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

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Другое Observational
  Observational study - no intervention

Первичные конечные точки

• Event-free survival (EFS) compared to historical controls [Срок оценки: 5 year]
• Overall survival (OS) compared to historical controls [Срок оценки: 5 year]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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 corresponding to (>10mg prednisolone/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 18.9.
• Female patients, who are breast-feeding.
• Essential data missing from the registration of characteristics at diagnosis (in consultation with the protocol chair).

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Швеция · 13 центров

• Sahlgrenska University Hospital, Section for Haematology and coagulation — Gothenburg
• Sahlgrenska University Hospital, Dept of Paediatric Haematology and Oncology — Gothenburg
• Linköping University Hospital, Dept of Haematology — Linköping
• Linköping University Hospital, Dept of Paediatrics — Linköping
• Skåne University Hospital, Dept of Haematology — Lund
• Skåne University Hospital, Dept of Paediatrics — Lund
• Örebro University Hospital, Section for Haematology — Örebro
• Karolinska University Hospital, Dept of Paediatric Oncology and Haematology — Stockholm
• … и ещё 5 центров

Финляндия · 10 центров

• Helsinki University Hospital, Dept of Haematology — Helsinki
• Helsinki University Hospital, Dept of Paediatrics — Helsinki
• Kuopio University Hospital, Dept of Haematology — Kuopio
• Kuopio University Hospital, Dept of Paediatrics — Kuopio
• Oulu University Hospital, Dept of Haematology, Dept of Medicine — Oulu
• Oulu University Hospital, Dept of Paediatrics — Oulu
• Tampere University Hospital, Dept of Haematology — Tampere
• Tampere University Hospital, Dept of Paediatrics — Tampere
• … и ещё 2 центра

Норвегия · 9 центров

• Haukeland University Hospital, Dept of Haematology — Bergen
• Haukeland University Hospital, Dept of Paediatrics — Bergen
• Oslo University Hospital, Dept of Haematology — Oslo
• Oslo University Hospital, Dept of paediatric haemato- and oncology — Oslo
• Stavanger University Hospital, Dept of Haematology — Stavanger
• University Hospital North Norway, Dept of Haematology — Tromsø
• University Hospital of North Norway, Dept of Paediatrics — Tromsø
• St. Olavs University Hospital, Dept of Paediatrics — Trondheim
• … и ещё 1 центр

Испания · 9 центров

• Hospital Universitario de Cruces — Barakaldo
• Hospital Universitario San Joan de Déu — Barcelona
• Hospital Universitario Vall d'Hebron — Barcelona
• Hospital Universitario La Paz — Fuencarral-El Pardo
• Hospital Infantil Universitario Nino Jesus — Madrid
• Hospital Universitario Son Espases — Palma de Mallorca
• Hospital Universitario Virgen del Rocio — Seville
• Hospital Universitario Politécnico La Fe — Valencia
• … и ещё 1 центр

Дания · 6 центров

• Aalborg University Hospital, Dept of Paediatrics — Aalborg
• Aarhus University Hospital — Aarhus
• Aarhus University Hospital, Child and Adolescent Health — Aarhus
• Rigshospitalet, Dept of Haematology — Copenhagen
• Rigshospitalet, Dept of Paediatrics — Copenhagen
• Odense University Hospital, Dept of Paediatrics — Odense

Эстония · 3 центра

• North Estonia Medical Centre, Dept of Haematology — Tallinn
• Tallinn Children´s Hospital, Dept of Paediatrics — Tallinn
• Tartu University Hospital — Tartu

Литва · 2 центра

• Children's Hospital, Affiliate of Vilnius University Hospital — Vilnius
• Vilnius University Hospital — Vilnius

Iceland · 1 центр

• Landspitali University Hospital, Children's Hospital — Reykjavik

Публикации

• 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. PMID 28819280
• 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. PMID 29966458
• 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 asp PMID 28751566
• 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. PMID 23395119
• 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. PMID 27269950
• Fermer J, van Bunningen H, Zhou O, Abrahamsson J, Borssen M, Donner I, Heyman M, Holmqvist AS, Valind A, Vogt H, Ranta S, Harila A. Early Toxicity in Childhood Acute Lymphoblastic Leukemia: A Comparison of NOPHO ALL2008 and ALLTogether Protocols in Sweden. Pediatr Blood Cancer. 2026 Feb;73(2):e32168. doi: 10.1002/pbc.32168. Epub 2025 Nov 20. PMID 41262029

Идентификаторы

NCT: NCT03911128 · ALLTogether1 pilot

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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