Blinatumumab Induces Responses in Extramedulary B-Cell Acute Lymphoid Leukemia (B-ALL) and Lymphoid Blast Crisis Chronic Myelogenous Leukemia (CML), and Rarely Results in CD19 Negative Relapse
Authors: Koprivnikar Jamie , Marcotulli Danielle , Jones Elizabeth , Perry Grace , Kuo Yen-Hong , Gagnon Joelle , Aviador Maritess , Stanislaus Genique , McCloskey James 
Published: October 2019

Abstract
Background: Blinatumumab (B), a bi-specific T-cell engaging CD3-CD19 antibody construct, has shown significant activity in patients (pts) with B-cell acute lymphoblastic leukemia (B-ALL). Despite this improvement, uncertainties remain regarding the optimal use of this drug. These include the efficacy in pts with extramedullary (EM) disease, rates of relapse with EM disease, the safety and efficacy of B therapy in combination with tyrosine kinase inhibitors (TKIs) and in pts with lymphoid blast crisis of chronic myeloid leukemia (CML), and the incidence of loss of expression of CD19 following B therapy.
Results: We report our retrospective experience with 28 adult pts treated with B since its commercial release. The median age at diagnosis was 45.5 years of age. More than half of the pts (N=16; 57%) received B for relapsed disease, while a quarter of pts (N=7; 25%) received treatment for refractory disease. The remaining 5 (18%) were treated for minimal residual disease (MRD). The median number of prior therapies was 2. The CR rate was 71% with nearly half of pts (45%) achieving a MRD negative remission following cycle 1 of B. Of note, MRD data was not available for 8 pts. Median progression free survival (PFS) was 9.8 months with a 1-year PFS rate of 41.7%. The overall survival following B therapy was 10.1 months. Among 20 pts who achieved an initial response with B therapy, half have expired at the time of this analysis. Median duration of response (DOR) was 5.85 months with maximum DOR of up to 41.5 months.
The median disease burden prior to treatment was 65% leukemic blasts in the bone marrow. There was no association between disease burden and response to B (P=0.523). There was also no association between line of therapy and response to B (P=0.782). Pts treated in the relapsed setting were more likely to respond than those treated in the refractory setting (43% versus 94% P=0.017). Five of 28 pts in our series had documented EM ALL prior to initiation of B therapy. Four of these 5 pts experienced a CR to treatment with B. An additional patient with a history of central nervous system (CNS) involvement by ALL demonstrated relapse of CNS disease while on B treatment while systemic disease remained under control. Of 11 pts with documented relapse following B therapy, the majority (7) of these pts had involvement of EM sites. Four of these 7 pts had documented EM disease prior to initiation of B therapy.
CD19 status was available for 12 pts with a relapse of their ALL following B therapy. Of these 12 pts, 11 retained their CD19 positivity. Nine pts (32%) treated with B had t (9;22). Two of these pts had lymphoid blast crisis of CML while the remainder of the pts had Ph+ B-ALL. All but one of the pts tolerated concurrent TKI and B. TKIs administered in this series included ponatinib, bosutinib, nilotinib, and dasatinib. The sole patient who was not able to tolerate dual therapy was receiving ponatinib and developed transaminitis with AST/ALT in the 3000s during the first 3 days of B therapy, which likely was in part due to cytokine release syndrome. Both pts with blast crisis CML were able to move to a transplant following therapy with B and both attained MRD negative status as measured by Bcr/Abl PCR values suggesting a potential role for B for treatment of pts with lymphoid blast phase of CML.
Discussion: While limited due to its retrospective nature and relatively small sample size, this data set begins to answer important questions often not addressed as part of clinical trials. Pts with EM disease did respond to treatment with B, however, most of these of these pts as well as others who relapsed following B had EM involvement, suggesting that B may not have long term efficacy for disease outside of the bone marrow and that systemic restaging studies should be considered for pts receiving B therapy. The safety of B given concurrently with TKI therapy is also supported by our results as is the need to be aware of potential overlapping toxicities between TKI and B, such as the hepatotoxicity seen in our patient. Our study demonstrates that response to B appears to be independent of disease burden and also suggests a role for B treatment in pts with lymphoid blast crisis of CML, a rare and difficult disease state to treat. Finally, we also demonstrate that loss of C19, which has relevance with regards to the potential benefit of subsequent CD19-directed therapies such as chimeric antigen receptor T-cell therapy is rare in pts treated with B.

Disclosures
Koprivnikar: Amgen Pharmaceuticals: Speakers Bureau; COTA: Equity Ownership; Otsuka Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Consultancy, Speakers Bureau. Stanislaus:Takeda Pharmacetucals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Novartis Pharmaceuticals: Consultancy, Speakers Bureau; Celgene Pharmaceuticals: Consultancy, Speakers Bureau. McCloskey:COTA: Equity Ownership; Amgen Pharmaceuticals: Speakers Bureau; Takeda Pharmaceuticals: Speakers Bureau; Jazz Pharmaeuticals: Speakers Bureau; Celgene Pharmaceuticals: Consultancy, Speakers Bureau.