p53-independent ibrutinib responses in an Eμ-TCL1 mouse model demonstrates efficacy in high-risk CLL

Abstract

Deletion of the short-arm of chromosome 17 (17p-) is one of the most critical genetic alterations used in chronic lymphocytic leukemia (CLL) risk stratification. The tumor suppressor TP53 maps to this region, and its loss or mutation accelerates CLL progression, hampers response to chemotherapy and shortens survival. Although florescent in situ hybridization analyses for 17p deletions are routinely performed during clinical diagnoses, p53 mutational status is often unexamined. Given the limited clinical data that exists for frontline treatment of patients with CLL harboring TP53 mutations, there is a need to understand the biology of CLL with TP53 mutations and identify treatment strategies for this subset of patients. Herein, we used a CLL mouse model (Eμ-TCL1) harboring one of the most common TP53 hot-spot mutations observed in CLL (p53R172H, corresponding to p53R175H in humans) to evaluate its impact on disease progression, survival, response to therapy and loss of the remaining wild-type Trp53 allele following ibrutinib treatment. We show that ibrutinib was effective in increasing survival, activating cellular programs outside the p53 pathway and did not place selective pressure on the remaining wild-type Trp53 allele. These data provide evidence that ibrutinib acts as an effective treatment for aggressive forms of CLL with TP53 mutations.

The γ-secretase inhibitors enhance the anti-leukemic activity of ibrutinib in B-CLL cells

“…Similar trend was observed also in Pt.#2 (from 73% to 50%) and in Pt.#4 (from 95% to 54%) after 12 months of Ibrutinib therapy (Figure 1 ). These findings reinforce the notion of the efficacy of Ibrutinib in B-CLL carrying TP53 mutations [ 18 , 19 ], and provide the first evidence concerning the ability of Ibrutinib to target the TP53 mut clones.…”

Ibrutinib in B-cell lymphoma: single fighter might be enough?

“…The possible reason to interpret the mechanism of ibrutinib on the p53 mutation might be that ibrutinib does not require a fully functional p53 pathway. In other words, ibrutinib plays its role regardless of p53 mutation status [4].…”

“…The possible reason to interpret the mechanism of ibrutinib on the p53 mutation might be that ibrutinib does not require a fully functional p53 pathway. In other words, ibrutinib plays its role regardless of p53 mutation status [ 4 ]. Until 2019, the largest scale study about ibrutinib in patients with 17p− was reported by Jones and his colleagues.…”

“…In recent decades, the efficacy and safety of ibrutinib monotherapy or combined with other agents have been explored in different subtypes of B-cell lymphomas [3,4]. Even ibrutinib monotherapy has been the first-line treatment for some patients suffering symptomatic chronic lymphocytic lymphoma/small lymphocytic lymphoma (CLL/SLL) or elder/frail patients with primary central nervous system lymphoma (PCNSL) who can not endure high-dose methotrexate [5,6].…”

Molekularna patogeneza przewlekłej białaczki limfocytowej

“…Dlatego rekomenduje się rutynowe badanie chorych ze wskazaniem do leczenia pod kątem mutacji/delecji TP53 w celu doboru terapeutyków, które będą prowadzić do śmierci komórek białaczkowych na drodze mechanizmu p53-niezależnego [42]. Do związków takich należą zarejestrowane do leczenia inhibitory szlaku B-komórkowego (ibrutynib, idelalizyb) i antyapoptotycznego białka BCL2 (wenetoklaks) oraz intensywnie badane w ostatnich latach w obszarze przedklinicznym inhibitory kinaz PIM [43][44][45][46].…”