TBI OR CHEMOTHERAPY BASED CONDITIONING FOR CHILDREN AND ADOLESCENTS WITH ALL: A PROSPECTIVE RANDOMIZED MULTICENTER-STUDY 'FORUM' ON BEHALF OF THE AIEOP-BFM-ALL-SG, IBFM-SG, INTREALL-SG AND EBMT-PD-WP
Author(s): ,
Christina Peters
Affiliations:
Stem Cell Transplantation Unit,St. Anna Children's Hospital,Vienna,Austria
,
Jean-Hugues Dalle
Affiliations:
Robert Debré Hospital and Paris Diderot University,Paris,France
,
Franco Locatelli
Affiliations:
Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesù, Sapienza, University of Rome,Rome ,Italy
,
Ulrike Poetschger
Affiliations:
Children's Cancer Research Institute (CCRI),Vienna,Austria
,
Herbert Pichler
Affiliations:
Stem Cell Transplantation Unit, St. Anna Children's Hospital,Vienna,Austria
,
Petr Sedlacek
Affiliations:
University Hospital Motol, 2nd Medical School, Charles University Prague,Prague,Czech Republic
,
Jochen Buechner
Affiliations:
Oslo University Hospital,Oslo,Norway
,
Peter J Shaw
Affiliations:
The Children`s Hospital at Westmead Oncology Unit,Sydney,Australia
,
Raquel Staciuk Staciuk
Affiliations:
Hospital Garrahan, Ciudad Autónoma de Buenos Aires ,Buenos Aires,Argentina
,
Marianne Ifversen Ifversen
Affiliations:
Copenhagen University Hospital, Rigshospitalet Copenhagen,Copenhagen,Denmark
,
Kim Vettenranta
Affiliations:
Hospital for Children and Adolescents, University of Helsinki,Helsinki,Finland
,
Peter Svec
Affiliations:
National Institute of Childrens Diseases and Comenius University,Bratislava,Slovakia
,
Olga Aleinikova
Affiliations:
Belarusian Research Center for Pediatric Oncology, Hematology and Immunology,Minsk,Belarus
,
Jerry Stein
Affiliations:
Schneider Children's Medical Center of Israel,Petach Tikva,Israel
,
Tayfun Güngör
Affiliations:
University Children's Hospital Zürich,Zürich,Switzerland
,
Jacek Toporski
Affiliations:
Children's Hospital, Skåne University Hospital,Lund,Sweden
,
Tony H. Truong
Affiliations:
Alberta Children's Hospital,Calgary,Canada
,
Cristina Diaz De Heredia
Affiliations:
Hospital Universitario Vall D'Hebron,Barcelona,Spain
,
Marc Bierings
Affiliations:
Princess Máxima Center for Pediatric Oncology,Utrecht,Netherlands
,
Hany Ariffin
Affiliations:
University of Malaya Medical Centre,Kuala Lumpur,Malaysia
,
Mohammed Essa
Affiliations:
King Abdullah Specialist Children's Hospital, King Saud bin Abdulaziz University for Health Sciences,Riyadh,Saudi Arabia
,
Arjan Lankester
Affiliations:
Leiden University Medical Center,Leiden,Netherlands
,
Marc Ansari
Affiliations:
University Hospital of Geneva,Geneva,Switzerland
,
Martin Schrappe
Affiliations:
University Medical Centre Schleswig-Holstein,Kiel,Germany
,
Arend von Stackelberg
Affiliations:
Charité Universitätsmedizin Berlin, Charité Campus Virchow,Berlin,Germany
,
Adriana Balduzzi
Affiliations:
Clinica Pediatrica, Universita' degli Studi di Milano-Bicocca,Monza,Italy
,
Selim Corbacioglu
Affiliations:
University of Regensburg,Regensburg,Germany
Peter Bader
Affiliations:
Goethe University, University Hospital, Department for Children and Adolescents, Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine,Frankfurt am Main,Germany
(Abstract release date: 05/14/20) EHA Library. Peters C. 06/12/20; 294922; S102
Prof. Dr. C Peters
Prof. Dr. C Peters
Contributions
Abstract
This abstract is embargoed until Friday, June 12, 08:30 CEST.

