Blinatumomab in Combination with Immune Checkpoint Inhibitors of PD-1 and CTLA-4 in Adult Patients with Relapsed/Refractory (R/R) CD19 Positive B-Cell Acute Lymphoblastic Leukemia (ALL): Preliminary Results of a Phase I Study
Authors: Webster Jonathan , Luskin Marlise R. , Prince Gabrielle T. , DeZern Amy E. , DeAngelo Daniel J. , Levis Mark J. , Blackford Amanda , Sharon Elad , Streicher Howard , Luznik Leo , Gojo Ivana 
Published: October 2019

Abstract
Background: Blinatumomab, a CD19/CD3 bispecific T cell engager antibody construct, leads to improved outcomes in patients with R/R CD19+ ALL compared to standard chemotherapy. However, most adults fail to achieve complete remission (CR) with blinatumomab, and the median duration of remission is only 7.3 months. Preclinical studies have shown significantly increased PD-L1 expression on leukemic blasts in patients who are refractory to or relapse after response to blinatumomab. Additionally, expression of the exhaustion markers PD-1 and TIM-3 on bone marrow (BM) CD3+ T cells is significantly higher among ALL patients than controls. The addition of PD-1 blockade +/- CTLA-4 blockade to blinatumomab and ALL blasts in vitro leads to increased T cell proliferation and enhanced blinatumomab-mediated cytotoxicity (Feucht et al, Oncotarget 2016). Thus, blockade of co-inhibitory pathways represents a viable strategy to enhance blinatumomab efficacy. We describe early results of a multi-center phase I study combining blinatumomab with monoclonal antibodies targeting PD-1 (nivolumab) +/- CTLA-4 (ipilimumab) in R/R CD19+ ALL.
Methods: This phase I dose-escalation study evaluates the safety and tolerability (MTD) of blinatumomab in combination with nivolumab +/- ipilimumab using a 3+3 design. Patients ≥16 years-old with R/R CD19+ Pre-B ALL or MPAL are eligible including those with prior blinatumomab and/or prior allogeneic transplant (allo-SCT). Patients ≥60 years may be untreated and those 16-21 must be R/R to ³2 lines of therapy. The trial started at dose level (DL) A1 (Fig. 1). Upon determining the MTD for the combination of blinatumomab and nivolumab, dose escalation will add ipilimumab (DLB1). Patients may receive up to 5 cycles of blinatumomab and 1 year of nivolumab/ipilimumab. Patients achieving CR may proceed to allo-SCT. Patients removed from the study during the blinatumomab lead-in (days 1-10) will be replaced.
Results: As of July 31, 2018, 8 adults (4 males/4 females) had enrolled at DLA1. The median age was 55 (range, 25-75) and baseline BM blast percentage was 73% (range, 8-98%). Baseline characteristics are presented in Figure 2. Seven patients received cytoreduction before treatment (6 steroids only and 1 steroids + Cytoxan). Two patients previously treated with blinatumomab were withdrawn from the study during the blinatumomab lead-in (1 for G3 pericardial effusion 2/2 disease progression and 1 for G3 hyperbilirubinemia). Among the 5 patients who received nivolumab to date, drug-related non-hematologic AEs of grade ≥3 included elevated AST (20%), ALT (20%), amylase (20%), and lipase (G4, 20%); hypophosphatemia (20%); rash (20%); infusion-related reaction (G4, 20%); and hypotension (20%). The elevated AST, ALT, amylase and lipase occurred prior to nivolumab dosing and resolved. One patient was removed from the study for a G4 infusion-related reaction following the 2nd dose of nivolumab that was considered a DLT. One patient in CR developed G4 neutropenia in cycles 2 + 3 but recovered spontaneously. Among the 5 evaluable patients, 4 (80%) achieved CR without MRD (2 after 1 cycle and 2 after 2 cycles of blinatumomab) with 3 ongoing remissions (median f/u 5 months) and 1 extramedullary relapse at day 125. Data on biomarkers including changes in T cell subpopulations in both BM and PB, and co-signaling molecule expression will be presented.
Conclusions: Combination therapy with blinatumomab and nivolumab in R/R ALL with is feasible with acceptable toxicity. The MRD-negative CR rate was (80%) despite heavily pre-treated patients with significant baseline disease burden. The last patient treated at DLA1 is undergoing treatment before dose escalation to include ipilimumab.

Disclosures
DeAngelo: Shire: Honoraria; ARIAD: Consultancy, Research Funding; Takeda: Honoraria; BMS: Consultancy; Amgen: Consultancy; Blueprint Medicines: Honoraria, Research Funding; Pfizer Inc: Consultancy, Honoraria; Glycomimetics: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Luznik:WIndMIL Therapeutics: Equity Ownership, Patents & Royalties. Gojo:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Merck inc: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.