Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemia: Therapy, excluding Transplantation: Advances in Immunotherapy
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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