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1.
Blood ; 120(26): 5185-7, 2012 Dec 20.
Article in English | MEDLINE | ID: mdl-23024237

ABSTRACT

Persistence or recurrence of minimal residual disease (MRD) after chemotherapy results in clinical relapse in patients with acute lymphoblastic leukemia (ALL). In a phase 2 trial of B-lineage ALL patients with persistent or relapsed MRD, a T cell-engaging bispecific Ab construct induced an 80% MRD response rate. In the present study, we show that after a median follow-up of 33 months, the hematologic relapse-free survival of the entire evaluable study cohort of 20 patients was 61% (Kaplan-Meier estimate). The hema-tologic relapse-free survival rate of a subgroup of 9 patients who received allogeneic hematopoietic stem cell transplantation after blinatumomab treatment was 65% (Kaplan-Meier estimate). Of the subgroup of 6 Philadelphia chromosome-negative MRD responders with no further therapy after blinatumomab, 4 are in ongoing hematologic and molecular remission. We conclude that blinatumomab can induce long-lasting complete remission in B-lineage ALL patients with persistent or recurrent MRD. The original study and this follow-up study are registered at www.clinicaltrials.gov as NCT00198991 and NCT00198978, respectively.


Subject(s)
Antibodies, Bispecific/therapeutic use , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy , Adult , Antineoplastic Agents/therapeutic use , Combined Modality Therapy , Disease-Free Survival , Follow-Up Studies , Hematopoietic Stem Cell Transplantation , Humans , Kaplan-Meier Estimate , Neoplasm, Residual , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/blood , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Recurrence , Survival Analysis , Transplantation, Homologous
2.
Blood ; 119(26): 6226-33, 2012 Jun 28.
Article in English | MEDLINE | ID: mdl-22592608

ABSTRACT

T cell-engaging CD19/CD3-bispecific BiTE Ab blinatumomab has shown an 80% complete molecular response rate and prolonged leukemia-free survival in patients with minimal residual B-lineage acute lymphoblastic leukemia (MRD(+) B-ALL). Here, we report that lymphocytes in all patients of a phase 2 study responded to continuous infusion of blinatumomab in a strikingly similar fashion. After start of infusion, B-cell counts dropped to < 1 B cell/µL within an average of 2 days and remained essentially undetectable for the entire treatment period. By contrast, T-cell counts in all patients declined to a nadir within < 1 day and recovered to baseline within a few days. T cells then expanded and on average more than doubled over baseline within 2-3 weeks under continued infusion of blinatumomab. A significant percentage of reappearing CD8(+) and CD4(+) T cells newly expressed activation marker CD69. Shortly after start of infusion, a transient release of cytokines dominated by IL-10, IL-6, and IFN-γ was observed, which no longer occurred on start of a second treatment cycle. The response of lymphocytes in leukemic patients to continuous infusion of blinatumomab helps to better understand the mode of action of this and other globally T cell-engaging Abs. The trial is registered with www.clinicaltrials.gov identifier NCT00560794.


Subject(s)
Antibodies, Bispecific/administration & dosage , Antigens, CD19/immunology , CD3 Complex/immunology , Immune System/drug effects , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy , Adult , Antibodies, Bispecific/adverse effects , Antibodies, Bispecific/pharmacokinetics , Antilymphocyte Serum/administration & dosage , Antilymphocyte Serum/adverse effects , Antilymphocyte Serum/metabolism , Cytotoxicity, Immunologic/drug effects , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , Immunologic Factors/pharmacokinetics , Immunotherapy/adverse effects , Immunotherapy/methods , Infusion Pumps , Lymphocyte Activation/drug effects , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Treatment Outcome
3.
J Clin Oncol ; 29(18): 2493-8, 2011 Jun 20.
Article in English | MEDLINE | ID: mdl-21576633

ABSTRACT

PURPOSE: Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. In acute lymphoblastic leukemia (ALL), persistence or relapse of minimal residual disease (MRD) after chemotherapy indicates resistance to chemotherapy and results in hematologic relapse. A phase II clinical study was conducted to determine the efficacy of blinatumomab in MRD-positive B-lineage ALL. PATIENTS AND METHODS: Patients with MRD persistence or relapse after induction and consolidation therapy were included. MRD was assessed by quantitative reverse transcriptase polymerase chain reaction for either rearrangements of immunoglobulin or T-cell receptor genes, or specific genetic aberrations. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dose of 15 µg/m2/24 hours. RESULTS: Twenty-one patients were treated, of whom 16 patients became MRD negative. One patient was not evaluable due to a grade 3 adverse event leading to treatment discontinuation. Among the 16 responders, 12 patients had been molecularly refractory to previous chemotherapy. Probability for relapse-free survival is 78% at a median follow-up of 405 days. The most frequent grade 3 and 4 adverse event was lymphopenia, which was completely reversible like most other adverse events. CONCLUSION: Blinatumomab is an efficacious and well-tolerated treatment in patients with MRD-positive B-lineage ALL after intensive chemotherapy. T cells engaged by blinatumomab seem capable of eradicating chemotherapy-resistant tumor cells that otherwise cause clinical relapse.


Subject(s)
Antibodies, Bispecific/therapeutic use , Drug Delivery Systems , Immunotherapy/methods , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy , T-Lymphocytes, Cytotoxic/drug effects , Adult , Agammaglobulinemia/chemically induced , Aged , Aged, 80 and over , Antibodies, Bispecific/adverse effects , Antibodies, Bispecific/pharmacokinetics , Antibody Specificity , Antigens, CD19/immunology , Antigens, Neoplasm/immunology , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Bone Marrow/pathology , CD3 Complex/immunology , Cell Lineage , Combined Modality Therapy , Disease-Free Survival , Drug Resistance, Neoplasm , Female , Humans , Kaplan-Meier Estimate , Lymphocyte Activation , Lymphopenia/chemically induced , Male , Middle Aged , Molecular Targeted Therapy , Neoplasm, Residual , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Remission Induction , T-Cell Antigen Receptor Specificity/drug effects , T-Cell Antigen Receptor Specificity/immunology , T-Lymphocytes, Cytotoxic/immunology , Young Adult
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