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  • 1
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    Tumor Regression in Cancer Patients by Very Low Doses of a T Cell–Engaging Antibody
    American Association for the Advancement of Science (AAAS) ; 2008
    In:  Science Vol. 321, No. 5891 ( 2008-08-15), p. 974-977
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 321, No. 5891 ( 2008-08-15), p. 974-977
    Abstract: Previous attempts have shown the potential of T cells in immunotherapy of cancer. Here, we report on the clinical activity of a bispecific antibody construct called blinatumomab, which has the potential to engage all cytotoxic T cells in patients for lysis of cancer cells. Doses as low as 0.005 milligrams per square meter per day in non–Hodgkin's lymphoma patients led to an elimination of target cells in blood. Partial and complete tumor regressions were first observed at a dose level of 0.015 milligrams, and all seven patients treated at a dose level of 0.06 milligrams experienced a tumor regression. Blinatumomab also led to clearance of tumor cells from bone marrow and liver. T cell–engaging antibodies appear to have therapeutic potential for the treatment of malignant diseases.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1158545
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2008
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  • 2
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    Treatment of Patients with Non-Hodgkin Lymphoma (NHL) with CD19/CD3 Bispecific Antibody Blinatumomab (MT103): Double-Step Dose Increase to Continuous Infusion of 60 μg/m2/d Is Tolerable and Highly Effective
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 2880-2880
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2880-2880
    Abstract: Abstract 2880 Blinatumomab (MT103) is a single-chain bispecific antibody construct with specificity for CD19 and CD3 belonging to the class of bispecific T cell engager (BiTE®). We have previously reported that blinatumomab delivered as single agent to patients with relapsed NHL and B-precursor acute lymphoblastic leukemia by continuous intravenous (CIV) infusion over 4–8 weeks depleted peripheral B cells, expanded T effector cells, and resulted in clinical responses. In this phase I study 52 patients (41 males, 11 females) have been treated, 21 with FL, 21 with MCL and 10 with other subtypes of lymphoma (MZL, SLL, LPL, CLL). Patients have received a median of 3 prior regimens (range 1 to 12). Ninety percent of the patients had prior exposure to rituximab and 45% to fludarabine. Patients were treated at a dose range from 0.5 to 90 μg/m2/d. The most common adverse events (AEs) occurred early, were transient, reversible and did not require discontinuation of treatment. The most common clinical AEs regardless of causality were pyrexia (75%), headache (45%) and fatigue (37%). The most common laboratory abnormality AEs regardless of causality were lymphopenia (75%), leukopenia (57%), thrombocytopenia (39%), C-reactive protein increase (53%) and fibrin D dimer increase (37%). The medically most important AEs that resulted in permanent discontinuation were CNS events. Signs and symptoms observed included kinetic tremor, speech impairment, disorientation, apraxia and seizure. All CNS events were fully reversible without sequelae and no pathological findings by MRI imaging were reported. Out of the 52 patients treated, 9 had to discontinue treatment permanently in the first cycle due to these CNS events. At a dose of 90 μg/m2/d two DLTs were observed which were CNS events during the DLT period of the first 2 weeks of treatment. Therefore 60μg/m2/d is the currently recommended dose. A low B to T cell ratio ( 〈 1:8) determined by FACS analysis in peripheral blood was found to be a risk factor for CNS events. No CNS events requiring treatment discontinuation occurred in 32 out of 34 patients with a high B:T cell ratio (≥1:8) up to 60μg/m2/d. In the 18 patients with low B:T cell ratio, 7 had CNS events requiring treatment discontinuation. Patients with low B:T cell ratio were subsequently treated with an alternative dosing schedule in which reduced doses of either 5 and 15 μg/m2/d were sequentially administered for 1 week respectively followed by an increase to 60 μg/m2/d. First single-step dosing was applied. However, CNS events leading to treatment discontinuation were still observed. Therefore a double-step regimen was implemented; in the initial cohort of 3 patients with low B:T cell ratio there were no treatment discontinuations due to CNS events. Overall 18 patients with FL or MCL were treated with constant or step dosing regimens at or reaching 60 μg/m2/d dose level. Eight out of the 9 patients with constant dosing showed an objective response