Clinical trial NCT04307576: A Treatment Study Protocol for Participants 0-45 Years With Acute Lymphoblastic Leukaemia
Official title: ALLTogether1 - A Treatment Study Protocol of the ALLTogether Consortium for Children and Young Adults (0-45 Years of Age) With Newly Diagnosed Acute Lymphoblastic Leukaemia (ALL)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Leukemia, Acute Lymphoblastic
Keywords: Leukemia
Acute Leukemia
ALL
ALLTogether
Leukaemia
Inotuzumab ozogamicin
Besponsa
ALLTogether1
Blinatumomab
Blincyto
6-tioguanine
6-thioguanine
Lead sponsor: Karolinska University Hospital
Sponsor class: OTHER
Collaborators: name: The Swedish Research Council
name: The Swedish Childhood Cancer Foundation
name: Pfizer
name: Servier
name: NordForsk
name: Aamu Pediatric Cancer Foundation
name: German Society for Pediatric Oncology and Hematology GPOH gGmbH
name: Clinical Trial Center North (CTC North GmbH & Co. KG)
name: Belgium Health Care Knowledge Centre
name: Karolinska Institutet
name: Cancer Research UK
name: Fundação Rui Osório de Castro
name: Acreditar - Associação de Pais e Amigos das Crianças com Cancro
name: Grupo Português De Leucemias Pediátricas
name: Amgen
name: Nova Laboratories Limited
name: Danish Child Cancer Foundation
name: Danish Cancer Society
name: The Novo Nordic Foundation
name: Assistance Publique - Hôpitaux de Paris
name: Direction Générale de l'Offre de Soins
First posted: 2020-03-13
Enrollment: 6430
Sex: ALL
Minimum age (years): 0
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Master protocol with risk-stratification. The risk-stratified groups will proceed to non-randomised or randomised interventions in single arm (TKI) and (Blinatumomab) and parallel (R1/R2/R3) models respectively.
Primary purpose: TREATMENT

Brief summary: ALLTogether 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 master 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 and interventional trials included in the study-design.

Detailed description: ALLTogether is a European clinical treatment study for acute lymphoblastic leukaemia (ALL) in infants, children and young adults. The aims are to improve survival and quality of survival. In young people, ALL has excellent outcome with an overall survival of about 92% in children and 75% in young adults. Infants with BCP-ALL and KMT2A-rearrangements have a worse outcome and are treated according to separate protocols, but infants with KMT2A-germline and T-cell ALL have acceptable outcome on standard ALL therapy. However, patients still die of disease - from relapse because of under-treatment and a large fraction of patients are also over-treated: All patients risk treatment-related death and some suffer long-term side-effects or secondary cancer. To show improvement with such good survival, large populations are needed.

Study groups from Sweden, Norway, Iceland, Denmark, Finland, Estonia and Lithuania (NOPHO), the UK (UKALL), the Netherlands (DCOG), Germany (COALL), Belgium (BSPHO), Portugal (SHOP), Ireland (PHOAI), and France (SFCE), have designed a common treatment protocol.

The study has a complex clinical trial design with sub-protocols (the randomisations / intervention) connected to a master protocol. The master protocol consists of well established therapy-elements and in its design typical for current ALL therapy. The master protocol therapy is in the study design considered as standard of care (SOC) therapy for infants, children and young adults with ALL.

The study structure is defined by a master protocol onto which randomised and interventional sub-protocols as well as sub-studies may be added, run and stop in a modular fashion.

The randomisations / intervention may identify therapy that is less toxic, but equally efficacious for sub-groups of patients and innovative therapy that may reduce relapses and death from ALL. In the master protocol, improved risk-stratification is likely to increase survival and reduce unnecessary toxicity and the introduction of therapeutic drug monitoring (TDM) of Asparaginase activity will make the use of Asparaginase more rational and efficient and may thus improve overall outcomes.

The investigators hypothesise that patients stratified to the standard-risk group are over-treated. Therefore, it will be tested if the treatment can be safely reduced. In the R1 randomisation, patients will be randomised to receiving the Delayed Intensification (DI) phase of therapy with or without the anthracycline Doxorubicin.

