CLL Research: Umbralisib, A Dual PI3Kδ/CK1ε Inhibitor

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CLL Research: Umbralisib, A Dual PI3Kδ/CK1ε Inhibitor in Chronic Lymphocytic Leukemia (CLL)

The dual PI3Kδ/CK1ε inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells. This article co-authored by Dr. Javier Pinilla-Ibarz, M.D., Ph.D., the Director of the CLL Program at H. Lee Moffitt Cancer Center and Research Institute in Tampa (and others), was recently published in Blood Advances, a publication of the American Society of Hematology (ASH).

Dr. Pinilla is my current CLL Specialist, and he maintains a very active clinical practice and significant CLL research efforts, both in clinical trials and basic science of CLL.

In clinical practice, the phosphatidylinositol 3-kinase (PI3K) inhibitors idelalisib (Zydelig®) and duvelisib (Copiktra®) show high response and progression-free survival in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Like the BTK inhibitors, ibrutinib (Imbruvica®) and acalabrutinib (Calquence®), PI3K inhibitors affect the B-cell receptor signaling pathway that plays a role in the proliferation (rapid growth) of malignant b-cells. Unfortunately, an increased incidence of adverse events has led to frequent discontinuations of the current PI3K drugs. These negative effects and the subsequent need to discontinue therapy have limited use of these agents and further development as a potentially long-term treatment for CLL. The toxicities of the two commercial PI3K drugs (idelalisib and duvelisib) appear to be immune-mediated. They include colitis (inflammation of the inner lining of the colon), pneumonitis (non-infectious inflammation of the lung tissue), and liver toxicity.

In contrast, umbralisib, a next-generation dual inhibitor of PI3K gamma (δ) and casein-kinase 1-ε (CK1ε), has shown an improved safety profile characterized by less severe adverse events, even with long-term follow-up. Umralisib (Ukoniq™) was recently (Feb. 2021) approved for two other blood cancers but remained an investigational agent for CLL treatment. According to www.clinicaltrials.gov, there are currently thirteen clinical trials evaluating umbralisib alone or in combination with other agents for the treatment of CLL.

According to current theory, T cells may modulate or be responsible for the PI3K inhibitor-related adverse events or side effects.

Cytokines are small proteins that play a role in cell signaling. Inflammatory cytokines, coupled with a decreased number of regulatory T cells (Tregs), have been associated with idelalisib. Of interest, younger treatment-naïve patients who likely have more robust immune systems were at higher risk of developing toxicities (adverse events.)

In another study, no increase in immune-mediated adverse events was seen in CLL patients on umbralisib plus ublituximab and pembrolizumab, beyond that expected with umbralisib or pembrolizumab alone. Patients on this combination maintained steady levels of Tregs over time.
These findings show a clear need to understand the effects of PI3K inhibition in T cells and other immune populations.

Idelalisib received approval from the FDA in 2014 to treat patients with relapsed follicular B-cell non-Hodgkin lymphoma (FL), and small lymphocytic leukemia (SLL) had received two or more prior treatments. For CLL patients, idelalisib, in combination with rituximab, was also approved. Despite high response rates and increased overall survival, many patients had severe adverse events associated with idelalisib. The high incidence of AEs caused the halt of many front-line clinical trials. Idelalisib is currently used only for relapsed or refractory CLL.
Duvelisib was tested as a monotherapy and in combination with other agents. Duvelisib appears to be more potent than idelalisib. The FDA approved duvelisib for CLL and FL patients after failing two or more lines of therapy. The toxicity profile for duvelisib is similar to idelalisib and includes transaminitis (high levels of liver enzymes), neutropenia (low levels of neutrophils), colitis, and pneumonitis.

Umbralisib appears to have enhanced selectivity over other PI3K isoforms and is unique in that it also inhibits CK1ε. The CK1ε enzyme plays a role in the activation of the protein P53, which leads to cell cycle arrest and apoptosis (cell death.)

Clinical trials of the dual PI3Kδ/CK1ε Inhibitor, umbralisib have demonstrated high response rates and progression-free survival similar (PFS) to idelalisib. Notably, umbralisib has an improved safety profile with fewer immune-mediated adverse events and the need to discontinue therapy due to side effects. CLL patients treated with umbralisib reportedly retain circulating Tregs over time. In animal studies, mice treated with umbralisib experienced the lowest immune-mediated toxicity profile among the three PI3K drugs studied.

Umbralisib is a next-generation dual inhibitor of PI3K gamma (δ) and casein-kinase 1-ε (CK1ε). There currently is a lack of sufficient long-term data from patients treated with umbralisib; a prediction from these animal studies is that the improved safety profile of umbralisib will correlate with sustained Tregs in treated patients. The differential impact of umbralisib on Tregs compared with other PI3K inhibitors has several clinical implications. First, the dual inhibition of PI3Kδ andCK1ε uniquely provides multiple pathways of antitumor efficacy. Secondly, the lack of Treg inhibition may negate potential Treg-mediated antitumor effects in B-cell malignancies.
Conclusions - Umbralisib, A Dual PI3Kδ/CK1ε Inhibitor in Chronic Lymphocytic Leukemia (CLL)

This paper is an example of basic science research performed to better understand the mechanisms of action and the causes of a drug or drug’s side effects. Like many pre-clinical/basic science studies, there is an animal component in which mice are the study subjects. The mice used in this study had CLL induced via injection of leukemic cells.

CLL specialists participate in both clinical trials involving human patients and pre-clinical or bench studies. Clinical trials evaluate a new drug or combination of drugs against some existing approved treatment for CLL. Cancer trials never compare the study drug(s) to placebo, which would be unethical. The pre-clinical trials generally occur before a clinical trial, while bench studies can occur both before or simultaneously with clinical trials

This particular trial points to the further need for further study to better understand the role of regulatory T cells and their role in immune-mediated side effects

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