by Cheson criteria. All responders had a high B:T cell ratio. One patient with a low B:T cell ratio was discontinued due to a CNS AE. Six out of 9 patients with low B:T cell ratio enrolled for step dosing showed an objective response. One patient (single step dosing) discontinued treatment because of a CNS AE and 2 patients discontinued because of tumor progression. As of June 15th 2010, response duration ranged from 1 to 30+ months. Median for response duration was 26 months with 5 out of 14 responses ongoing. Table 1: Response evaluation in patients enrolled in 60 μg/m2/d cohorts. Dose Level Cohort Patients Complete Response Partial Response Overall Response FL MCL Total FL MCL Total FL MCL Total FL MCL Total 60 μg/m2/d Constant 6 3 9 2 1 3 4 1 5 6 2 8 5 or 15 then 60 μg/m2/d Single step 3 3 6 2 0 2 1 1 2 3 1 4 5/15/60 μg/m2/d Double Step 2 1 3 0 0 0 2 0 2 2 0 2 Total 11 7 18 4 1 5 7 2 9 11 3 14 These data confirm high single-agent activity of blinatumomab with long lasting remissions. Initial data with double step dosing demonstrate that this approach maintains clinical activity without discontinuations due to CNS AEs. Evaluation of safety and clinical efficacy of this uniform double step schedule including other subtypes of NHL is ongoing. Disclosure: Scheele: Micromet Inc.: Employment. Zugmaier:Micromet Inc.: Employment. Nagorsen:Micromet Inc.: Employment. Klinger:Micromet Inc.: Employment. Schmidt:Micromet Inc.: Employment. Klappers:Micromet. Inc: Employment. Kufer:Micromet Inc.: Employment. Bargou:Micromet Inc.: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.2880.2880
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 3
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    Sustained Response Duration Seen after Treatment with Single Agent Blinatumomab (MT103/MEDI-538) in the Ongoing Phase I Study MT103- 104 in Patients with Relapsed NHL
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 267-267
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 267-267
    Abstract: Introduction: Blinatumomab (MT103/MEDI-538), a BiTE antibody targeting the CD19 antigen, is a member of a novel class of molecules that redirect T cells for lysis of target cells. A Phase 1 dose escalation study is being conducted in patients with advanced NHL. Methods: Relapsed NHL patients requiring treatment were included. Most patients were pre-treated, with a median of 3 previous chemo/immunotherapy regimens. To date, 7 dose levels ranging from 0.0005 to 0.09 mg/m2/24 h have been tested. Blinatumomab was continuously infused as single agent over a period of 4–8 weeks. Objective responses were assessed by Cheson criteria and centrally reviewed. Results: To date 39 patients have been treated. Most common adverse events (AEs) included lymphopenia, pyrexia, and leukopenia. The majority of AEs ( & gt;95%) improved or resolved during treatment. Permanent treatment discontinuation due to AEs occurred in a total of 8 patients, of which 6 had fully reversible CNS events. One patient with a history of nearly fatal sepsis, pre-existing hypogammaglobulinemia and bone marrow affection by chemotherapy, experienced a fatal sepsis 5 weeks after treatment start. Dose-dependent activity was observed in mantle cell lymphoma, follicular lymphoma and CLL with responses observed in 11 out of 27 patients treated at doses of 0.015 mg/m2/24 h and higher. Five of those patients had complete and six had partial responses. At the dose level of 0.060 mg/m2/24 h, 7 out of 7 patients have shown objective responses. Beside one relapse after 14 months, no treatment failure has so far been observed for responders at dose levels of 0.030 mg/m2/24 h and 0.060 mg/m2/24 h. Five patients at these dose levels have ongoing responses for more than 6 months. Interestingly, partial remissions converted into complete remissions in two patients four weeks after end of infusion suggesting either reduction in lesion size due to efflux of a previously expanded T cell pool or prolonged T cell activity. Conclusions: Blinatumomab as single agent induced apparently durable responses in pre-treated B-NHL patients with the highest response rate at a dose level of 0.06 mg/m2/24 h. Recruitment is ongoing.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.267.267
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 4
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    Confirmation of Safety, Efficacy and Response Duration in Non-Hodgkin Lymphoma Patients Treated with 60 μg/m2/d of BiTE® Antibody Blinatumomab.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 2723-2723
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2723-2723
