Combination Therapy for Patients With Philadelphia Chromosome-Positive ALL

The combination of dasatinib (Sprycel) and venetoclax (Venclexta) may have the potential to improve the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), according to Oregon researchers. They recently published a study in ScienceTranslational Medicine confirming the tolerability of this drug combination and demonstrating its superior antileukemic efficacy compared to either agent alone for the treatment of primary Ph+ALL patient samples in xenografted immunodeficient mice.  

“In our research, we have shown that at least in cell cultures and in an animal model of Ph+ALL venetoclax seems to work together with the TKIs (tyrosine kinase inhibitors), particularly dasatinib in our studies, to more effectively treat this disease. The drugs work by two different mechanisms. The TKIs stop the mutation that is driving the disease, and venetoclax turns off proteins that prevent apoptosis,” said study investigator Jessica Leonard, MD, instructor in the Department of Hematology/Oncology at the Oregon Health & Science University (OHSU) Knight Cancer Institute, Portland, Ore., in an interview with OncoTherapy Network.

Dr. Leonard explains that Ph+ALL currently is very difficult to treat and single-drug treatment is usually ineffective. However, these two drugs work together synergistically in vitro and in preclinical models, and may offer a promising approach to improving outcomes. Dr. Leonard said historically PH+ALL was considered the most aggressive subtype of ALL, with the median overall survival for adults estimated to be 11 months. However, with the introduction of TKIs, which specifically target the abnormal Philadelphia chromosome, the 5-year overall survival averages are now between 30%-45%. 

“While this represents a great advance, there is still much room for improvement. The primary reason for the low survival rate remains disease relapse, as many patients will eventually develop resistance to the TKIs. As this is a disease primarily of older adults, other reasons for the low survival rate include toxicity from chemotherapy as well as mortality related to bone marrow transplant. For this reason, we desperately need new therapies that can target Ph+ALL along with dasatinib but do not carry the toxicity of conventional chemotherapy,” said Dr. Leonard.

Venetoclax, which is a selective inhibitor of B cell lymphoma 2, has previously been shown to have activity against hematologic malignancies and this oral agent is already approved by the US Food and Drug Administration for the treatment of a subtype of chronic lymphocytic leukemia (CLL).  Dr. Leonard said the hope now is that the combination of dasatinib and venetoclax will be a more potent treatment regimen than dasatinib alone, and that the combination will delay the time to the development of drug resistance and disease progression. 

“This combination would be particularly beneficial for older adults, who may be able to take an oral regimen and avoid the toxicities of chemotherapy. The first step however is to conduct a clinical trial to first show that the combination of dasatinib and venetoclax is safe and well tolerated, particularly in the older population who carry the main burden of this disease,” explained Dr. Leonard.