Conventional treatments for prebiotic T lymphocytic leukemia (T-PLL), such as cytotoxic chemotherapy and alen monoantigen (alen monoantitor), have limited efficacy and are more toxic.
new drug categories have shown preclinical activity in T-PLL, including inhibitors for JAK/STAT and TCR pathps, as well as histone deacetylase (HDAC) inhibitors.
recently, the BCL-2 inhibitor ventoclax has also shown some clinical activity in T-PLL.
Herbaux et al. tried to identify new combination therapies to treat the disease by symptoms of functional apoptosis dependence of T-PLL, the results of which were published recently in the journal Blood.
BH3 map analysis is a functional analysis method to assess apoptosis tendency ("start") and cells' relative dependence on different anti-apoptosis proteins.
Herbaux et al. conducted BH3 map analysis on samples from 24 primary T-PLL patients and found that the apoptosis start-up level of the original T-PLL cells was relatively low, mainly dependent on BCL-2 and MCL-1 survival.
drug inhibits BCL-2 or MCL-1 to induce primary T-PLL cell death.
the targeting of jaK/STAT paths with the JAK1/2 inhibitor ruxolitinib, or the targeting of HDAC with belinostat, can independently increase the dependence of T-PLL cells on BCL-2 (without changing dependence on MCL-1), thereby enhancing the sensitivity of T-PLL cells to ventoclax.
based on these results, the researchers treated two refractic T-PLL patients with ventoclax and rusotinini: patients with JAK3 mutations received deep remission and stable conditions in patients without mutations.
addition, based on the functional method of precision medicine, this study makes it clear that HDAC and JAK/STAT path-inhibitors are promising joint drug options for ventoclax, and it is worth further exploring this joint solution in T-PLL-related clinical trials.