A similar hypothesis of over-treatment will also be tested in patients stratified to the intermediate risk-low group. In the R2 randomisation patients will be randomly assigned to either removal of Doxorubicin during the DI phase or removal of Vincristine and Dexamethasone pulses during the maintenance phase or to the control group, which will be treated with Doxorubicin in DI as well as Vincristine and Dexamethasone pulses during maintenance. Patients will only be randomised once.

Randomisation R1 and R2 are only considered for children since adults have worse outcome and very poor survival after relapse, but the risk-stratification is likely to reduce the number of high-risk cases also in the adult-group.

Patients stratified as intermediate risk-high (IR-high) are identified as having an increased risk of relapse and thus a less favourable prognosis than the standard- and intermediate risk-low groups, but a more favourable prognosis than the high risk patients. The majority of all relapses in childhood ALL is expected to occur in the IR-high group. Following a relapse, only approximately 40% of the children can be successfully treated again and for adults the corresponding figure is less than 20 %, so preventing relapses is very important. New treatment options that improves the antileukaemic efficacy and which have an improved safety profile are urgently needed.

For IR-high patients Randomisation 3 (R3) is available. In R3 patients will be randomised to receive either:

1. the addition of two cycles of Inotuzumab ozogamicin (InO) - Besponsa®, before start of the maintenance phase. After these cycles, the patients randomised to the InO arm will receive maintenance for the same duration as in the control arm.
2. the addition of low dose 6-tioguanine (6TG) as an addition to the standard maintenance therapy.
3. standard maintenance therapy

Patients with ABL-class fusions in their leukaemic clone will, as a non-randomised experimental intervention, be treated with an addition of a tyrosine-kinase inhibitor during the induction phase (for patients \<25 years) and from the consolidation phase (patients ≥25 years). This intervention may shift therapy for previously resistant cases to lower intensity treatment with the associated reduced morbidity and may also reduce the number of relapses in analogy with the results in Ph+ ALL. The reason for not performing a randomised comparison is the rarity of the aberration and also the diversity of ABL-class fusions, reducing statistical power for any comparison further. For this reason, the results of this intervention may be pooled with other study-groups trying similar approaches.

A new intervention is introduced for Down syndrome patients with CD19 positive ALL: ALLTogether1 DS (NRI2). For Down syndrome-ALL patients who have end of Induction MRD detectable but \<25% two conventional chemotherapy consolidation blocks will be replaced with two blocks of Blinatumomab.

For high-risk B-lineage patients, CAR-T therapy can be an alternative to high-risk blocks and stem-cell transplant, but in this case the intervention (CAR-T infusion) will be performed outside the ALLTogether1 study. However, the stratification-system in ALLTogether1 will define the population with a potential CAR-T indication.

ALLTogether1 also includes five sub-studies:

Efficacy and pharmacokinetics of Imatinib in ABL-class fusion positive ALL

Target population: All ABL-class patients enrolled in the ALLTogether study. Biomaterials to be collected at diagnosis, during TKI treatment, follow-up and relapse.

Aims

1. To determine the efficacy and dosing target of imatinib in the treatment of ABL-class leukemia
2. To find the best discriminative biomarkers for TKI response in ABL-class ALL
3. To determine the frequency of intrinsic (at diagnosis) and acquired TKI resistance (due to treatment), including backtracking of mutations using imatinib PK/PD findings during treatment
4. To find causes of TKI resistance in ABL-class patients
5. To describe the pharmacokinetics of Imatinib in TKI-treated patients

