PERSONNEL INVOLVED IN THE RESEARCH
Rambaldi Alessandro [PI]
PERSONNEL INVOLVED IN THE RESEARCH
Core Team Members
Name
Date of birth
Institution
Role on project
Doctor Alessandro Rambaldi
22/08/1955
Doctor Peruta Barbara
20/02/1981
Doctor Tosi Manuela
01/10/1975
Doctor Spinelli Orietta
04/03/1968
Borleri Gianmaria
22/09/1959
Doctor Intermesoli Tamara
15/01/1975
Azienda Ospedaliera Papa Giovanni
XXIII
Azienda Ospedaliera Papa Giovanni
XXIII
Azienda Ospedaliera Papa Giovanni
XXIII
Azienda Ospedaliera Papa Giovanni
XXIII
Azienda Ospedaliera Papa Giovanni
XXIII
Azienda Ospedaliera Papa Giovanni
XXIII
Clinician
Financial support/yr
Man/Year effort
Principal Investigator
Y
N
0,20
Fellow
N
€ 22.000,00
1,00
Fellow
N
N
1,00
Internal Collaborator
N
N
0,30
Technician
N
N
0,20
Internal Collaborator
Y
N
0,20
Total Man/Year on project
2,9
Supporting documentation available in:
Addendum A - PERSONNEL INVOLVED IN THE RESEARCH - CURRICULUM VITAE
Codice Riferimento: 16105
Page 14 of 39
DESCRIPTION OF THE WORK FOR EVERY UNIT OF PERSONNEL
Rambaldi Alessandro [PI]
Description of work of each personnel
Rambaldi Alessandro, MD Head of Hematology and Bone Marrow Transplant Unit, is the
principal investigator of acute leukemia clinical trials active in the Unit.
Intermesoli Tamara, MD Senior consultant, is full time involved in management of patients
enrolled in clinical studies for acute and chronic leukemia.
Spinelli Orietta, PhD Senior Investigator, is full time involved in molecular study of minimal
residual disease in ALL patients. She will coordinate the sample analysis of selected patients to be
studied with HTS technology.
Manuela Tosi, PhD. Research fellow, involved in molecular study of minimal residual disease in
ALL patients.
Barbara Peruta, Biol. Sci., Research fellow will be involved in the following tasks:
 Analysis of the diagnostic material of the patients enrolled into the clinical trials for clonal
rearrangements identification and subsequent MRD analysis.
 Preparation and quality evaluation of samples for HTS procedure.
 Analysis of the output sequences, identification of clonal markers and MRD levels.
 Correlation of molecular results to clinical outcome of patients
Gianmaria Borleri, Senior technician is full time involved in the diagnostic workup (morphology,
flow cytometry and cell preparation of acute leukemia samples)
A schematic representation of the activity addressed to the various tasks is shown below:
Organizational chart
A.R. P.I.: Coordination and supervision of the research throughout the project
Coordination of activities related to clinical trials
T.I.
O.S. Coordination of activities related to minimal residual disease analysis
Analysis with HTS technique
 Sequencing on the HTS platform
 Analysis of the output sequences to identify Ig/TCR gene rearrangements
 Comparison between Ig/TCR gene rearrangements identified by the new
HTS platform and by the conventional EuroMRD approach.
 HTS sequencing of the end of consolidation samples of the same10 patients
and comparison of MRD results with those obtained with conventional AOSQPCR.
HTS analysis of the MRD unknown cohort of patients
 Sequencing of MRDunk cohort of patients on the HTS platform
M.T.
B.P.
 Analysis of the output sequences to identify Ig/TCR gene rearrangements
G.B.
 Outcome analysis of MRDunk cohort newly re-classified as MRDpos or
MRDneg.
Prospective application of the HTS technique in parallel with conventional method
on newly diagnosed ALL patients
 Prospective Ig/TCR gene rearrangements identification with new HTS
technique.
 Analysis of MRD on samples collected at the end of consolidation therapy
with the new HTS method.
 Evaluation of feasibility and applicability of this analysis in a prospective
clinical trial in which treatment are decided based on MRD results.
Codice Riferimento: 16105
Page 15 of 39
BUDGET FORM AND JUSTIFICATIONS
Rambaldi Alessandro [PI]
BUDGET FORM AND JUSTIFICATIONS
1st year
2nd year
3rd year
Total
Direct Research costs
- Consumables and supplies
€ 40.000,00
€ 40.000,00
€ 39.000,00
€ 119.000,00
€ 0,00
€ 0,00
€ 0,00
€ 0,00
€ 5.000,00
€ 5.000,00
€ 5.000,00
€ 15.000,00
- Maintenance contracts
€ 0,00
€ 0,00
€ 0,00
€ 0,00
- Publication costs
€ 0,00
€ 0,00
€ 1.000,00
€ 1.000,00
€ 1.000,00
€ 1.000,00
€ 1.000,00
€ 3.000,00
€ 22.000,00
€ 22.000,00
€ 22.000,00
€ 66.000,00
€ 6.460,00
€ 6.460,00
€ 6.460,00
€ 19.380,00
€ 74.460,00
€ 74.460,00
€ 74.460,00
€ 223.380,00
€ 7.446,00
€ 7.446,00
€ 7.446,00
€ 22.338,00
€ 81.906,00
€ 81.906,00
€ 81.906,00
€ 245.718,00
- Small bench instrumentation
- Services
- Meetings and travel costs
Personnel costs
Indirect costs (9,5%)
SUBTOTAL
Overheads (10,0%)
Total
Proponent's signature
_____________________
Rambaldi Alessandro
Codice Riferimento: 16105
Legal Representative's signature
_____________________
Nicora Carlo
Page 16 of 39
Date
18 mar 2014
BUDGET FORM AND JUSTIFICATIONS
Rambaldi Alessandro [PI]
CONSUMABLES AND SUPPLIES
High Throughput Sequencing kit and reagents, disposable plasticware, ficoll, DNA extraction kits, antibodies for flowcytometry analysis,
ASO-QPCR reagents.Chips for DNA quality evaluation with Bioanalyzer
SMALL BENCH INSTRUMENTATION
not requested
SERVICES
service for allele specific oligonucleotide synthesis
MAINTENANCE CONTRACTS
not requested
PUBLICATIONS COSTS
estimated cost for publication and/or abstract submission at meetings with fee, including expenses for poster printing for the last year project
MEETING AND TRAVEL COSTS
Estimated costs for two young fellow participation to meeting and congresses related to the project
PERSONNEL COSTS
Annual estimated cost for research fellowship involved in the following tasks:
• Analysis of the diagnostic material of the patients enrolled into the clinical trials for clonal rearrangements identification and subsequent
MRD analysis.
• Preparation and quality evaluation of samples for HTS procedure.
• Analysis of the output sequences, identification of clonal markers and MRD levels.
• Correlation of molecular results to clinical outcome of patients
Letter of Indirect Costs/Overheads available in:
Addendum B - BUDGET FORM AND JUSTIFICATIONS
Codice Riferimento: 16105
Page 17 of 39
BIOGRAPHICAL SKETCH
Rambaldi Alessandro [PI]
BIOGRAPHICAL SKETCH
PERSONAL DATA OF THE PI
Surname
Rambaldi
Position
Head
Name
Alessandro
Date of birth
22/08/1955
EDUCATION AND TRAINING (INCLUDES DEGREES AND POST-DOCTORAL TRAINING)
Duration
(from/to)
Oct 1987/
Nov 1991
Oct 1982/
Jul 1985
Sep 1975/
Nov 1981
Degree/Training
Field of study
Institution
City
Specialist
Hematology
Bari
Specialist
Clinical Pharmacology
Medical degree
Medicine
Università degli Studi di Bari
Aldo Moro
Università degli Studi di
Milano
Università degli Studi di
Milano
Milan
Milan
RESEARCH AND PROFESSIONAL EXPERIENCE
Duration
(from/to)
Jan 2006/
Mar 2014
Dec 1999/
Dec 2006
Dec 1994/
Dec 1999
Jan 1991/
Dec 1994
Dec 1989/
Dec 1994
Jan 1988/
Dec 1989
Jan 1986/
Dec 1987
Jan 1982/
Dec 1985
Codice Riferimento: 16105
Position
Institution
Head of Hematology and Bone
Marrow Transplant Unit
Azienda Ospedaliera
Papa Giovanni XXIII
Azienda Ospedaliera
Head of Bone Marrow Transplant
Ospedali Riuniti di
Program
Bergamo
Azienda Ospedaliera
Senior Consultant in Hematology
Ospedali Rinuti di
Bergamo
Istituto
di Ricerche
Head Unit of Molecular Biology and Farmacologiche
"Mario
Blood Diseases
Negri" I.R.C.C.S.
Azienda Ospedaliera
Physician staff, Hematology Division
Ospedali Riuniti di
Bergamo
Istituto di Ricerche
Senior Scientist
Farmacologiche "Mario
Negri" I.R.C.C.S.
Dana Farber Cancer
Research associate
Institute, Harvard
Medical School
Istituto di Ricerche
Research associate
Farmacologiche "Mario
Negri" I.R.C.C.S.
Page 18 of 39
City
Country
Bergamo
Italy
Bergamo
Italy
Bergamo
Italy
Milano
Italy
Bergamo
Italy
Milano
Italy
Boston
United States of
America
Milano
Italy
NARRATIVE BIOSKETCH
Rambaldi Alessandro [PI]
Rambaldi’s scientific achievements
1)
Development of innovative strategies for the molecular diagnosis and
monitoring of genetic abnormalities in hematologic malignancies.
2)
Pioneering the clinical development of Rituximab in Follicular non Hodgkin
Lymphoma.
3)
Pioneering risk adapted treatment strategy in adult ALL. This approach based
on a real time evaluation of molecular minimal residual disease has become a
standard of care for this disease.
4)
Introducing new cellular therapies in patients relapsing after allogeneic stem
cell transplantation.
Codice Riferimento: 16105
Page 19 of 39
PI TRACK RECORD SUMMARY
Rambaldi Alessandro [PI]
PI TRACK RECORD SUMMARY (2009-2014)
Principal Investigator's Full Name
Rambaldi Alessandro
Total number of papers
46
Total number of papers with IF
46
Total IF
342,467
Average IF (of papers with IF)
7,4
Number of papers as First, Last, or Corresponding Author (all journals)
13
Number of papers as First, Last, or Corresponding Author (journals with IF)
13
Active IF
89,002
Average Active IF
6,8
Number of papers relevant for cancer research
45
Number of papers with acknowledgement to AIRC
26
This track record summary is based on the publications by the PI in the last five years, listed in the following page(s).
The summary does not​ include Papers in press.
The applicant certifies that all publications have been carefully checked and correctly flagged for authorship.
Codice Riferimento: 16105
Page 20 of 39
PUBLICATIONS OF THE PI
Rambaldi Alessandro [PI]
PUBLICATIONS OF THE PI
Title, list of authors and complete reference of all publications from the last 5 years (2009 - 2014)
FA/CoF = First Author/Co-First Author
LA/CoL/CA/CC = Last Author/Co-Last Author/Corresponding Author/Co-Corresponding Author
Principal Investigator's Full Name: Rambaldi Alessandro
Publication
IF
FA/CoF LA/CoL
/CA/CC Relev.
Ackn.
Allogenic hematopoietic stem cell transplantation in patients with polycythemia or essential thrombocythemia transformed to myelofibrosis
or acute myeloid leukemia: report from the MPN subcommittee of the Chronic Malignancies Working Party of the European Group for
Blood and Marrow Transplantation.
Lussana F, Rambaldi A, Finazzi MC, van Biezen A, Scholten M, Oldani E, Carobbio A, Iacobelli S, Finke J, Nagler A, Volin L, Lamy T,
Arnold R, Mohty M, Michallet M, De Witte T, Olavarria E, Kröger N
5,935
X
4,138
X
9,06
X
1,4
X
HAEMATOL-HEMATOL J 2014 Feb; :
Discriminating between essential thrombocythemia and masked polycythemia vera in JAK2 mutated patients.
Barbui T, Thiele J, Carobbio A, Guglielmelli P, Rambaldi A, Vannucchi AM, Tefferi A
AIRC
AM J HEMATOL 2014 Feb; :
Distinct clustering of symptomatic burden amongst myeloproliferative neoplasm patients: retrospective assessment in 1470 patients.
Geyer HL, Emanuel RM, Dueck AC, Kiladjian JJ, Xiao Z, Slot S, Zweegman S, Sackmann F, Kerguelen Fuentes A, Hernández-Maraver D,
Döhner K, Harrison CN, Radia D, Muxi P, Besses C, Cervantes F, Johansson PL, Andreasson B, Rambaldi A, Barbui T, Vannucchi AM,
Passamonti F, Samuelsson J, Birgegard G, Mesa RA
