Can Next-Generation PI3K Inhibitors Unlock the Full Potential of the Class in Patients With B-Cell Lymphoma?

Phillips, Tycel; Michot, Jean‐Marie; Ribrag, Vincent

doi:10.1016/j.clml.2020.08.022

Cited by 26 publications

(49 citation statements)

References 89 publications

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“…Side effects of PI3Kδ inhibitors encompass infections, hepatotoxicity, diarrhea and/or colitis, and pneumonitis [ 4 , 5 , 6 , 101 , 102 , 103 , 104 , 105 , 106 ] ( Table 2 ). In clinical trials with idelalisib, serious adverse events have also included deaths related to cytomegalovirus infections, pneumonias caused by Pneumocystis jirovencii , in addition to respiratory events possibly caused by infections [ 107 ].…”

Section: Potential Toxicities Linked With Pi3kδ Inhibition In T-cellsmentioning

confidence: 99%

“…Phosphoinositide 3-kinases (PI3Ks) are a class of enzymes fundamental in the regulation of cell metabolism, proliferation and survival [ 1 , 2 , 3 , 4 , 5 , 6 ]. PI3Ks are active in most human cancers, often representing oncogenic drivers due to genetic events directly targeting their coding genes or determining the constitutive activation or upstream components of the signaling cascade [ 1 , 4 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…The p85α and its splicing variants p55α and p50α ( PIK3R1 ), p85β ( PIK3R2 ), and p55γ ( PIK3R3 ) can bind PI3Kα, PI3Kβ, or PI3Kδ (class IA PI3Ks), while p101 ( PIK3R5 ) or p87 ( PIK3R6) bind PI3Kγ (Class IB PI3Ks). PI3Kδ and PI3Kγ are largely restricted to leukocytes, while PI3Kα and PI3Kβ are ubiquitously expressed [ 1 , 4 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…The development of small molecules able to block specific or multiple PI3K isoforms is a heavily pursued effort in oncology: Table 1 shows the PI3Kδ inhibitors that have entered clinical development. Multiple preclinical and clinical studies showed the anti-tumor activity of PI3Kδ inhibitors in patients affected by chronic lymphocytic leukemia (CLL), B- and T-cell lymphomas and these data have been extensively summarized elsewhere [ 3 , 4 , 5 , 6 , 7 , 8 ]. Importantly, PI3Ks are expressed not only in the cancer cells, but also in the non-neoplastic cells, in which PI3K inhibitors contribute to their pro- or anti-tumor effects, and they can be used to improve the response to immunomodulatory and immunotherapeutic agents [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

PI3Kδ Inhibitors as Immunomodulatory Agents for the Treatment of Lymphoma Patients

Tarantelli

Argnani

Zinzani

et al. 2021

Cancers

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The development of small molecules able to block specific or multiple isoforms of phosphoinositide 3-kinases (PI3K) has already been an active field of research for many years in the cancer field. PI3Kδ inhibitors are among the targeted agents most extensively studied for the treatment of lymphoma patients and PI3Kδ inhibitors are already approved by regulatory agencies. More recently, it became clear that the anti-tumor activity of PI3K inhibitors might not be due only to a direct effect on the cancer cells but it can also be mediated via inhibition of the kinases in non-neoplastic cells present in the tumor microenvironment. T-cells represent an important component of the tumor microenvironment and they comprise different subpopulations that can have both anti- and pro-tumor effects. In this review article, we discuss the effects that PI3Kδ inhibitors exert on the immune system with a particular focus on the T-cell compartment.

