ALLTogether1

Acute lymphoblastic leukaemia (ALL)

Randomized, prospective, international clinical phase III trail

Study objectives

• For a substantial group of patients (VLR and IR – Low), who are identified for a low risk of relapse, it will be tested in a randomized fashion, if the omission of anthracyclines at the end of consolidation is possible without loss in the event free survival. This phase of the therapy is associated with frequent severe therapy complications and cardio-vasculare late effects. A reduction of the treatment intensity could make a difference in the incidence of acute and late therapy-related toxicities.
• In the IR-Low arm it will be tested in a randomized fashion, whether the omission of Dexamethasone/Vincristine pulses in the maintenance therapy is possible without an increased risk of relapse.
• Inotuzumab (InO) will be tested in a randomized fashion in patients with an increased risk of relapse (IR-high) after the end of consolidation. InO is as an antibody-drug conjugate (ADC) composed of a monoclonal CD22-targeted antibody linked to calicheamicin, which is a potent cytotoxic antitumour antibiotic. Once the monoclonal antibody drug conjugates to the tumour antigen, the antigen-antibody complex is internalised and the cytotoxic agent is delivered inside the targeted leukaemic cells. For the first time, this antibody will be used in a first-line therapy for children with ALL in Europe in a randomized set-up against an intensified maintenance therapy with additional Thiaoguanin. Pharmakokinetic studies of the NOPHO-study group showed that the addition of Thioguanin induced a higher treatment intensity and reduction of the occurence of relapse.
• For patients with "BCR/ABL-like" genetic signature it will be tested, if the addition of Imatinib with the beginning of day 15 of the induction is effective and safe.
• The CoALL-ACT therapy protocol offers a primary immunotherapy with CAR-T cells for patients with an insufficient therapy response with the conventional therapies. The pretreatment in the ALLTogether protocol and the logistic preparation for the administration of the CAR-T cell therapy are necessary conditions for the participation in this first CAR-T cell trial for first-line ALL patients.

All patients are treated with a rsik-adapted induction therapy. After induction patients with a B-precursor leukaemia will be stratified according to clinical, genetic and response factors (MRD) to the following arms:
-standard arm (SR)
-intermediate arm (IR)
-high-risk arm (HR).
within the intermediate arm, a second stratification into IR-Low and IR-High will take place.
In the high-risk arm a second stratification into HR-Chemo and HR-HSCT will take place. HR-Patients can be considered for CAR-T cell therapy.
Patients with a Down-syndrome, a T-cell leukaemia or a BCR/ABL fusion will be treated in seperate study arms.

Masterprotokoll

• 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-rearranged (KMT2A-r) BCP ALL (see exclusion criteria below).
• 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.
• For each intervention/randomisation an additional set of inclusion criteria is provided.

Masterprotokoll

• Age < 365 days at diagnosis and KMT2A-r BCP-ALL (documented presence of a KMT2A-split by FISH and/or a KMT2A transcript). These patients will be transferred to an appropriate trial for KMT2A-r BCP-ALL infant ALL if available.
• Age >45 years at diagnosis (from the 46th birthday onwards)
• Patients with a previous malignant diagnosis (ALL as a second malignant neoplasm - SMN). However, patients with a history of skin cancer (except melanoma) with only local treatment are eligible.
• Relapse of ALL.
• Patients with mature B-ALL (as defined by Surface Ig positivity or documented presence of one of the t(8;14)(q24;q32), t(2;8)(p12;q24), t(8;22)(q24;q11) translocations involving the MYC gene and breakpoints as in mature B-NHL/ALL).
• 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.
• 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 any chemotherapeutic agents during the 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 treatment according to the protocol).
• 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).