BLOOD 2014 Feb; :
Highly aggressive T-cell acute lymphoblastic leukemia with t(8;14)(q24;q11): extensive genetic characterization and achievement of early
molecular remission and long-term survival in an adult patient.
Parolini M, Mecucci C, Matteucci C, Giussani U, Intermesoli T, Tosi M, Rambaldi A, Bassan R
BLOOD CANCER J 2014; 4: e176
Predictive factors for the outcome of allogeneic transplantation in patients with myelodysplastic syndrome stratified according to the revised
International Prognostic Scoring System (IPSS-R).
Della Porta MG, Alessandrino EP, Bacigalupo A, van Lint MT, Malcovati L, Pascutto C, Falda M, Bernardi M, Onida F, Guidi S, Iori AP,
Cerretti R, Marenco P, Pioltelli P, Angelucci E, Oneto R, Ripamonti F, Bernasconi P, Bosi A, Cazzola M, Rambaldi A
BLOOD 2014 Feb; :
Codice Riferimento: 16105
Page 21 of 39
9,06
X
X
AIRC
PUBLICATIONS OF THE PI
Rambaldi Alessandro [PI]
Results of a randomized trial comparing high-dose chemotherapy plus Auto-SCT and R-FC in CLL at diagnosis.
Magni M, Nicola MD, Patti C, Scimè R, Mulè A, Rambaldi A, Intermesoli T, Viero P, Tarella C, Gueli A, Bergui L, Trentin L, Barzan A,
Benedetti F, Ambrosetti A, Di Raimondo F, Chiarenza A, Parvis G, Billio A, Attolico I, Olivieri A, Montanari M, Carlo-Stella C, Matteucci
P, Devizzi L, Guidetti A, Viviani S, Valagussa P, Gianni AM
3,541
X
3,94
X
AIRC
X
AIRC
10,164
X
AIRC
5,935
X
BONE MARROW TRANSPL 2014 Jan; :
Treatment of Graft versus Host Disease with Mesenchymal Stromal Cells: A Phase I Study on 40 Adult and Pediatric Patients.
Introna M, Lucchini G, Dander E, Galimberti S, Rovelli A, Balduzzi A, Longoni D, Pavan F, Masciocchi F, Algarotti A, Micò C, Grassi A,
Deola S, Cavattoni I, Gaipa G, Belotti D, Perseghin P, Parma M, Pogliani E, Golay J, Pedrini O, Capelli C, Cortelazzo S, D'Amico G, Biondi
A, Rambaldi A, Biagi E
BIOL BLOOD MARROW TR 2014 Mar; 20: 375-81
A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 inhibitor, in patients with advanced polycythemia vera who are refractory or
intolerant to hydroxyurea.
Verstovsek S, Passamonti F, Rambaldi A, Barosi G, Rosen PJ, Rumi E, Gattoni E, Pieri L, Guglielmelli P, Elena C, He S, Contel N,
Mookerjee B, Sandor V, Cazzola M, Kantarjian HM, Barbui T, Vannucchi AM
5,201
CANCER-AM CANCER SOC 2013 Oct; :
Cytokine Induced Killer (CIK) cells for the treatment of haematological neoplasms.
Introna M, Golay J, Rambaldi A
2,337
X
IMMUNOL LETT 2013 Sep-Oct; 155: 27-30
Elevated C-reactive protein is associated with shortened leukemia-free survival in patients with myelofibrosis.
Barbui T, Carobbio A, Finazzi G, Guglielmelli P, Salmoiraghi S, Rosti V, Rambaldi A, Vannucchi AM, Barosi G
LEUKEMIA 2013 Oct; 27: 2084-6
High cure rates in Burkitt lymphoma and leukemia: a Northern Italy Leukemia Group study of the German short intensive rituximabchemotherapy program.
Intermesoli T, Rambaldi A, Rossi G, Delaini F, Romani C, Pogliani EM, Pagani C, Angelucci E, Terruzzi E, Levis A, Cassibba V, Mattei D,
Gianfaldoni G, Scattolin AM, Di Bona E, Oldani E, Parolini M, Gökbuget N, Bassan R
HAEMATOL-HEMATOL J 2013 Nov; 98: 1718-25
Mutations and chromosomal rearrangements of JAK2: not only a myeloid issue.
Salmoiraghi S, Montalvo ML, D'Agostini E, Amicarelli G, Minnucci G, Spinelli O, Rambaldi A
EXPERT REV HEMATOL 2013 Aug; 6: 429-39
Codice Riferimento: 16105
Page 22 of 39
2,382
X
X
AIRC
PUBLICATIONS OF THE PI
Rambaldi Alessandro [PI]
Retinoic acid and arsenic trioxide for acute promyelocytic leukemia.
Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona
M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von
Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri 51,658
F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF,
Platzbecker U, Gruppo Italiano Malattie Ematologiche dell'Adulto, German-Austrian Acute Myeloid Leukemia Study Group, Study Alliance
Leukemia
X
AIRC
NEW ENGL J MED 2013 Jul; 369: 111-21
Telomere shortening in Ph-negative chronic myeloproliferative neoplasms: A biological marker of polycythemia vera and myelofibrosis,
regardless ofhydroxycarbamide therapy.
Ruella M, Salmoiraghi S, Risso A, Carobbio A, Buttiglieri S, Spatola T, Sivera P, Ricca I, Barbui T, Tarella C, Rambaldi A
2,907
X
X
AIRC
10,164
X
X
AIRC
X
AIRC
EXP HEMATOL 2013 Jul; 41: 627-34
The CIBMTR score predicts survival of AML patients undergoing allogeneic transplantation with active disease after a myeloablative or
reduced intensity conditioning: a retrospective analysis of the Gruppo Italiano Trapianto Di Midollo Osseo.
Todisco E, Ciceri F, Oldani E, Boschini C, Micò C, Vanlint MT, Donnini I, Patriarca F, Alessandrino PE, Bonifazi F, Arcese W, Barberi W,
Marenco P, Terruzzi E, Cortelazzo S, Santarone S, Proia A, Corradini P, Tagliaferri E, Falcioni S, Irrera G, Dallanegra L, Castagna L,
Santoro A, Camboni A, Sacchi N, Bosi A, Bacigalupo A, Rambaldi A
LEUKEMIA 2013 Oct; 27: 2086-91
The lymphocyte to monocyte ratio improves the IPI-risk definition of diffuse large B-cell lymphoma when rituximab is added to
chemotherapy.
Rambaldi A, Boschini C, Gritti G, Delaini F, Oldani E, Rossi A, Barbui AM, Caracciolo D, Ladetto M, Gueli A, De Crescenzo A, Passera R,
Devizzi L, Patti C, Gianni AM, Tarella C
4,138
X
AM J HEMATOL 2013 Dec; 88: 1062-7
A novel murine model of myeloproliferative disorders generated by overexpression of the transcription factor NF-E2.
Kaufmann KB,Gründer A,Hadlich T,Wehrle J,Gothwal M,Bogeska R,Seeger TS,Kayser S,Pham KB,Jutzi JS,Ganzenmüller L,Steinemann
D,Schlegelberger B,Wagner JM,Jung M,Will B,Steidl U,Aumann K,Werner M,Günther T,Schüle R,Rambaldi A,Pahl HL
13,214
X
J EXP MED 2012 Jan; 209: 35-50
A novel, highly sensitive and rapid Allele Specific-Loop mediated Amplification assay for the detection of the JAK2V617F mutation in
chronic myeloproliferative neoplasms.
Minnucci G,Amicarelli G,Salmoiraghi S,Spinelli O,Guinea Montalvo ML,Giussani U,Adlerstein D,Rambaldi A
5,935
X
X
AIRC
4,942
X
X
AIRC
HAEMATOL-HEMATOL J 2012 Sep; 97: 1394-400
ASXL1 mutations in primary and secondary myelofibrosis.
Ricci C,Spinelli O,Salmoiraghi S,Finazzi G,Carobbio A,Rambaldi A
BRIT J HAEMATOL 2012 Feb; 156: 404-7
Codice Riferimento: 16105
Page 23 of 39
PUBLICATIONS OF THE PI
Rambaldi Alessandro [PI]
CD20 expression has no prognostic role in Philadelphia-negative B-precursor acute lymphoblastic leukemia: new insights from the molecular
study of minimal residual disease.
Mannelli F, Gianfaldoni G, Intermesoli T, Cattaneo C, Borlenghi E, Cortelazzo S, Cavattoni I, Pogliani EM, Fumagalli M, Angelucci E,
Romani C, Ciceri F, Corti C, Scattolin A, Cortelezzi A, Mattei D, Audisio E, Spinelli O, Oldani E, Bosi A, Rambaldi A, Bassan R
5,935
X
3,541
X
10,164
X
HAEMATOL-HEMATOL J 2012 Apr; 97: 568-71
Chronic GVHD is associated with lower relapse risk irrespective of stem cell source among patients receiving transplantation from unrelated
donors.
Signori A, Crocchiolo R, Oneto R, Sacchi N, Sormani MP, Fagioli F, Rambaldi A, Ciceri F, Bacigalupo A
BONE MARROW TRANSPL 2012 Nov; 47: 1474-8
Mesenchymal stromal cells for the treatment of graft-versus-host disease: understanding the in vivo biological effect through patient immune
monitoring.
Dander E, Lucchini G, Vinci P, Introna M, Masciocchi F, Perseghin P, Balduzzi A, Bonanomi S, Longoni D, Gaipa G, Belotti D, Parma M,
Algarotti A, Capelli C, Golay J, Rovelli A, Rambaldi A, Biondi A, Biagi E, D'Amico G
LEUKEMIA 2012 Jul; 26: 1681-4
Outcome of patients activating an unrelated donor search: the impact of transplant with reduced intensity conditioning in a large cohort of
consecutive high-risk patients.
Rambaldi A,Bacigalupo A,Fanin R,Ciceri F,Bonifazi F,Falda M,Lambertenghi-Deliliers G,Benedetti F,Bruno B,Corradini P,Alessandrino
PE,Iacopino P,Arcese W,Scimè R,Raimondi R,Sica S,Castagna L,Lamparelli T,Oneto R,Lombardini L,Pollichieni S,Algarotti A,Carobbio
A,Sacchi N,Bosi A
10,164
X
X
AIRC
LEUKEMIA 2012 Aug; 26: 1779-85
p38aMAPK interacts with and inhibits RARa: suppression of the kinase enhances the therapeutic activity of retinoids in acute myeloid
leukemia cells.
Gianni M, Peviani M, Bruck N, Rambaldi A, Borleri G, Terao M, Kurosaki M, Paroni G, Rochette-Egly C, Garattini E
10,164
X
2,866
X
AIRC
2,907
X
AIRC
LEUKEMIA 2012 Aug; 26: 1850-61
Results of a lymphoblastic leukemia-like chemotherapy program with risk-adapted mediastinal irradiation and stem cell transplantation for
adult patients with lymphoblastic lymphoma.
Cortelazzo S, Intermesoli T, Oldani E, Ciceri F, Rossi G, Pogliani EM, Mattei D, Romani C, Cortelezzi A, Borlenghi E, Corti C, Peruta B,
Spinelli O, Rambaldi A, Bassan R
ANN HEMATOL 2012 Jan; 91: 73-82
The HDAC Inhibitor Givinostat Modulates the Hematopoietic Transcription Factors NFE2 and C-MYB in JAK2V617F Myeloproliferative
Neoplasm Cells.
Calzada AA,Todoerti K,Donadoni L,Pellicioli A,Tuana G,Gatta R,Neri A,Finazzi G,Mantovani R,Rambaldi A,Introna M,Lombardi L,Golay
J
EXP HEMATOL 2012 Aug; 40: 634-45.e10
Codice Riferimento: 16105
Page 24 of 39
PUBLICATIONS OF THE PI
Rambaldi Alessandro [PI]
AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance.
Avvisati G, Lo-Coco F, Paoloni FP, Petti MC, Diverio D, Vignetti M, Latagliata R, Specchia G, Baccarani M, Di Bona E, Fioritoni G,
Marmont F, Rambaldi A, Di Raimondo F, Kropp MG, Pizzolo G, Pogliani EM, Rossi G, Cantore N, Nobile F, Gabbas A, Ferrara F, Fazi P,
Amadori S, Mandelli F, GIMEMA, AIEOP, and EORTC Cooperative Groups
9,06
X
9,06
X
AIRC
9,06
X
AIRC
X
AIRC
5,52
X
AIRC
4,942
X
9,06
X
BLOOD 2011 May; 117: 4716-25
Dual-functional capability of CD3+CD56+ CIK cells, a T-cell subset that acquires NK function and retains TCR-mediated specific
cytotoxicity.
Pievani A, Borleri G, Pende D, Moretta L, Rambaldi A, Golay J, Introna M
BLOOD 2011 Sep; 118: 3301-10
Enhanced killing of human B-cell lymphoma targets by combined use of cytokine-induced killer cell (CIK) cultures and anti-CD20
antibodies.
Pievani A, Belussi C, Klein C, Rambaldi A, Golay J, Introna M
BLOOD 2011 Jan; 117: 510-8
Inflammation and thrombosis in essential thrombocythemia and polycythemia vera: different role of C-reactive protein and pentraxin 3.
Barbui T, Carobbio A, Finazzi G, Vannucchi AM, Barosi G, Antonioli E, Guglielmelli P, Pancrazzi A, Salmoiraghi S, Zilio P, Ottomano C,
Marchioli R, Cuccovillo I, Bottazzi B, Mantovani A, Rambaldi A, AGIMM and IIC Investigators
5,935
X
HAEMATOL-HEMATOL J 2011 Feb; 96: 315-8
Mechanism of action of type II, glycoengineered, anti-CD20 monoclonal antibody GA101 in B-chronic lymphocytic leukemia whole blood
assays in comparison with rituximab and alemtuzumab.
Bologna L, Gotti E, Manganini M, Rambaldi A, Intermesoli T, Introna M, Golay J
J IMMUNOL 2011 Mar; 186: 3762-9
Mutations of CD79A, CD79B and EZH2 genes in immunodeficiency-related non-Hodgkin lymphomas.
Capello D, Gloghini A, Martini M, Spina M, Tirelli U, Bertoni F, Rinaldi A, Morra E, Rambaldi A, Sinigaglia F, Larocca LM, Carbone A
BRIT J HAEMATOL 2011 Mar; 152: 777-80
Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype.
Grossmann V, Tiacci E, Holmes AB, Kohlmann A, Martelli MP, Kern W, Spanhol-Rosseto A, Klein HU, Dugas M, Schindela S, Trifonov
V, Schnittger S, Haferlach C, Bassan R, Wells VA, Spinelli O, Chan J, Rossi R, Baldoni S, De Carolis L, Goetze K, Serve H, Peceny R,
Kreuzer KA, Oruzio D, Specchia G, Di Raimondo F, Fabbiano F, Sborgia M, Liso A, Farinelli L, Rambaldi A, Pasqualucci L, Rabadan R,
Haferlach T, Falini B
BLOOD 2011 Dec; 118: 6153-63
Codice Riferimento: 16105
Page 25 of 39
AIRC
PUBLICATIONS OF THE PI
Rambaldi Alessandro [PI]
Chemotherapy-phased imatinib pulses improve long-term outcome of adult patients with Philadelphia chromosome-positive acute
lymphoblastic leukemia: Northern Italy Leukemia Group protocol 09/00.
Bassan R, Rossi G, Pogliani EM, Di Bona E, Angelucci E, Cavattoni I, Lambertenghi-Deliliers G, Mannelli F, Levis A, Ciceri F, Mattei D,
Borlenghi E, Terruzzi E, Borghero C, Romani C, Spinelli O, Tosi M, Oldani E, Intermesoli T, Rambaldi A
18,038
X
X
AIRC
3,94
X
X
AIRC
5,935
X
AIRC
4,942
X
10,164
X
2,907
X
4,942
X
J CLIN ONCOL 2010 Aug; 28: 3644-52
Feasibility and safety of adoptive immunotherapy with CIK cells after cord blood transplantation.
Introna M, Pievani A, Borleri G, Capelli C, Algarotti A, Micò C, Grassi A, Oldani E, Golay J, Rambaldi A
BIOL BLOOD MARROW TR 2010 Nov; 16: 1603-7
Pleiotropic anti-myeloma activity of ITF2357: inhibition of interleukin-6 receptor signaling and repression of miR-19a and miR-19b.
Todoerti K, Barbui V, Pedrini O, Lionetti M, Fossati G, Mascagni P, Rambaldi A, Neri A, Introna M, Lombardi L, Golay J
HAEMATOL-HEMATOL J 2010 Feb; 95: 260-9
Single nucleotide polymorphism-arrays provide new insights in the pathogenesis of post-transplant diffuse large B-cell lymphoma.
Rinaldi A, Capello D, Scandurra M, Greiner TC, Chan WC, Bhagat G, Rossi D, Morra E, Paulli M, Rambaldi A, Rancoita PM, Inghirami G,
Ponzoni M, Moreno SM, Piris MA, Mian M, Chigrinova E, Zucca E, Favera RD, Gaidano G, Kwee I, Bertoni F
BRIT J HAEMATOL 2010 May; 149: 569-77
Standardized MRD quantification in European ALL trials: proceedings of the Second International Symposium on MRD assessment in Kiel,
Germany, 18-20 September 2008.
Brüggemann M, Schrauder A, Raff T, Pfeifer H, Dworzak M, Ottmann OG, Asnafi V, Baruchel A, Bassan R, Benoit Y, Biondi A, Cavé H,
Dombret H, Fielding AK, Foà R, Gökbuget N, Goldstone AH, Goulden N, Henze G, Hoelzer D, Janka-Schaub GE, Macintyre EA, Pieters R,
Rambaldi A, Ribera JM, Schmiegelow K, Spinelli O, Stary J, von Stackelberg A, Kneba M, Schrappe M, van Dongen JJ, European Working
Group for Adult Acute Lymphoblastic Leukemia (EWALL), International Berlin-Frankfurt-Münster Study Group (I-BFM-SG)
LEUKEMIA 2010 Mar; 24: 521-35
Therapeutic efficacy of the pan-cdk inhibitor PHA-793887 in vitro and in vivo in engraftment and high-burden leukemia models.
Alzani R, Pedrini O, Albanese C, Ceruti R, Casolaro A, Patton V, Colotta F, Rambaldi A, Introna M, Pesenti E, Ciomei M, Golay J
EXP HEMATOL 2010 Apr; 38: 259-269.e2
A short low-dose imatinib trial allows rapid identification of responsive patients in hypereosinophilic syndromes.
Intermesoli T, Delaini F, Acerboni S, Salmoiraghi S, Spinelli O, Guerini V, Vannucchi AM, Mappa S, Rossi G, Rossi V, Di Bona E, Paratore
S, Carobbio A, Rambaldi A, Barbui T, Bassan R
BRIT J HAEMATOL 2009 Dec; 147: 681-5
Codice Riferimento: 16105
Page 26 of 39
AIRC
PUBLICATIONS OF THE PI
Rambaldi Alessandro [PI]
HLA matching affects clinical outcome of adult patients undergoing haematopoietic SCT from unrelated donors: a study from the Gruppo
Italiano Trapianto di Midollo Osseo and Italian Bone Marrow Donor Registry.
Crocchiolo R, Ciceri F, Fleischhauer K, Oneto R, Bruno B, Pollichieni S, Sacchi N, Sormani MP, Fanin R, Bandini G, Bonifazi F, Bosi A,
Rambaldi A, Alessandrino PE, Falda M, Bacigalupo A
3,541
X
9,06
X
BONE MARROW TRANSPL 2009 Nov; 44: 571-7
Identification of patients with poorer survival in primary myelofibrosis based on the burden of JAK2V617F mutated allele.
Guglielmelli P, Barosi G, Specchia G, Rambaldi A, Lo Coco F, Antonioli E, Pieri L, Pancrazzi A, Ponziani V, Delaini F, Longo G,
Ammatuna E, Liso V, Bosi A, Barbui T, Vannucchi AM
BLOOD 2009 Aug; 114: 1477-83
Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute
lymphoblastic leukemia (ALL).
Bassan R, Spinelli O, Oldani E, Intermesoli T, Tosi M, Peruta B, Rossi G, Borlenghi E, Pogliani EM, Terruzzi E, Fabris P, Cassibba V,
Lambertenghi-Deliliers G, Cortelezzi A, Bosi A, Gianfaldoni G, Ciceri F, Bernardi M, Gallamini A, Mattei D, Di Bona E, Romani C,
Scattolin AM, Barbui T, Rambaldi A
9,06
X
X
AIRC
8,65
X
AIRC
2,907
X
3,952
X
BLOOD 2009 Apr; 113: 4153-62
Inhibition of the peptidyl-prolyl-isomerase Pin1 enhances the responses of acute myeloid leukemia cells to retinoic acid via stabilization of
RARalpha and PML-RARalpha.
Gianni' M, Boldetti A, Guarnaccia V, Rambaldi A, Parrella E, Raska, Rochette-Egly C, Del Sal G, Rustighi A, Terao M, Garattini E
CANCER RES 2009 Feb; 69: 1016-26
JAK2V617F allele burden and thrombosis: a direct comparison in essential thrombocythemia and polycythemia vera.
Carobbio A, Finazzi G, Antonioli E, Guglielmelli P, Vannucchi AM, Dellacasa CM, Salmoiraghi S, Delaini F, Rambaldi A, Barbui T
EXP HEMATOL 2009 Sep; 37: 1016-21
Molecular monitoring of residual disease in chronic myeloid leukemia by genomic DNA compared with conventional mRNA analysis.
Mattarucchi E, Spinelli O, Rambaldi A, Pasquali F, Lo Curto F, Campiotti L, Porta G
J MOL DIAGN 2009 Sep; 11: 482-7
Supporting documentation available in:
Addendum C - PUBLICATIONS OF THE PI
Codice Riferimento: 16105
Page 27 of 39
BIO-ETHICAL REQUIREMENTS
Rambaldi Alessandro [PI]
BIO-ETHICAL REQUIREMENTS
Research on humans
Does the research plan include clinical trials with patients and/or healthy volunteers, or involve the use of human biological
samples, genetic material or data collection?
YES
NO
If yes, you MUST check one of the following boxes:
I have obtained the clearance from the competent Ethics Committee/Institutional Review Board, and I am attaching it to
the application, together with a copy of the informed consent if requested by the competent Ethics
Committee/Institutional Review Board.
I have not obtained the clearance from the competent Ethics Committee/Institutional Review Board yet, but I have
requested it and will send it to the AIRC Peer Review Office by the deadline indicated in the Call, together with a copy
of the informed consent if requested by the competent Ethics Committee/Institutional Review Board.
In any case, if the research deals with human biological samples, genetic material or data collection the applicant declares that
the research plan includes information about:
1) how the samples, material or data are collected;
2) whether the samples, material or data are collected specifically for the proposed research project;
3) how the samples, material or data are dismissed.
Proponent's signature
_____________________
Rambaldi Alessandro
Date
18 mar 2014
Research on animals
Does the proposed research involve animal experimentation?
YES
NO
If yes, you MUST check one of the following boxes:
I have obtained the clearance from the competent animal research ethics committee to carry out the described animal
experimentation, and I am attaching it to the application;
I have not obtained the clearance from the competent animal research ethics committee yet, but I have requested it and
will send it to the AIRC Peer Review Office by the deadline indicated in the Call;
there is not an active animal research ethics committee in my Institute, but the procedures related to animal use have
been communicated to the Italian Ministry of Health and a copy of this communication is attached to the current
application;
there is not an active animal research ethics committee in my Institute; I have yet to communicate the procedures related
to animal use to the Italian Ministry of Health but I will do so and I will send a copy of this communication to the AIRC
Peer Review Office by the deadline indicated in the Call.
In any case, the applicant declares that the research studies are accurately described in the proposal and conform to all
regulations protecting animals used for research purposes, including those of the DL 116/92. The experiments described in the
proposal will be performed following the guidelines described in: Workman P. et al.: 'Guidelines for the welfare and use of
animals in cancer research'. Br. J. Cancer (2010) 102: 1555-1577.
In addition, the applicant declares that the principles of the three Rs (Replacement, Reduction, Refinement) have beeen
implemented in the research plan, as described in the attached PDF file.
Animal experimentation: Principles of the 3Rs
Proponent's signature
_____________________
Rambaldi Alessandro
Date
18 mar 2014
Supporting documentation available in:
Addendum D - BIO-ETHICAL REQUIREMENTS
Codice Riferimento: 16105
Page 28 of 39
Addendum A - PERSONNEL INVOLVED IN THE RESEARCH - CURRICULUM VITAE
Rambaldi Alessandro [PI]
Personal Information
Name
Address
Phone number
E-mail
Nationality
Date and place of birth
BARBARA PERUTA
(+39) 0352673766
Italian
20/02/1981
Educational Background
2005:
Academic Degree in Medical Biotechnology with the full marks (110/110 cum laude) at the
University of Milan-Bicocca, Italy.
The title of the dissertation work was: “Adult acute lumphoblastic leukemia: prognostic impact of minimal
residual disease evaluation in allogeneic stem cells transplated patients”.
Positions and Employment
2013-2014
Fellow, Division of Molecular Hematology, A.O. “Papa Giovanni XXIII”, Bergamo, Italy
2006-2012
Fellow, Division of Molecular Hematology, Ospedali Riuniti di Bergamo, Italy
2004-2005
Student Fellow, Division of Molecular Hematology, Ospedali Riuniti di Bergamo, Italy
Other Experience and Professional Memberships:
2008-2014:
member of the EUROMRD group. The EuroMRD Consortium was established in 2001 and
consists of 43 MRD-PCR laboratories across 18 countries in Europe, Israel, Singapore, Japan and Australia.
The main aims of EuroMRD are:
1. Organisation of a quality-control program twice per year;
2. Collaborative development and evaluation of new MRD strategies and techniques;
3. Development of guidelines for the interpretation of RQ-PCR-based MRD data.
Work Experience:
Cell biology techniques: cell culture, immunohistochemistry, immunophenotyping (basic level), tumor
antigens targeting (basic level).
Molecular Biology: RNA and DNA extraction and preparation, RT-PCR, PCR and real time PCR, DNA
sequence, primer design, set up of multiplex fluorescence PCR, Genescan and fragment analysis
Specialist of molecular diagnosis of adult acute lymphoid Leukemias and lymphoblastic lymphomas and
molecular monitoring of minimal residual disease (MRD) in adult lymphoblastic diseases.
Publications