Objectives

1. To determine the percent of ABL-class patients who need to switch from IR-high to HR because of high MRD levels
2. To determine the effect of imatinib exposure on clinical outcome, including pharmacokinetic measurements of imatinib
3. To determine the molecular response to imatinib by monitoring fusion gene levels and mutational spectrum at diagnosis and during follow up
4. To determine whether the molecular response parameters reflect the Ig/TCR MRD or flow-MRD response or are a better predictor of therapy failure than Ig/TCR or flow-based MRD monitoring
5. To determine the phosphorylation status of ABL-class proteins and presence of TKI-resistance associated mutations in ABL genes prior to imatinib treatment and the emergence of such mutations during treatment with imatinib
6. To determine the presence of mutations in regulatory /other genes before and during imatinib treatment and functionally address the importance of these mutations in TKI resistance
7. To determine whether the efficacy of TKIs depends on the type of fusion gene
8. To describe inter- and intraindividual variations in imatinib PK (=trough levels) during therapy of ABL-class ALL
9. To describe associations between PK of imatinib and end-of-induction MRD (\<25 yrs only) and end-of-consolidation MRD (all patients)
10. To describe associations between imatinib PK and relapse rates (overall, bone-marrow and CNS), event-free survival as well as overall survival;
11. To describe associations between imatinib PK and toxicities (including e.g. height z-scores at diagnosis and end of therapy, pancreatitis, treatment delays) with focus on those toxicities that are routinely monitored in ALLTogether.

Biomarkers to Reform Approaches to therapy-Induced Neurotoxicity (BRAIN)

Target population: All patients registered on ALLTogether1 aged ≥ 4 years at end of therapy (Arm A) and all patients registered on ALLTogether1 aged 4-21 years at start of therapy (Arm B) and without:

1. Pre-existing neurodevelopmental delay (e.g Trisomy 21) prior to diagnosis of ALL
2. Significant visual or motor impairment preventing use of a touch screen ipad

All centres are invited to enrol to arm A (Main BRAIN) of the study. Arm B (Longitudinal BRAIN) will be carried out in selected centres.

Aims

1. To implement universal screening of all children for adverse neurocognitive outcomes at the end of treatment using a validated user-friendly computer software programme (CogState) and compare neurocognitive outcomes by treatment allocation (Arm A).
2. To identify risk factors for adverse outcomes including whether acute neurotoxic events are associated with poor performance on cognitive tests at end of therapy compared to patients without acute neurotoxicity (Arm A).
3. To examine changes in neurocognitive performance over time and the risk/protective factors associated with differences in outcome, such as demographic, clinical, and physical/psychosocial factors (Arm B).

Primary end-point

a. Proportion of children with a z-score \<1.5 on detection and/or identification CogState tasks in each treatment arm at the end of ALL therapy. A z-score \< 1.5 correlates with moderate cognitive impairment at a level that may require additional support.

Secondary and exploratory end-points

1. Association between CogState scores at end of treatment and overt neurotoxic episodes as recorded on the trial adverse event database.
2. Association between Cogstate scores and clinical and demographic variables - age, sex, ethnicity, CNS status.
3. Proportion of children with scores \<1.5SD for one card learning (learning), one back (working memory) and Groton's maze (executive function) on different treatment arms.
4. Association between CogState scores and patient reported outcome measures/Quality of life measurements collected as part of the main ALLTogether1 trial.
5. Changes in neurocognitive scores over time, including CogState and BRIEF-2/BRIEF-A scores.
6. Association between neurocognitive scores over time and interactions with demographic variables (age, sex), clinical variables (treatment arm, neurotoxicity), social-emotional and physical functioning (SDQ, PedsQL 4.0 Generic; PedsQL 3.0 Fatigue), and family factors (MEES; PedsQL FIM)

Association between asparaginase activity levels and outcome

Target population: All patients included in the ALLTogether1 protocol are eligible for participation.

Primary aim

To study the association between asparaginase activity levels and outcome (MRD, relapse, survival)

Secondary aims

1. To evaluate the association between asparaginase activity levels and toxicities, such as pancreatitis, infections and deep venous thrombosis (DVT)
2. To evaluate the association between asparaginase activity levels and hepatotoxicity in a subset of patients

CSF-Flow

Target population: All patients included in the ALLTogether1 protocol are eligible for participation

Aims

1. To use cerebrospinal fluid (CSF) flow cytometry (FCM) to improve the accuracy of diagnostic tests for CNS leukaemia compared to conventional CSF cytology. An associated objective will be to develop a recommended protocol for CSF flow cytometry with external quality assessment to ensure uniformity of measurement across the ALLTogether consortium.
2. To investigate whether negative FCM identifies a group of children at very low risk of CNS relapse, suitable for testing de-escalation of CNS-directed therapy in future trials.
3. To investigate whether positive FCM can identify children at increased risk of CNS relapse and whether patients with persistent positivity (FCM positive at day 15 onwards) might benefit from studies testing escalated CNS-directed therapy or a switch to more intensive treatment arms.
4. To collect matching CSF supernatant for studies comparing CSF FCM with soluble biomarkers (e.g. metabolic, cell-free DNA, proteomic and microRNA).

