Clinical trial NCT01949129: Allogeneic Stem Cell Transplantation for Children and Adolescents With Acute Lymphoblastic Leukaemia
Official title: Allogeneic Stem Cell Transplantation for Children and Adolescents With Acute Lymphoblastic Leukaemia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Acute Lymphoblastic Leukaemia
Keywords: stem cell transplantation
children and adolescents
high risk acute lymphoblastic leukaemia
Lead sponsor: St. Anna Kinderkrebsforschung
Sponsor class: OTHER
Collaborators: name: ALL SCTped Forum
name: European Society for Blood and Marrow Transplantation
name: ALL-BFM Study Group
name: Assistance Publique - Hôpitaux de Paris
name: Dutch Childhood Oncology Group
name: Swiss Pediatric Oncology Group
name: Australian & New Zealand Children's Haematology/Oncology Group
First posted: 2013-09-24
Enrollment: 1800
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The ALL SCTped 2012 FORUM is a multinational, multi-centre, controlled, prospective phase III study for the therapy and therapy optimisation for children and adolescents with ALL in complete morphological remission (CR, less than 5% bone marrow blasts, no blasts in cerebrospinal fluid, no other extramedullary leukemia), who have an indication for HSCT with a myeloablative conditioning regimen.

The stratification of patients in first and following remissions according to the individual transplantation modalities rests upon an indication for allogeneic HSCT and the availability of a suitable donor within the individual transplantation groups.

Detailed description: Acute and late side effects of TBI in combination with other chemotherapeutic are manifold to the growing organism and include severe organ dysfunction/failure due to toxicity. Although transplant associated mortality was reduced after HSCT in the last decade due to better HLA matching, infection prevention and control, the burden of late complications is still a matter of concern. Growth retardation, hormonal dysfunction, sterility and the risk of secondary cancer are the late consequences of TBI in children. However, so far no prospective study has demonstrated similar outcomes in paediatric ALL using chemo-conditioning regimen before HSCT. The reason for that is manifold: only a minority of children with ALL qualifies for allogeneic HSCT as most patients are cured with sole modern chemotherapy approaches. Those with dismal prognosis are treated in HSCT centres offering a care to patients with different diseases. Therefore it is nearly impossible to answer the complex outcome questions in single centres or even in single countries. International cooperation is essential to allow prospective investigation within comparable patient cohorts.

The trial was initiated to investigate whether chemotherapy based conditioning could replace TBI in pediatric patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). It was registered and approved as a prospective, randomized, controlled, open-label, international, multicenter, phase III, non-inferiority trial. Pediatric patients with acute lymphoblastic leukemia (ALL) aged ≤18 years at diagnosis and 4-21 years at HSCT in complete remission pre-HSCT, and with an HLA-compatible related (MSD) or unrelated donor (MD) were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine (Flu), thiotepa (Thio), and either busulfan (Bu) or treosulfan (Treo). The decision to use the irradiation-free conditioning or Flu/Thio/Treo or Flu/Thio/ivBu was country specific. Patients aged \< 4 years received irradiation-free conditioning. Patients with a mismatched donor (MMD) were stratified according to the donor's stem cell source (cordblood, haploidentical tx or bone marrow/peripheral blood stem cells).

The stopping rule was applied on March 31, 2019 following a suspension of random assignment in December 2018 after the chemoconditioning was proven to be significantly inferior to TBI. As a result, TBI/VP16 conditioning remains the standard for patients older than 4 years with MSD/MD, but the age limit for TBI/VP16-based conditioning may be optionally lowered to 2 years.The use of Flu/Thio/Treo or Flu/Thio/ivBu conditioning in this age group is made at centre level based on individual patient assessment. Alternatively, patients aged 0-2 years may receive Bu/VP16/Cy at the discretion of the treating physician.

The MSD/MD randomised patients remain in a follow-up to explore the impact of risk factors on the incidence of Adverse Events of Special Interest (AESIs) and on overall survival and event free survival in the entire MSD/MD cohort.