Cortelazzo S, Intermesoli T, Oldani E, Ciceri F, Rossi G, Pogliani EM, Mattei D, Romani C,
Cortelezzi A, Borlenghi E, Corti C, Peruta B, Spinelli O, Rambaldi A, Bassan R.
Results of a lymphoblastic leukemia-like chemotherapy program with risk-adapted mediastinal
irradiation and stem cell transplantation for adult patients with lymphoblastic lymphoma.
Ann Hematol. 2012 Jan;91(1):73-82.
Bassan R, Spinelli O, Oldani E, Intermesoli T, Tosi M, Peruta B, Rossi G, Borlenghi E, Pogliani
EM, Terruzzi E, Fabris P, Cassibba V, Lambertenghi-Deliliers G, Cortelezzi A, Bosi A, Gianfaldoni
G, Ciceri F, Bernardi M, Gallamini A, Mattei D, Di Bona E, Romani C, Scattolin AM, Barbui T,
Rambaldi A.
Improved risk classification for risk-specific therapy based on the molecular study of minimal
residual disease (MRD) in adult acute lymphoblastic leukemia (ALL).
Blood. 2009 Apr 30;113(18):4153-62.
Spinelli O, Peruta B, Tosi M, Guerini V, Salvi A, Zanotti MC, Oldani E, Grassi A, Intermesoli T,
Micò C, Rossi G, Fabris P, Lambertenghi-Deliliers G, Angelucci E, Barbui T, Bassan R, Rambaldi
A.
Clearance of minimal residual disease after allogeneic stem cell transplantation and the prediction of
the clinical outcome of adult patients with high-risk acute lymphoblastic leukemia.
Haematologica. 2007 May;92(5):612-8.
Codice Riferimento: 16105
Page 29 of 39
Addendum A - PERSONNEL INVOLVED IN THE RESEARCH - CURRICULUM VITAE
Rambaldi Alessandro [PI]
Personal Information
Name
TOSI MANUELA
Address
Phone number (+39) 0352673766
E-mail
[email protected]
Nationality
Italian
Date and place of birth
01/10/1975
Educational Background
2005 Postgraduate in Clinical Biochemistry
2000 Academic degree in Biological Sciences
Research experience
1999-2000
Student fellow Division of Molecular Hematology, A.O. Ospedali Riuniti di Bergamo Italy
2000-2009
Fellow, Division of Molecular Hematology, A.O. Papa Giovanni XXIII Bergamo - Italy
Technical skills and competences:
Molecular Biology: RNA and DNA preparation, RT-PCR, PCR and real time PCR, DNA sequence.
specialist of molecular diagnosis of myeloid and lymphoid Leukemias and molecular monitoring of minimal
Publications
1. Bassan R, Rossi G, Pogliani EM, Di Bona E, Angelucci E, Cavattoni I, Lambertenghi-Deliliers
G, Mannelli F, Levis A, Ciceri F, Mattei D, Borlenghi E, Terruzzi E, Borghero C, Romani C,
Spinelli O, Tosi M, Oldani E, Intermesoli T, Rambaldi A.
Chemotherapy-phased imatinib pulses improve long-term outcome of adult patients with
Philadelphia chromosome-positive acute lymphoblastic leukemia: Northern Italy Leukemia
Group protocol 09/00.
J Clin Oncol. 2010 Aug 1;28(22):3644-52. 20606084.
2. Bassan R, Spinelli O, Oldani E, Intermesoli T, Tosi M, Peruta B, Rossi G, Borlenghi E, Pogliani
EM, Terruzzi E, Fabris P, Cassibba V, Lambertenghi-Deliliers G, Cortelezzi A, Bosi A,
Gianfaldoni G, Ciceri F, Bernardi M, Gallamini A, Mattei D, Di Bona E, Romani C, Scattolin
AM, Barbui T, Rambaldi A.
Improved risk classification for risk-specific therapy based on the molecular study of
minimal residual disease (MRD) in adult acute lymphoblastic leukemia(ALL).
Blood. 2009 Apr 30;113(18):4153-62.
3. Spinelli O, Peruta B, Tosi M, Guerini V, Salvi A, Zanotti MC, Oldani E, Grassi A, Intermesoli T,
Micò C, Rossi G, Fabris P, Lambertenghi-Deliliers G, Angelucci E, Barbui T, Bassan R,
Rambaldi A.
Clearance of minimal residual disease after allogeneic stem cell transplantation and the
prediction of the clinical outcome of adult patients with high-risk acute lymphoblastic
leukemia.
Haematologica.2007 May;92(5):612-8. PubMed PMID: 17488684.
Codice Riferimento: 16105
Page 30 of 39
Addendum B - BUDGET FORM AND JUSTIFICATIONS
Rambaldi Alessandro [PI]
Codice Riferimento: 16105
Page 31 of 39
Addendum C - PUBLICATIONS OF THE PI
Rambaldi Alessandro [PI]
Manuscript no. HAEMATOL/2010/031070 entitled “Inflammation and thrombosis in
essential thrombocythemia and polycythemia vera: different role of C-reactive
protein and pentraxin 3 “
Authors: Tiziano Barbui, Alessandra Carobbio, Guido Finazzi, Alessandro M.
Vannucchi, Giovanni Barosi, Elisabetta Antonioli, Paola Guglielmelli, Alessandro
Pancrazi, Silvia Salmoiraghi, Pio Zilio, Cosimo Ottomano, Roberto Marchioli, Ivan
Cuccovillo, Barbara Bottazzi, Alberto Mantovani, and Alessandro Rambaldi
Information about the contributions of each person named as having participated in
the study
1) Guarantor(s), i.e., person(s) who is (are) responsible for the integrity of the work as a whole:
• Tiziano Barbui
According to the International Committee of Medical Journal Editors (ICMJE)
(http://www.icmje.org/ethical_1author.html): “Authorship credit should be based on: 1)
substantial contributions to conception and design, acquisition of data, or analysis and
interpretation of data; 2) drafting the article or revising it critically for important intellectual
content; and 3) final approval of the version to be published. Authors should meet conditions 1,
2, and 3 ……………………. Acquisition of funding, collection of data, or general supervision of the
research group alone does not constitute authorship”.
The guarantors of this manuscript confirm that all persons designated as authors qualify for
authorship, and that each author has participated sufficiently in the work to take public
responsibility for appropriate portions of the content.
2) Authors who participated in the conception of the study: Tiziano Barbui, Alessandro M.
Vannucchi, Giovanni Barosi, Alberto Mantovani, and Alessandro Rambaldi
3) Design & Methods. The following authors were responsible for specific investigations (please
detail):
• Alessandra Carobbio was responsible for statistical methods
• Elisabetta Antonioli, Paola Guglielmelli, Alessandro Pancrazzi were responsible for collecting
clinical data
• Silvia Salmoiraghi, Pio Zilio, Cosimo Ottomano, Ivan Cuccovillo and Barbara Bottazzi were
responsible for collecting laboratory data
4) Results. The following authors were responsible for specific portions of the results, including
figures and tables (please indicate the person responsible for each figure and each table):
• Alessandra Carobbio, Guido Finazzi, Roberto Marchioli and Tiziano Barbui were responsible for
Table 1
• Alessandra Carobbio, Guido Finazzi, Roberto Marchioli and Tiziano Barbui were responsible for
Table 2
• Alessandra Carobbio, Guido Finazzi, Roberto Marchioli and Tiziano Barbui were responsible for
Table 3
• Alessandra Carobbio, Guido Finazzi, Roberto Marchioli and Tiziano Barbui were responsible for
Table and Figure in the On-line Appendix
5) Writing the manuscript. The following authors were responsible for writing the manuscript:
• Tiziano Barbui, Alessandra Carobbio, Guido Finazzi, Alessandro M. Vannucchi, Giovanni Barosi,
Roberto Marchioli, Ivan Cuccovillo, Barbara Bottazzi, Alberto Mantovani, and Alessandro
Rambaldi were responsible for revising the drafts and writing the final version of the paper
6) Contributors Listed in Acknowledgments: NA
page
Codice Riferimento: 16105
Page 32 of 39
1
Addendum D - BIO-ETHICAL REQUIREMENTS: Research on humans (Clearance from Ethics Committee)
Rambaldi Alessandro [PI]
Codice Riferimento: 16105
Page 33 of 39
Addendum D - BIO-ETHICAL REQUIREMENTS: Research on humans (Clearance from Ethics Committee)
Rambaldi Alessandro [PI]
Codice Riferimento: 16105
Page 34 of 39
Addendum D - BIO-ETHICAL REQUIREMENTS: Research on humans (Clearance from Ethics Committee)
Rambaldi Alessandro [PI]
AZIENDA OSPEDALIERA
OSPEDALI RIUNITI DI BERGAMO
di rilievo nazionale e di alta specializzazione
USC EMATOLOGIA
Direttore Prof. Alessandro Rambaldi
NOTA INFORMATIVA PER LA RACCOLTA, LA CONSERVAZIONE E L’USO
DI MATERIALE BIOLOGICO
Gentile Signore/Signora,
oggi la ricerca medica rappresenta una parte integrante delle attività di diagnosi e cura delle malattie e
compie costantemente grandi passi avanti, soprattutto grazie alle nuove tecnologie che permettono di
analizzare nei dettagli molecolari i processi biologici che le determinano. La possibilità di decodificare il
DNA (il codice della vita) ha permesso di individuare molti di tali dettagli, ma ancora molto deve essere
fatto per comprendere appieno e quindi curare le malattie.
Per poter eseguire tali ricerche è indispensabile avere a disposizione i materiali biologici dei pazienti
affetti da queste malattie; solo così sarà possibile capire quali sono i meccanismi molecolari e genetici che
determinano la loro insorgenza. Una volta identificate le alterazioni molecolari fondamentali che causano
i tumori, sarà possibile studiare nuove molecole in grado di interferire con tali alterazioni molecolari per
ripristinare le condizioni di normalità. In gergo scientifico si parla di terapie mirate (o terapia a bersaglio)
per sottolineare come i nuovi farmaci sono studiati per interferire con uno specifico “bersaglio
molecolare”; tali farmaci oltre ad essere più efficaci rispetto alle terapie convenzionali, sono più selettivi
e quindi producono minori effetti collaterali rispetto ai farmaci chemioterapici oggi utilizzati.
Attualmente i campioni biologici che Le vengono prelevati sono analizzati ai fini diagnostici nei
Laboratori dell’Unità di Ematologia: qui vengono sottoposti ad analisi al microscopio per classificare la
malattia sulla base del loro aspetto (diagnosi istologica) e sulla base delle loro caratteristiche molecolari
(diagnosi immunoistochimica, biomolecolare e citofluorimetrica). Il resto dei campioni non utilizzato ai
fini diagnostici, viene smaltito e distrutto come rifiuto speciale. Tale materiale in eccedenza può tuttavia
rappresentare una miniera di informazioni per la ricerca medico-scientifica.
Per questo motivo l’Unità di Ematologia si propone di raccogliere e conservare questi materiali in
eccedenza, per poterli utilizzare a scopo di ricerca medica presso i due Laboratori Divisionali: il
Laboratorio di Terapia Celulare “G. Lanzani” e il Laboratorio di Diagnostica Ematologica.
Per preservarne l’integrità i campioni vengono conservati a temperature estremamente basse. A tal scopo i
Laboratori dispongono di alcuni particolari congelatori nei quali i materiali biologici sono conservati a
temperature variabili da – 80° C (freezer meccanici) a – 196° C (contenitori con azoto liquido). Inoltre
dispongono di un sistema informatico che gestisce tutti i dati relativi ai materiali conservati.
Se Lei acconsente il materiale biologico rimanente al termine delle normali analisi di routine che Lei
effettuerà potrà essere conservato e analizzato a scopo di ricerca scientifica per un tempo non superiore a
20 anni. Nel caso Lei non acconsenta il materiale eccedente verrà smaltito e distrutto.
Per tutelare la riservatezza Le garantiamo che tutti i campioni raccolti saranno trattati in forma anonima e
nel rispetto delle condizioni descritte qui sotto.
Nel caso Lei acconsenta, il materiale biologico sarà soggetto alle seguenti condizioni di utilizzo:

