Blinatumomab in Adult Patients With Minimal Residual Disease (MRD) of B-precursor Acute Lymphoblastic Leukemia

Transfer of patients to alloHSCT after one cycle or after a subsequent cycle is considered as per protocol discontinuation and as premature treatment discontinuation.

In case of hematological or extramedullary relapse, the study treatment will be permanently discontinued.

There will be a safety follow-up visit at 30 days after end of the last infusion. There will be efficacy follow-up until 18 months after treatment start. In patients scheduled for SCT the 30-day safety-visit may be performed at the latest time point possible before initiation of subsequent treatment.

Inclusion criteria

• Patients with CD19 positive B-precursor ALL in complete hematological remission defined as less than 5% blasts in bone marrow after at least three intense chemotherapy blocks (e.g., GMALL induction I-II/consolidation I).
• Presence of minimal residual disease (MRD) after an interval of at least 8 days from last systemic chemo-therapy

• at a level of ≥10-4 - <10-3 (molecular failure or molecular relapse) in an assay with a minimum sensitivity of 10-4 documented after an interval of at least 2 weeks from last systemic chemotherapy OR
• at levels below 10-4 documented after an interval of at least 2 weeks from last systemic chemotherapy:

• Positive <10-4, non quantifiable (MolNE1) OR
• Positive <10-4 (MolNE2) OR
• Presence of minimal residual disease (MRD), non quantifiable (MolNE3).
• For evaluation of MRD patients must have at least one molecular marker based on individual rearrangements of immunoglobulin, TCR-genes or other suitable genes evaluated by the reference laboratory of the trial
• Bone marrow function as defined below:

• ANC (Neutrophils) >= 1,000/µL
• Platelets >= 50,000/µL (transfusion permitted)
• HB level >= 9g/dl (transfusion permitted)
• Renal and hepatic function as defined below:

• AST (GOT), ALT (GPT), and AP < 5 x upper limit of normal (ULN)
• Total bilirubin < 1.5 x ULN (unless related to Gilbert's Meulengracht disease)
• Creatinine < 1.5x ULN
• Creatinine clearance >= 60 mL/min (e.g. calculated according Cockroft&Gault)
• Negative HIV test, negative hepatitis B (HbsAg) and hepatitis C virus (anti-HCV) test
• Negative pregnancy test in women of childbearing potential
• ECOG Performance Status 0 or 1
• Age >=18 years
• Ability to understand and willingness to sign a written informed consent
• Signed and dated written informed consent is available
• Participation in the registry of the German Multicenter Study Group for Adult ALL (GMALL)

Exclusion criteria

• Ph/BCR-ABL positive ALL
• Presence of circulating blasts or current extramedullary involvement by ALL
• History or presence of clinically relevant CNS pathology (e.g. seizure, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome or psychosis)
• Current detection of ALL blast cells in cerebro-spinal fluid
• History of or active relevant autoimmune disease
• Systemic cancer chemotherapy within 2 weeks prior to study treatment (except for intrathecal prophylaxis)
• Radiotherapy within 4 weeks prior to study treatment
• Live vaccination within 2 weeks before the start of study treatment
• Autologous hematopoietic stem cell transplantation (SCT) within six weeks prior to study treatment
• Allogeneic SCT within 12 weeks before the start of study treatment
• Any active acute Graft-versus-Host Disease (GvHD), grade 2-4 according to the Glucksberg criteria or active chronic GvHD requiring systemic treatment
• Any systemic therapy against GvHD within 2 weeks before start of study treatment
• Therapy with monoclonal antibodies (rituximab, alemtuzumab) within 4 weeks prior to study treatment
• Treatment with any investigational product within four weeks prior to study treatment
• Previous treatment with blinatumomab or other anti-CD19-therapy
• Known hypersensitivity to immunoglobulins or to any other component of the study drug formulation
• History of malignancy other than ALL diagnosed within 5 years prior to start of protocol-specified therapy with the exception of:

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated cervical carcinoma in situ without evidence of disease
• Adequately treated breast ductal carcinoma in situ without evidence of disease
• Prostatic intraepithelial neoplasia without evidence of prostate cancer
• Active infection, any other concurrent disease or medical condition that are deemed to interfere with the conduct of the study as judged by the investigator
• Nursing women
• Woman of childbearing potential and is not willing to use 2 highly effective methods of contraception while receiving study treatment and for an additional 3 months after the last dose of study treatment.
• Male who has a female partner of childbearing potential, and is not willing to use 2 highly effective forms of contraception while receiving study treatment and for at least an additional 3 months after the last dose of study treatment