    Abstract: Abstract 2723 Poster Board II-699 Indolent and mantle cell lymphoma (MCL) are predominantly treated with chemotherapy or a combination of chemotherapy with monoclonal antibodies. Despite high initial response rates, eventually almost all patients however relapse, leaving the disease incurable. Moreover, with increasing numbers of regimens administered, the responsiveness of patients is reduced. Blinatumomab is a single-chain bispecific antibody construct with specificity for CD19 and CD3, belonging to the class of bispecific T cell engager (BiTE®). Here, we report on patients in an ongoing phase 1 trial treated at a dose of 60 μg/m2/d for 4–8-week by continuous i.v. infusion with single-agent blinatumomab. In total, 12 patients with indolent mainly follicular lymphoma or MCL were treated at 60 μg/m2/d during the first treatment cycle. 11/12 patients showed an objective response (7 PR and 4 CR). As of July 2009, median response duration was 12 months with 6 out of 11 responses still ongoing. The single non-responding patient experienced a reversible, neurological adverse event leading to early discontinuation of treatment. Of the 11 responders, one patient developed a port infection and 4 patients showed neurological symptoms, which were all fully reversible. In order to mitigate neurological adverse events during first dosing, which can occur in a defined subset of patients, patients were treated for 1–2 weeks with a lower initial dose (5 and/or 15 μg/m2/d) followed by a maintenance dose of 60 μg/m2/d. A lower starting dose appeared to ameliorate initial adverse events to an extent that treatment could be continued without interruption. Taken together, our data confirm a high single-agent activity of 60 μg/m2/d blinatumomab infused for 4–8 week with long lasting remissions and a favorable risk/benefit profile. The confirmed dose will be considered for further clinical development of blinatumomab in follicular lymphoma and MCL. New data on patients treated with a dose of 90 μg/m2/d will be presented. Disclosures: Nagorsen: Micromet: Employment, Equity Ownership. Zugmaier:Micromet: Employment, Equity Ownership. Schmidt:Micromet: Employment, Equity Ownership. Klappers:Micromet: Employment, Equity Ownership. Baeuerle:Micromet: Employment, Equity Ownership. Kufer:Micromet: Employment, Equity Ownership, Patents & Royalties. Bargou:Micromet: Consultancy, Patents & Royalties.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.2723.2723
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 5
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    Effect of anti-CD19 BiTE blinatumomab on complete remission rate and overall survival in adult patients with relapsed/refractory B-precursor ALL.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 6500-6500
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 6500-6500
    Abstract: 6500^ Background: Blinatumomab is a bispecific T-cell engaging (BiTE) antibody that directs cytotoxic T-cells to CD19 expressing target cells. Methods: In adult patients with relapsed/refractory B-precursor ALL, a phase II dose ranging trial is being conducted to evaluate efficacy and safety of blinatumomab. The primary endpoint is the rate of hematological complete remission (CR) or CR with partial hematological recovery (CRh*) within 2 cycles of blinatumomab treatment. Blinatumomab is administered by continuous intravenous infusion for 28-days followed by a 14-day treatment-free interval. Responding patients can receive 3 additional cycles of treatment or proceed to bone marrow transplantation. Three dose levels were explored as shown in the table. Results: In total 36 patients have been enrolled, 25 are currently evaluable. Seventeen out of 25 treated patients (68%) reached a hematological CR/CRh* and a minimal residual disease (MRD) response (MRD level 〈 10 -4 ) within the first 2 cycles. Five out of 17 responders (29%) showed a CRh* due to partial recovery of platelets. For the first 18 patients, response duration is 7.1 months and the median follow-up time for overall survival (OS) is 9.7 months (median not reached). Six cases of relapses have been recorded of which 3 were CD19 + , and 3 CD19 - . As final dose 5 µg/m²/day in week 1 and 15 µg/m²/day for the remaining treatment (cohort 2a and 3) was selected. In these cohorts (n=12), the most common treatment emergent adverse events (TEAEs, all grade 1-2) were pyrexia (67%), headache (33%) and tremor (33%). TEAEs of grade ≥3 (7 in 5 patients, no grade 4), irrespective of relationship, were infections, confusion, epilepsy, hypertension and thrombocytopenia. Conclusions: The final dose was well-tolerated and produced an exceptionally high complete remission rate. A global phase 2 study to confirm these data is underway. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.6500
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 6