In MMD patients, event free survival (EFS) after HSCT from HLA mismatched donors using mismatched unrelated donors (MMD), mismatched cord blood or HLA haplo-identical family members is observed

Eligibility criteria: Inclusion Criteria:

Patients with ALL (except for patients with B-ALL) who fulfil the following criteria:

* age at diagnosis ≤ 18 years. Age at HSCT ≤ 21 years
* indication for allogeneic HSCT
* complete remission (CR) before HSCT
* written consent of the parents (legal guardian) and, if necessary, the minor patient via "Informed Consent Form"
* no pregnancy
* no secondary malignancy
* no previous HSCT
* HSCT is performed in a study participating centre

Exclusion Criteria:

* patients who do not fulfil the inclusion criteria
* Non Hodgkin-Lymphoma
* the whole protocol or essential parts are declined either by patient himself/herself or the respective legal guardian
* no consent is given for saving and propagation of anonymous medical data for study reasons
* severe concomitant disease that does not allow treatment according to the protocol at the investigator's discretion (e.g. malformation syndromes, cardiac malformations, metabolic disorders)
* Karnofsky / Lansky score \< 50%
* subjects unwilling or unable to comply with the study procedures

Primary outcomes:
measure: Overall Survival (OS) Stratum 1a (randomisation TBI+ chemo-conditioning vs. chemo-conditioning only)
timeFrame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years
measure: Event free survival (EFS) Stratum 2 (mismatched donor transplantation)
timeFrame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years
measure: Overall Survival (OS), Stratum 1b: MSD/MD without randomisation
timeFrame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years
Secondary outcomes:
measure: EFS (Stratum 1a and 1b)
timeFrame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years
measure: TRM
timeFrame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years
measure: Relapse/progression
timeFrame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years
measure: Acute and late toxicity for Stratum 1a, 1b and 2
timeFrame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years
measure: OS (Stratum 2)
timeFrame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years
Other outcomes:
measure: Acute Graft versus Host Disease (aGVHD)
timeFrame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years
measure: Secondary malignancies
timeFrame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years
measure: Chronic Graft-versus-host disease (cGvHD)
timeFrame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years
Locations:
city: Buenos Aires
country: Argentina
facility: Hospital de Pediatria "Juan P. Garrahan" Combate de Los Pozos N°1800 CABA
city: La Plata
country: Argentina
facility: Hospital Sor Maria Ludovica, Department Hematology Stem Cell Transplant Unit
city: Melbourne
country: Australia
facility: Children's Cancer Centre The Royal Children's Hospital
city: Perth
country: Australia
facility: Princess Margaret Hospital for Children
city: Randwick
country: Australia
facility: Sydney Children's Hospital
city: South Brisbane
country: Australia
facility: Lady Cilento Children's Hospital
city: Sydney
country: Australia
facility: The Children's Hospital at Westmead Oncology Unit
city: Graz
country: Austria
facility: Universitätsklinik für Kinder- und Jugendheilkunde, Abt. f. Hämato-Onkologie
city: Innsbruck
country: Austria
facility: Universitätsklinik für Kinder- und Jugendheilkunde
city: Vienna
country: Austria
facility: St. Anna Children's Hospital, Vienna, Austria
city: Minsk
country: Belarus
facility: Belarusian Research Center for Pediatric Oncology, Hematology and Immunology
city: Brussels
country: Belgium
facility: Hôpital Universitaire des Enfants Reine Fabiola (HUDERF)
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc (UCL) Hématologie et oncologie pédiatrique
city: Gent
country: Belgium
facility: University Hospital Gent Pediatrische hemato-oncologie
city: Leuven
