A Treatment Protocol for Participants 0-45 Years With Acute Lymphoblastic Leukaemia

A Treatment Study Protocol of the ALLTogether Consortium for Infants, Children and Young Adults (0-45 Years of Age) With Newly Diagnosed Acute Lymphoblastic Leukaemia (ALL): a Pilot Study

The pilot study collects the experience of previously successful treatment of infants, children and young adults, with ALL from a number of well-renowned study groups into a new platform protocol, which is both a comprehensive system for stratification and treatment of ALL in this age-group as well as the basis for several randomised trials included in the study-design.

The pilot study is implemented as a master protocol without study specific interventions, thus as an observational study. The pilot study is for countries/study-groups who intend to join ALLTogether1 (including experimental interventions). For these countries the pilot study is crucial to optimise diagnostics, registration systems, collaborations with vendors, logistics and data-checks before starting the main study.

The study only includes "standard of care" treatment included in the master protocol.

Study Overview

• Status: Recruiting
• Conditions: Leukemia, Acute Lymphoblastic
• Intervention / Treatment: Other: Observational

Detailed Description

The aims of the ALLTogether study are to improve survival and quality of survival for children and young adults with ALL. ALL in young people has excellent outcome with >90% survival in children and about 75% in young adults. However, patients still die of disease - after relapse as a result of under-treatment.

Furthermore, a considerable fraction of younger patients are over-treated: All patients risk treatment-related death and some suffer long-term side-effects or secondary cancer. The rates of death from disease and death from therapy are almost the same for children. To show improvement with such good survival, large populations are needed.

Study groups from the five Nordic countries, Estonia and Lithuania (NOPHO), the UK (UKALL), the Netherlands (DCOG), Germany (COALL), Belgium (BSPHO), Ireland (PHOAI), Portugal (SHOP) and France (SFCE) have designed a common treatment protocol as new standard of care for children and young adults with ALL. The risk-stratification is based on a novel, personalised algorithm using clinical characteristics, genetic changes in the leukaemia and response to therapy.

The protocol will, based on a personalised risk-approach, define a platform for diagnosis and treatment onto which randomized as well as non-randomised interventions and translational studies can be added. This platform can also be used by countries joining the collaboration at a later date to prepare for full participation.

High-risk B-lineage patients may be stratified to Chimeric Antigen Receptor T-cell (CAR-T) therapy as an alternative to high-risk blocks and stem-cell transplant to reduce the side-effects.

Translational and other therapy-related research will be promoted by the common master protocol.

• Study Type: Observational
• Enrollment (Estimated): 500

Contacts and Locations

• Study Contact: Name: Mats Heyman, M.D. PhD; Phone Number: +46 8 517 704 07; Email: mats.heyman@ki.se
• Study Contact Backup: Name: Karin Flood, M.Sc.; Phone Number: +46 70 321 49 22; Email: karin.flood@ki.se