il campione raccolto rimanente sarà conservato presso il Laboratorio di Terapia Celulare “G. Lanzani”
e/o presso il Laboratorio di Diagnostica Ematologica con le procedure idonee a garantirne l’integrità;
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
il materiale biologico ed i relativi dati potranno essere utilizzati e/o ceduti (in forma anonima) a
Istituti universitari o ad altri Istituti di ricerca italiani o esteri per il solo fine di ricerca scientifica e
solo nell’ambito di ricerche rispettose della dignità umana, previa approvazione del Comitato Etico
competente;

il campione ed i relativi dati potranno essere utilizzati ad esclusivo scopo di ricerca scientifica e mai a
scopo di lucro diretto. Non potranno dunque essere oggetto di compravendita, come espressamente
vietato dalla Convenzione di Oviedo del 1997. Tuttavia nei limiti e nelle forme previste dalla legge 22
febbraio 2006, n. 78 (riguardante i limiti e condizioni per la brevettabilità del corpo umano) una
invenzione ottenuta a partire dai campioni biologici conservati presso i due Laboratori potrebbe essere
oggetto di brevetto, il cui sfruttamento potrebbe originare dei profitti per l’Ente che ha effettuato la
scoperta. La concessione del brevetto anche in ambito di ricerca medica è un riconoscimento
all’attività dell’inventore; gli eventuali profitti derivanti dallo sfruttamento del brevetto sono pertanto
considerati il frutto dalla capacità tecnico-scientifica di chi ha svolto la ricerca e quindi saranno gestiti
e apparterranno unicamente a tale Istituzione;

