ALLTogether collects the experience of previously successful treatment of 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
ALLTogether is a European clinical treatment study for acute lymphoblastic leukaemia (ALL) in
children and young adults. The aims are to improve survival and quality of survival for
children and young adults with ALL. In young people, ALL has excellent outcome with an
overall survival of about 92% in children and 75% in young adults. 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 for children
and young adults with ALL.
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
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 occur in the IR-high group. Following a relapse, 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
antileukemic efficacy and which have an improved safety profile are urgently needed.
For IR-high patients the R3 randomisation is available. In R3 patients will be randomised to
the addition of two cycles of Inotuzumab ozogamicin (InO) - Besponsa®, before the start of
the maintenance phase or no addition. The patients randomised to the InO arm will receive
maintenance for the same duration as in the control arm.
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.
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.
- 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
- Age ≥ 365 days and < 46 years (one day before 46th birthday) at the time of diagnosis.
- 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
- Age < 365 days at diagnosis (infant ALL) or >45 years at diagnosis.
- Patients with a previous malignant diagnosis (ALL as a second malignant neoplasm -
- Relapse of ALL.
- Patients with mature B-ALL (as defined by Surface Ig positivity or documented presence
of one of the t(8;14), t(2;8), t(8;22) translocations and breakpoint as in B-ALL).
- 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 adequate trial
for t(9;22) if available.
- ALL prone syndromes (e.g. Li-Fraumeni syndrome, germline ETV6 mutation), except for
Down syndrome. Exploration for such ALL prone syndromes is not mandatory.
- 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
- 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
- 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