Abstract
A Phase 1 study of the novel gamma-secretase inhibitor PF-03084014 in patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma
Highlights
T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) are aggressive malignancies derived from neoplastic transformation of precursor T cells
Current treatment with intensive chemotherapy regimens may achieve a cure rate of 80% in children with T-ALL, treatment of adult patients leads to a lower response rate.[2]
Results from a number of studies have demonstrated a key role for the deregulation of NOTCH signaling pathways in the oncogenic transformation leading to the development of T-ALL and T-LBL, providing a rationale for the development of gammasecretase inhibitors as a novel targeted therapy for these hematologic malignancies.[3,4,5,6,7]
Summary
A Phase 1 study of the novel gamma-secretase inhibitor PF-03084014 in patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Evaluation by the more sensitive deep-sequencing method revealed a known activating mutation, L1679P, in exon 27 of NOTCH1 in the T-ALL patient with a CR, which was confirmed in an independent bone marrow sample collected at a different time point (25% blasts; Table 2). Deep-sequencing analysis revealed a known activating NOTCH1 mutation (V1677D) in bone marrow mononuclear cells from a non-responding patient with T-LBL This suggests that mutation status does not consistently predict response to PF-03084014, in line with prior clinical trials.[3] Further, it may indicate differences in the biology of the disease and in the role played by NOTCH-mediated signaling pathways in T-LBL versus T-ALL (for example, the degree of 'NOTCH addiction' in tumor cells) or, alternatively, a resistance to treatment with gamma-secretase inhibitors in T-LBL cells, mediated by other pathways (for example, PI3/mTOR kinase signaling).[11,12].
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