Blinatumomab in Combination with Tyrosine Kinase Inhibitors Safely and Effectively Induces Rapid, Deep, and Durable Molecular Responses in Relapsed and Refractory Philadelphia Positive Acute Leukemias
Authors: McCloskey James K , Gagnon Joelle , McCabe Tara , Charlon Jocelyn , Wang Shuqi , Fan Ruzong , Goldberg Stuart L. , Koprivnikar Jamie 
Published: November 2019

Background
The addition of tyrosine kinase inhibitors (TKIs) to chemotherapy improves the prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Single agent blinatumomab, a bi-specific T-cell engaging CD3-CD19 antibody construct, is more effective than multi-agent chemotherapy in relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and successfully achieves minimal residual disease (MRD) negativity in MRD positive patients. Limited data is available on the safety and efficacy of these agents in combination and uncertainties remain regarding the optimal use of blinatumomab +TKIs. Dual therapy with blinatumomab and TKIs may offer a safe and effective treatment option for relapsed and refractory patients without the incorporation of chemotherapy.
Patients and Methods
We report our retrospective experience in 18 patients who received blinatumomab +TKI for relapsed/refractory (R/R) Ph+ ALL (n=14), MRD+ Ph+ ALL (n=2) and chronic myeloid leukemia in lymphoid blast crisis (CML-LBC) (n=2). Ten patients received ponatinib; 8 patients received second generation TKIs (dasatinib, n=5; nilotinib, n=2; bosutinib, n=1). Blinatumomab was administered according to the package insert and TKI was initiated on day 1. Median follow up was 15 months and median number of blinatumomab +TKI cycles was 2 (range, 1-5). The median age was 47 years (range, 22-77). The median number of prior therapies was 2 (range, 1-8) and the median number of prior TKIs was 2 (range 1-4). Preexisting T315I mutations were present in one third of patients and 5 patients had relapsed following allogeneic stem cell transplant (alloHSCT).
Results
Transient grade 2-3 transaminase elevation was observed in 3 patients (ponatinib=2, dasatinib=1). Cytokine Release syndrome was observed in 2 patients. Transient neurotoxicity was observed in 3 patients (1patient with grade 3). All grade 2 and 3 toxicities were observed during the first cycle and all patients were successfully able to complete induction with blinatumomab +TKI. One patient on dasatinib experienced a PICC-associated DVT. There were no other vascular events observed.
For patients with r/r disease the CR rate was 88% (14/16) with most of these remissions being MRD negative by flow and PCR (12/14). Both of the patients treated for MRD positivity achieved an MRD negative response. Among T315I mutated patients, 5/6 achieved a CR and 4/5 were MRD negative. The median time to remission was 35 days. The 1 year survival was 80% and the median overall survival following blinatumomab therapy was 45 months. Among 16 pts who achieved an initial response to blinatumomab +TKI, six have expired at the time of this analysis. At the time of relapse on combination therapy, 3/8 pts exhibited new T315I mutations. Of note, all of these were treated with blinatumomab in combination with a second generation TKI. All patients maintained their CD19 positivity at the time of relapse. Both pts with CML-LBC were able to move to a transplant following therapy with blinatumomab +TKI and both attained MRD negative status as measured by Bcr/Abl PCR values. In total, 10 patients treated with blinatumomab +TKI proceeded to alloHSCT, 7 of these are still alive. Median duration of response (DOR) was 5.1 months with maximum DOR of 23.3 months.
Discussion
While limited due to its retrospective nature and relatively small sample size, this data set begins to answer important regarding the safety and efficacy of blinatumomab +TKI. Combination therapy was effective at achieving rapid and deep responses in this refractory patient population. The toxicities observed with blinatumomab +TKI were in keeping with those seen with blinatumomab alone. However, care should be taken in regard to potential overlapping toxicities of TKIs and blinatumomab, such as hepatotoxicity. The study also suggests a role for blinatumomab treatment in patients with CML-LBC, a rare and difficult disease state to treat. The identification of T315I mutation at relapse in 40% of patients on blinatumomab +second generation TKIs supports further prospective studies with ponatinib and blinatumomab in combination. Finally, 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 was not seen in patients treated with blinatumomab +TKI.

Disclosures
McCloskey: Jazz: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau; Novartis: Speakers Bureau. Gagnon:Amgen: Speakers Bureau. Goldberg:Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; Bristol-Myers Squibb: Consultancy; COTA: Equity Ownership. Koprivnikar:Amgen: Speakers Bureau; Pfizer: Honoraria; Novartis: Speakers Bureau; Abbvie: Speakers Bureau.