title: Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study.
abstract: Purpose Few therapeutic options are available for patients with Philadelphia chromosome-positive (Ph+) B-precursor acute lymphoblastic leukemia (ALL) who progress after failure of tyrosine kinase inhibitor (TKI) -based therapy. Here, we evaluated the efficacy and tolerability of blinatumomab in patients with relapsed or refractory Ph+ALL. Patients and Methods This open-label phase II study enrolled adults with Ph+ALL who had relapsed after or were refractory to at least one second-generation or later TKI or were intolerant to second-generation or later TKIs and intolerant or refractory to imatinib. Blinatumomab was administered in 28-day cycles by continuous intravenous infusion. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh) during the first two cycles. Major secondary end points included minimal residual disease response, rate of allogeneic hematopoietic stem-cell transplantation, relapse-free survival, overall survival, and adverse events (AEs). Results Of 45 patients, 16 (36%; 95% CI, 22% to 51%) achieved CR/CRh during the first two cycles, including four of 10 patients with the T315I mutation; 88% of CR/CRh responders achieved a complete minimal residual disease response. Seven responders (44%) proceeded to allogeneic hematopoietic stem-cell transplantation, including 55% (six of 11) of transplantation-naïve responders. Median relapse-free survival and overall survival were 6.7 and 7.1 months, respectively. The most frequent AEs were pyrexia (58%), febrile neutropenia (40%), and headache (31%). Three patients had cytokine release syndrome (all grade 1 or 2), and three patients had grade 3 neurologic events, one of which (aphasia) required temporary treatment interruption. There were no grade 4 or 5 neurologic events. Conclusion Single-agent blinatumomab showed antileukemia activity in high-risk patients with Ph+ALL who had relapsed or were refractory to TKIs. AEs were consistent with previous experience in Ph-ALL.
authors.affiliation: Giovanni Martinelli and Cristina Papayannidis, Institute of Hematology and Medical Oncology "L. and A. Seràgnoli", Bologna; Alessandro Rambaldi, University of Milan Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; Nicolas Boissel, University Paris Diderot, Hôpital Saint-Louis, Paris; Patrice Chevallier, Centre Hospitalier Universitaire Nantes, Nantes, France; Oliver Ottmann, Cardiff University, Cardiff; Adele K. Fielding, University College London Cancer Institute, London, United Kingdom; Nicola Gökbuget, University Hospital, Goethe University, Frankfurt; Max S. Topp, Universitätsklinikum Würzburg, Würzburg, Germany; Ellen K. Ritchie, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY; Lulu Ren Sterling, Amgen, San Francisco; Jonathan Benjamin, Amgen, Thousand Oaks; and Anthony Stein, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.affiliation: Giovanni Martinelli and Cristina Papayannidis, Institute of Hematology and Medical Oncology "L. and A. Seràgnoli", Bologna; Alessandro Rambaldi, University of Milan Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; Nicolas Boissel, University Paris Diderot, Hôpital Saint-Louis, Paris; Patrice Chevallier, Centre Hospitalier Universitaire Nantes, Nantes, France; Oliver Ottmann, Cardiff University, Cardiff; Adele K. Fielding, University College London Cancer Institute, London, United Kingdom; Nicola Gökbuget, University Hospital, Goethe University, Frankfurt; Max S. Topp, Universitätsklinikum Würzburg, Würzburg, Germany; Ellen K. Ritchie, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY; Lulu Ren Sterling, Amgen, San Francisco; Jonathan Benjamin, Amgen, Thousand Oaks; and Anthony Stein, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Boissel
authors.affiliation: Giovanni Martinelli and Cristina Papayannidis, Institute of Hematology and Medical Oncology "L. and A. Seràgnoli", Bologna; Alessandro Rambaldi, University of Milan Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; Nicolas Boissel, University Paris Diderot, Hôpital Saint-Louis, Paris; Patrice Chevallier, Centre Hospitalier Universitaire Nantes, Nantes, France; Oliver Ottmann, Cardiff University, Cardiff; Adele K. Fielding, University College London Cancer Institute, London, United Kingdom; Nicola Gökbuget, University Hospital, Goethe University, Frankfurt; Max S. Topp, Universitätsklinikum Würzburg, Würzburg, Germany; Ellen K. Ritchie, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY; Lulu Ren Sterling, Amgen, San Francisco; Jonathan Benjamin, Amgen, Thousand Oaks; and Anthony Stein, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA.
