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679 Complete Molecular and Hematologic Response in Adult Patients with Relapsed/Refractory (R/R) Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia (ALL) Following Treatment with Blinatumomab: Results from a Phase 2 Single-Arm, Multicenter Study (ALCANTARA)Clinically Relevant Abstract

Acute Lymphoblastic Leukemia: Therapy, excluding Transplantation
Program: Oral and Poster Abstracts
Type: Oral
Session: 614. Acute Lymphoblastic Leukemia: Therapy, excluding Transplantation: Advances in Immunotherapy
Monday, December 7, 2015: 2:45 PM
W224CDGH, Level 2 (Orange County Convention Center)

Giovanni Martinelli, MD1*, Hervé Dombret2, Patrice Chevallier, MD, PhD3*, Oliver G. Ottmann, MD4*, Nicola Goekbuget, MD5, Max S. Topp, MD6, Adele K. Fielding, MB BS, PhD7, Lulu Ren Sterling, PhD8*, Jonathan Benjamin, MD9 and Anthony Selwyn Stein, MD10

1Institute of Hematology, S.Orsola-Malpighi University Hospital, Bologna, Italy
2Hematology, Hôpital Saint-Louis, Paris, France
3Department of Hematology, Nantes University Hospital, Nantes, France
4Department of Haematology, Cardiff University, Cardiff, United Kingdom
5Department of Medicine II, Goethe University, Frankfurt, Germany
6Department of Internal Medicine II, Division of Hematology and Medical Oncology, Wuerzburg University Medical Center, Wuerzburg, Germany
7Department of Hematology, UCL Cancer Institute, London, United Kingdom
8Amgen Inc., San Francisco, CA
9Amgen Inc., Thousand Oaks, CA
10Gehr Leukemia Center, City of Hope Medical Center, Duarte, CA

Introduction. Prognosis of patients (pts) with R/R Philadelphia chromosome-positive (Ph+) ALL is dismal despite the introduction of tyrosine kinase inhibitors (TKI) which may be used as single agents or in combination regimens.  Blinatumomab is a bispecific T-cell engaging (BiTE®) antibody construct that has shown antileukemic activity.  Among adults with R/R Ph-negative ALL receiving blinatumomab, 43% achieved complete remission (CR) or CR with partial hematologic recovery (CRh) during the first two cycles (Topp MS et al. Lancet Oncol 2015;16:57).  We evaluated the efficacy and tolerability of blinatumomab in pts with R/R Ph+ ALL who progressed after or were intolerant to a 2nd or later (2+) generation TKI.

Methods. Eligible adult pts (≥ 18 years) had Ph+ B-precursor ALL and had relapsed after or were refractory to at least one 2+ generation TKI; or were intolerant to 2+ generation TKI and intolerant or refractory to imatinib.  All pts had to have >5% blasts in the bone marrow and Eastern Cooperative Oncology Group performance status ≤ 2.  Blinatumomab was dosed by continuous IV infusion (4 weeks on/2 weeks off) for up to 5 cycles (9 μg/d on days 1-7 in cycle 1, and 28 μg/d thereafter).  The primary endpoint was CR or CRh during the first two cycles; minimal residual disease (MRD) response based on RT-PCR amplification of BCR-ABL per central laboratory, relapse-free survival (RFS), overall survival (OS), and allogeneic hematopoietic stem cell transplant (alloHSCT) rate were key secondary endpoints.  Complete MRD response was defined as no RT-PCR amplification of BCR-ABL at a sensitivity of 10‑5.

