Outcomes of Patients with Relapsed/Refractory (R/R) B-Cell Acute Lymphocytic Leukemia (ALL) Post Blinatumomab Failure
Authors: Dahl Jenny , Kantarjian Hagop M. , Yilmaz Musa , Kadia Tapan , Garcia-Manero Guillermo , Ravandi Farhad , Borthakur Gautam , Cortes Jorge E. , Ferrajoli Alessandra , Sasaki Koji , Chahoud Jad , Autry Jane , Garris Rebecca , Jabbour Elias 
Published: October 2019

Abstract
Introduction: Blinatumomab is a first-in-class Bispecific T-cell engaging (BiTE) antibody targeting CD19-positive malignant cells and CD3-positive T cells. It has shown activity in both R/R B-cell ALL and with persistent minimal residual disease (MRD). However, despite a 50% response rate with blinatumomab, the duration of response is very short with many pts experiencing relapse. The goal of this study is to assess the outcome of patients with R/R B-cell ALL post blinatumomab failure.
Methods: We reviewed 40 patients with R/R ALL treated with blinatumomab at our institution between 1/2012 and 1/2015. Of the 40 patients treated, 30 were either refractory (n=18) or lost their response (n=12) after initially achieving a complete response or complete response with incomplete count recovery (CRi). We analyzed the clinical characteristics and survival of these 30 patients who failed blinatumomab.
Results: Clinical characteristics of the 30 patients with blinatumomab failure are summarized in Table 1. Best response to blinatumomab was CR in 9 pts and CRi in 3 with a median duration of response of 3 months (range, 1-8 months). After a median follow-up of 6.8 months (range 4.8- 31 months) from blinatumomab failure, 8 patients (27%) remain alive. The median overall survival was 6.4 months and the estimated 12-month survival rate was 36%. The median survival was 3 and 11 months for patients refractory to blinatumomab and those who relapsed after a previous response, respectively (p=0.179). Furthermore, there was a trend for better outcome post blinatumomab failure if the drug was administered as first, second, or third and beyond salvage therapy with a median survival of 19, 11, and 5 months, respectively (p= 0.248). Following blinatumomab failure, 11 patients received inotuzumab ozogamicin salvage therapy as a single agent in 5 or in combination with mini-hyper-CVD in 6 [Jabbour E et al; EHA 2015]. Eight patients responded for an overall response rate of 73% for a median duration of 6 months (range, 1.2-30 months). Overall, 9 patients underwent allogeneic stem cell transplant (allo-SCT), 5 of them post salvage therapy with inotuzumab. Seven of them remain alive in CR at the last follow-up. The 1-year survival rates were 83% and 11% for patients who received an allo-SCT and those who did not, respectively (p<0.001).
Conclusions: Overall, the outcome of patients with R/R ALL post blinatumomab failure is poor with a median survival of 6.4 months. Inotuzumab ozogamicin is a good salvage therapy option allowing patients with refractory disease to proceed with allo-SCT that remains the only curative approach for these patients.
Table 1. Clinical Characteristics of Patients with Blinatumomab Failure N=30 Parameter N (%)/Median [Range] Age (years) 29 [19-76] Sex (Male) 23 (77) Performance Status 1 [0-2] Cytogenetics Diploid 9 (30) t(4;11) 1 (3) Miscellaneous 15 (50) t(9;22) 1 (3) Insufficient Metaphase 4 (14) WBC at start (x 109/L) 2.75 [0.4-24] % PB blasts at start 8 [0-98] % BM Blasts at start 80 [10-98] WBC at failure (x 109/L) 3.4 [0-224] % BM Blasts at failure 69 [2-98] # Prior therapies, median 3 [1-6] # Blinatumomab courses 2 [1-5] Best response to blinatumomab CR 9 (30) CRi 3 (10) Median duration of response (months) 3 [1-8] Follow up, median (months) 6.8 [4.8-31]

Disclosures
Cortes: Teva: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; BerGenBio AS: Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.