i dati derivanti dai campioni saranno trattati nel rispetto del D.Lgs. 196/2003 nonché
dall’Autorizzazione al trattamento dei dati genetici emanata dal Garante per la protezione dei dati
personali. In particolare i dati ed i relativi campioni saranno trattati esclusivamente da personale
autorizzato dai Responsabili dei Laboratori e l’accesso ai sistemi informatici e ai locali ove essi sono
custoditi sarà controllato mediante idonee misure di sicurezza. Saranno adottate tutte le misure
tecnologiche idonee a prevenire la diffusione dei dati personali o il loro utilizzo da parte di soggetti
non autorizzati;

i campioni ed i dati ad essi relativi vengono gestiti in forma codificata, ossia mediante l’attribuzione
di un codice assegnato da un sistema informatico. I ricercatori che studieranno i campioni avranno a
disposizione campioni e dati contraddistinti unicamente dal codice segreto, che impedisce loro
qualsiasi possibilità di associare i dati delle indagini scientifiche con l’identità dei donatori. Il
Responsabile del laboratorio, o un suo delegato, potranno attivare una procedura per associare i dati e
i campioni alla identità dei donatori solo in due situazioni: quando sia indispensabile per condurre uno
specifico progetto di ricerca o quando risponda a precise esigenze cliniche nell’interesse del donatore;

