Project Term
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Project Summary
T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive leukemia in adults with 5-year survival rate of only about 10% in patients with relapsed/refractory (R/R) disease, but LCK and BCL2 are novel therapeutic targets. In this project, we aim to conduct a Phase II clinical trial evaluating LCK inhibitor, ponatinib and BCL2 antagonist, venetoclax combination therapy in R/R T-ALL, with correlative biology studies to define biological mechanisms of drug response and resistance.
Lay Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a blood cancer of T-cells which can occur in both children and adults. The outcomes of adult patients whose leukemia relapses after initial chemotherapy are poor. No effective targeted therapy is available for these patients, and the 5-year survival rate is only about 10%. Therefore, there is a significant need to develop new therapies for these patients.
Our group at MD Anderson Cancer Center (MDACC) in collaboration with St. Jude Children’s Research Hospital recently identified that about 40% of patients with T-ALL have increased level of an enzyme called LCK. Importantly, drugs that inhibit this enzyme (drugs such as dasatinib and ponatinib) are effective against this leukemia in cell line models and mice. We also identified that in an individual patient, there are leukemia cells that are sensitive to LCK enzyme inhibitor, but there are other cells which are more sensitive to BCL2 inhibitor (venetoclax). Therefore, combining these 2 classes of drugs (both LCK inhibitor and BCL2 inhibitor) may be able to target majority of cancer cells in an individual patient.
Based on these laboratory data, we have developed a clinical trial to investigate ponatinib and venetoclax combination therapy in patients with T-ALL whose leukemia has relapsed after initial chemotherapy. The trial will be conducted at MDACC. We plan to enroll 26 adult patients on this clinical trial. Patients will receive combination of ponatinib, venetoclax and low intensity chemotherapy. We will assess patients for toxicity and efficacy. We will collect blood and bone marrow samples from the patient prior to starting any therapy and at serial time-points during therapy. We will analyze these samples for levels of LCK, BCL2 and other proteins and assess if levels at baseline or with therapy predict for response or resistance to treatment.
Because ponatinib has already been integrated into leukemia therapy for patients with another subtype of leukemia (Philadelphia chromosome positive leukemia), we believe that incorporation of this drug into T-ALL therapy is highly feasible. This work is likely to have a high impact, based on the novelty of LCK-targeted therapy in T-ALL, and if successful, our work may substantially shift the treatment landscape for patients with T-ALL.
Program