Study Locations

• Denmark
  • Aalborg, Denmark, 9000
    • Active, not recruiting
    • Aalborg University Hospital, Dept of Paediatrics
  • Aarhus, Denmark, 8000
    • Active, not recruiting
    • Aarhus University Hospital
  • Aarhus, Denmark, 8200
    • Active, not recruiting
    • Aarhus University Hospital, Child and Adolescent Health
  • Copenhagen, Denmark, 2100
    • Active, not recruiting
    • Rigshospitalet, Dept of Haematology
  • Copenhagen, Denmark, 2100
    • Active, not recruiting
    • Rigshospitalet, Dept of Paediatrics
  • Odense, Denmark, 5000
    • Active, not recruiting
    • Odense University Hospital, Dept of Paediatrics
• Estonia
  • Tallinn, Estonia, 13419
    • Not yet recruiting
    • North Estonia Medical Centre, Dept of Haematology
    • Principal Investigator: Katrin Palk, M.D.
  • Tallinn, Estonia, 13419
    • Not yet recruiting
    • Tallinn Children´s Hospital, Dept of Paediatrics
    • Principal Investigator: Kristi Lepik, M.D.
  • Tartu, Estonia, 50406
    • Not yet recruiting
    • Tartu University Hospital
    • Principal Investigator: Mari Punab, M.D.
• Finland
  • Helsinki, Finland, 00029
    • Active, not recruiting
    • Helsinki University Hospital, Dept of Haematology
  • Helsinki, Finland, 00029
    • Active, not recruiting
    • Helsinki University Hospital, Dept of Paediatrics
  • Kuopio, Finland, 70029
    • Active, not recruiting
    • Kuopio University Hospital, Dept of Haematology
  • Kuopio, Finland, 70029
    • Active, not recruiting
    • Kuopio University Hospital, Dept of Paediatrics
  • Oulu, Finland, 90029
    • Not yet recruiting
    • Oulu University Hospital, Dept of Haematology, Dept of Medicine
    • Principal Investigator: Timo Siitonen, M.D.
    • Contact: Timo Siitonen, M.D.
  • Oulu, Finland, 90029
    • Active, not recruiting
    • Oulu University Hospital, Dept of Paediatrics
  • Tampere, Finland, 33521
    • Not yet recruiting
    • Tampere University Hospital, Dept of Haematology
    • Principal Investigator: Johanna Rimpiläinen, M.D.
  • Tampere, Finland, 33521
    • Active, not recruiting
    • Tampere University Hospital, Dept of Paediatrics
  • Turku, Finland, 20520
    • Not yet recruiting
    • Turku University Hospital, Clinical Haematology and Stem Cell Transplantation Unit
    • Principal Investigator: Urpu Salmenniemi, M.D.
  • Turku, Finland, 20520
    • Active, not recruiting
    • Turku University Hospital, Dept of Paediatrics
• Iceland
  • Reykjavík, Iceland, 101
    • Active, not recruiting
    • Landspitali University Hospital, Children's Hospital
• Lithuania
  • Vilnius, Lithuania, 08406
    • Active, not recruiting
    • Children's Hospital, Affiliate of Vilnius University Hospital
  • Vilnius, Lithuania, 08661
    • Active, not recruiting
    • Vilnius University Hospital
• Norway
  • Bergen, Norway, 5021
    • Active, not recruiting
    • Haukeland University Hospital, Dept of Haematology
  • Bergen, Norway, 5021
    • Active, not recruiting
    • Haukeland University Hospital, Dept of Paediatrics
  • Oslo, Norway, 0372
    • Active, not recruiting
    • Oslo University Hospital, Dept of Haematology
  • Oslo, Norway, 0424
    • Active, not recruiting
    • Oslo University Hospital, Dept of paediatric haemato- and oncology
  • Stavanger, Norway, 4011
    • Active, not recruiting
    • Stavanger University Hospital, Dept of Haematology
  • Tromsø, Norway, 9019
    • Active, not recruiting
    • University Hospital North Norway, Dept of Haematology
  • Tromsø, Norway, 9038
    • Active, not recruiting
    • University Hospital of North Norway, Dept of Paediatrics
  • Trondheim, Norway, 7006
    • Active, not recruiting
    • St. Olavs University Hospital, Dept of Paediatrics
  • Trondheim, Norway, 7030
    • Active, not recruiting
    • St. Olavs University Hospital, Dept of Haematology
• Spain
  • Barcelona, Spain
    • Recruiting
    • Hospital Universitario San Joan de Déu
    • Principal Investigator: Jose Luis Dapena, M.D.
  • Madrid, Spain
    • Recruiting
    • Hospital Infantil Universitario Nino Jesus
    • Principal Investigator: Blanca Herrero Velasco, M.D.
• Sweden
  • Gothenburg, Sweden, 41345
    • Active, not recruiting
    • Sahlgrenska University Hospital, Section for Haematology and coagulation
  • Gothenburg, Sweden, 41685
    • Active, not recruiting
    • Sahlgrenska University Hospital, Dept of Paediatric Haematology and Oncology
  • Linköping, Sweden, 58185
    • Active, not recruiting
    • Linköping University Hospital, Dept of Haematology
  • Linköping, Sweden, 58185
    • Active, not recruiting
    • Linköping University Hospital, Dept of Paediatrics
  • Lund, Sweden, 22185
    • Active, not recruiting
    • Skåne University Hospital, Dept of Haematology
  • Lund, Sweden, 22185
    • Active, not recruiting
    • Skåne University Hospital, Dept of Paediatrics
  • Stockholm, Sweden, 17176
    • Active, not recruiting
    • Karolinska University Hospital, Dept of Paediatric Oncology and Haematology
  • Stockholm, Sweden, 17176
    • Active, not recruiting
    • Karolinska University Hospital, Patient area Haematology
  • Umeå, Sweden, 90185
    • Active, not recruiting
    • Norrland University Hospital, Dept of Haematology
  • Umeå, Sweden, 90185
    • Active, not recruiting
    • Norrland University Hospital, Dept of Paediatrics
  • Uppsala, Sweden, 75185
    • Active, not recruiting
    • Uppsala University Hospital, Dept of Haematology
  • Uppsala, Sweden, 75185
    • Active, not recruiting
    • Uppsala University Hospital, Dept of Paediatric Haematology and Oncology
  • Örebro, Sweden, 70185
    • Active, not recruiting
    • Örebro University Hospital, Section for Haematology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 43 years (Child, Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Participants 0-45 years with newly diagnosed acute lymphoblastic leukaemia. The protocol has no gender-bias. The total estimated recruitment in the pilot study is 500 participants.