i Laboratori non si ritengono responsabili per eventuali danni o incidenti che possano verificarsi sui
campioni conservati e si riservano la facoltà di eliminare in qualsiasi momento il campione ed i dati
ad esso relativi;
la diffusione dei dati scientifici potrà avvenire solo in forma anonima per sole finalità scientifiche. In
pratica, i risultati delle ricerche scientifiche, potranno essere presentati nell’ambito di Convegni
ovvero su riviste specializzate senza mai permettere la precisa identificazione dei pazienti donatori.
Spesso peraltro i dati scientifici sono il risultato della analisi di grandi gruppi di campioni biologici,
provenienti da numerosissimi pazienti, per cui i risultati finali potranno essere presentati e pubblicati
in forma aggregata. Ad esempio, la identificazione di una mutazione genetica significativa per un dato
tipo di tumore può essere ottenuta solo analizzando centinaia di campioni diversi dello stesso tipo
tumorale. La divulgazione di tale scoperta sarà pertanto effettuata descrivendo la sua frequenza
all’interno di un dato gruppo di pazienti e la relazione tra mutazione, evoluzione clinica e risposta alle
terapie;
in caso in cui l’attività di raccolta e bancaggio campioni dovesse essere interrotta, la corretta
conservazione e utilizzo dei campioni sarà garantita dal Direttore dell’Unità di Ematologia degli
Ospedali Riuniti di Bergamo a cui afferiscono i Laboratori;
in ogni momento Lei potrà comunicare eventuali cambiamenti di opinione in merito a quanto
dichiarato. Nel caso desideri accedere alle informazioni relative ai propri campioni biologici, o
desideri ottenere ulteriori informazioni, si potrà rivolgere ai Responsabili dei Laboratori: Dott.
Martino Introna (Laboratorio di Terapia Cellulare G. Lanzani) e Dott.ssa Orietta Spinelli (Laboratorio
di Diagnostica ematologica) o comunque al Direttore dell’Unità di Ematologia Prof. Alessandro
Rambaldi presso l’Azienda Ospedaliera Ospedali Riuniti di Bergamo. Tutte le informazioni raccolte
saranno trattate nel rispetto della normativa italiana sulla tutela dei dati personali (D.Lgs. 196/2003)
ed il trattamento dei suoi dati è avviato con la sottoscrizione del consenso informato ed al trattamento



