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.
OBJECTIVE
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.


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.


CONCLUSIONS
The data support further investigation of blinatumomab for the treatment of adult patients with relapsed or refractory ALL in a larger confirmatory study.
Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD. topp_m@ukw.de.
Max S
MS
Topp
Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD.
Nicola
N
Gökbuget
Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD.
Gerhard
G
Zugmaier
Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD.
Petra
P
Klappers
Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD.
Matthias
M
Stelljes
Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD.
Svenja
S
Neumann
Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD.
Andreas
A
Viardot
Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD.
Reinhard
R
Marks
Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD.
Helmut
H
Diedrich
Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD.
Christoph
C
Faul
Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD.
Albrecht
A
Reichle
Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD.
Heinz-August
HA
Horst
Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD.
Monika
M
Brüggemann
Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD.
Dorothea
D
Wessiepe
Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD.
Chris
C
Holland
Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD.
Shilpa
S
Alekar
Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD.
Noemi
N
Mergen
Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD.
Hermann
H
Einsele
Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD.
Dieter
D
Hoelzer
Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Universitätsklinikum Würzburg, Würzburg; Nicola Gökbuget, Goethe University; Dieter Hoelzer, Onkologikum, Frankfurt; Gerhard Zugmaier, Petra Klappers, and Noemi Mergen, Amgen Research; Dorothea Wessiepe, Metronomia, Munich; Matthias Stelljes, University of Münster, Münster; Svenja Neumann, Heinz-August Horst, and Monika Brüggemann, University Schleswig Holstein, City Hospital, Kiel; Andreas Viardot, University of Ulm, Ulm; Reinhard Marks, Universitätsklinikum Freiburg, Freiburg; Helmut Diedrich, Medizinische Hochschule Hannover, Hannover; Christoph Faul, Universitätsklinikum Tübingen, Tübingen; Albrecht Reichle, Universitätsklinikum Regensburg, Regensburg, Germany; and Chris Holland and Shilpa Alekar, Amgen, Rockville, MD.
Ralf C
RC
Bargou
D000293:Adolescent; D000328:Adult; D000368:Aged; D018033:Antibodies, Bispecific / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D018365:Neoplasm, Residual; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D012008:Recurrence; D012074:Remission Induction
D018033:Antibodies, Bispecific; C510808:blinatumomab