Allogeneic Stem Cell Transplantation for Children and Adolescents With Acute Lymphoblastic Leukaemia

Acute Lymphoblastic Leukaemia Clinical Trial

Official title:

Allogeneic Stem Cell Transplantation for Children and Adolescents With Acute Lymphoblastic Leukaemia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01949129
• Other study ID #: ALL SCTped FORUM 2012
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: April 2013
• Est. completion date: April 2030

Study information

• Verified date: January 2024
• Source: St. Anna Kinderkrebsforschung
• Contact: Christina Peters, Prof. MD PhD
• Phone: +43140170
• Email: christina.peters[@]stanna.at
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1800
• Est. completion date: April 2030
• Est. primary completion date: June 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Month to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukaemia
• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• VP16
60 mg/kg BW,1 day in TBI/VP16 conditioning; 40 mg/kg BW in Bu/VP16/Cy conditioning

Radiation:
• TBI
2 x 2Gy/day , 3 days (total 12Gy)

Drug:
• Thiotepa
2x5 mg/kg BW, 1 day
• Treosulfan
14g/m² BS, 3 days
• Fludarabine
30 mg/m² BS, 5 days
• Busulfan
iV, dosage according therapeutic drug monitoring, 4 days
• ATG Thymoglobulin
MD: ATG Thymo: 2,5mg/kg BW/d 3 days.
• Cyclophosphamide
as part of conditioning 60 mg/kg BW 2 days or as GvHD Prophylaxis 50mg/kg BW/d 2 days with Mesna
• Grafalon
MD: 15mg/kg BW/d 3 days MMD: 10mg/kg BW/d 3 days