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    Phase II Trial of the Anti-CD19 Bispecific T Cell–Engager Blinatumomab Shows Hematologic and Molecular Remissions in Patients With Relapsed or Refractory B-Precursor Acute Lymphoblastic Leukemia
    American Society of Clinical Oncology (ASCO) ; 2014
    In:  Journal of Clinical Oncology Vol. 32, No. 36 ( 2014-12-20), p. 4134-4140
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 36 ( 2014-12-20), p. 4134-4140
    Abstract: Patients with relapsed or refractory acute lymphoblastic leukemia (ALL) have a dismal prognosis. CD19 is homogenously expressed in B-precursor ALL and can be targeted by the investigational bispecific T cell–engager antibody blinatumomab. A phase II trial was performed to determine clinical activity in this patient cohort. Patients and Methods Thirty-six patients with relapsed or refractory B-precursor ALL were treated with blinatumomab in cycles of 4-week continuous infusion followed by a 2-week treatment-free interval in a single-arm study with a dose-finding stage and an extension stage. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh). Major secondary end points included minimal residual disease (MRD) response, rate of allogeneic hematopoietic stem-cell transplantation (HSCT) realization, relapse-free survival (RFS), overall survival (OS), and incidence of adverse events (AEs). Results Median age was 32 years (range, 18 to 77 years). Twenty-five patients (69%) achieved a CR or CRh, with 88% of the responders achieving an MRD response. Median OS was 9.8 months (95% CI, 8.5 to 14.9), and median RFS was 7.6 months (95% CI, 4.5 to 9.5). Thirteen responders (52%) underwent HSCT after achieving a CR or CRh. The most frequent AE during treatment was pyrexia (grade 1 or 2, 75%; grade 3, 6%). In six patients with nervous system or psychiatric disorder AEs and in two patients with cytokine release syndrome, treatment had to be interrupted or discontinued. These medical events were resolved clinically. Conclusion The data support further investigation of blinatumomab for the treatment of adult patients with relapsed or refractory ALL in a larger confirmatory study.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2014.56.3247
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
    detail.hit.zdb_id: 2005181-5
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  • 7
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    Anti-CD19 BiTE Blinatumomab Induces High Complete Remission Rate and Prolongs Overall Survival in Adult Patients with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 670-670
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 670-670
    Abstract: Abstract 670 Introduction: Relapsed/refractory B-precursor ALL in adults has a dismal prognosis with only 35–40% of patients reaching a hematological complete remission (CR) with a median overall survival of 4–6 months. An exploratory phase II trial was conducted in this patient population with blinatumomab, a bispecific T-cell engaging (BiTE®) antibody that directs cytotoxic T-cells to CD19 expressing target cells. Methods: The primary endpoint was hematological CR or CR with partial hematological recovery (CRh*) within 2 cycles of blinatumomab. Secondary endpoints included overall survival (OS) and safety. Blinatumomab was administered by continuous intravenous infusion for 28 days followed by a 14-day treatment-free interval. Responding patients had the option to receive 3 additional cycles of treatment or to proceed to allogeneic hematopoietic stem cell transplantation (HSCT). Three dosing regimens were explored (Table 1) to identify the optimal regimen with respect to efficacy and toxicity. Results: 36 patients were treated; 26 out of the 36 treated patients (72%) achieved a hematological CR/CRh*. Ten out of 26 (38%) responders had a CRh*. 24 out 26 (92%) responders achieved also a molecular response (minimal residual disease level below 10−4 as measured by PCR) within the first 2 cycles. Twenty out of 21 (95%) patients in first relapse responded whereas only 6 out of 15 (40%) of the remaining patients achieved a hematological CR/CRh*. Thirteen patients proceeded to allogeneic HSCT in CR/CRh* after blinatumomab treatment, and one of them developed a medullary CD19− relapse after allogeneic HSCT. The other 13 responders did not receive allogeneic HSCT. Eight of these 13 patients relapsed: 2 relapses were CD19− (1 medullary and 1 extramedullary); 3 were CD19+ (1 medullary and 2 extramedullary), and 3 were with pending CD19 status (all 3 medullary). The median survival for all 36 treated patients is 9.0 months with a median follow-up time for OS of 10.7 months. For patients who achieved a CR/CRh*, the median survival is 14.1 months whereas for patients who failed blinatumomab therapy the median