country: Belgium
facility: University Hospitals Leuven Kinderhemato-oncologie
city: Liège
country: Belgium
facility: Centre Hospitalier Universitaire de Liège Domaine Universitaire du Sart Tilman
city: Calgary
country: Canada
facility: Alberta Children's Hospital Division of Pediatric Oncology
city: Montral
country: Canada
facility: Montreal Children's Hospital
city: Montreal
country: Canada
facility: CHU Sainte-Justine Hematology-Oncology Division
city: Toronto
country: Canada
facility: Hospital for Sick Children University of Toronto Division of Haematology/Oncology
city: Vancouver
country: Canada
facility: BC Children's Hospital
city: Winnipeg
country: Canada
facility: CancerCare Manitoba/University of Manitoba
city: Santiago
country: Chile
facility: Hospital Dr Luis Calvo Mackenna
city: Zagreb
country: Croatia
facility: Department of Pediatrics, UHC Zagreb
city: Prague
country: Czechia
facility: Department of Pediatric Hematology and Oncology Teaching Hospital Motol, 2nd Medical School, Charles University
city: Copenhagen
country: Denmark
facility: Paediatric Stem Cell Transplant and Immune Deficiency, Dept. for children and adolescents 4072, Rigshospitalet
city: Helsinki
country: Finland
facility: Division of Hematology-Oncology and Stem Cell Transplantation, Hospital for Children and Adolescents, Univ. of Helsinki
city: Bordeaux
country: France
facility: CHU Bordeaux
city: Clermont-Ferrand
country: France
facility: CHU Clermont-Ferrand
city: Grenoble
country: France
facility: CHU Grenoble - Clinique Universitaire de Pédiatrie, Hôpital Couple Enfant
city: Lille
country: France
facility: CHRU Lille, Service d'Hématologie Pédiatrique
city: Lyon
country: France
facility: IHOP / Lyon, Service Hématologie et d'Oncologie pédiatrique
city: Marseille
country: France
facility: Hopital la Timone Adulte
city: Montpellier
country: France
facility: Hopital Arnaud de Villeneuve
city: Nancy
country: France
facility: CHU Nancy - Hopital d'Enfants
city: Nantes
country: France
facility: CHU Nantes, Service d'onco hémato pédiatrie
city: Paris
country: France
facility: Hôpital Robert Debré
city: Rennes
country: France
facility: CHU de Rennes, Serive d'Onco-Pédiatrie
city: Rouen
country: France
facility: CHU de Rouen, Hopital des Enfants, Service d' Immuno-Hématologie Oncologie Pédiatrique
city: Strasbourg
country: France
facility: CHU Strasbourg, Service d'hématologie et d'oncologie pédiatrique
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen, Kinder- und Jugendmedizin
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn, Abteilung für Pädiatrische Hämatologie und Onkologie
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf, Klinik für Kinder-Onkologie, -Hämatologie und Klinische Immunologie
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen, Kinder- und Jugendklinik
city: Essen
country: Germany
facility: Universitätsklinikum Essen, Klinik für Kinderheilkunde III
city: Frankfurt am Main
country: Germany
facility: Klinikum der Johann Wolfgang Goethe-Universität, Klinik für Kinder- und Jugendmedizin (KKJM)
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg, Zentrum für Kinder- und Jugendmedizin
city: Gießen
country: Germany
facility: Universitätsklinikum Gießen, Zentrum für Kinder- und Jugendmedizin
city: Greifswald
country: Germany
facility: Universitätsmedizin Greifswald, Klinik und Poliklinik für Kinder- und Jugendmedizin
city: Halle
country: Germany
facility: Universitätsklinikum Halle (Saale), Universitätsklinik und Poliklinik für Kinder- und Jugendmedizin
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Pädiatrische Hämatologie und Onkologie
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover, Zentrum Kinderheilkunde und Jugendmedizin
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg, Zentrum für Kinder- und Jugendmedizin
city: Jena
country: Germany
facility: Universitätsklinikum Jena, Sektion für Stammzelltransplantation
city: Kiel
country: Germany
facility: UKSH - Universitätsklinikum Schleswig-Holstein, Klinik für Allgemeine Pädiatrie
