Therapeutic Targets in Acute Lymphoblastic Leukemia

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The NOTCH1 gene encodes a transmembrane receptor, which transfers signals that stimulate proliferation, says Dan Douer, MD. Mutations in NOTCH1 are common in T-cell acute lymphoblastic leukemia (ALL), and data suggest that the presence of these mutations confers a poor prognosis, states Douer.

Inhibition of the Notch signaling pathway has been explored as a potential therapy for patients with ALL; however, diarrhea has been associated with NOTCH1 inhibition. Other cell signaling inhibitors, such as mTOR and JAK inhibitors, are being studied in Philadelphia chromosome—negative ALL, notes Raoul Tibes, MD. These agents have shown promise in clinical trials and will continue to be explored.

Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to the antitumor antibiotic calicheamicin, has demonstrated activity in ALL. In a clinical trial, 19% of patients with ALL experienced a complete response (CR) with inotuzumab, 30% had a CR with no platelet recovery, and 9% a bone marrow CR. The objective response rate was 58%. Clinical trials continue to assess inotuzumab ozogamicin as a treatment for patients with ALL, Douer notes.