Locations

Country	Name	City	State
Argentina	Hospital de Pediatria "Juan P. Garrahan" Combate de Los Pozos N°1800 CABA	Buenos Aires
Argentina	Hospital Sor Maria Ludovica, Department Hematology Stem Cell Transplant Unit	La Plata
Australia	Children's Cancer Centre The Royal Children's Hospital	Melbourne
Australia	Princess Margaret Hospital for Children	Perth
Australia	Sydney Children's Hospital	Randwick
Australia	Lady Cilento Children's Hospital	South Brisbane
Australia	The Children's Hospital at Westmead Oncology Unit	Sydney
Austria	Universitätsklinik für Kinder- und Jugendheilkunde, Abt. f. Hämato-Onkologie	Graz
Austria	Universitätsklinik für Kinder- und Jugendheilkunde	Innsbruck
Austria	St. Anna Children's Hospital, Vienna, Austria	Vienna
Belarus	Belarusian Research Center for Pediatric Oncology, Hematology and Immunology	Minsk
Belgium	Cliniques Universitaires Saint-Luc (UCL) Hématologie et oncologie pédiatrique	Brussels
Belgium	Hôpital Universitaire des Enfants Reine Fabiola (HUDERF)	Brussels
Belgium	University Hospital Gent Pediatrische hemato-oncologie	Gent
Belgium	University Hospitals Leuven Kinderhemato-oncologie	Leuven
Belgium	Centre Hospitalier Universitaire de Liège Domaine Universitaire du Sart Tilman	Liège
Canada	Alberta Children's Hospital Division of Pediatric Oncology	Calgary
Canada	Montreal Children's Hospital	Montral
Canada	CHU Sainte-Justine Hematology-Oncology Division	Montreal
Canada	Hospital for Sick Children University of Toronto Division of Haematology/Oncology	Toronto
Canada	BC Children's Hospital	Vancouver
Canada	CancerCare Manitoba/University of Manitoba	Winnipeg
Chile	Hospital Dr Luis Calvo Mackenna	Santiago
Croatia	Department of Pediatrics, UHC Zagreb	Zagreb
Czechia	Department of Pediatric Hematology and Oncology Teaching Hospital Motol, 2nd Medical School, Charles University	Prague
Denmark	Paediatric Stem Cell Transplant and Immune Deficiency, Dept. for children and adolescents 4072, Rigshospitalet	Copenhagen
Finland	Division of Hematology-Oncology and Stem Cell Transplantation, Hospital for Children and Adolescents, Univ. of Helsinki	Helsinki
France	CHU Bordeaux	Bordeaux
France	CHU Clermont-Ferrand	Clermont-Ferrand
France	CHU Grenoble - Clinique Universitaire de Pédiatrie, Hôpital Couple Enfant	Grenoble
France	CHRU Lille, Service d'Hématologie Pédiatrique	Lille
France	IHOP / Lyon, Service Hématologie et d'Oncologie pédiatrique	Lyon
France	Hopital la Timone Adulte	Marseille
France	Hopital Arnaud de Villeneuve	Montpellier
France	CHU Nancy - Hopital d'Enfants	Nancy
France	CHU Nantes, Service d'onco hémato pédiatrie	Nantes
France	Hôpital Robert Debré	Paris
France	CHU de Rennes, Serive d'Onco-Pédiatrie	Rennes
France	CHU de Rouen, Hopital des Enfants, Service d' Immuno-Hématologie Oncologie Pédiatrique	Rouen
France	CHU Strasbourg, Service d'hématologie et d'oncologie pédiatrique	Strasbourg
Germany	Uniklinik RWTH Aachen, Kinder- und Jugendmedizin	Aachen
Germany	Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum	Berlin
Germany	Universitätsklinikum Bonn, Abteilung für Pädiatrische Hämatologie und Onkologie	Bonn
Germany	Universitätsklinikum Düsseldorf, Klinik für Kinder-Onkologie, -Hämatologie und Klinische Immunologie	Düsseldorf
Germany	Universitätsklinikum Erlangen, Kinder- und Jugendklinik	Erlangen
Germany	Universitätsklinikum Essen, Klinik für Kinderheilkunde III	Essen
Germany	Klinikum der Johann Wolfgang Goethe-Universität, Klinik für Kinder- und Jugendmedizin (KKJM)	Frankfurt am Main
Germany	Universitätsklinikum Freiburg, Zentrum für Kinder- und Jugendmedizin	Freiburg
Germany	Universitätsklinikum Gießen, Zentrum für Kinder- und Jugendmedizin	Gießen
Germany	Universitätsmedizin Greifswald, Klinik und Poliklinik für Kinder- und Jugendmedizin	Greifswald
Germany	Universitätsklinikum Halle (Saale), Universitätsklinik und Poliklinik für Kinder- und Jugendmedizin	Halle
Germany	Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Pädiatrische Hämatologie und Onkologie	Hamburg
Germany	Medizinische Hochschule Hannover, Zentrum Kinderheilkunde und Jugendmedizin	Hannover
Germany	Universitätsklinikum Heidelberg, Zentrum für Kinder- und Jugendmedizin	Heidelberg
Germany	Universitätsklinikum Jena, Sektion für Stammzelltransplantation	Jena
Germany	UKSH - Universitätsklinikum Schleswig-Holstein, Klinik für Allgemeine Pädiatrie	Kiel
Germany	Universitätsmedizin Leipzig, Abteilung für Pädiatrische Onkologie, Hämatologie und Hämostaseologie	Leipzig
Germany	Klinikum der Universität München, Dr. von Haunersches Kinderspital	München
