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FAMILY HAPLO-IDENTICAL HAEMATOPOIETIC STEM CELL TRANSPLANTATION

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					                          EBMT (ALWP and PDWP) study – September 2005
                            Haplo-identical HSCT for paediatric leukaemia




FAMILY HAPLO-IDENTICAL HAEMATOPOIETIC STEM
 CELL TRANSPLANTATION FOR PAEDIATRIC ACUTE
LEUKAEMIA – A EUROPEAN RETROSPECTIVE STUDY
   ON BEHALF OF THE ACUTE LEUKAEMIA AND
  PAEDIATRIC WORKING PARTIES OF THE EBMT.




                  J Cornish
                 T Klingebiel
                 Giorgio Dini




                September 2005




                      1
                                   EBMT (ALWP and PDWP) study – September 2005
                                     Haplo-identical HSCT for paediatric leukaemia

TABLE OF CONTENTS                                            PAGE


1.0   SUMMARY…………………………………………………..…. 3
1.1   Title………………………………………………………………… 3
1.2   Study Design……………………………………………………….. 3
1.3   Objective…………………………………………………………… 3
1.4   Inclusion Criteria……………………………………………………3
1.5   Primary End-Point…………………………………………………..3
1.6   Secondary End-Points……………………………………………… 3

2.0   RATIONALE………………...………………………………… 4
2.1   Introduction………………………………………………………… 4

3.0   END-POINTS…………………………………………………... 4
3.1   Primary…………………………………………………………….. 4
3.2   Secondary…………………………………………………………... 4

4.0   PATIENT SELECTION…………….………………………. 5
4.1   Data Source………………………………………………………… 5
4.2   Patient Inclusion Criteria…………………………………………... 5

5.0   STATISTICAL CONSIDERATIONS…………………… 5
5.1   Definition Of Outcome…………………………………………….. 5
5.2   Statistical Methods…………………………………………………. 6

6.0   PUBLICATION RULES…………….………………………. 6

7.0   REFERENCES……………………...…………………………. 7

8.0   ABSTRACT ………………………...…………………………. 8




                               2
                                               EBMT (ALWP and PDWP) study – September 2005
                                                 Haplo-identical HSCT for paediatric leukaemia

1.0   SUMMARY



1.1   TITLE
      A European, Retrospective Study Of Family Haplo-Identical Haematopoietic
      Stem Cell Transplantation For Paediatric Acute Leukaemia

1.2   STUDY DESIGN
      Retrospective, multicentre study using the EBMT database and national registries.


1.3   OBJECTIVE
      To evaluate the outcome of haplo-identical haematopoietic stem cell
      transplantation for paediatric acute leukaemia.
      To establish an appropriate EBMT registry category for such transplants.


1.4   INCLUSION CRITERIA
      Paediatric patients receiving a haplo-identical haemoatopoietic stem cell
      transplant for acute leukaemia between January 1995 - December 2004.


1.5   PRIMARY END-POINT
      Leukaemia-free survival at 2 years


1.6   SECONDARY END-POINTS
      Engraftment rates, incidence of Grades II-IV GVHD chronic GVHD, severe
      infections, relapse, overall survival and TRM




                                           3
                                                EBMT (ALWP and PDWP) study – September 2005
                                                  Haplo-identical HSCT for paediatric leukaemia

2.0    RATIONALE

2.1    INTRODUCTION

Allogeneic bone marrow (BM) and peripheral blood stem cell (PBSC) transplantation
have become the standard of care for selected patients with acute leukaemia (Gratwohl et
al, 2003). However, many patients are precluded from this potentially curative approach
because of a lack of suitably HLA matched related or unrelated donors (Confer, 1997) or
as a result of the time required to obtain unrelated donor cells (Dini et al, 2003). These
limitations have prompted the search for alternative sources of haemopoietic stem cells
(HSC). Over the last 15 years, transplantation of HSC from haplo-identical family
members has emerged as a viable alternative approach in children with high risk acute
leukaemia (Klingebiel et al, 2004;Veys et al, 2003). Critical procedural developments,
including substantial T cell depletion of the graft to prevent severe graft versus host
disease, escalating stem cell dose to overcome the barrier to engraftment and
improvements in supportive care have established this as an acceptable approach for
selected high-risk patients (Klingebiel et al, 2004;Veys et al, 2003). This study will
define the current status of haplo-identical HSCT for paediatric acute leukaemia in
Europe.