authors.forename: Patrice
authors.initials: P
authors.lastname: Chevallier
authors.affiliation: Giovanni Martinelli and Cristina Papayannidis, Institute of Hematology and Medical Oncology "L. and A. Seràgnoli", Bologna; Alessandro Rambaldi, University of Milan Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; Nicolas Boissel, University Paris Diderot, Hôpital Saint-Louis, Paris; Patrice Chevallier, Centre Hospitalier Universitaire Nantes, Nantes, France; Oliver Ottmann, Cardiff University, Cardiff; Adele K. Fielding, University College London Cancer Institute, London, United Kingdom; Nicola Gökbuget, University Hospital, Goethe University, Frankfurt; Max S. Topp, Universitätsklinikum Würzburg, Würzburg, Germany; Ellen K. Ritchie, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY; Lulu Ren Sterling, Amgen, San Francisco; Jonathan Benjamin, Amgen, Thousand Oaks; and Anthony Stein, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Ottmann
authors.affiliation: Giovanni Martinelli and Cristina Papayannidis, Institute of Hematology and Medical Oncology "L. and A. Seràgnoli", Bologna; Alessandro Rambaldi, University of Milan Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; Nicolas Boissel, University Paris Diderot, Hôpital Saint-Louis, Paris; Patrice Chevallier, Centre Hospitalier Universitaire Nantes, Nantes, France; Oliver Ottmann, Cardiff University, Cardiff; Adele K. Fielding, University College London Cancer Institute, London, United Kingdom; Nicola Gökbuget, University Hospital, Goethe University, Frankfurt; Max S. Topp, Universitätsklinikum Würzburg, Würzburg, Germany; Ellen K. Ritchie, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY; Lulu Ren Sterling, Amgen, San Francisco; Jonathan Benjamin, Amgen, Thousand Oaks; and Anthony Stein, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Gökbuget
authors.affiliation: Giovanni Martinelli and Cristina Papayannidis, Institute of Hematology and Medical Oncology "L. and A. Seràgnoli", Bologna; Alessandro Rambaldi, University of Milan Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; Nicolas Boissel, University Paris Diderot, Hôpital Saint-Louis, Paris; Patrice Chevallier, Centre Hospitalier Universitaire Nantes, Nantes, France; Oliver Ottmann, Cardiff University, Cardiff; Adele K. Fielding, University College London Cancer Institute, London, United Kingdom; Nicola Gökbuget, University Hospital, Goethe University, Frankfurt; Max S. Topp, Universitätsklinikum Würzburg, Würzburg, Germany; Ellen K. Ritchie, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY; Lulu Ren Sterling, Amgen, San Francisco; Jonathan Benjamin, Amgen, Thousand Oaks; and Anthony Stein, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA.
authors.forename: Max S
authors.initials: MS
authors.lastname: Topp
authors.affiliation: Giovanni Martinelli and Cristina Papayannidis, Institute of Hematology and Medical Oncology "L. and A. Seràgnoli", Bologna; Alessandro Rambaldi, University of Milan Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; Nicolas Boissel, University Paris Diderot, Hôpital Saint-Louis, Paris; Patrice Chevallier, Centre Hospitalier Universitaire Nantes, Nantes, France; Oliver Ottmann, Cardiff University, Cardiff; Adele K. Fielding, University College London Cancer Institute, London, United Kingdom; Nicola Gökbuget, University Hospital, Goethe University, Frankfurt; Max S. Topp, Universitätsklinikum Würzburg, Würzburg, Germany; Ellen K. Ritchie, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY; Lulu Ren Sterling, Amgen, San Francisco; Jonathan Benjamin, Amgen, Thousand Oaks; and Anthony Stein, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA.
authors.forename: Adele K
authors.initials: AK
authors.lastname: Fielding
authors.affiliation: Giovanni Martinelli and Cristina Papayannidis, Institute of Hematology and Medical Oncology "L. and A. Seràgnoli", Bologna; Alessandro Rambaldi, University of Milan Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; Nicolas Boissel, University Paris Diderot, Hôpital Saint-Louis, Paris; Patrice Chevallier, Centre Hospitalier Universitaire Nantes, Nantes, France; Oliver Ottmann, Cardiff University, Cardiff; Adele K. Fielding, University College London Cancer Institute, London, United Kingdom; Nicola Gökbuget, University Hospital, Goethe University, Frankfurt; Max S. Topp, Universitätsklinikum Würzburg, Würzburg, Germany; Ellen K. Ritchie, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY; Lulu Ren Sterling, Amgen, San Francisco; Jonathan Benjamin, Amgen, Thousand Oaks; and Anthony Stein, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rambaldi
authors.affiliation: Giovanni Martinelli and Cristina Papayannidis, Institute of Hematology and Medical Oncology "L. and A. Seràgnoli", Bologna; Alessandro Rambaldi, University of Milan Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; Nicolas Boissel, University Paris Diderot, Hôpital Saint-Louis, Paris; Patrice Chevallier, Centre Hospitalier Universitaire Nantes, Nantes, France; Oliver Ottmann, Cardiff University, Cardiff; Adele K. Fielding, University College London Cancer Institute, London, United Kingdom; Nicola Gökbuget, University Hospital, Goethe University, Frankfurt; Max S. Topp, Universitätsklinikum Würzburg, Würzburg, Germany; Ellen K. Ritchie, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY; Lulu Ren Sterling, Amgen, San Francisco; Jonathan Benjamin, Amgen, Thousand Oaks; and Anthony Stein, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA.
