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The EBMT Adult Registration Study – AL
st
December 1 2003
STRATEGIES OF TREATMENT IN ADULTS WITH ACUTE
LEUKAEMIAS
WHO ARE CANDIDATES FOR A HEMATOPOIETIC STEM CELL
TRANSPLANT
“THE REGISTRATION STUDY”
A JOINT EUROPEAN BONE AND BLOOD MARROW TRANSPLANT GROUP (EBMT) STUDY ON
BEHALF OF ACUTE LEUKAEMIA, PAEDIATRIC DISEASES AND IMMUNOBIOLOGY W ORKING
PARTIES
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The EBMT Adult Registration Study – AL
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1. Writing committee (alphabetical order)
J. Apperley (j.apperley@ic.ac.uk)
W. Arcese (arcese@bce.med.uniroma1.it )
F. Frassoni (francesco.frassoni@hsanmartino.liguria.it)
E. Gluckman (eliane.Gluckman@sls.ap-hop-paris.fr)
HJ. Kolb (kolb@med3.med.uni-muenchen.de)
M.F. Martelli (ematol@unipg.it)
Y Reisner (Yair.Reisner@weizmann.ac.il)
V. Rocha (vanderson.rocha@sls.ap-hop-paris.fr)
A. Urbano-Ispizua (aurbano@clinic.ub.es)
R. Willemze (willemze.hematology@lumc.nl)
2. Statistical analysis, coordination and data management
M. Labopin (labopin@ext.jussieu.fr)
V. Rocha (vanderson.rocha@sls.ap-hop-paris.fr)
E. Polge (polge@ext.jussieu.fr)
EBMT-ALWP Paris Office
Institut des Cordeliers 15, rue de l’Ecole de Medecine 75006 Paris
Tel +33 1 40469524
Fax +33 1 40469607
3. Participating centres
All EBMT transplant centres which have agreed to enrol their consecutive patients with
acute leukaemias (AL) to this study
All chemotherapy centres which have agreed to register patients with AL HLA typed.
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TABLE OF CONTENTS
SUMMARY OF THE STUDY p4
1. RATIONALE p5
1.1 Introduction p5
1.2 Questions and Hypothesis p6
2. OBJECTIFS p9
2.1 Main objectives p9
2.2 Secondary objectives p9
3. CRITERIA OF PATIENTS SELECTION p9
3.1 EBMT centres criteria of inclusion p9
3.2 Patients criteria of inclusion p 10
4. STATISTICAL ASPECTS OF THE ANALYSIS p 10
4.3 Definition of outcomes p 10
4.2 Statistical analysis p 11
5. PRATICAL ASPECTS, DATA MANAGEMENT p 13
5.1 Data collection and validation p 13
5.2 Calendar p 14
6. GENERAL ASPECTS p 15
7. REFERENCES p 15
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The EBMT Adult Registration Study – AL
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December 1 2003
SUMMARY OF THE STUDY
Title : Strategies of Treatment for Adults with AL who are candidates for a
Hematopoietic Stem Cell Transplant
Type of study:
Cohort prospective, multicentre, non-randomised study.
Primary objective:
To evaluate the contribution of different strategies of treatment (HLA-identical siblings
and alternative stem cell transplant) for adult patients with AL.
Secondary objectives:
First step. To evaluate the policy of each centre, the feasibility of each transplant
modality, the time to transplant.
Second step. To evaluate the risk of relapse, the transplant related mortality and the
overall survival after different treatment strategies
Inclusion criteria:
All adults with high risk acute leukaemia (ALL or AML) with an indication of stem cell
transplant according to National criteria registered at time of HLA typing results by
participating EBMT transplant centres.
Period of inclusion:
December 2003 to July 2005 (could be postponed according to the number of
patients included).
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1. Rationale
1.1 Introduction
Allogeneic hematopoietic stem cell transplants play an important role in
treating patients with high-risk acute leukaemia. However, 70 percent of the patients
who might benefit from this therapy lack an HLA identical sibling donor. Despite the
establishment of bone marrow donor registries with more than 7 million unrelated
volunteer donors worldwide, finding a fully HLA matched unrelated donor remains a
problem for many patients because of HLA polymorphism (1,2). Because of this,
efforts have turned toward using HLA partially mismatched unrelated or related
donors (3-5) and other sources of stem cells such as umbilical cord blood cells (6,7)
or G-CSF mobilized T-cell-depleted peripheral blood hematopoietic stem cells
provided by related haploidentical donors (8,9).
