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 randomized, 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 itensity could make a difference in the incidence of acute and late therapy-related toxicities.
• In the IR-Low arm it will be tested randomized, if the omission of Dexamethasone/Vincristine pulses in the maintenance therapy is possible without an increased risk of relapse.
• Inotuzumab (InO) will be tested randomized 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 antitumor antibiotic. Once the monoclonal antibody-drug conjugates to the tumor antigen, the antigen-antibody complex is internalised and the cytotoxic agent is delivered inside the targeted leukemic 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. Phramakokinetic studies of the NOPHO-studygroup 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 preperation 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 ALLpatients.

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

• Primary acute lymphoblastic leukaemia (ALL) or
• ALL as a second malignancy or
• Acute biphenotypical leukaemia (after consultation and approval by the study coordination centre) or
• Acute undifferentiated leukaemia (after consultation and approval by the study coordination centre) or
• Non-Hodgkin Lymphomas: T-NHL or B-precursor-NHL, if there is no participation in the LBL 2018 study or
• „Special“ cases of ALL-associated diseases (after consultation and approval by the study coordination centre) or
• ALL relapse without participation in one of the IntReALL studies
• Age at diagnosis < 18 or >= 18 (after consultation and approval by the study coordination centre
• Admission to an accredited paediatric oncology centre in accordance with the GBA decision "Paediatric Oncology"
• Consent of the patient and legal representative

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).