Patients with T-cell prolymphocytic leukemia (T-PLL) have limited effectiveness with conventional therapies. Novel agents have shown promise in preclinical studies, particularly with venetoclax. HDAC and JAK/STAT pathway inhibitors combined with venetoclax may provide effective therapies for T-PLL, according to research published in Blood.
T-PLL is a rare, aggressive T-lymphoid malignancy, and cytotoxic chemotherapy with alemtuzumab rarely produces durable remission at a cost of high levels of toxicity. Allogeneic stem cell transplantation is next for patients who achieve a response with alemtuzumab, but the median overall survival is about 20 months. Research now is focused on finding targeted agents.
In the study, the authors used BH3 profiling of 24 samples of patients with primary T-PLL to understand apoptotic dependencies. They used 24 samples from treatment-naïve chronic lymphocytic leukemia (CLL) as the comparison for baseline BH3 profiling.
The authors used BH3 profiling to evaluate drugs that target 3 main pathways in T-PLL cells: belinostat (an HDAC inhibitor), ruxolitinib (a JAK 1/2 inhibitor), and ibrutinib (a Bruton tyrosine kinase inhibitor).
T-PLL cells depend on BCL-2 and MCL-1 for survival. Inhibiting both MCL-1 and BCL-2 induced cell death in preclinical studies. Ruxolitinib plus belinostat increased the cells’ dependence on BCL-2, thereby sensitizing the T-PLL cells for venetoclax.
The authors used the preclinical data gathered to treat 2 patients with refractory T-PLL who were not candidates for standard treatment options. They received venetoclax plus ruxolitinib. One patient had JAK3 mutation and experienced a deep partial response that remained for 10 months. The second patient without a JAK-STAT pathway mutation achieved stable disease.
The preclinical studies found that JAK1 inhibition may be stronger in mutated T-PLL, which may explain the stronger response in the patient with JAK3 mutation.
Based on these findings, the study authors suggest that combining different classes of drugs using a functional, precision medicine approach will lead to the best responses.
“These results, along with our preclinical data, strongly support the development of a prospective clinical trial to evaluate the safety and efficacy of this combination in T-PLL,” the researchers concluded.
Herbaux C, Kornauth C, Poulain S, et al. BH3 profiling identifies ruxolitinib as a promising partner for venetoclax to treat T-cell prolymphocytic leukemia. Blood. Published online February 17, 2021. doi:10.1182/blood.2020007303