With better characterization of HLA types, improvements in GVHD prophylaxis
and treatment of infectious diseases, results of HLA-matched unrelated donor
transplants have become comparable to HLA matched sibling transplants in patients
with AL (10). Also, T cell-depleted HLA-matched and mismatched unrelated Bone
Marrow Transplants have also shown promising results (5, 11-15).
With the establishment of cord blood banks, more than 80,000 cord blood
units have been made available for transplantation (16-19) and facilitated more than
2,000 unrelated umbilical cord blood transplants (UCBT) mainly in children with either
malignant or non-malignant diseases. Recently, promising results of unrelated cord
blood transplants have been reported in adults patients (20, 21).
Another approach in case of absence of an HLA identical sibling donor is the
use of haplo-identical related donor. Transplantation across the histocompatibility
barrier has been made possible by extensive T-cell depletion of the graft to prevent
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GVHD and transplantation of large number of peripheral hematopoietic cells
mobilized by growth factors have helped to overcome rejection. Recently reports of
the Perugia and other teams using Haploidentical T-cell depleted peripheral blood
transplants have been very encouraging, becoming possible that all patients with
leukaemias candidate to a stem cell transplant can have a graft donor (8, 9, 22).
Consequently, the number of allogeneic BMT using alternative donors is
increasing, as is the difficulty in choosing the best donor for a specific patient.
1.2 Questions and Hypothesis
Comparative studies of outcomes after different transplant modalities, mainly after
alternative donor transplants are scarce in the literature. They are retrospective
registry based studies with many differences among the cohort analysed, and most of
them do not include consecutive patients of each participating centres. In addition
collected information is not homogenous and do not take into account the availability
of the donor and the policy of the centres performing each transplant modality.
Moreover outcomes are influenced by factors related to patient, disease, transplant
factors and also time to find a donor.
As an example, a retrospective study of the AIEOP (Associazione Italiana di
Ematologia ed Oncologia Pediatrica) (23), analyzed a cohort of 167 consecutive
children with second remission ALL after a first marrow relapse, for whom an
unrelated bone marrow donor search was activated between 1989 and 1998. Ninety-
four children (56%) relapsed before finding a donor at a median interval of 4 months
(range 10 days-56 months) from search activation, whereas the median time to
identify a donor was 5.4 months (range 1.6-15.6 months). Therefore there were
overall more relapses than donors identified.
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This example shows that many patients relapse or die before a transplant has
been performed.
In order to evaluate the modalities of treatment of patients with leukemia
candidates for a hematopoietic stem cell transplant (HSCT), the joint ALWP, PDWP
and IWP of the EBMT decided to conduct a prospective, multi-center, non
randomized trial.
In summary the following schema (Figure 1) reflects the question of this study.
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Figure 1: Schema of the study
Patient (children or adult) with acute leukaemia with an indication of SCT
HLA typing result Genoidentical SCT (registered and followed)
(registered)
No HLA matched sibling donor
Q1 : does he/she need an alternative donor?
Q2 : what type of SCT are you looking for? No (Q3 : does he/she has to have
(Decision reported ) an autologous SCT?)
(registered and followed )
MUD CB Haplo
(registered and followed)
yes no yes no
Would you perform an Haplo ?
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2. Objectives
2.1 Primary
To evaluate the contribution of different strategies of treatment (HLA-identical
siblings and other alternative treatment including alternative stem cell
transplant) for adults with AL.
2.2 Secondary
To compare
First step
Policy of each centre
Feasibility of each transplant modality
Time to transplant
Second step
Leukaemia free survival according to different transplants strategies
Relapse
Transplant related mortality (i.e. non-leukaemic deaths)
Overall survival
3. Criteria of patients selection
3.1 Criteria of inclusion of transplant centres
Transplants centres, which
are members of European Blood and Marrow Transplant Group
report their consecutive transplant results to the EBMT registry
have given their agreement to participate
In order to avoid any selections ,also chemotherapy centres will be allowed to
register the patients HLA typed.
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3.2 Patients criteria of inclusion
an HLA typing result is available
Patients have signed an informed consent to share clinical data according
to National rules
All adults with Acute Lymphoblastic Leukaemia or with Acute
Myeloblastic Leukaemia candidates for a stem cell transplant according
to National criteria in EBMT centres for whom an HLA typing result is
available.