authors.forename: Ellen K
authors.initials: EK
authors.lastname: Ritchie
authors.affiliation: Giovanni Martinelli and Cristina Papayannidis, Institute of Hematology and Medical Oncology "L. and A. Seràgnoli", Bologna; Alessandro Rambaldi, University of Milan Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; Nicolas Boissel, University Paris Diderot, Hôpital Saint-Louis, Paris; Patrice Chevallier, Centre Hospitalier Universitaire Nantes, Nantes, France; Oliver Ottmann, Cardiff University, Cardiff; Adele K. Fielding, University College London Cancer Institute, London, United Kingdom; Nicola Gökbuget, University Hospital, Goethe University, Frankfurt; Max S. Topp, Universitätsklinikum Würzburg, Würzburg, Germany; Ellen K. Ritchie, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY; Lulu Ren Sterling, Amgen, San Francisco; Jonathan Benjamin, Amgen, Thousand Oaks; and Anthony Stein, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Papayannidis
authors.affiliation: Giovanni Martinelli and Cristina Papayannidis, Institute of Hematology and Medical Oncology "L. and A. Seràgnoli", Bologna; Alessandro Rambaldi, University of Milan Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; Nicolas Boissel, University Paris Diderot, Hôpital Saint-Louis, Paris; Patrice Chevallier, Centre Hospitalier Universitaire Nantes, Nantes, France; Oliver Ottmann, Cardiff University, Cardiff; Adele K. Fielding, University College London Cancer Institute, London, United Kingdom; Nicola Gökbuget, University Hospital, Goethe University, Frankfurt; Max S. Topp, Universitätsklinikum Würzburg, Würzburg, Germany; Ellen K. Ritchie, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY; Lulu Ren Sterling, Amgen, San Francisco; Jonathan Benjamin, Amgen, Thousand Oaks; and Anthony Stein, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA.
authors.forename: Lulu Ren
authors.initials: LR
authors.lastname: Sterling
authors.affiliation: Giovanni Martinelli and Cristina Papayannidis, Institute of Hematology and Medical Oncology "L. and A. Seràgnoli", Bologna; Alessandro Rambaldi, University of Milan Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; Nicolas Boissel, University Paris Diderot, Hôpital Saint-Louis, Paris; Patrice Chevallier, Centre Hospitalier Universitaire Nantes, Nantes, France; Oliver Ottmann, Cardiff University, Cardiff; Adele K. Fielding, University College London Cancer Institute, London, United Kingdom; Nicola Gökbuget, University Hospital, Goethe University, Frankfurt; Max S. Topp, Universitätsklinikum Würzburg, Würzburg, Germany; Ellen K. Ritchie, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY; Lulu Ren Sterling, Amgen, San Francisco; Jonathan Benjamin, Amgen, Thousand Oaks; and Anthony Stein, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Benjamin
authors.affiliation: Giovanni Martinelli and Cristina Papayannidis, Institute of Hematology and Medical Oncology "L. and A. Seràgnoli", Bologna; Alessandro Rambaldi, University of Milan Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; Nicolas Boissel, University Paris Diderot, Hôpital Saint-Louis, Paris; Patrice Chevallier, Centre Hospitalier Universitaire Nantes, Nantes, France; Oliver Ottmann, Cardiff University, Cardiff; Adele K. Fielding, University College London Cancer Institute, London, United Kingdom; Nicola Gökbuget, University Hospital, Goethe University, Frankfurt; Max S. Topp, Universitätsklinikum Würzburg, Würzburg, Germany; Ellen K. Ritchie, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY; Lulu Ren Sterling, Amgen, San Francisco; Jonathan Benjamin, Amgen, Thousand Oaks; and Anthony Stein, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Stein
mesh_terms: D000328:Adult; D018033:Antibodies, Bispecific / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010677:Philadelphia Chromosome; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; C510808:blinatumomab