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Section: Potential Toxicities Linked With Pi3kδ Inhibition In T-cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

PI3Kδ Inhibitors as Immunomodulatory Agents for the Treatment of Lymphoma Patients

Tarantelli

Argnani

Zinzani

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…Combinatorial approaches with approved PI3K inhibitors are currently ongoing and have been nicely detailed in a recent review [ 47 ]. In the cooperative group trial, when idelalisib was combined with R2, there was significant hepatic toxicity with 2 of 7 enrolled patients passing away from toxicity, one from hepatic failure and another from complications related to colitis leading to premature closure of the study [ 48 ].…”

Section: Relapsed/refractory Follicular Lymphoma-approved and Investigational Approachesmentioning

confidence: 99%

Evolving therapeutic landscape in follicular lymphoma: a look at emerging and investigational therapies

Hanel

Epperla

2021

J Hematol Oncol

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Follicular Lymphoma (FL) is the most common subtype of indolent B cell non-Hodgkin lymphoma. The clinical course can be very heterogeneous with some patients being safely observed over many years without ever requiring treatment to other patients having more rapidly progressive disease requiring multiple lines of treatment for disease control. Front-line treatment of advanced FL has historically consisted of chemoimmunotherapy but has extended to immunomodulatory agents such as lenalidomide. In the relapsed setting, several exciting therapies that target the underlying biology and immune microenvironment have emerged, most notable among them include targeted therapies such as phosphoinositide-3 kinase and Enhancer of Zeste 2 Polycomb Repressive Complex 2 inhibitors and cellular therapies including chimeric antigen receptor T cells and bispecific T cell engagers. There are several combination therapies currently in clinical trials that appear promising. These therapies will likely reshape the treatment approach for patients with relapsed and refractory FL in the coming years. In this article, we provide a comprehensive review of the emerging and investigational therapies in FL and discuss how these agents will impact the therapeutic landscape in FL.

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Risk of cutaneous adverse events in cancer patients treated with phosphatidylinositol‐3‐kinase inhibitors: A systematic review and meta‐analysis of randomized controlled trials

Wang

et al. 2022

Cancer Medicine

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Background Cutaneous adverse effects (AEs) are common following the phosphoinositide‐3‐kinase (PI3K) inhibitors treatment. We aim to estimate the incidence and risk of PI3K inhibitor‐related cutaneous AEs. Methods The protocol was submitted to the PROSPERO registry. We searched ClinicalTrials.gov and international databases up to July 29, 2022. Meta‐analysis was conducted by using risk ratios (RRs) with 95% confidence intervals (CIs). Results Fourteen randomized controlled trials (RCTs) comprising 3877 patients were analyzed in this study. Compared with control arms, PI3K inhibitors showed a significant increase in the risk of all‐grade rash, high‐grade rash, and serious rash events (RR 2.29, 95% CI 1.58–3.31, p < 0.00001; RR 9.34, 95% CI 4.21–20.69, p < 0.00001; RR 5.11, 95% CI 2.11–12.36, p = 0.0003). The overall incidences of all‐grade rash and high‐grade rash were 26.2% (592/2257) and 4.4% (66/1487). Subgroup analyses of all‐grade rash according to cancer types and PI3K inhibitor assignations identified the significant associations. PI3K inhibitors also significantly increased the risk of pruritus and dry skin (RR 1.63, 95% CI 1.14–2.33, p = 0.007; RR 3.34, 95% CI 2.30–4.85, p < 0.00001), with incidences of 13.4% (284/2115) and 9.8% (141/1436) in the treatment group. Conclusion There is a significantly increased risk of some cutaneous AEs in patients using PI3K inhibitors. Advance intervention is recommended in case of severe and life‐threatening events. Further research is required to investigate the risk factors and pathogenesis.

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Can Next-Generation PI3K Inhibitors Unlock the Full Potential of the Class in Patients With B-Cell Lymphoma?

Cited by 26 publications

References 89 publications

PI3Kδ Inhibitors as Immunomodulatory Agents for the Treatment of Lymphoma Patients

PI3Kδ Inhibitors as Immunomodulatory Agents for the Treatment of Lymphoma Patients

Evolving therapeutic landscape in follicular lymphoma: a look at emerging and investigational therapies

Risk of cutaneous adverse events in cancer patients treated with phosphatidylinositol‐3‐kinase inhibitors: A systematic review and meta‐analysis of randomized controlled trials

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