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
Authors: Topp Max S. , Goekbuget Nicola , Zugmaier Gerhard , Viardot Andreas , Stelljes Matthias , Neumann Svenja , Horst Heinz A. , Reichle Albrecht , Marks Reinhard E , Brueggemann Monika , Ritgen Matthias , Klappers Petra , Mergen Noemi , Goebeler Marie-Elisabeth , Einsele Hermann , Hoelzer Dieter , Bargou Ralf 
Published: October 2019

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.