BLINATUMOMAB IMPROVED OVERALL SURVIVAL IN PATIENTS WITH RELAPSED OR REFRACTORY PHILADELPHIA NEGATIVE B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA IN A RANDOMIZED, OPEN-LABEL PHASE 3 STUDY (TOWER)
Author(s): ,
Max S Topp
Affiliations:
Medizinische Klinik II,Universitätsklinikum Würzburg,Würzburg,Germany
,
Anthony Stein
Affiliations:
Hematology and Bone Marrow Transplant, Gehr Family Center for Leukemia, City of Hope Medical Center,Duarte CA,United States
,
Nicola Gökbuget
Affiliations:
Medizinische Klinik II - Hämatologie Onkologie,Universitätsklinikum,Frankfurt am Main,Germany
,
Adele Fielding
Affiliations:
Department of Oncology,University College London Hospital Cancer Institute,London,United Kingdom
,
Andre Schuh
Affiliations:
Medical Oncology And Hematology,Princess Margaret Cancer Centre,Toronto ON,Canada
,
Josep Maria Ribera Santasusana
Affiliations:
Clinical Hematology Department,ICO-Hospital Universitari Germans Trias i Pujol, Jose Carreras Leukemia Research Institute,Badalona,Spain
,
Andrew Wei
Affiliations:
Department of Clinical Haematology,The Alfred Hospital and Monash University,Melbourne,Australia
,
Hervé Dombret
Affiliations:
Institut Universitaire d'Hématologie,Hôpital Saint-Louis,Paris,France
,
Robin Foà
Affiliations:
Hematology, Dipartimento di Biotecnologie Cellulari ed Ematologia,Università Sapienza,Roma,Italy
,
Renato Bassan
Affiliations:
Unità Operativa Ematologia,Azienda Unità Locale Socio Sanitaria 12 Veneziana Ospedale Dell Angelo,Venezia,Italy
,
Onder Arslan
Affiliations:
Hemotoloji Bilim Dali,Ankara Universitesi, Tip Fakültesi, Cebeci Arastirma ve Uygulama Hastanesi,Ankara,Turkey
,
Miguel A Sanz
Affiliations:
Servicio de Hematologia,Hospital Universitari i Politecnic La Fe,Valencia,Spain
,
Julie Bergeron
Affiliations:
Department of Hematology,CIUSSS de lest de lile de Montreal - Hopital Maisonneuve Rosemont,Montreal QC,Canada
,
Fatih Demirkan
Affiliations:
Hematology,Dokuz Eylul Universitesi Tip Fakultesi,Izmir,Turkey
,
Ewa Lech-Maranda
Affiliations:
Klinika Hematologii,Instytut Hematologii i Transfuzjologii and Centrum Medyczne Ksztalcenia Podyplomowego,Warszawa,Poland
,
Alessandro Rambaldi
Affiliations:
University of Milan, Ematologia,Ospedale Papa Giovanni XXIII,Bergamo,Italy
,
Xavier Thomas
Affiliations:
Service Hematologie,Centre Hospitalier Lyon Sud,Pierre-Benite,France
,
Alex Fleishman
Affiliations:
Global Biostatistical Sciences,Amgen Inc.,Thousand Oaks CA,United States
,
Dirk Nagorsen
Affiliations:
Global Clinical Development,Amgen Inc.,Thousand Oaks CA,United States
,
Christopher Holland
Affiliations:
Global Biostatistical Sciences,Amgen Inc.,Rockville MD,United States
,
Zachary Zimmerman
Affiliations:
Global Clinical Development,Amgen Inc.,Thousand Oaks CA,United States
Hagop Kantarjian
Affiliations:
Department of Leukemia,University of Texas MD Anderson Cancer Center,Houston TX,United States
EHA Library. Topp M. Jun 10, 2016; 135182; S149 Topic: 3Aa B lymphoblastic leukemia/lymphoma
Disclosure(s): Universitätsklinikum Würzburg
Dr. Max Topp
Dr. Max Topp
Contributions
×
Abstract
Abstract: S149