Maintenance therapy pharmacokinetics/-dynamics study

Target population: All patients included in the ALLTogether1 protocol are eligible for participation. For IR-high patients participating in the randomised InO- and TEAM sub-protocols, the monitoring of 6-mercaptopurine (6MP)/Methotrexate (MTX) metabolites at three months intervals is mandatory.

Aims and specific objectives

1. To map pharmacokinetics of 6MP and MTX during maintenance therapy in all patients in the ALLTogether protocol.
2. To associate metabolite profiles with TPMT and NUDT15 variants, as routinely analysed in ALLTogether.
3. To explore the association of event-free survival with DNA-TG and other 6MP/MTX metabolites.
4. To explore the association between risk of second cancers with DNA-TG and other 6MP/MTX metabolites.
5. To explore the association of risk of invasive infections with DNA-TG and other 6MP/MTX metabolites.
6. To explore the association of risk of osteonecrosis with DNA-TG and other 6MP/MTX metabolites.
7. To explore the association of sinusoidal obstruction syndrome with DNA-TG and other 6MP/MTX metabolites.

Eligibility criteria: 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 Haematopoetic 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-rearranged (KMT2A-r) BCP ALL.
* 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 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.
* For each intervention/randomisation an additional set of inclusion-criteria is provided.

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).
* 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::ABL 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.
* Female patients, who are breast-feeding.
* Essential data missing from the registration of characteristics at diagnosis (in consultation with the protocol chair).
* For each intervention/randomisation an additional set of exclusion-criteria is provided.

