Long-Term Outcomes after Blinatumomab Treatment: Follow-up of a Phase 2 Study in Patients (Pts) with Minimal Residual Disease (MRD) Positive B-Cell Precursor Acute Lymphoblastic Leukemia (ALL)

[Graphic][1] Introduction. MRD in ALL is defined as detection of leukemic cells in bone marrow by polymerase chain reaction (PCR) or flow cytometry with hematologic complete remission (CR). Pts with persistent/recurrent MRD after first-line induction therapy have a higher risk of relapse than those with complete MRD response (no detectable MRD with minimum sensitivity 0.01%). Interventions, including hematopoietic stem cell transplantation (HSCT), are used to improve the outcome of these pts. Blinatumomab, a bispecific T cell engager (BiTE®) antibody construct, redirects CD3+ T cells to CD19+ target cells, resulting in serial lysis of CD19+ B cells. In a multicenter, international phase 2 study in MRD+ ALL (Goekbuget N et al. Blood 2014;124:379), blinatumomab resulted in complete MRD response in cycle 1 in 78% of pts including multiple subgroups such as pts in second-line treatment, those with high MRD burden, and older pts. No subgroups with higher MRD complete response rates were identified. This analysis evaluated long-term outcomes, including overall survival (OS), relapse-free survival (RFS), and duration of remission (DOR). Methods. Adults (≥18 years) with B-cell precursor ALL with hematologic CR (<5% blasts in bone marrow) and MRD ≥10-3 after ≥3 intensive chemotherapy treatments were eligible. Pts with CNS pathology or extramedullary disease, previous allogeneic HSCT, or Philadelphia-chromosome positive (Ph+) ALL eligible for tyrosine kinase inhibitors were excluded. Blinatumomab 15 µg/m²/day was given by continuous IV infusion for 4 weeks, followed by a 2-week break (1 cycle). MRD was measured by a central laboratory using PCR per EuroMRD guidelines. MRD responders in cycle 1 received up to 3 additional cycles or underwent HSCT. Pts with hematologic relapse discontinued treatment. We report here preliminary follow-up data as of 1 July 2015. Final data from the preplanned 18-mo follow-up analysis will be available for the meeting. Results. 116 pts enrolled and received blinatumomab. Median age was 45 years (range 18-76); 15 (13%) pts were age ≥65 years. 90 (78%) pts received HSCT after blinatumomab. 62 (53%) pts were still being followed. 35 pts relapsed and 26 pts died in CR (23 of them after subsequent HSCT). Median OS, with median follow-up of 29.5 mo, was 36.5 mo (95% CI, 19.1 mo to not reached [n.r.]): 40.4 vs 12.0 ( P =.001) in pts with (n=88) or without (n=24) MRD complete response in cycle 1. 110 pts were evaluable (CR at study entry, Ph-) for RFS and DOR. Median RFS was 18.9 mo (95% CI, 12.3 to 35.2 mo): 24.6 vs 11.0 ( P =0.005) in pts treated in first (n=75) vs later (n=35) remission; and 35.2 vs 7.1 ( P =0.002) in pts alive and relapse-free after 45 days with (n=85) or without (n=15) MRD complete response in cycle 1 (Figure). Median DOR was n.r. (95% CI, 24.6 mo to n.r.): n.r. vs 15.0 mo ( P =0.002) in pts treated in first vs later remission; and n.r. vs 15.0 mo ( P =0.015) in pts with DOR ≥ 45 days with (n=85) or without (n=13) MRD complete response in cycle 1. In time-dependent Cox model analyses, HSCT vs no HSCT were not different for OS (hazard ratio [HR], 1.39; 95% CI, 0.68 to 2.82; P =0.368) or RFS (HR, 0.89; 95% CI, 0.47 to 1.69; P =0.730); DOR (treating death as a competing risk) was longer for HSCT vs no HSCT (HR, 0.36; 95% CI, 0.17 to 0.77; P =0.008). All pts experienced at least one AE. The most clinically relevant were neurologic events, including tremor (30%), aphasia (13%) dizziness (8%), ataxia and paraesthesia (6% each), and encephalopathy (5%). Rates decreased over time (cycles 1, 2, 3, and 4) for any neurologic event (47%, 24%, 15%, and 15%) and any grade ≥3 neurologic event (10%, 4%, 0%, and 0%). 12 (10%) pts interrupted treatment due to grade ≥3 neurologic events: 5 resumed without another interruption and 2 resumed then stopped treatment for another neurologic event. Investigators reported 4 deaths as fatal AEs during follow-up (brain injury, disease progression, gastrointestinal hemorrhage, and multiorgan failure); all 4 pts received HSCT after blinatumomab. Conclusion. In this long-term follow-up analysis of the first large prospective trial with an experimental compound in MRD+ ALL, MRD complete response induced by single-agent blinatumomab treatment was associated with longer OS, RFS, and DOR compared with not achieving an MRD complete response after blinatumomab treatment. This strengthens the current strategy of MRD-based treatment in ALL before occurrence of clinical relapse. [Figure][2] Disclosures Gokbuget: Sanofi: Equity Ownership; Pfizer: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Erytech: Consultancy; Eusapharma/Jazz: Consultancy, Honoraria, Research Funding; Gilead Sciences: Consultancy; Kite: Consultancy; Medac: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Bayer: Equity Ownership; SigmaTau: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Off Label Use: Blinatumomab (BLINCYTO®) is approved for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). It has not been approved for use in patients in hematologic remission, but with presence of minimal residual disease (MRD), from ALL. Dombret: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bonifacio: Amgen: Consultancy; Ariad Pharmaceuticals: Consultancy; Pfizer: Consultancy; Novartis Farma: Research Funding. Reichle: University Hospital Regensburg: Employment. Graux: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Faul: Amgen: 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. Bruggemann: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria. Horst: Pfizer: Research Funding; MSD: Research Funding; Gilead: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Boehringer Ingleheim: Research Funding. Stieglmaier: Amgen Research (Munich) GmbH: Employment; Amgen Inc: Equity Ownership. Wessels: Amgen: Employment. Haddad: Amgen Ltd.: Employment; Amgen Inc.: Equity Ownership. Zugmaier: Amgen Res. Munich: Employment. Nagorsen: Amgen: Employment, Equity Ownership, Patents & Royalties: Inventor on blinatumomab-related patent. Bargou: University of Wuerzburg, Germany: Employment; Novartis: Consultancy, Honoraria; GEMoaB GmbH: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Patents & Royalties: Patent for blinatumomab. [1]: /embed/inline-graphic-2.gif [2]: pending:yes