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
Authors: Viardot Andreas , Goebeler Mariele , Scheele Jurgen S. , Zugmaier Gerhard , Noppeney Richard , Knop Stefan , Topp Max S , Nagorsen Dirk , Klinger Matthias , Schmidt Margit , Klappers Petra , Kufer Peter , Einsele Hermann , Bargou Ralf 
Published: October 2019

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.