Germany	Städt. Krankenhaus München Schwabing, Universitätskinderklinik der TU München	München
Germany	Universitätsklinikum Münster, Klinik für Kinder- und Jugendmedizin	Münster
Germany	Universitätsklinikum Regensburg, Klinik und Poliklinik für Kinder- und Jugendmedizin	Regensburg
Germany	Universitätsklinik für Kinder- und Jugendmedizin Tübingen	Tübingen
Germany	Universitätsklinikum Ulm, Klinik für Kinder- und Jugendmedizin	Ulm
Germany	Universitäts-Kinderklinik Würzburg	Würzburg
Greece	Saint Sophia Children's Hospital BMT Unit	Athens
Hungary	National Institute of Haematology and Infectious Disease, Hospital of Southern Pest, Paediatric Bone Marrow Transplantation Unit	Budapest
Israel	Rambam Medical Center	Haifa
Israel	Schneider Children's Medical Center of Israel	Petach-Tikva
Israel	Dana Children's Hospital	Tel Aviv
Italy	Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi di Bologna	Bologna
Italy	Ospedale Mayer di Firenze SODc Tumori Pediatrici e TMO	Florence
Italy	Istituto Gaslini Genova Oncoematologia Pediatrica-	Genoa
Italy	A.O. San Gerardo di Monza Clinica Pediatrica	Monza
Italy	A.O.R.N. Santobono Pausilipon, Dipartimento di Oncoematologia	Napoli
Italy	Azienda Ospedaliera di Padova Oncoematologia Pediatrica	Padova
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia
Italy	Azienda Ospedaliero Universitaria Pisana U.O. di Oncoematologia Pediatrica A.O.	Pisa
Italy	Ospedale Pediatrico Bambino Gesù, Sapienza, University of Rome	Rome
Italy	Ospedale Infantile Regina Margherita SC Oncoematologia e Centro Trapianti	Torino
Malaysia	University of Malaya, Department of Paediatrics	Kuala Lumpur
Mexico	Instituto Nacional de Peditria	Ciudad de México
Netherlands	Leiden University Medical Center Department of Pediatrics/BMT unit	Leiden
Netherlands	Princess Máxima Center for Pediatric Oncology	Utrecht
New Zealand	Starship Children's Hospital	Auckland
Norway	Oslo University Hospital Rikshospitalet	Oslo
Poland	University Hospital No.1, Collegium Medicum UMK, department of Paediatrics, Oncology, Hematology and Paediatric Transplantology	Bydgoszcz
Poland	University Children's Hospital in Krakow, Department of Transplantation	Kraków
Poland	Children's University Hospital, Dept. Pediatric Hematology, Oncology, and Transplantology	Lublin
Poland	Poznan University of Medical Sciences, Department of Pediatric Onology, Hematology & HSCT	Poznan
Poland	Cape of Hope, Wroclaw Medical University	Wroclaw
Romania	IInsitutul Clinic Fundeni, Sectia de Transplant Medular	Bukarest
Romania	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	Timisoara
Saudi Arabia	King Abdullah specialists children hospital	Riyadh
Slovakia	University Children's Hospital	Bratislava
Slovenia	University childrens' hospital, UMCL	Ljubljana
Spain	Hospital Santa Creu i Sant Pau	Barcelona
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Hospital Materno Infantil de Málaga	Málaga
Spain	Hospital Virgen de la Arrixaca	Murcia
Spain	Hospital Universitario Central de Asturias	Oviedo
Sweden	Queen Silvia Children's Hospital, Department of Pediatric Oncology (Avdelnig 321-322)	Göteborg
Sweden	Skane University Hospital, Dept. of Pediatrics, Section for Hematology and Oncology	Lund
Sweden	Karolinska University Hospital, Department of Pediatrics	Stockholm
Sweden	University Children's Hospital, Dept. of Women's & Children's Health Section for Pediatrics	Uppsala
Switzerland	Universitäts-Kinderspital beider Basel (UKBB)	Basel
Switzerland	HUG Hôpitaux Universitaire de Genève	Geneva
Switzerland	Universitäts-Kinderspital Zurich	Zurich
Turkey	Ankara University School of Medicine Pediatric Stem Cell Transplantation Unit	Ankara
Turkey	Gazi University School of Medicine Pediatric Stem Cell Transplantation Unit	Ankara
Turkey	Gülhane Training and Research Hospital	Ankara
Turkey	Akdeniz University School of Medicine Pediatric Stem Cell Transplantation Unit	Antalya
Turkey	Bahcesehir University School of Medicine Pediatric Stem Cell Transplantation Unit	Antalya
Turkey	Acibadem University Atakent Hospital Pediatric Stem Cell Transplantation Unit	Istanbul
Turkey	Bahcelievler Medicalpark Hospital Pediatric Stem Cell Transplantation Unit	Istanbul
Turkey	Bahcesehir University School of Medicine Pediatric Stem Cell Transplantation Unit	Istanbul
Turkey	Medipol Mega Üniversite Hastanesi	Istanbul
Turkey	Dokuzeylul University School of Medicine Pediatric Stem Cell Transplantation Unit	Izmir
Turkey	Ege University School of Medicine Pediatric Stem Cell Transplantation Unit	Izmir
Turkey	Erciyes University School of Medicine Pediatric Stem Cell Transplantation Unit	Kayseri