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Addendum D - BIO-ETHICAL REQUIREMENTS: Research on humans (Clearance from Ethics Committee)
Rambaldi Alessandro [PI]
dei dati personali, previa lettura della presente Nota informativa. Ogni partecipante ha, in ogni
momento, facoltà di esercitare i diritti di cui all’art. 7 del D.Lgs. 196/2003, qui di seguito riportato:
1.
2.
3.
4.
Diritto di accesso ai dati personali ed altri diritti
L'interessato ha diritto di ottenere la conferma dell'esistenza o meno di dati personali che lo
riguardano, anche se non ancora registrati, e la loro comunicazione in forma intelligibile.
L'interessato ha diritto di ottenere l'indicazione:
a) dell'origine dei dati personali;
b) delle finalita' e modalita' del trattamento;
c) della logica applicata in caso di trattamento effettuato con l'ausilio di strumenti elettronici;
d) degli estremi identificativi del titolare, dei responsabili e del rappresentante designato ai sensi
dell'articolo 5, comma 2;
e) dei soggetti o delle categorie di soggetti ai quali i dati personali possono essere comunicati o che
possono venirne a conoscenza in qualita' di rappresentante designato nel territorio dello Stato, di
responsabili o incaricati.
L'interessato ha diritto di ottenere:
a) l'aggiornamento, la rettificazione ovvero, quando vi ha interesse, l'integrazione dei dati;
b) la cancellazione, la trasformazione in forma anonima o il blocco dei dati trattati in violazione di
legge, compresi quelli di cui non e' necessaria la conservazione in relazione agli scopi per i quali i
dati sono stati raccolti o successivamente trattati;
c) l'attestazione che le operazioni di cui alle lettere a) e b) sono state portate a conoscenza, anche per
quanto riguarda il loro contenuto, di coloro ai quali i dati sono stati comunicati o diffusi,
eccettuato il caso in cui tale adempimento si rivela impossibile o comporta un impiego di mezzi
manifestamente sproporzionato rispetto al diritto tutelato.
L'interessato ha diritto di opporsi, in tutto o in parte:
a) per motivi legittimi al trattamento dei dati personali che lo riguardano, ancorche' pertinenti allo
scopo della raccolta;
b) al trattamento di dati personali che lo riguardano a fini di invio di materiale pubblicitario o di
vendita diretta o per il compimento di ricerche di mercato o di comunicazione commerciale.
Il Titolare del Trattamento dei dati personali (ex. D.lgs 196/2003) è il Dott. Carlo Nicora
Il Responsabile del Trattamento dei dati personali (ex. D.lgs 196/2003) è il Prof. Alessandro Rambaldi
In conclusione, ci auguriamo che questo documento redatto in accordo alle “Linee Guida” della
Presidenza del Consiglio dei Ministri, messo a punto dal Gruppo congiunto (Comitato Nazionale di
Bioetica e Comitato Nazionale per le Biotecnologie e Scienze della Vita) ) e in accordo con i
suggerimenti del Centro Nazionale di Epidemiologia, Sorveglianza e Protezione della Salute dell’ Istituto
Superiore di Sanità, possa aver con chiarezza illustrato i motivi che ci spingono a conservare e studiare il
materiale biologico ottenuto dai nostri pazienti.
Non esiti a contattarci per qualunque aspetto richieda ulteriori chiarimenti da parte nostra ai recapiti sotto
riportati.
Grazie per la collaborazione
Unità di Ematologia
Direttore Prof. Alessandro Rambaldi
A. O. Ospedali Riuniti di Bergamo, L.go Barozzi, 1 – 24128, Bergamo tel. 035.269492
fax 035.266147
Laboratorio di Terapia Cellulare “G. Lanzani”
Responsabile Dott. Martino Introna
Presidio Matteo Rota, Via G. Garibaldi, 11/13 – 24124, Bergamo tel. 035.2278684 fax 035.2278674
Laboratorio di Diagnostica Ematologica
Dott.ssa Orietta Spinelli
A. O. Ospedali Riuniti di Bergamo, L.go Barozzi, 1 – 24128, Bergamo tel. 035.266810
Codice Riferimento: 16105
Page 37 of 39
fax 035.266659
Addendum D - BIO-ETHICAL REQUIREMENTS: Research on humans (Clearance from Ethics Committee)
Rambaldi Alessandro [PI]
AZIENDA OSPEDALIERA
OSPEDALI RIUNITI DI BERGAMO
di rilievo nazionale e di alta specializzazione
USC EMATOLOGIA
Direttore Prof. Alessandro Rambaldi
MODULO PER L’ACQUISIZIONE DEL CONSENSO INFORMATO
PER LA RACCOLTA, LA CONSERVAZIONE E L’USO DI MATERIALE BIOLOGICO
Il sottoscritto/a ________________________________ nato/a a _________________ il __/__/____
Residente in _____________________________________ CAP _____________ Prov. _________
Via _____________________________________ n° _______ tel.___________________________
dichiara di:

aver letto e compreso tutte le informazioni, anche per la parte relativa al “Trattamento dei dati
personali”, riportate nella Nota Informativa relativa a: “raccolta, conservazione e uso di materiale
biologico”, di cui ha ricevuto una copia da conservare.

essere consapevole che la propria partecipazione è libera, gratuita e volontaria e che ci si può
spontaneamente ritirare, avendo ricevuto la certezza che nè il rifiuto alla donazione, nè l’eventuale
ritiro della adesione comporteranno discriminazioni.

aver ricevuto garanzia che per ulteriori informazioni potrà rivolgersi al Responsabile del trattamento
dati personali* per la conservazione dei campioni biologici o persona da lui designata.

essere stato informato che il materiale biologico prelevato nel corso dello studio
...............................………......, potrà essere conservato presso il Laboratorio di Terapia Cellulare “G.
Lanzani”, e/o presso il Laboratorio di Diagnostica Ematologica afferenti all’Unità di Ematologia per
un tempo non superiore a 20 anni, sotto la diretta responsabilità dei Responsabili dei Laboratori (Dott.
Martino Introna del Laboratorio di Terapia Cellulare “G. Lanzani”, e dott.ssa Orietta Spinelli del
Laboratorio di Diagnostica Ematologica).

essere stato informato che il materiale biologico prelevato potrà essere utilizzato per ulteriori indagini
(oltre a quelle previste nell’ambito dello studio .................…….....................), comunque sempre a
scopo esclusivo di ricerca in campo onco-ematologico finalizzato al miglioramento delle procedure
diagnostiche, prognostiche, predittive e terapeutiche, mai a fini di lucro diretto, e che le ricerche
suddette saranno previamente sottoposte al vaglio del Comitato Etico competente.

essere stato informato che saranno attuate tutte le misure atte a garantire la riservatezza e la
anonimizzazione reversibile (codifica e criptazione) del materiale biologico, sia nell’ambito delle
indagini sia nella raccolta e conservazione dei campioni, in base alla vigente normativa.

essere stato informato che saranno attuate tutte le procedure idonee a garantire l’idoneità del materiale
biologico conservato; nonostante ciò, il Laboratorio di Terapia Cellulare “G. Lanzani” e il Laboratorio
di Diagnostica Ematologica non si ritengono responsabili per eventuali danni e incidenti che possano
verificarsi e esitare nella perdita del materiale biologico conservato.

aver ricevuto garanzia che in ogni momento potrà comunicare eventuali cambiamenti di opinione in
merito a quanto autorizzato; e che in caso di ritiro dell’adesione, il campione ed i relativi dati saranno
eliminati e non potranno essere utilizzati per future ricerche, oppure verranno (su richiesta
dell’interessato) resi irreversibilmente anonimi per cui non sarà più possibile identificare il donatore.
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Addendum D - BIO-ETHICAL REQUIREMENTS: Research on humans (Clearance from Ethics Committee)
Rambaldi Alessandro [PI]
Pertanto:
1
 autorizza /  non autorizza
la raccolta, conservazione e l’uso del materiale biologico qui sotto specificato, secondo le modalità
previste dall’Informativa
 sangue periferico
 sangue midollare
 altro_________________________________
appartenente a:
 se stesso
 _______________________________ di cui il sottoscritto/a è _________________________*
nome e cognome
genitore/tutore
* Al momento del compimento dei 18 anni, questo consenso verrà risottomesso all’attenzione e alla firma
del diretto interessato
2
 acconsente /  non acconsente
all’utilizzo di detto materiale biologico per ricerca in campo onco-ematologico come sopra specificato per
studi promossi e/o condotti dall’Unità di Ematologia previamente approvati dal Comitato Etico competente
3
 acconsente /  non acconsente
alla comunicazione, nei Suoi confronti, di eventuali risultati che abbiano valore clinico e/o diagnostico
derivanti dai suddetti studi e ricerche
4
 acconsente /  non acconsente
al trattamento dei dati personali, anche di carattere genetico relativi al materiale in oggetto, per le finalità
di raccolta, mantenimento e utilizzo del materiale biologico (in base alle disposizioni del d.lgs. 196/2003)
5
 acconsente /  non acconsente
all’eventuale cessione (in forma anonima) dei dati personali e/o del campione biologico a Istituti
universitari o ad altri Istituti di ricerca italiani o esteri per il solo fine di ricerca scientifica;
Bergamo, li |__|__| / |__|__| / |__|__|__|__|
Firma dell’interessato/a ___________________________
Per l’ interessato/a se non è in grado di firmare
Bergamo, li |__|__| / |__|__| / |__|__|__|__|
Firma __________________________________________
genitore o tutore
Bergamo, li |__|__| / |__|__| / |__|__|__|__|
Firma __________________________________________
genitore o tutore
Il Sanitario che ha raccolto il consenso:
Bergamo, li |__|__| / |__|__| / |__|__|__|__|
cognome e nome _____________________________________
Firma__________________________________________
firma e timbro
I Responsabili dei Laboratori:
Dott. Martino Introna per il Laboratorio di Terapia Cellulare “G. Lanzani”,
Dott.ssa Orietta Spinelli per il Laboratorio di Diagnostica Ematologica
garantiscono il rispetto delle suddette dichiarazioni.
Codice Riferimento: 16105
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CERTIFICATO DI PUBBLICAZIONE
-----------------------------------------------------
Pubblicata all’Albo Pretorio on-line
dell’Azienda Ospedaliera
“Papa Giovanni XXIII” Bergamo
per 15 giorni
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