Abstract: S102

Type: Presidential Symposium

Session title: Presidential Symposium

Background
TBI is the most commonly applied myeloablative strategy in ALL-patients undergoing allogeneic HSCT.

Aims
With the aim of avoiding acute and late toxicities of total body irradiation (TBI) in patients (pts) with acute lymphoblastic leukemia (ALL) undergoing haematopoietic stem cell transplantation (HSCT), we conducted a prospective, randomized, global trial (“FORUM”) to investigate whether chemotherapy-based conditioning (CC) could supplant TBI.  Here we report the initial outcome results of the randomized trial.

Methods
Children aged 4 years and older with a matched sibling donor (MSD) or matched unrelated donor (MUD) were randomized to either CC (fludarabine/thiotepa/busulfan (flu/thio/bu) or flu/thio/treosulfan (treo)) versus TBI/etoposide (TBI/eto). 75 centers in 17 countries worldwide participated. Overall survival (OS) was the primary endpoint, with an aim to demonstrate non-inferiority of the chemoconditioning. With one-sided 95% confidence intervals and a non-inferiority margin of 8%, 1000 patients were required for power of 80%. A futility-stopping rule was established to halt randomization if the CC showed significant inferiority.

Results

Between 2013 and 2018, 404 of 413 randomized pts underwent HSCT with either TBI/eto (n=202), flu/thio/bu (n=99) or flu/thio/treo (n=93). Nine patients received TBI instead of chemo-conditioning and 6 patients received chemoconditioning instead of TBI.  Patients were transplanted in CR1 (54%), CR2 (40%) and CR3 (4%). Among CR2 patients, 13% had experienced very early, 34% early and 53% late relapse. Stem cell source was BM for 337 patients (82%), PBSC for 50 patients (12%) or cord blood for 17 patients (4%). Due to significantly inferior outcome with CC, the randomization was stopped in Dec 2018. As of Nov 2019, the 2-year OS was 0.75±0.04 for CC and 0.91±0.02 for TBI/eto (med follow-up 2.1 years, intention to treat p< 0.001). In per-protocol analysis, OS after flu/thio/bu, flu/thio/treo and TBI/eto was 0.77±0.05, 0.77±0.05% and 0.91+0.02 respectively (p=0.003). The 2-year and Kaplan-Meier 5-year estimates for event-free survival (EFS), treatment related mortality (TRM), and cumulative incidence of relapse (CIR) is shown in Table1 and Figure1 respectively.

Table1: Summary of 2-yr outcome

2-yr Outcome

TBI/eto

flu/thio/bu

flu/thio/treo

P-value

OS

0.91±0.02 

0.77±0.05 

0.77±0.05 

<0.001

EFS

0.85±0.03 

0.64±0.06 

0.58±0.06 

0.003

TRM

0.03±0.01 

0.06±0.03

0.12±0.04

NS

CIR

0.12±0.04

0.30±0.05

0.31±0.05

0.004

Conclusion

Overall survival in patients ≥ 4 years of age following HSCT from a MSD or MUD with TBI/eto conditioning is superior as compared to chemo-conditioning regimen due to significantly lower relapse-incidence. Busulfan- or treosulfan-based chemo-conditioning regimen including fludarabine and thiotepa are valuable alternative options for patients who are ineligible for TBI either because of age or co-morbidity.  There was no significant difference in 2-yr TRM or incidence of acute and chronic GVHD. Prospective monitoring of late complications, endocrine functions and incidence of secondary malignancies will contribute to better define the advantages and limitations of the 3 conditioning approaches.