city: Leipzig
country: Germany
facility: Universitätsmedizin Leipzig, Abteilung für Pädiatrische Onkologie, Hämatologie und Hämostaseologie
city: München
country: Germany
facility: Klinikum der Universität München, Dr. von Haunersches Kinderspital
city: München
country: Germany
facility: Städt. Krankenhaus München Schwabing, Universitätskinderklinik der TU München
city: Münster
country: Germany
facility: Universitätsklinikum Münster, Klinik für Kinder- und Jugendmedizin
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg, Klinik und Poliklinik für Kinder- und Jugendmedizin
city: Tübingen
country: Germany
facility: Universitätsklinik für Kinder- und Jugendmedizin Tübingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm, Klinik für Kinder- und Jugendmedizin
city: Würzburg
country: Germany
facility: Universitäts-Kinderklinik Würzburg
city: Athens
country: Greece
facility: Saint Sophia Children's Hospital BMT Unit
city: Budapest
country: Hungary
facility: National Institute of Haematology and Infectious Disease, Hospital of Southern Pest, Paediatric Bone Marrow Transplantation Unit
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Petach-Tikva
country: Israel
facility: Schneider Children's Medical Center of Israel
city: Tel Aviv
country: Israel
facility: Dana Children's Hospital
city: Bologna
country: Italy
facility: Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi di Bologna
city: Florence
country: Italy
facility: Ospedale Mayer di Firenze SODc Tumori Pediatrici e TMO
city: Genoa
country: Italy
facility: Istituto Gaslini Genova Oncoematologia Pediatrica-
city: Monza
country: Italy
facility: A.O. San Gerardo di Monza Clinica Pediatrica
city: Napoli
country: Italy
facility: A.O.R.N. Santobono Pausilipon, Dipartimento di Oncoematologia
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova Oncoematologia Pediatrica
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana U.O. di Oncoematologia Pediatrica A.O.
city: Rome
country: Italy
facility: Ospedale Pediatrico Bambino Gesù, Sapienza, University of Rome
city: Torino
country: Italy
facility: Ospedale Infantile Regina Margherita SC Oncoematologia e Centro Trapianti
city: Kuala Lumpur
country: Malaysia
facility: University of Malaya, Department of Paediatrics
city: Ciudad de México
country: Mexico
facility: Instituto Nacional de Peditria
city: Leiden
country: Netherlands
facility: Leiden University Medical Center Department of Pediatrics/BMT unit
city: Utrecht
country: Netherlands
facility: Princess Máxima Center for Pediatric Oncology
city: Auckland
country: New Zealand
facility: Starship Children's Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital Rikshospitalet
city: Bydgoszcz
country: Poland
facility: University Hospital No.1, Collegium Medicum UMK, department of Paediatrics, Oncology, Hematology and Paediatric Transplantology
city: Kraków
country: Poland
facility: University Children's Hospital in Krakow, Department of Transplantation
city: Lublin
country: Poland
facility: Children's University Hospital, Dept. Pediatric Hematology, Oncology, and Transplantology
city: Poznań
country: Poland
facility: Poznan University of Medical Sciences, Department of Pediatric Onology, Hematology & HSCT
city: Wrocław
country: Poland
facility: Cape of Hope, Wroclaw Medical University
city: Bukarest
country: Romania
facility: IInsitutul Clinic Fundeni, Sectia de Transplant Medular
city: Timişoara
country: Romania
facility: University of Medicine and Pharmacy V. BABES, Emergency Children's Hospital LOUIS TURCANU, III. Clinic of Pediatrics , Department of Onco-hematology and Bone Marrow Transplantation
city: Riyadh
country: Saudi Arabia
facility: King Abdullah specialists children hospital
city: Bratislava
country: Slovakia
facility: University Children's Hospital
city: Ljubljana
country: Slovenia
facility: University childrens' hospital, UMCL
city: Barcelona
country: Spain
facility: Hospital Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Murcia
country: Spain
facility: Hospital Virgen de la Arrixaca