Sponsors (8)

Lead Sponsor	Collaborator
St. Anna Kinderkrebsforschung	ALL SCTped Forum, ALL-BFM Study Group, Assistance Publique - Hôpitaux de Paris, Australian & New Zealand Children's Haematology/Oncology Group, Dutch Childhood Oncology Group, European Society for Blood and Marrow Transplantation, Swiss Pediatric Oncology Group

Countries where clinical trial is conducted

Argentina,  Australia,  Austria,  Belarus,  Belgium,  Canada,  Chile,  Croatia,  Czechia,  Denmark,  Finland,  France,  Germany,  Greece,  Hungary,  Israel,  Italy,  Malaysia,  Mexico,  Netherlands,  New Zealand,  Norway,  Poland,  Romania,  Saudi Arabia,  Slovakia,  Slovenia,  Spain,  Sweden,  Switzerland,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Acute Graft versus Host Disease (aGVHD)	According to the modified Seattle Glucksberg criteria	first: 18 months after inclusion of first patient, afterwards annually up to 10 years
Other	Secondary malignancies	Incidence, type and timepoint of occurence	first: 18 months after inclusion of first patient, afterwards annually up to 10 years
Other	Chronic Graft-versus-host disease (cGvHD)	Chronic GVHD is diagnosed using criteria created through the NIH consensus development project	first: 18 months after inclusion of first patient, afterwards annually up to 10 years
Primary	Overall Survival (OS) Stratum 1a (randomisation TBI+ chemo-conditioning vs. chemo-conditioning only)	Stratum 1 - randomisation related question was closed in December 2018; patients are in active follow-up: To show that a non total body irradiation (TBI) containing conditioning (Flu/Thio/ivBu or Flu/Thio/Treo) results in a non-inferior survival as compared to conditioning with TBI/Etoposide in children older than 4 years after HSCT from a Human leucocyte antigen (HLA) identical sibling donor (MSD) or a HLA matched donor (MD). The primary endpoint is the OS calculated from the date of the randomisation. Death from any cause will be considered an event.	first: 18 months after inclusion of first patient, afterwards annually up to 10 years
Primary	Event free survival (EFS) Stratum 2 (mismatched donor transplantation)	EFS after allogeneic HSCT. EFS calculated from date of recruitment to disease progression or relapse, secondary neoplasm and death from any cause.	first: 18 months after inclusion of first patient, afterwards annually up to 10 years
Primary	Overall Survival (OS), Stratum 1b: MSD/MD without randomisation	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	first: 18 months after inclusion of first patient, afterwards annually up to 10 years
Secondary	EFS (Stratum 1a and 1b)	EFS calculated from date of randomization (1a) or recruitment (1b) to disease progression or relapse, secondary neoplasm and death from any cause. Patients lost to follow-up without event will be censored at the date of their last follow-up evaluation.	first: 18 months after inclusion of first patient, afterwards annually up to 10 years
Secondary	TRM	Cumulative Incidence of Treatment-related mortality (TRM) for Stratum 1 and 2.	first: 18 months after inclusion of first patient, afterwards annually up to 10 years
Secondary	Relapse/progression	Cumulative Incidence of Relapse for Stratum 1a, 1b and 2.	first: 18 months after inclusion of first patient, afterwards annually up to 10 years
Secondary	Acute and late toxicity for Stratum 1a, 1b and 2	according a preselection out of CTC3	first: 18 months after inclusion of first patient, afterwards annually up to 10 years
Secondary	OS (Stratum 2)	The primary endpoint is the OS calculated from the date of the recruitment . Death from any cause will be considered an event.	first: 18 months after inclusion of first patient, afterwards annually up to 10 years

External Links

•   Peters C et al. 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
•   St. Anna Kinderkrebsforschung
•   St. Anna Kinderspital