Description

Inclusion Criteria:

• Patients newly diagnosed with T-lymphoblastic (T-cell) or B-lymphoblastic precursor (BCP) leukaemia (ALL) according to the WHO-classification of Tumours of Haematopoietic and Lymphoid Tissues (Revised 4th edition 2017) and with a diagnosis confirmed by an accredited laboratory at a participating paediatric oncology or adult haematology centre.
• Age 0 - < 46 years (one day before 46th birthday) at the time of diagnosis, with the exception of infants with KMT2A-r BCP ALL (see exclusion criteria below).
• Patients with surface immunoglobulin negative (sIG-) BCP-ALL and an IG::MYC rearrangement, unless they have a concurrent BCL2/6 rearrangement. T-ALL patients with MYC translocations.
• Informed consent signed by the patient and/or parents/legal guardians according to country-specific age related guidelines
• The ALL diagnosis should be confirmed by an accredited laboratory at a participating paediatric oncology or adult haematology centre.
• The patient should be diagnosed and treated at a participating paediatric oncology or adult haematology centre in the participating countries.
• The patient should be a resident in one of the participating countries on a permanent basis or should intend to settle in a participating country, for instance by an application for asylum. Patients who are visiting the country as tourists should not be included. However, returning expatriots and patients who intend to stay at least for the duration of the treatment with primary diagnosis abroad may be included if no treatment has been administered and the diagnostic procedures are repeated at a participating centre.
• All women of childbearing potential (WOCBP) have to have a negative pregnancy test within 2 weeks prior to the start of treatment.

Exclusion Criteria:

• Age < 365 days and KMT2A-rearranged (KMT2A-r) BCP-ALL (documented presence of a KMT2A-split by FISH and/or a KMT2A fusion transcript). These patients will be transferred to an appropriate trial for infant KMT2A-r BCP-ALL, if available.
• Age >45 years at diagnosis.
• Patients with a previous malignant diagnosis (ALL as a second malignant neoplasm - SMN).
• Relapse of ALL.
• Patients with mature B-ALL (as defined by surface IG positivity) or any patients with IG::MYC and a concurrent BCL2/6 rearrangement.
• Patients with Ph-positive ALL (documented presence of t(9;22)(q34;q11) and/or of the BCR::ABL1 fusion transcript). These patients will be transferred to an appropriate trial for t(9;22) if available.
• Previously known ALL prone syndromes (e.g. Li-Fraumeni syndrome, germline ETV6 mutation), except for Down syndrome. Exploration for such ALL prone syndromes is not mandatory and patients in whom genetic work-up reveals a new germ-line mutation (index-cases) will remain in the study.
• Treatment with systemic corticosteroids (>10mg/m2/day) for more than one week and/or other chemotherapeutic agents in a 4-week interval prior to diagnosis (pre-treatment).
• Pre-existing contraindications to any treatment according to the ALLTogether protocol (constitutional or acquired disease prior to the diagnosis of ALL preventing adequate treatment).
• Any other disease or condition, as determined by the investigator, which could interfere with the participation in the study according to the study protocol, or with the ability of the patients to cooperate and comply with the study procedures.
• Women of childbearing potential who are pregnant at the time of diagnosis.
• Women of childbearing potential and fertile men who are sexually active and are unwilling to use adequate contraception during therapy. Efficient birth control is required, see section 17.8.
• Female patients, who are breast-feeding.
• Essential data missing from the registration of characteristics at diagnosis (in consultation with the protocol chair).

