Combinations of idelalisib with rituximab and/or bendamustine in patients with recurrent indolent non-Hodgkin lymphoma

Vos, Sven de; Wagner‐Johnston, Nina D.; Coutré, Steven; Flinn, Ian W.; Schreeder, Marshall T.; Fowler, Nathan; Sharman, Jeff P.; Boccia, Ralph V.; Barrientos, Jacqueline C.; Kanti, R.; Boyd, Thomas E.; Furman, Richard R.; Kim, Yeon-Hee; Godfrey, Wayne R.; Leonard, John P.

doi:10.1182/bloodadvances.2016000976

Cited by 16 publications

(8 citation statements)

References 22 publications

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“…This isoform is almost specific to hematopoietic cells and seems to play a minor role in platelet activation. The first-in-class oral selective inhibitor of p110δ isoform Idelalisib has been approved for the treatment of hematological malignancies including chronic lymphocytic leukemia (CLL), follicular B-cell non-Hodgkin lymphoma (FL), and small lymphocytic lymphoma (SLL) [ 15 , 16 ], and has shown considerable antitumor activity in the treatment of hematological cancer [ 17 ]. In this respect, Idelalisib is currently combined with rituximab as a second-line agent in intractable patients or patients with other co-morbidities [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential

Barrachina

Izquierdo

Hermida-Nogueira

et al. 2021

IJMS

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Background: Clinical management of ischemic events and prevention of vascular disease is based on antiplatelet drugs. Given the relevance of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) as a candidate target in thrombosis, the main goal of the present study was to identify novel antiplatelet agents within the existing inhibitors blocking PI3K isoforms. Methods: We performed a biological evaluation of the pharmacological activity of PI3K inhibitors in platelets. The effect of the inhibitors was evaluated in intracellular calcium release and platelet functional assays, the latter including aggregation, adhesion, and viability assays. The in vivo drug antithrombotic potential was assessed in mice undergoing chemically induced arterial occlusion, and the associated hemorrhagic risk evaluated by measuring the tail bleeding time. Results: We show that PI3K Class IA inhibitors potently block calcium mobilization in human platelets. The PI3K p110δ inhibitor Idelalisib inhibits platelet aggregation mediated by ITAM receptors GPVI and CLEC-2, preferentially by the former. Moreover, Idelalisib also inhibits platelet adhesion and aggregation under shear and adhesion to collagen. Interestingly, an antithrombotic effect was observed in mice treated with Idelalisib, with mild bleeding effects at high doses of the drug. Conclusion: Idelalisib may have antiplatelet effects with minor bleeding effects, which provides a rationale to evaluate its antithrombotic efficacy in humans.

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Section: Discussionmentioning

confidence: 99%

The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential

Barrachina

Izquierdo

Hermida-Nogueira

et al. 2021

IJMS

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“…For instance, the combination of idelalisib plus lenalidomide and rituximab in FL and MCL resulted in >70% treatment discontinuation [ 61 ]. A phase 1 study of idelalisib with rituximab and/or bendamustine demonstrated high response rates in heavily treated R/R B-NHL, although later phase trials showed an increase in toxicity not evident in the original phase 1 [ 62 ]. Other combination studies include idelalisib in combination with obinutuzumab in FL (NCT03890289) or WM [ 63 ], duvelisib with acalabrutinib in B-NHL (NCT04836832), umbralisib with rituximab in FL/MCL (NCT03919175), with ublituximab in FL (NCT03828448) or with ublituximab-CHOP in MCL (NCT04692155).…”

Section: Review Of Approved Small Molecule Inhibitorsmentioning

confidence: 99%

Targeted Agents in the Treatment of Indolent B-Cell Non-Hodgkin Lymphomas

Minson

Tam

Dickinson

et al. 2022

Cancers

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Targeted therapies continue to change the landscape of lymphoma treatment, resulting in improved therapy options and patient outcomes. Numerous agents are now approved for use in the indolent lymphomas and many others under development demonstrate significant promise. In this article, we review the landscape of targeted agents that apply to the indolent lymphomas, predominantly follicular lymphoma, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinaemia and marginal zone lymphoma. The review covers small molecule inhibitors, immunomodulators and targeted immunotherapies, as well as presenting emerging and promising combination therapies.

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“…however, due to the potential for serious toxicities in combinations with idelalisib, the authors warn of the necessity to perform phase 3 studies to rule out any possible toxicities. 71 Dactolisib in combination with abiraterone acetate or everolimus has been investigated in phase 1 studies in patients with solid malignancies; however, both studies reported poor tolerability at the doses tested. 72,73 Many clinical trials incolving dactolisib have been withdrawn or teminated, with no currently ongoing trials registered on ClinicalTrials.gov (accessed 05 June 2020).…”

Section: Rationale For Combination Treatmentmentioning

confidence: 99%

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

Phillips

Michot

Ribrag

2021

Clinical Lymphoma Myeloma and Leukemia

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Combinations of idelalisib with rituximab and/or bendamustine in patients with recurrent indolent non-Hodgkin lymphoma

Abstract: Key Points Combining phosphatidylinositol-3-kinase δ inhibition with rituximab, bendamustine, or both is feasible and active in relapsed iNHL. The safety of novel combinations should be proven in phase 3 trials before adoption in clinical practice.

Cited by 16 publications

References 22 publications

The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential

The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential

Targeted Agents in the Treatment of Indolent B-Cell Non-Hodgkin Lymphomas

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

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