Type: Presidential Symposium

Presentation during EHA21: On Friday, June 10, 2016 from 16:35 - 16:47

Location: Hall A1

Background
Blinatumomab, a bispecific T-cell engager antibody construct, binds specifically to CD19 (B cells) and CD3 (T cells) to facilitate lysis of CD19-positive target B-lineage cells. Based on a single-arm phase 2 study, blinatumomab received approvals in the US (accelerated) and EU (conditional) for the treatment of Philadelphia chromosome-negative (Ph–) relapsed/refractory (r/r) B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Aims
This phase 3, randomized, open-label study investigated the effect of blinatumomab on overall survival (OS) compared with standard of care (SOC) chemotherapy in adult patients with Ph– r/r BCP-ALL.

Methods
Patients with r/r BCP-ALL (if first relapse, within 1 y) were randomized 2:1 to receive either blinatumomab or SOC chemotherapy (investigator's choice of 1 of 4 defined regimens). Randomization was stratified by age, prior salvage therapy, and prior allogeneic stem cell transplant (alloSCT). Blinatumomab was given in 6-week cycles of 4 weeks on (continuous infusion of 9 µg/d in week 1 of cycle 1, then 28 µg/d) and 2 weeks off; dexamethasone was given pre-dose to prevent cytokine release syndrome. Patients in remission after 2 induction cycles were eligible to continue therapy until relapse. OS was the primary efficacy endpoint. Complete remission (CR) and combined CR or CR with partial or incomplete hematologic recovery (CR/CRh/CRi) were secondary efficacy endpoints. The primary analysis was scheduled to occur after 330 deaths had accrued. This prespecified interim analysis for an independent data monitoring committee (DMC) occurred after 248 deaths (75%).

Results
A total of 405 patients were randomized to blinatumomab (n=271) or SOC (n=134) and analyzed for efficacy; 2% and 19%, respectively, elected to receive no study treatment. Baseline characteristics were balanced between treatment groups (blinatumomab, SOC): median age (37y, 37y); median bone marrow blasts (80%, 79%); prior salvage therapy (56%, 52%); and prior alloSCT (35%, 34%). Using results from the DMC analysis, median OS was 7.8 months (95%CI: 5.7, 10.0) for blinatumomab and 4.0 months (95%CI: 2.9, 5.4) for SOC (stratified log-rank test p=.011; hazard ratio=0.71), surpassing the prespecified O’Brien-Fleming boundary p value of 0.0183. Improvement in OS was consistent between subgroups based on age, prior salvage therapy, or prior alloSCT. Response rates were higher for blinatumomab vs SOC, including CR (39% vs 19%; p<.001) and CR/CRh/CRi (46% vs 28%, p=.001). A total of 373 patients received ≥1 dose of blinatumomab (N=266) or SOC (N=107; 47 FLAG ± anthracycline; 19 HiDAC-based; 22 high-dose methotrexate-based; and 19 clofarabine-based) and were analyzed for safety; 57% and 25%, respectively, started at least 2 cycles. Safety outcomes were similar between blinatumomab and SOC (table).Table. Incidence Rates of Adverse Events (AE), Regardless of Causality

















 

















 


















  Blinatumomab (N=266) SOC (N=107)
Any AE, % (per 100 patient-months)   Any grade 3 AE, %   Any grade 4 AE, %   Any grade 5/fatal AE, %      Grade 5 infection, % 99% (631.3)38%29%19%11% 99% (764.4)34%40%19%12%
Any serious AE, % (per 100 patient-months)   Infection, %   Blood/lymphatic, %   Nervous system, %   Cytokine release syndrome, % 62% (26.4)28%14%7%3% 45% (38.1)31%16%3%0%





Conclusion
This prespecified interim analysis showed that blinatumomab, as compared with SOC chemotherapy, improved the primary endpoint of OS in the phase 3 TOWER study of adults with Ph– r/r BCP-ALL. Remission rates also were higher in the blinatumomab group. AEs in the blinatumomab group were consistent with previous studies. Based on these findings, the DMC recommended stopping the TOWER study for efficacy before the planned final analysis.

Session topic: Presidential Symposium

Keyword(s): B cell acute lymphoblastic leukemia, CD19, Immunotherapy, Survival

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