Please note that National criteria may be different, and all information
concerning characteristics of disease must be completed in the Clinical
Report Forms (CRF).
.
4. Statistical consideration
4.1. Definition of outcomes
i) Leukaemia-free survival (LFS) is defined as time interval from transplant
to first event (either relapse or death in complete remission)
ii) Transplant-related mortality (TRM) is defined as all causes of non-
leukemic deaths
iii) Relapse incidence (RI) is defined on the basis of morphological evidence
of leukaemia in bone marrow, or other extramedullary organs. To evaluate
probability of relapse
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iv) Hematopoietic recovery: Neutrophil and platelet recoveries were
analysed separately, and defined by a neutrophil count of 0.5 x 109/L for
three consecutive days and non transfused platelet count of 50 x109/l for
seven consecutive days, respectively.
v) Graft versus host disease: Acute graft versus host disease (aGVHD) is
diagnosed and graded at each transplant centre according to Seattle
criteria. Only patients with grade II or superior are considered as having
GHVD. Chronic GVHD (cGVHD) is defined according to standard criteria .
Patients surviving without relapse for more than 100 days post-transplant
with sustained donor engraftment are considered as evaluable for chronic
GVHD.
4.2. Statistical methods:
Patients will be analysed separately according to their Country, to the diagnosis (ALL
or AML) and to their status at time of HLA typing (CR1, CR2, >CR2).
The predictive effect of each of the following variables will be assessed:
- modalities of treatment:
o HLA identical sibling
o Marrow unrelated donor transplant
o Unrelated Cord blood transplant
o Haplo-identical donor
The analysis will be done according to the initial treatment decision for the primary
endpoint.
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For the other endpoints, comparisons will be done according to the type of treatment
received.
The intention to treat will be defined, for each patient by:
1) the choice of the treatment reported to be planned by the center in each
questionnaire (figure 1)
2) the real modality performed according to the last option and donor
availability.
For example, patients with an available HLA identical sibling donor, but who
relapse or die before being transplanted will be analysed in the group of “HLA
identical siblings”. The same example is valid for the others modalities, when
the indication of a specific transplant has been made.
Analyses will be adjusted for other potential prognostic factors:
Patient-related variables
Recipient sex ( Male versus Female)
Recipient age
Country
Disease-related variables
White blood cell count at diagnosis
Immunophenotype
Karyotype and or important molecular markers
Donor-related variables
- Gender match (male-female vs. female-male vs. gender match)
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Disease history from HLA typing to transplant
- relapse or not
- date of relapse
- date of subsequent remission
- Karnofsky score at time of transplant
Transplant-related factors
- Source of stem cells
- Conditioning regimen (TBI vs. none, BUCY vs. others)
- Immunosuppression (ATG/monoclonal antibody vs. none)
Statistical tools used to estimate incidences and to assess the influence of each
factor on either outcome, either lonely or jointly, are the Kaplan Meier estimator and
the Cox regression model. However, since relapse and non leukemic deaths are
events that compete, estimations of incidence of these events relied of the non
parametric estimator of cumulative incidence curves while predictive analyses will be
based on the proportional hazards model for these subdistribution of competing risks.
5. Practical aspects, data management
5.1 Data collection and validation
Specific questionnaires (see annex) are used to collect all data related to patients,
donors, disease and transplants. These questionnaires are compatible with MED-B
forms and MED-C items will be added in PROMISE if possible to allow entering data
via Internet.
A medical doctor will be in charge for the clinical validation of the data, and all
queries will be asked to the transplant centres before entering the data or, in case of
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Promise, all the data will be checked by the acute leukaemia WP. This imply that the
participating investigator must contact Emmanuelle Polge before entering the data.
5.2. Calendar
This study encompasses different steps at different times. The date of the registration
of the patient will be considered as the date of HLA typing test. For each step, a
specific questionnaire has to be completed:
1) REGISTRATION FORM : this form includes information on patients,
disease and availability of a HLA identical donor. It includes also the
results of HLA typing of the patient and potential family donor (HLA
identical or not). The centre will be asked to answer Q1 and Q2 and Q3
(see figure 1) according to patient and disease characteristics and to the
results of the HLA typing.