Results. Of 45 treated pts, 44 were resistant to 2+ generation TKI; one patient was resistant to imatinib and never exposed to 2+ generation TKI (protocol deviation).  53% of pts were men.  Median (range) age was 55 (23–78) years (≥ 65 years, 27%).  Ten pts (22%) had a BCR-ABL gene with T315I mutation.  All pts had received prior TKI (dasatinib, 87%; ponatinib, 51%; imatinib, 56%; nilotinib, 36%; bosutinib, 2%), with 60% having received ≥ 2 prior 2+ generation TKI; most pts (96%) had received prior chemotherapy.  38% of pts had ≥ 2 prior relapses and 44% had prior alloHSCT.  Efficacy outcomes for key endpoints are shown in the table.  16 pts achieved CR/CRh during the first two cycles for a response rate of 36% (95% CI: 22%, 51%); of those, 14 pts achieved CR, most of them (10/14, 71%) in cycle 1.  The patient who never received 2+ generation TKI did not respond to treatment.  12 of the 14 pts (86%) with CR and two of the two pts with CRh achieved a complete MRD response.  Among the 10 pts with T315I mutation, four achieved CR/CRh; all four also achieved a complete MRD response.  Eight CR/CRh responders (50%) relapsed, three during treatment (including two with CR who did not achieve complete MRD response).  One patient died in CR post alloHSCT.  Median (95% CI) RFS was 6.7 (4.4, not estimable) months (median follow-up, 9.0 months); median OS was 7.1 (5.6, not estimable) months (median follow-up, 8.8 months).  Patient incidence of grade ≥ 3 treatment-emergent adverse events (AEs) was 82%, most commonly febrile neutropenia (27%), thrombocytopenia (22%), anemia (16%), and pyrexia (11%).  Five pts had fatal AEs; one (septic shock) was considered treatment-related by the investigator.  Three pts discontinued because of AEs.  Cytokine release syndrome (CRS) occurred in three pts (all grade 1 or 2).  21 pts (47%) had neurologic events (paraesthesia, 13%; confusional state, 11%; dizziness, 9%; tremor, 9%); three pts had grade 3 neurologic events (aphasia, hemiplegia; and depressed level of consciousness and nervous system disorder), one of which (aphasia) required treatment interruption.

Conclusion. In this population of pts with R/R Ph+ ALL who have very poor prognosis after failure of 2+ generation TKI therapy, treatment with CD19-targeted immunotherapy blinatumomab as single agent showed antileukemic activity.  AEs were consistent with those previously reported for pts with R/R Ph-negative ALL treated with blinatumomab.


Disclosures: Martinelli: Novartis: Speakers Bureau ; BMS: Speakers Bureau ; Pfizer: Consultancy , Speakers Bureau ; ARIAD: Consultancy ; Roche: Consultancy ; MSD: Consultancy . Dombret: Amgen: Honoraria , Membership on an entity’s Board of Directors or advisory committees , Research Funding . Ottmann: Astra Zeneca: Honoraria , Membership on an entity’s Board of Directors or advisory committees ; Bristol Myers Squibb: Honoraria , Membership on an entity’s Board of Directors or advisory committees ; Ariad: Consultancy , Honoraria , Membership on an entity’s Board of Directors or advisory committees ; Novartis: Consultancy , Honoraria , Membership on an entity’s Board of Directors or advisory committees , Research Funding ; Pfizer: Consultancy , Honoraria , Membership on an entity’s Board of Directors or advisory committees . Goekbuget: Bayer: Equity Ownership ; Eusapharma/Jazz: Consultancy , Honoraria , Research Funding ; Erytech: Consultancy ; Pfizer: Consultancy , Honoraria , Research Funding ; Medac: Consultancy , Honoraria , Research Funding ; Novartis: Consultancy , Honoraria , Research Funding ; Mundipharma: Consultancy , Honoraria , Research Funding ; SigmaTau: Consultancy , Honoraria , Research Funding ; Kite: Consultancy ; Gilead Sciences: Consultancy ; Sanofi: Equity Ownership ; Amgen: Consultancy , Honoraria , Research Funding ; GlaxoSmithKline: Honoraria , Research Funding ; Bristol-Myers Squibb: Honoraria . Topp: Astra: Consultancy ; Regeneron: Consultancy ; Affimed: Consultancy , Research Funding ; Roche: Consultancy , Other: Travel Support ; Jazz: Consultancy ; Pfizer: Consultancy ; Amgen: Consultancy , Honoraria , Other: Travel Support . Fielding: Amgen: Consultancy , Honoraria . Sterling: Amgen: Employment , Equity Ownership . Benjamin: Amgen: Employment , Equity Ownership . Stein: Amgen: Consultancy , Honoraria , Membership on an entity’s Board of Directors or advisory committees , Speakers Bureau ; Seattle Genetics: Research Funding .

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