survival is 6.6 months. Cytokine release syndrome (CRS) and CNS events were reported as medically important events. Two patients with high tumor burden and no cytoreductive prephase required treatment interruption or discontinuation. CRS syndrome could be either prevented or treated by adapting a dexamethasone regimen for patients resulting in no further treatment interruption due to CRS. Fully reversible adverse drug events of the CNS leading to treatment interruption were observed in 6 patients: 3 patients with seizures and 3 patients with encephalopathy. CNS symptoms fully resolved, and all 6 patients were able to resume treatment at a lower dose; however, 2 out of these 6 patients had a recurrent event and permanently discontinued. One patient stopped treatment due to fungal infection leading to death. As final dose and schedule, 5 μg/m2/day in week 1 and 15 μg/m2/day for the remaining treatment (as in cohorts 2a and 3) was selected for further investi-gation based on safety and efficacy considerations. In the extension cohort, cohort 3 (n=18), the most common treatment emergent adverse events (TEAE) were pyrexia (70%), headache (39%), tremor (30%) and fatigue (30%). Summary: The final dosing regimen of blinatumomab produced exceptionally high complete hematological and molecular remission rates and was well-tolerated. Updated follow-up information regarding duration of response and survival will be presented. A global phase II study to confirm these data is being conducted. Disclosures: Topp: Amgen: Consultancy; Affimed: Consultancy. Goekbuget:AMGEN: Consultancy, Honoraria, Research Funding. Zugmaier:Amgen: Employment. Mergen:Amgen Research Munich GmbH: Employment. Bargou:Amgen: Consultancy, Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.670.670
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
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    Transient Laboratory Findings Upon First Dosing with T-Cell Engaging BiTE® Antibody Blinatumomab in Non-Hodgkin Lymphoma Patients.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 4798-4798
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 4798-4798
    Abstract: Abstract 4798 Blinatumomab is a single-chain bispecific antibody construct with specificity for CD19 and CD3 belonging to the class of bispecific T cell engager (BiTE®). It has shown high response rates as single agent after treatment of patients with indolent and mantle cell lymphoma and B-precursor acute lymphocytic leukemia. We here report from an ongoing phase 1 trial in non-Hodgkin lymphoma patients on transient laboratory findings seen upon start of continuous i.v. infusion of blinatumomab. The vast majority of adverse events (AEs) during 4-8 weeks of infusion occurred within the first two days of treatment. Lymphopenia (up to CTCAE grade 4) was the most frequent early laboratory AE, and can be explained by rapid B cell depletion and initial redistribution of T cells. Except for B cell decline, all laboratory parameters were transient and normalized within days during continued treatment. Dose-dependent increases were seen for AST and ALT (maximally grade 1/2), CRP, and D-dimer during the first days of treatment. Dose-dependent declines during the first days of treatment were observed for platelets and hemoglobin, which normalized after a few days. Of note, no drug-related thromboembolic events were observed. Serum levels of cytokines IL-6, IL-2, IFNγ, and IL-10 showed small dose-dependent increases, which reversed to baseline within hours. No association between cytokine levels and thrombocytopenia was found. Moreover, there was no evident correlation between any laboratory abnormality and clinical adverse event observed during the first days of treatment. The laboratory AEs induced by blinatumomab appear to reflect consequences of the onset of redirected target cell lysis, T cell activation and bystander effects. In conclusion, blinatumomab causes characteristic laboratory findings during the first days of treatment, which are transient, not associated with clinically relevant AEs and do not require treatment interruption. Compared to AEs caused by chemotherapy regimens, the laboratory findings observed after start of blinatumomab treatment are considered rather mild. Disclosures: Nagorsen: Micromet: Employment, Equity Ownership. Zugmaier:Micromet: Employment, Equity Ownership. Kufer:Micromet: Employment, Equity Ownership, Patents & Royalties. Klinger:Micromet: Employment, Equity Ownership. Schmidt:Micromet: Employment, Equity Ownership. Klappers:Micromat: Employment, Equity Ownership. Wolf:Micromet: Employment, Equity Ownership. Brandl:Micromet: Employment, Equity Ownership. Baeuerle:Micromet: Employment, Equity Ownership. Bargou:Micromet: Consultancy, Patents & Royalties.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.4798.4798