Primary outcomes:
measure: Event-free survival (EFS) for the whole protocol
timeFrame: 5 year estimates from the time of diagnosis will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
measure: Event-free survival (EFS) for the TKI intervention
timeFrame: From the start of TKI (day 15 or day 30), 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up for all interventions except Inotuzumab-randomisation (minimum 2-year follow-up).
measure: Disease-free survival (DFS) R1 + R2
timeFrame: 5 and 8 year estimates from the time of randomisation will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
measure: Disease-free survival (DFS) R3
timeFrame: 5 year estimates from the time of randomisation will be measured but adequate follow-up for these estimates will be ensured: at least 2-year follow-up
measure: MRD response after 1 cycle of Blinatumomab
timeFrame: End of first Blinatumomab infusion +/- 1 week
Secondary outcomes:
measure: Overall survival (OS) for the whole protocol
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
measure: Overall survival (OS) for R1 + R2
timeFrame: 5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
measure: Overall survival (OS) for R3
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
measure: Overall survival (OS) for R3-TEAM associated with DNA-TG
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
measure: Overall survival (OS) for TKI
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up (TKI).
measure: Overall survival (OS) for ALLTogether1 DS
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
measure: Induction death
timeFrame: From diagnosis until death before remission (at the earliest, day 29) or in case of no CR day 29, completion of induction and consolidation 1 (protocol day 99 - Down) and in addition 3 high-risk blocks (protocol day 134 - all other patients)
measure: Resistant disease
timeFrame: From diagnosis until achieved complete remission (at the earliest, day 29) or in case of no CR day 29, assessment after induction and consolidation 1 (protocol day 99-Down patients) and in addition 3 high-risk blocks (protocol day 134-all other patients)
measure: Cumulative incidence of relapse for the whole protocol
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
measure: Cumulative incidence of relapse for R1 + R2
timeFrame: 5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
measure: Cumulative incidence relapse for R3
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
measure: Cumulative incidence relapse for R3-TEAM in association with DNA-TG
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
measure: Cumulative incidence CD22 negative relapse for R3
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
measure: Cumulative incidence relapse for TKI
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up
measure: Cumulative incidence relapse for ALLTogether1 DS
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up
measure: Cumulative incidence of CD19 negative relapse for ALLTogether1 DS
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up
measure: Cumulative incidence of second malignant neoplasm (SMN) for the whole protocol
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
measure: Cumulative incidence of second malignancy for R1+R2
timeFrame: 5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
measure: Cumulative incidence of second malignancy for R3
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up.
measure: Cumulative incidence of second malignancy for R3-TEAM in association with DNA-TG
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up.
measure: Cumulative incidence of second malignancy for TKI
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
measure: Cumulative incidence of second malignancy for ALLTogether1 DS
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
measure: Cumulative incidence of death in complete remission for the whole protocol
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
measure: Cumulative incidence of death in complete remission for R1+R2
timeFrame: 5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up.
measure: Cumulative incidence of death in complete remission for R3
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
measure: Cumulative incidence of death in complete remission for TKI
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up
measure: Cumulative incidence of death in complete remission for ALLTogether1 DS
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up
measure: Cumulative incidence of treatment-related mortality for the whole protocol
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
measure: Cumulative incidence of treatment-related mortality R1+R2
timeFrame: 5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up.
measure: Cumulative incidence of treatment-related mortality R3
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
measure: Cumulative incidence of treatment-related mortality TKI
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up
