IntReALL BCP 2020 – International Study for Treatment of Childhood Relapsed Precursor B-cell ALL 2020

Prior treatment

• Severe concomitant disease that, according to the treating physician, does not allow treatment according to the protocol at the investigator’s discretion (e.g. malformation syndromes, cardiac malformations, metabolic disorders)
• Pregnancy or positive pregnancy test in female patients (urine sample positive for β-HCG > 10 U/l) at screening or within 7 days prior to the initiation of study treatment
• Sexually active adolescents and adults not willing to use highly effective contraceptive method (pearl index <1) until 12 months after end of anti-leukemic therapy
• Women not willing to refrain from Bbreast feeding until 12 months after end of anti-leukemic therapy
• Relapse post chimeric antigen receptor T-cell (CAR-T) therapy
• Specific for SR induction randomization: Patients with insufficient expression of CD22 (< 80%) on leukemic blasts, they are assigned to the control chemotherapy arm
• Specific for blinatumomab treatment: Evidence of current CNS (CNS 2, CNS 3) involvement by ALL. Subjects with CNS relapse at the time of relapse are eligible if CNS is successfully treated prior to enrollment
• Specific for SR induction randomization: Prior confirmed severe (grade 3 or 4) or ongoing VOD/SOS

Other illness

• Known hypersensitivity to the active substances or excipients of the IMP’s or the SOC drugs, except to PEG-asparaginase which can be replaced by Erwinase
• Specific for blinatumomab treatment: Clinically relevant CNS pathology requiring treatment (eg, unstable epilepsy)
• Specific for SR induction randomization: Serious ongoing hepatic disease (e.g., cirrhosis, active hepatitis) not related to the current ALL relapse or current diagnostic/therapeutic measures

Lab values

• Left ventricular ejection fraction (LVEF) < 50% or fractional shortening < 25%, and/or current or prior treatment for cardiomyopathy and/or history of clinically significant arrhythmias
• Patients with any concurrent medical condition, laboratory abnormality, concomitant treatment, or comorbidity that, in the investigator’s clinical judgment would- compromise the patient’s ability to safely receive or tolerate inotuzumab ozogamicin and/or blinatumomab - significantly interfere with assessment of treatment efficacy or safety - make it unlikely that the patient would derive clinical benefit from protocol therapy - preclude adherence to study procedures or follow-up requirements
• Specific for SR induction randomization: ALT > 2,5 x ULN (at relapse diagnosis before start of cytoreduction) and/or bilirubin > 1.5 x ULN

Other

• Subjects unwilling or unable to comply with the study procedures
• Subjects who are legally detained in an official institute
• Relapse post allogeneic HSCT
• Specific for SR induction randomization: Patients with intolerance to PEG-asparagniase and also to Erwinase are stratified to the inotuzumab arm
• The whole protocol or essential parts are declined either by patient himself/herself or the respective legal guardian
• Objection to the study participation by a minor patient
• Patients in a dependent or subordinate relationship to the investigator or site staff (e.g. employees, relatives, or students)
• No consent is given for saving and propagation of pseudonymized medical data for study reasons

• All study questions: Confirmed diagnosis of 1st relapsed B-cell precursor ALL
• All study questions: Start of treatment falling into the study period
• Meeting SR criteria: No previous history of veno-occlusive disease (VOD)/ sinusoidal obstruction syndrome (SOS)
• All study questions: No participation in other clinical trials 30 day prior to study enrolment that interfere with this protocol, except trials for primary ALL
• Specific for SR induction randomization: Meeting SR criteria
• Meeting SR criteria: BM involvement (≥ 1% leukemic blasts)
• Meeting SR criteria: CD22 positive ALL (>80% confirmed by flow-cytometry)
• Specific for SR MRD poor response consolidation: Meeting SR criteria with bone marrow involvement at relapse diagnosis
• Specific for SR MRD poor response consolidation: M1/CR2 and MRD ≥ 10-4 after induction
• Specific for SR MRD poor response consolidation: CD19 positive ALL at relapse (>10%)
• Specific for SR MRD good response consolidation: Meeting SR criteria with bone marrow involvement at relapse diagnosis
• Specific for HR consolidation arm: M1/CR2 after induction therapy
• Specific for SR MRD good response consolidation: M1/CR2 and MRD < 10-4 after induction
• Specific for SR MRD good response consolidation: CD19 positive ALL at relapse (>10%)
• Specific for HR consolidation arm: Meeting HR or VHR (in case of no possibility to be treated with CAR T cells) criteria
• All study questions: Patients ≥ 1 year and less than 18 years of age at diagnosis of primary ALL and less than 21 years of age at date of inclusion into the study
• Specific for HR consolidation arm: CD19 positive ALL at relapse (>10%)
• Specific for IEM arm: Histology or cytology proven extramedullary relapse
• Specific for IEM arm: No bone marrow involvement (M1 at relapse diagnosis) and bone marrow MRD <1%
• Specific for IEM arm: CD19 positive ALL at relapse (>10%)
• All study questions: Patient enrolled in a participating center
• All study questions: Written informed consent (IC)