Concomitant use of a dual ABL/Src kinase inhibitor eliminates the in vitroefficacy of blinatumomab against Ph+ ALL.

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Blinatumomab is currently approved for use as a single agent in relapsed and refractory Acute Lymphoblastic Leukemia. Cytotoxicity is mediated via signaling through the T-cell Receptor (TCR). There is now much interest in combining blinatumomab with targeted therapies, particularly in Philadelphia Chromosome positive ALL (Ph+ALL). However, some second and third generation ABL inhibitors also potently inhibit Src family kinases that are important in TCR signaling. We combined ABL inhibitors and dual ABL/Src inhibitors with blinatumomab in vitro from both healthy donor samples as well as in primary samples from patients with Ph+ALL. Blinatumomab alone led to both T-cell proliferation and elimination of target CD19+ cells, as well as enhanced production of IFN-gamma. The addition of the ABL inhibitors imatinib or nilotinib to blinatumomab did not inhibit T-cell proliferation nor IFN-gamma production. However, the addition of dasatinib or ponatinib inhibited T-cell proliferation and IFN-gamma production. Importantly, there was no loss of CD19+ cells treated with blinatumomab plus dasatinib or ponatinib in healthy samples as well as samples with a resistant ABL T315I mutation by dasatinib in combination with blinatumomab. These in vitro findings bring pause to the excitement of combination therapies highlighting the importance of maintaining T-cell function with targeted therapies.


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