measure: Leukaemia specific mortality for the whole protocol
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
measure: Leukaemia specific mortality for R1+R2
timeFrame: 5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
measure: Leukaemia specific mortality for R3
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
measure: Leukaemia specific mortality for TKI
timeFrame: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up
measure: Incidence of Adverse Events of Special Interest (AESIs) per treatment-phase in the whole protocol and TKI intervention
timeFrame: From time of diagnosis after each treatment-phase (one extra in the middle of maintenance) and annually until 5 years from discontinuation of therapy.
measure: Incidence of Adverse Events of Special Interest (AESIs) extra assessment (R1+R2)
timeFrame: Cumulative incidence of AESIs estimated 3 months after start of maintenance (R1+R2) and at the end of maintenance (R2)
measure: Incidence of Adverse Events of Special Interest (AESIs) extra assessment (R3)
timeFrame: Cumulative incidence of AESIs estimated at the end of maintenance.
measure: Incidence of Serious Adverse Events (SAEs) and Adverse Events (AEs) related to R3
timeFrame: From time of randomisation until the end of maintenance therapy (approximately 77 weeks from randomisation)
measure: Quantitative measures of toxicity R1+R2
timeFrame: From time of randomisation, assessment after delayed intensification and 6 weeks after start of maintenance
measure: Metabolic consequences of steroid exposure (R2)
timeFrame: At the end of therapy (approximately 94 weeks from randomisation) and 5 years after discontinuation of treatment
measure: Association of Disease-free survival (DFS) with DNA-TG for R3-TEAM
timeFrame: 5 year estimates from the time of randomisation will be measured but adequate follow-up for these estimates will be ensured: at least 2-year follow-up
measure: Cumulative incidence of Sinusoidal Obstruction Syndrome (SOS) and Nodular Regenerative Hyperplasia (NRH) for R3-TEAM
timeFrame: Cumulative incidence of SOS/NRH estimated at the end of follow-up.
measure: Cumulative incidence of Osteonecrosis for R3-TEAM
timeFrame: Cumulative incidence of osteonecrosis estimated at the end of follow-up.
measure: Event-free survival (EFS) for ALLTogether1 DS
timeFrame: From the start of Blinatumomab, 5 year estimate will be measured but adequate follow-up for this estimate will be ensured: at least 5 years follow-up.
measure: Incidence of Blinatumomab refractory disease for ALLTogether1 DS
timeFrame: From the start of Blinatumomab until end of 2nd cycle of Blinatumomab (each cycle is 4 weeks followed by a 2-week treatment free period)
measure: Incidence of Protocol Therapy Failure for ALLTogether1 DS
timeFrame: From the start of Blinatumomab until the end of Consolidation 1 (85-140 days: 15-70 days of Blinatumomab therapy + 70 days of Consolidation 1)
Other outcomes:
measure: 6-mercaptopurine and Methotrexate metabolite pharmacokinetics (i.e. Ery-TGN/MeMP/MTXpg) for R3-TEAM
timeFrame: From start of Maintenance therapy until the end of Maintenance therapy (protocol week 38 until protocol week 108)
measure: Abnormal liver function parameters (including hypoglycemia) for R3-TEAM
timeFrame: From start of Maintenance therapy until the end of Maintenance therapy (protocol week 38 until protocol week 108)
Locations:
city: Brussels
country: Belgium
facility: L'hôpital Universitaire des enfants Reine Fabiola (Huderf)
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc (UCL)
city: Edegem
country: Belgium
facility: University Hospital Antwerp
city: Ghent
country: Belgium
facility: University Hospital Ghent
city: Leuven
country: Belgium
facility: University Hospital Leuven, Dept of Paediatrics
city: Liège
country: Belgium
facility: CHC MontLégia, Boulevard Patience et Beaujonc 2
city: Liège
country: Belgium
facility: CHR de la Citadelle
city: Aalborg
country: Denmark
facility: Aalborg University Hospital, Dept of Paediatrics
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Aarhus
country: Denmark
facility: Aarhus University Hospital, Child and Adolescent Health
city: Copenhagen
country: Denmark
facility: Rigshospitalet, Dept of Haematology
city: Copenhagen
country: Denmark
facility: Rigshospitalet, Dept of Paediatrics
city: Odense
country: Denmark
facility: Odense University Hospital, Dept of Paediatrics
city: Tallinn
country: Estonia
facility: North Estonia Medical Centre, Dept of Haematology
city: Tallinn
country: Estonia
facility: Tallinn Children´s Hospital, Dept of Paediatrics
city: Tartu
country: Estonia
facility: Tartu University Hospital
city: Helsinki
country: Finland
facility: Helsinki University Hospital, Dept of Haematology
city: Helsinki
country: Finland
facility: Helsinki University Hospital, Dept of Paediatrics
city: Kuopio
country: Finland
facility: Kuopio University Hospital, Dept of Haematology
city: Kuopio
country: Finland
facility: Kuopio University Hospital, Dept of Paediatrics
city: Oulu
country: Finland