city: Málaga
country: Spain
facility: Hospital Materno Infantil de Málaga
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias
city: Göteborg
country: Sweden
facility: Queen Silvia Children's Hospital, Department of Pediatric Oncology (Avdelnig 321-322)
city: Lund
country: Sweden
facility: Skane University Hospital, Dept. of Pediatrics, Section for Hematology and Oncology
city: Stockholm
country: Sweden
facility: Karolinska University Hospital, Department of Pediatrics
city: Uppsala
country: Sweden
facility: University Children's Hospital, Dept. of Women's & Children's Health Section for Pediatrics
city: Basel
country: Switzerland
facility: Universitäts-Kinderspital beider Basel (UKBB)
city: Geneva
country: Switzerland
facility: HUG Hôpitaux Universitaire de Genève
city: Zurich
country: Switzerland
facility: Universitäts-Kinderspital Zurich
city: Ankara
country: Turkey
facility: Ankara University School of Medicine Pediatric Stem Cell Transplantation Unit
city: Ankara
country: Turkey
facility: Gazi University School of Medicine Pediatric Stem Cell Transplantation Unit
city: Ankara
country: Turkey
facility: Gülhane Training and Research Hospital
city: Antalya
country: Turkey
facility: Akdeniz University School of Medicine Pediatric Stem Cell Transplantation Unit
city: Antalya
country: Turkey
facility: Bahcesehir University School of Medicine Pediatric Stem Cell Transplantation Unit
city: Istanbul
country: Turkey
facility: Acibadem University Atakent Hospital Pediatric Stem Cell Transplantation Unit
city: Istanbul
country: Turkey
facility: Bahcelievler Medicalpark Hospital Pediatric Stem Cell Transplantation Unit
city: Istanbul
country: Turkey
facility: Bahcesehir University School of Medicine Pediatric Stem Cell Transplantation Unit
city: Istanbul
country: Turkey
facility: Medipol Mega Üniversite Hastanesi
city: Izmir
country: Turkey
facility: Dokuzeylul University School of Medicine Pediatric Stem Cell Transplantation Unit
city: Izmir
country: Turkey
facility: Ege University School of Medicine Pediatric Stem Cell Transplantation Unit
city: Kayseri
country: Turkey
facility: Erciyes University School of Medicine Pediatric Stem Cell Transplantation Unit
Study officials:
affiliation: St. Anna Kinderspital, Vienna, Austria
name: Christina Peters, Prof. MD PhD
role: STUDY_CHAIR
affiliation: Goethe University
name: Peter Bader, Prof. MD PhD
role: STUDY_CHAIR
affiliation: Ospedale Pediatrico Bambino Gesù, Rome, Italy
name: Franco Locatelli, Prof. MD PhD
role: STUDY_CHAIR
References:
citation: Gomez SM, Varela MA, Ruiz C, Sung L. Comparable Outcomes of Matched Sibling Donor and Matched Unrelated Donor Stem Cell Transplantation in Children With Acute Leukemia in Argentina. J Pediatr Hematol Oncol. 2021 Oct 1;43(7):e1020-e1024. doi: 10.1097/MPH.0000000000002174.
citation: Peters C, Dalle JH, Locatelli F, Poetschger U, Sedlacek P, Buechner J, Shaw PJ, Staciuk R, Ifversen M, Pichler H, Vettenranta K, Svec P, Aleinikova O, Stein J, Gungor T, Toporski J, Truong TH, Diaz-de-Heredia C, Bierings M, Ariffin H, Essa M, Burkhardt B, Schultz K, Meisel R, Lankester A, Ansari M, Schrappe M; IBFM Study Group;; von Stackelberg A; IntReALL Study Group; Balduzzi A; I-BFM SCT Study Group; Corbacioglu S; EBMT Paediatric Diseases Working Party; Bader P. Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study. J Clin Oncol. 2021 Feb 1;39(4):295-307. doi: 10.1200/JCO.20.02529. Epub 2020 Dec 17.
citation: Tasian SK, Peters C. Targeted therapy or transplantation for paediatric ABL-class Ph-like acute lymphocytic leukaemia? Lancet Haematol. 2020 Dec;7(12):e858-e859. doi: 10.1016/S2352-3026(20)30369-0. No abstract available.
citation: Choong E, Uppugunduri CRS, Marino D, Kuntzinger M, Doffey-Lazeyras F, Lo Piccolo R, Chalandon Y, Peters C, Daali Y, Ansari M. Therapeutic Drug Monitoring of Busulfan for the Management of Pediatric Patients: Cross-Validation of Methods and Long-Term Performance. Ther Drug Monit. 2018 Feb;40(1):84-92. doi: 10.1097/FTD.0000000000000468.