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 9
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    Anti-CD19 BiTE Blinatumomab Induces High Complete Remission Rate In Adult Patients with Relapsed B-Precursor ALL: Updated Results of An Ongoing Phase II Trial
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 252-252
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    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 252-252
    Abstract: Abstract 252 Adult patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL) have a dismal prognosis with low complete remission (CR) rates with intensive salvage chemotherapy which are not durable. Blinatumomab is a bispecific T-cell engaging (BiTE®) antibody construct that directs cytotoxic T-cells to CD19 expressing B-cells. In collaboration with the German Multicenter Study Group for Adult Lymphoblastic Leukemia (GMALL), an open-label, multicenter, single-arm, exploratory phase II trial is being conducted to evaluate efficacy and safety of blinatumomab in adult patients with relapsed/refractory B-precursor ALL. The primary endpoint for this trial is the rate of patients who reach CR or CR with partial hematological recovery (CRh*) within 2 cycles of blinatumomab treatment. Secondary endpoints are the rate of minimal residual disease (MRD) response (defined by an MRD level below the quantitative detection limit of 10−4), time to hematological relapse and overall survival. Blinatumomab is administered by continuous intravenous infusion for 28-days followed by a 14-day treatment-free interval. Responding patients could proceed to allogeneic hematopoietic stem cell transplantation (HSCT) or receive a total of up to 5 cycles of blinatumomab treatment. Three dose levels have been explored as shown in Table 1.Table 1.Summary of Dose Cohorts and OutcomesCohortPatients TreatedInitial Dose Week 1, Cycle 1 μg/m2/dayDose Week 2, Cycle 1 μg/m2/dayDose Weeks 3–4, Cycle 1 μg/m2/dayMaintenance Dose, Subsequent Cycles μg/m2/dayCR or CRh*Serious Adverse EventsnPts171515151551562a551515154222b65153030354310 planned5151515n.a.n.a.n.a. As of June 30, 2011, 43 cycles have been administered to a total of 18 patients (range 1–5; median 2). Twelve out of 18 patients have reached a complete remission within the first 2 cycles of single agent blinatumomab corresponding to a response rate of 67%. Of these 12 responding patients, 75% had complete hematologic recovery of peripheral blood counts. All 12 responders reached MRD negativity within the first 2 cycles and included 3 patients with t(4;11) and 1 patient with Ph-positive B-precursor ALL. Four responders proceeded to allogeneic HSCT; one experienced a CD19-negative hematological relapse after HSCT. Two responders relapsed during treatment; one had a CD19-positive extramedullary, and one a CD19-negative bone marrow relapse. The remaining 6 non-transplanted responders are still in hematological complete remission. The most common adverse events were pyrexia and chills. In cohort 1, one patient with a high tumor burden developed disseminated intravascular coagulation (DIC)/cytokine release syndrome (CRS) leading to treatment discontinuation. The implementation of a cytoreductive pre-phase and a lower initial dosing at 5μg/m2/day during the first week prevented further treatment discontinuations in such patients. Four patients had fully reversible CNS serious adverse events that led in 1 patient to discontinuation of treatment, and in 3 patients to temporary interruption of treatment. These 3 patients resumed treatment at a lower dose without further interruptions during the following cycles. There were no deaths related to blinatumomab. Blinatumomab as single agent induced an unprecedented high rate of complete hematological and MRD responses in adult patients with relapsed/refractory B-precursor ALL. A lower dose of 5μg/m2/day for the initial week of treatment, as tested in cohort 2a, demonstrated a favorable safety profile while maintaining efficacy. A maintenance dose of 30μg/m2/day, as tested in cohort 2b, did not further improve the already high efficacy but increased the number of adverse events. Therefore, the dosing of cohort 2a was selected as the basis for cohort 3 and will be applied to further clinical development in this patient population. Updated results of the study will be presented. Disclosures: Topp: Micromet: Consultancy, Honoraria. Goekbuget:Micromet: Consultancy. Zugmaier:Micromet: Employment. Klappers:Micromet AG: Employment. Mergen:Micromet Inc: Employment. Bargou:Micromet: Consultancy, Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.252.252
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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