3.0    END-POINTS

3.1    PRIMARY

       Leukemia-free survival at 2 years

3.3    SECONDARY

       Neutrophil engraftment
       Platelet engraftment
       Incidence of acute graft versus host disease (GVHD)
       Incidence of chronic GVHD
       Relapse
       Overall survival
       Transplant related mortality (TRM)




                                            4
                                              EBMT (ALWP and PDWP) study – September 2005
                                                Haplo-identical HSCT for paediatric leukaemia

4.0    PATIENT SELECTION

4.1    DATA SOURCE

       EBMT and National Registries
       Missing data updated by institution data managers

4.2    PATIENT INCLUSION CRITERIA

       Age less than 16 years
       Diagnosis of de novo acute leukaemia
       Haplo-identical transplant (haplo-identical defined as ≥2/6 HLA A, B and DRB1
       antigen mismatched) between January 1995 – December 2004.


5.0    STATISTICAL CONSIDERATIONS

5.1    DEFINITION OF OUTCOME

        Outcome                                      Definition
 Neutrophil engraftment     Number of days to achieve a neutrophil count of ≥0.5x109/l
                            for 3 consecutive days
 Platelet engraftment       Number of days to achieve an unsupported platelet count of
                            ≥20x109/l
 Acute GVHD                 According to Seattle criteria.
                            Report grade II-IV only
 Chronic GVHD               According to Seattle criteria
                            Evaluable if surviving without relapse for more than 100
                            days with sustained donor engraftment
 Relapse                    Defined on the basis of morphological evidence of leukemia
                            in bone marrow, or other extra-medullary organs
 TRM                        All deaths without relapse
 LFS                        Time from transplant to relapse or death in CR




                                          5
                                                EBMT (ALWP and PDWP) study – September 2005
                                                  Haplo-identical HSCT for paediatric leukaemia

5.2    STATISTICAL METHODS


Patient, disease, and transplant-related variables will be analyzed as prognostic
factors for outcomes. Variables that will be considered are: recipient age at time
of transplantation (median), gender, cytomegalovirus (CMV) serological status
(positive vs negative), disease characteristics (ALL vs AML, FAB classification for
AML, phenotype for ALL, cytogenetics), donor characteristics (age, gender, HLA 2 or
3 antigens mismtached and KIR if HLA-C is available), disease status at transplant
(first complete remission (CR1), CR2 or more advanced disease), transplant
characteristics including year of transplant (median), previous autologous
transplant, conditioning regimen (TBI based, use of ALG/ATG), GvHD prophylaxis
(type of T cell depletion); and nucleated and CD34 cell dose.


Cumulative incidence curves will be used in a competing risks setting, death being
treated as a competing event to calculate probabilities of acute and chronic GvHD,
neutrophil recovery, TRM , relapse and infections. Probabilities of survival and LFS
will be calculated using the Kaplan-Meier estimate; the log-rank test will be used
for univariate comparisons. Risk factors for outcomes will be evaluated in
multivariate analyses, using Cox proportional hazards for LFS and survival, and
proportional sub-distribution hazard regression model of Fine and Gray for other
outcomes. All p-values will be two-sided with type I error rate fixed at 0.05. Statistical
analyses will be performed with SPSS (Inc., Chicago) and Splus (MathSoft, Inc,
Seattle) software packages.



6.0    PUBLICATION RULES

EBMT rules of publication will be used. All participating centres will receive the draft of
the manuscript to allow them to give their input. The order of the authors will be
discussed in function of the amount of work given on each manuscript and the number of
cases included. All centres will be included either in the authors or if there are too many
names in an appendix.




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                                               EBMT (ALWP and PDWP) study – September 2005
                                                 Haplo-identical HSCT for paediatric leukaemia

7.0           REFERENCES

Confer,D.L. (1997) Unrelated marrow donor registries. Curr.Opin.Hematol., 4, 408-412.

