Strategies of Treatment in Patients with Acute leukaemias by pptfiles

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    STRATEGIES OF TREATMENT IN CHILDREN WITH ACUTE
                    LEUKAEMIAS (AL)
   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 W ORKING

                           PARTIES AND EUROCORD




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1. Writing committee (alphabetical order)
J. Cornish                 (jacqueline.cornish@ubht.swest.nhs.uk)
G. Dini                    (giorgiodini@ospedale-gaslini.ge.it)
E. Gluckman                (eliane.gluckman@sls.ap-hop-paris.fr)
T. Klingebiel              (thomas.klingebiel@kgu.de)
F. Locatelli               (f.locatelli@smatteo.pv.it)
J. Ortega                  (jortega.hmi@cs.vhebron.es)


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 (see appendix, to be completed after
sending this synopsis to EBMT centres).
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 11
4.3 Definition of outcomes                                          p 11
4.2 Statistical analysis                                            p 12

5. PRATICAL ASPECTS, DATA MANAGEMENT                                p 14
5.1 Data collection and validation                                  p 14
5.2 Calendar                                                        p 15

6. GENERAL ASPECTS                                                  p 16

7. REFERENCES                                                       p 16




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                              SUMMARY OF THE STUDY


Title : Strategies of Treatment for Children 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 children with ALL or AML .



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 children with high risk 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. The age of children to be included is below 18 years.



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-Eurocord 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, or another alternative treatment including alternative      stem cell

       transplant) for children with ALL or AML



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 patient 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

        Parents have signed an informed consent to share clinical data according

          to each national rules



All children 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.



Indications for stem cell transplantation according to commonly accepted high

risk criteria


       1) ALL

                o In CR1:

                         Non response at induction treatment

                         or

                         Philadelphia pos ALL and Prednisone Poor Response

                         or

                         High Load of MRD as defined in National Protocols

                o In CR2:

                         Isolated bone marrow relapse and duration of CR1 <30

                          months (<48 for AIEOP)

                     or

                         any duration of CR1 and high MRD load as defined in

                          National Protocols (not applicable for some Countries)


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                           T-ALL (AIEOP)

                 o In >CR2 Bone marrow relapses

          2) AML

          Criteria for transplantation are following national guidelines. However, patients

          fulfilling criteria defining low risk in AML (t(15;17), t(8;21) and inv(16)) are no

          candidates for transplantation in CR1.



          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

   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.



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   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.

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:




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       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)



Disease history from HLA typing to transplant

   -   relapse or not

   -   date of relapse


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   -   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

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.




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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.

          3.2) Each 3 months during the first year and twice a year for the following 2

          years, follow-up forms will be completed.




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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
      marrow transplantation for treatment of acute lymphoblastic leukemia in children.Blood.
      2002 Mar 15;99(6):2002-8.
11.   Hongeng S, Krance RA, Bowman LC et al. Outcomes of transplantation with matched-
      sibling and unrelated donor bone marrow in children with leukemia. The Lancet. 1997;
      350: 767-771.
12.   Green A, Clarke E, Hunt L et al. Children with acute lymphoblastic leukemia who receive
      T-cell-depleted HLA mismatched marrow allografts from unrelated donors have an
      increased incidence of primary graft failure but a similar overall transplant outcome.
      Blood. 1999; 94: 2236-2246.
13.   Lang P, Handgretinger R, Niethammer D, et al. Transplantation of highly purified CD34+
      progenitor cells from unrelated donors in pediatric leukemia Blood 2002
14.   Balduzzi A, Gooley T, Anasetti C et al. Unrelated donor marrow transplantation in
      children. Blood. 1995; 86: 3247-3256.
15.   Henslee-Downey PJ, Abhyankar SH, Parrish RS et al. Use of partially mismatched
      related donors extends access to allogeneic marrow transplant. Blood.1997; 89: 3864-
      3872.


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16. Rubinstein P, Rosenfield RD, Adamson JW, Stevens CE. Stored placental blood for
      unrelated bone marrow reconstitution. Blood 1993; 81: 1679-1690.
17. Rubinstein P, Dobrila L, Rosenfield RE et al. Processing and cryopreservation of
      placental/umbilical cord blood for unrelated bone marrow reconstitution. Proc. Natl. Acad.
      Sci. USA 1995; 92: 10119-10122.
18.   Lazzari L, Corsini C, Curioni Cet al. The Milan cord blood bank and the Italian cord blood
      network. J. of Hematotherapy. 1996; 5: 117-121
19.   Wernet P, Koegler G, Hakenberg P et al. Standards and Efficiency of cord blood banking
      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-
      22.
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.
22.   Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell
      alloreactivity         in         mismatched           hematopoietic           transplants.
      Science. 2002 295 (5562):2097-100.
23.   Dini G,Valsecchi MG,Giorgiani G, et al. Impact of marrow UD search duration on the
      outcome of children with ALL in second remission. Bone Marrow Transplantation.2003,in
      press




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