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Participants with newly diagnosed ALL	Other: Observational; Observational study - no intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Event-free survival (EFS) compared to historical controls	5 year
Overall survival (OS) compared to historical controls	5 year

Collaborators and Investigators

• Sponsor: Mats Heyman
• Collaborators: Nordic Society for Pediatric Hematology and Oncology; NordForsk; The Swedish Childhood Cancer Foundation
• Investigators: Study Chair: Mats Heyman, M.D. PhD, Karolinska University Hospital

Publications and helpful links

General Publications

• Toft N, Birgens H, Abrahamsson J, Griskevicius L, Hallbook H, Heyman M, Klausen TW, Jonsson OG, Palk K, Pruunsild K, Quist-Paulsen P, Vaitkeviciene G, Vettenranta K, Asberg A, Frandsen TL, Marquart HV, Madsen HO, Noren-Nystrom U, Schmiegelow K. Results of NOPHO ALL2008 treatment for patients aged 1-45 years with acute lymphoblastic leukemia. Leukemia. 2018 Mar;32(3):606-615. doi: 10.1038/leu.2017.265. Epub 2017 Aug 18.
• Schramm F, Zimmermann M, Jorch N, Pekrun A, Borkhardt A, Imschweiler T, Christiansen H, Faber J, Feuchtinger T, Schmid I, Beron G, Horstmann MA, Escherich G. Daunorubicin during delayed intensification decreases the incidence of infectious complications - a randomized comparison in trial CoALL 08-09. Leuk Lymphoma. 2019 Jan;60(1):60-68. doi: 10.1080/10428194.2018.1473575. Epub 2018 Jul 3.
• Mondelaers V, Suciu S, De Moerloose B, Ferster A, Mazingue F, Plat G, Yakouben K, Uyttebroeck A, Lutz P, Costa V, Sirvent N, Plouvier E, Munzer M, Poiree M, Minckes O, Millot F, Plantaz D, Maes P, Hoyoux C, Cave H, Rohrlich P, Bertrand Y, Benoit Y; Children-s Leukemia Group (CLG) of the European Organization for Research and Treatment of Cancer (EORTC). Prolonged versus standard native E. coli asparaginase therapy in childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma: final results of the EORTC-CLG randomized phase III trial 58951. Haematologica. 2017 Oct;102(10):1727-1738. doi: 10.3324/haematol.2017.165845. Epub 2017 Jul 27.
• Vora A, Goulden N, Wade R, Mitchell C, Hancock J, Hough R, Rowntree C, Richards S. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2013 Mar;14(3):199-209. doi: 10.1016/S1470-2045(12)70600-9. Epub 2013 Feb 7.
• Pieters R, de Groot-Kruseman H, Van der Velden V, Fiocco M, van den Berg H, de Bont E, Egeler RM, Hoogerbrugge P, Kaspers G, Van der Schoot E, De Haas V, Van Dongen J. Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group. J Clin Oncol. 2016 Aug 1;34(22):2591-601. doi: 10.1200/JCO.2015.64.6364. Epub 2016 Jun 6.

Study record dates

Study Major Dates

• Study Start (Actual): August 29, 2019
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 1, 2030

Study Registration Dates

• First Submitted: March 26, 2019
• First Submitted That Met QC Criteria: April 9, 2019
• First Posted (Actual): April 10, 2019

Study Record Updates

• Last Update Posted (Actual): March 19, 2024
• Last Update Submitted That Met QC Criteria: March 18, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: ALL; Leukemia; Acute Lymphoblastic; Leukaemia; ALLTogether
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Hematologic Diseases; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
• Other Study ID Numbers: ALLTogether1 pilot

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Individual participant data will be entered into the study database. The data will be used to inform the coming main study regarding safety and overall outcomes of the master protocol. As such, these outcomes may be published in the context of a comparison with the ALLTogether1 protocol (the master protocol including experimental interventions, NCT 04307576, or compared with legacy protocols of the participating study-groups, The data of the pilot protocol will be shared according to the same principles as ALLTogether1 data.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No