facility: Oulu University Hospital, Dept of Haematology, Dept of Medicine
city: Oulu
country: Finland
facility: Oulu University Hospital, Dept of Paediatrics
city: Tampere
country: Finland
facility: Tampere University Hospital, Dept of Haematology
city: Tampere
country: Finland
facility: Tampere University Hospital, Dept of Paediatrics
city: Turku
country: Finland
facility: Turku University Hospital, Clinical Haematology and Stem Cell Transplantation Unit
city: Turku
country: Finland
facility: Turku University Hospital, Dept of Paediatrics
city: Amiens Cedex 1
country: France
facility: CHU Amiens Groupe Hospitalier Sud
city: Angers Cedex 9
country: France
facility: CHU Angers
city: Besancon Cedex 03
country: France
facility: CHRU Besançon
city: Bordeaux Cedex
country: France
facility: CHU Bordeaux - Groupe Hospitalier Pellegrin
city: Brest Cedex
country: France
facility: CHRU Brest - Morvan
city: Caen Cedex 9
country: France
facility: Centre Hospitalier Universitaire Caen
city: Clermont-ferrand
country: France
facility: CHU Clermont-Ferrand
city: Dijon
country: France
facility: CHU Dijon Hôpital François Mitterrand
city: Grenoble Cedex 9
country: France
facility: CHU de Grenoble site Nord - Hôpital Albert Michallon
city: Lille Cedex
country: France
facility: CHRU de Lille - Hôpital Jeanne de Flandre
city: Limoges
country: France
facility: Hôpital de la mère et de l'enfant
city: Lyon Cedex 08
country: France
facility: CHU de Lyon HCL - GH Est-Institut d'hématologie et d'oncologie pédiatrique IHOP
city: Marseille Cedex 5
country: France
facility: CHU de Marseille - Hôpital de la Timone
city: Montpellier Cedex 5
country: France
facility: CHU de Montpellier - Hôpital Arnaud de Villeneuve
city: Nantes Cedex 01
country: France
facility: CHU Nantes-Hôpital enfant-adolescent
city: Nice
country: France
facility: CHU Nice - Hôpital l'Archet 2
city: Paris
country: France
facility: CHU Paris Saint Louis
city: Paris
country: France
facility: CHU Paris Armand Trousseau
city: Paris
country: France
facility: CHU Paris - Hôpital Robert Debré
city: Poitiers Cedex 6
country: France
facility: CHU Poitiers
city: Reims
country: France
facility: CHU Reims-American Hospital
city: Rennes Cedex 2
country: France
facility: CHU Rennes - Hôpital sud
city: Rouen Cedex
country: France
facility: CHU Rouen
city: Saint-Denis
country: France
facility: CHU De La Réunion - Site Nord (Hôpital Félix GUYON)
city: Saint-Étienne
country: France
facility: CHU Saint Etienne Hôpital Nord
city: Strasbourg Cedex
country: France
facility: CHU Strasbourg -Hôpital de Hautepierre
city: TOULOUSE Cedex 9
country: France
facility: CHU Toulouse
city: Tours
country: France
facility: CHRU Tours- Hôpital Clocheville
city: Vandoeuvre-les-nancy cedex
country: France
facility: CHU de Nancy - Hôpital de Brabois Enfant
city: Bielefeld
country: Germany
facility: Evangelisches Klinikum Bethel
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Bremen
country: Germany
facility: Klinikum Bremen Mitte
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Krefeld
country: Germany
facility: HELIOS Klinikum Krefeld
city: Mainz
country: Germany
facility: Universitätsmedizin Mainz
city: Reykjavík
country: Iceland
facility: Landspitali University Hospital, Children's Hospital
city: Dublin
country: Ireland
facility: Our Lady's Children's Hospital
city: Vilnius
country: Lithuania
facility: Children's Hospital, Affiliate of Vilnius University Hospital Santaros Klinikos
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital Santaros Klinikos
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht, Dept of Hematology
city: Utrecht
country: Netherlands
facility: Princess Máxima Center for Pediatric Oncology
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
city: Bergen
country: Norway
facility: Haukeland University Hospital, Dept of Haematology
city: Bergen
country: Norway
facility: Haukeland University Hospital, Dept of Paediatrics
city: Oslo
country: Norway
facility: Oslo University Hospital, Dept of Haematology
city: Oslo
country: Norway
facility: Oslo University Hospital, Dept of paediatric haemato- and oncology
city: Stavanger
country: Norway
facility: Stavanger University Hospital, Dept of Haematology
city: Tromsø
country: Norway
facility: University Hospital North Norway, Dept of Haematology
city: Tromsø
country: Norway
facility: University Hospital of North Norway, Dept of Paediatrics
city: Trondheim
country: Norway
facility: St. Olavs University Hospital, Dept of Paediatrics
city: Trondheim
country: Norway
facility: St. Olavs University Hospital, Dept of Haematology
city: Coimbra
country: Portugal
facility: Centro Hospitalar e Universitário de Coimbra, EPE - Hospital Pediátrico de Coimbra
city: Lisboa
country: Portugal
facility: Instituto Português de Oncologia de Lisboa Francisco Gentil, EPE
city: Porto
country: Portugal
facility: Instituto Português de Oncologia do Porto Francisco Gentil, EPE
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital, Section for Haematology and coagulation