Dini,G., Valsecchi,M.G., Micalizzi,C., Busca,A., Balduzzi,A., Arcese,W., Cesaro,S.,
       Prete,A., Rabusin,M., Mazzolari,E., Di Bartolomeo,P., Sacchi,N., Pession,A.,
       Giorgiani,G., Lanino,E., Lamparelli,T., Favre,C., Bosi,A., Manzitti,C.,
       Galimberti,S., & Locatelli,F. (2003) Impact of marrow unrelated donor search
       duration on outcome of children with acute lymphoblastic leukemia in second
       remission. Bone Marrow Transplant., 32, 325-331.

Gratwohl,A., Baldomero,H., Passweg,J., Frassoni,F., Niederwieser,D., Schmitz,N., &
      Urbano-Ispizua,A. (2003) Hematopoietic stem cell transplantation for
      hematological malignancies in Europe. Leukemia, 17, 941-959.

Klingebiel,T., Handgretinger,R., Lang,P., Bader,P., & Niethammer,D. (2004)
       Haploidentical transplantation for acute lymphoblastic leukemia in childhood.
       Blood Rev., 18, 181-192.

Veys,P., Amrolia,P., & Rao,K. (2003) The role of haploidentical stem cell transplantation
       in the management of children with haematological disorders. Br.J.Haematol.,
       123, 193-206.




                                           7
                                                EBMT (ALWP and PDWP) study – September 2005
                                                  Haplo-identical HSCT for paediatric leukaemia

7.0    ABSTRACT
8.0    ABSTRACT

Risk factors of outcomes after Haploidentical hematopoietic stem cell transplants
for children with high risk acute leukaemia. A survey on behalf of the AWLP and
PDWP of the EBMT

Jacqueline Cornish, Tomas Klingibiel, Myriam Labopin, Phillip Darbyshire, Rachel
Hough, Franco Locatelli, Dietrich Niethammer, Giorgio Dini, Vanderson Rocha

In the absence of an HLA identical donor, T-cell depleted haploidentical hematopoietic
stem cell transplantation (HSCT) is an alternative option to treat children with high risk or
relapsed acute leukaemia. However very few data is available in a large series of
children. With the aim to study risk factors of outcomes we have analyzed 196 children
(<16 years old) with ALL (n=131) or AML (n=65) transplanted with a T-cell depleted bone
marrow (n=18) or peripheral blood related haploidentical HSCT from 1995 to 2004 in
Europe. The median age was 8 years and median follow-up 22 months. In the AML
group, 13 (20%) children were transplanted in CR1, 22 (34%) in CR2 and 30 (46%) in
advanced phase and in ALL group, 28 (21%) in CR1, 74 (56%) in CR2 and 81 (62%) in
more advanced phase. The majority of the patients did not receive drugs for GVHD
prophylaxis and all received myeloablative conditioning (61% of TBI). Cumulative
incidence with competing risk and KM estimates were used to calculate outcomes
probabilities. The median days of neutrophil recovery was 14 days (4-72) and 85% of
patients had signs of engraftment. Acute GVHD II-IV was observed in 17% of the
patients (8% had grade III-IV). Two-years overall LFS, relapse incidence and TRM were
27±4%, 43±3%, 30±3%, respectively. Patients transplanted with AML or ALL had similar
outcomes. LFS was 28±6%for AML and 27±4% for ALL. Among the risk factors
analysed only the disease status at transplantation was associated with LFS and relapse
incidence. Outcomes are listed below according to disease status at transplant.
 Outcomes at two years              CR1 =41       CR2=74         Advanced=81            P value
 Transplant related mortality       32±8%         26±5%          33±5%                  0.44
 Relapse                            32±8%         40±6%          51±6%                  0.03
 Leukaemia free survival            36±8%         34±6%          16±4%                  <0.0001
In fact, in a multivariate analysis for LFS and relapse only patients transplanted in
remission had better LFS and decreased relapse incidence compared with non
remission patients ( p<0.001 and p=0.006, respectively). No risk factor was found to be
associated with TRM. Most frequently, causes of death were relapse (60%) or infections
(22%). In conclusion, haploidentical HSCT is an alternative option to treat children with
high risk acute leukaemia in the absence of HLA identical donor.




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