Session topic: 22. Stem cell transplantation - Clinical

Keyword(s): Acute lymphoblastic leukemia, Allogeneic stem cell transplant, Conditioning, Total body irradiation

This abstract is embargoed until Friday, June 12, 08:30 CEST.

Abstract: S102

Type: Presidential Symposium

Session title: Presidential Symposium

Background
TBI is the most commonly applied myeloablative strategy in ALL-patients undergoing allogeneic HSCT.

Aims
With the aim of avoiding acute and late toxicities of total body irradiation (TBI) in patients (pts) with acute lymphoblastic leukemia (ALL) undergoing haematopoietic stem cell transplantation (HSCT), we conducted a prospective, randomized, global trial (“FORUM”) to investigate whether chemotherapy-based conditioning (CC) could supplant TBI.  Here we report the initial outcome results of the randomized trial.

Methods
Children aged 4 years and older with a matched sibling donor (MSD) or matched unrelated donor (MUD) were randomized to either CC (fludarabine/thiotepa/busulfan (flu/thio/bu) or flu/thio/treosulfan (treo)) versus TBI/etoposide (TBI/eto). 75 centers in 17 countries worldwide participated. Overall survival (OS) was the primary endpoint, with an aim to demonstrate non-inferiority of the chemoconditioning. With one-sided 95% confidence intervals and a non-inferiority margin of 8%, 1000 patients were required for power of 80%. A futility-stopping rule was established to halt randomization if the CC showed significant inferiority.

Results

Between 2013 and 2018, 404 of 413 randomized pts underwent HSCT with either TBI/eto (n=202), flu/thio/bu (n=99) or flu/thio/treo (n=93). Nine patients received TBI instead of chemo-conditioning and 6 patients received chemoconditioning instead of TBI.  Patients were transplanted in CR1 (54%), CR2 (40%) and CR3 (4%). Among CR2 patients, 13% had experienced very early, 34% early and 53% late relapse. Stem cell source was BM for 337 patients (82%), PBSC for 50 patients (12%) or cord blood for 17 patients (4%). Due to significantly inferior outcome with CC, the randomization was stopped in Dec 2018. As of Nov 2019, the 2-year OS was 0.75±0.04 for CC and 0.91±0.02 for TBI/eto (med follow-up 2.1 years, intention to treat p< 0.001). In per-protocol analysis, OS after flu/thio/bu, flu/thio/treo and TBI/eto was 0.77±0.05, 0.77±0.05% and 0.91+0.02 respectively (p=0.003). The 2-year and Kaplan-Meier 5-year estimates for event-free survival (EFS), treatment related mortality (TRM), and cumulative incidence of relapse (CIR) is shown in Table1 and Figure1 respectively.

Table1: Summary of 2-yr outcome

2-yr Outcome

TBI/eto

flu/thio/bu

flu/thio/treo

P-value

OS

0.91±0.02 

0.77±0.05 

0.77±0.05 

<0.001

EFS

0.85±0.03 

0.64±0.06 

0.58±0.06 

0.003

TRM

0.03±0.01 

0.06±0.03

0.12±0.04

NS

CIR

0.12±0.04

0.30±0.05

0.31±0.05

0.004

Conclusion

Overall survival in patients ≥ 4 years of age following HSCT from a MSD or MUD with TBI/eto conditioning is superior as compared to chemo-conditioning regimen due to significantly lower relapse-incidence. Busulfan- or treosulfan-based chemo-conditioning regimen including fludarabine and thiotepa are valuable alternative options for patients who are ineligible for TBI either because of age or co-morbidity.  There was no significant difference in 2-yr TRM or incidence of acute and chronic GVHD. Prospective monitoring of late complications, endocrine functions and incidence of secondary malignancies will contribute to better define the advantages and limitations of the 3 conditioning approaches.

Session topic: 22. Stem cell transplantation - Clinical

Keyword(s): Acute lymphoblastic leukemia, Allogeneic stem cell transplant, Conditioning, Total body irradiation

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