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital, Dept of Paediatric Haematology and Oncology
city: Linköping
country: Sweden
facility: Linköping University Hospital, Dept of Haematology
city: Linköping
country: Sweden
facility: Linköping University Hospital, Dept of Paediatrics
city: Lund
country: Sweden
facility: Skåne University Hospital, Dept of Haematology
city: Lund
country: Sweden
facility: Skåne University Hospital, Dept of Paediatrics
city: Stockholm
country: Sweden
facility: Karolinska University Hospital, Dept of Paediatric Oncology and Haematology
city: Stockholm
country: Sweden
facility: Karolinska University Hospital, Patient area Haematology
city: Umeå
country: Sweden
facility: Norrland University Hospital, Dept of Haematology
city: Umeå
country: Sweden
facility: Norrland University Hospital, Dept of Paediatrics
city: Uppsala
country: Sweden
facility: Uppsala University Hospital, Dept of Haematology
city: Uppsala
country: Sweden
facility: Uppsala University Hospital, Dept of Paediatric Haematology and Oncology
city: Örebro
country: Sweden
facility: Örebro University Hospital, Section for Haematology
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary, Aberdeen
city: Aberdeen
country: United Kingdom
facility: Royal Aberdeen Children's Hospital, Aberdeen
city: Belfast
country: United Kingdom
facility: Royal Belfast Hospital for Sick Children, Belfast
city: Belfast
country: United Kingdom
facility: Belfast City Hospital, Belfast
city: Birmingham
country: United Kingdom
facility: The Queen Elizabeth Hospital, Birmingham
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital, Birmingham
city: Bristol
country: United Kingdom
facility: Bristol Royal Hospital for Children / Bristol Haematology and Oncology Centre
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital, Cambridge
city: Cardiff
country: United Kingdom
facility: Noah's Ark Children's Hospital for Wales, Cardiff
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales, Cardiff
city: Dundee
country: United Kingdom
facility: Ninewells Hospital, Dundee
city: Edinburgh
country: United Kingdom
facility: Western General Hospital, Edinburgh
city: Edinburgh
country: United Kingdom
facility: Royal Hospital for Children and Young People, Edinburgh
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre, Glasgow
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Children, Glasgow
city: Leeds
country: United Kingdom
facility: Leeds General Infirmary, Leeds
city: Leeds
country: United Kingdom
facility: Leeds St James University Hospital
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary, Leicester
city: Liverpool
country: United Kingdom
facility: Alder Hey Children's Hospital, Liverpool
city: Liverpool
country: United Kingdom
facility: The Clatterbridge Cancer Centre NHS Foundation Trust
city: London
country: United Kingdom
facility: University College London Hospital, London
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children, London
city: London
country: United Kingdom
facility: King's College Hospital
city: London
country: United Kingdom
facility: St. Bartholomews Hospital
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital, Manchester
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust (PTC)
city: Newcastle upon Tyne
country: United Kingdom
facility: Royal Victoria Infirmary, Newcastle
city: Newcastle
country: United Kingdom
facility: Freeman Hospital, Newcastle
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital, Nottingham
city: Nottingham
country: United Kingdom
facility: Nottingham Queen's Medical Centre
city: Oxford
country: United Kingdom
facility: Churchill Hospital, Oxford
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital, Oxford
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital, Sheffield
city: Sheffield
country: United Kingdom
facility: Sheffield Children's Hospital, Sheffield
city: Southampton
country: United Kingdom
facility: Southampton General Hospital, Southampton
city: Stoke
country: United Kingdom
facility: Royal Stoke University Hospital, Stoke
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital, Sutton
Study officials:
affiliation: Karolinska University Hospital
name: Mats Heyman, MD, PhD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Toksvang LN, Als-Nielsen B, Bacon C, Bertasiute R, Duarte X, Escherich G, Helgadottir EA, Johannsdottir IR, Jonsson OG, Kozlowski P, Langenskjold C, Lepik K, Niinimaki R, Overgaard UM, Punab M, Raty R, Segers H, van der Sluis I, Smith OP, Strullu M, Vaitkeviciene G, Wik HS, Heyman M, Schmiegelow K. Thiopurine Enhanced ALL Maintenance (TEAM): study protocol for a randomized study to evaluate the improvement in disease-free survival by adding very low dose 6-thioguanine to 6-mercaptopurine/methotrexate-based maintenance therapy in pediatric and adult patients (0-45 years) with newly diagnosed B-cell precursor or T-cell acute lymphoblastic leukemia treated according to the intermediate risk-high group of the ALLTogether1 protocol. BMC Cancer. 2022 May 2;22(1):483. doi: 10.1186/s12885-022-09522-3.