2) 3 months after the registration, the central office in Paris will send the
report “ 3 MONTHS FORM AFTER REGISTRATION” to be completed. In
addition to the disease history, this form will contain the information on the
transplant (if already done). At this time, the results of the donor search will
be asked as well as the decision of the transplant center. If the transplant
has not been performed at this time the same questionnaire will be sent
again 6 and 12 months later after registration. One year after the date of
the registration the same questionnaire will be sent once a year for those
patients not transplanted at this time.
3) ONCE THE PATIENT RECEIVED A TRANSPLANT
3.1) 100 days after the transplant, the ALLOTRANSPLANT FORM will be
sent.
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3.2) Each 3 months during the first year and twice a year for the following 2
years, follow-up forms will be completed.
6. GENERAL ASPECTS
6.1 Publications rules
Rules of publication of the EBMT will be used.
7. REFERENCES
1. Sasazuki T, Juji T, Morishima Y et al. Effect of matching of class I HLA alleles on clinical
outcome after transplantation of hematopoietic stem cells from an unrelated donor. N
Engl J Med. 1998; 339: 1177-1193.
2. Petersdorf EW, Gooley TA, Anasetti C et al. Optimizing outcome after unrelated marrow
transplantation by comprehensive matching of HLA class I and II alleles in the donor and
recipient. Blood. 1998; 92: 3515-3520.
3. Ash RC, Casper JT, Chitambar et al: Successful allogeneic transplantation of T-cell-
depleted bone marrow from closely HLA-matched unrelated donors. N Engl Journal Med.
1990; 322: 485-494.
4. Szydlo R, Goldman JM, Klein JP et al. Results of allogeneic bone marrow transplants for
leukemia using donors other than HLA identical siblings. J Clin. Oncol. 1997; 15: 1767-
1777.
5. Henslee-Downey PJ, Gluckman E. Allogeneic transplantation from donors other than
HLA-identical siblings. Hematology/Oncology clinics of North America. 1999; 13: 1017-
1039
6. Broxmeyer HE, Douglas GW, Hangoc G et al. Human umbilical cord blood as a potential
source of transplantable hematopoietic stem/progenitor cells. Proc-Natl-Acad-Sci-USA.
1989; 86: 3828-3832.
7. Gluckman E, Rocha V, Chevret S. Related and unrelated cord bloodtransplantation. In:
SBA Cohen, E. Gluckman, P. Rubinstein, JA Madrigal eds. Cord blood characteristics:
Role in stem cell transplantation. Martin Dunitz Ltd, London UK, 2000: 205-216.
8. Aversa F, Tabilio A, Velardi A, et al. Treatment of high-risk acute leukemia with T-cell-
depleted stem cells from related donors with one fully mismatched HLA haplotype. N
Engl J Med. 1998; 339: 1186-1193.
9. Handgretinger R, Klingebiel T, Lang P, et al. Megadose transplantation of purified
peripheral blood CD34+ progenitor cells from HAL-mismatched parental donors in
children Bone Marrow Transplantation 27: 777-783 (2001)
10. Woolfrey AE, Anasetti C, Storer Bet al. Factors associated with outcome after unrelated
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11. Hongeng S, Krance RA, Bowman LC et al. Outcomes of transplantation with matched-
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12. Green A, Clarke E, Hunt L et al. Children with acute lymphoblastic leukemia who receive
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Blood. 1999; 94: 2236-2246.
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13. Lang P, Handgretinger R, Niethammer D, et al. Transplantation of highly purified CD34+
progenitor cells from unrelated donors in pediatric leukemia Blood 2002
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children. Blood. 1995; 86: 3247-3256.
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related donors extends access to allogeneic marrow transplant. Blood.1997; 89: 3864-
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16. Rubinstein P, Rosenfield RD, Adamson JW, Stevens CE. Stored placental blood for
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by the international Netcord organization. Blood. 1999; 94: 344b.
20. Laughlin MJ, Barker J, Bambach B, et al. Hematopoietic engraftment and survival in adult
recipients of umbilical-cord blood from unrelated donors. N Engl J Med. 2001;344 :1815-
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21. Sanz GF, Saavedra S, Planelles D, et al. Standardized, unrelated donor cord blood
transplantation in adults with hematologic malignancies. Blood. 2001; 98 (8):2332-8.
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alloreactivity in mismatched hematopoietic transplants.
Science. 2002 295 (5562):2097-100.
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outcome of children with ALL in second remission. Bone Marrow Transplantation.2003,in
press
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