scholarly journals Comparing the PI3K Inhibitors in Hematological Malignancies: Review of Faers

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4508-4508
Author(s):  
Poornima Ramadas ◽  
Samip R Master
Keyword(s):  
Adverse Effects ◽  
Adverse Event Reporting System ◽  
Lymphocytic Leukemia ◽  
Phosphatidylinositol 3 Kinase ◽  
Real World Data ◽  
Casein Kinase 1 ◽  
Immune Mediated ◽  
Reported Data ◽  
Phosphatidylinositol 3 ◽  
Pi3k Delta

Abstract Background: Phosphatidylinositol 3-kinase inhibitors (PI3KI) are a novel class of drugs that are small molecular inhibitors of various isoforms of phosphatidylinositol 3-kinase (PI3K). Over the past decade, various PI3KI have been approved in follicular lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia. While Copanlisib inhibits P13K-alpha and P13K-delta isoforms, idelalisib inhibits P13K-delta, duvelisib inhibits PI3K-delta and PI3K-gamma, and the recently approved agent umbralisib targets PI3K-delta and casein kinase 1 epsilon with improved selectivity for the PI3K-delta. All the agents except Copanlisib are given orally. Immune-mediated adverse effects like colitis, marrow suppression with infections, and dermatological toxicities are known complications of PI3KI. We did a retrospective analysis of the adverse effects (AE) of the PI3KI in the FDA Adverse Event Reporting System (FAERS). Methods: FAERS public dashboard is a resource through which information related to AEs of treatments reported to the FDA is made available to the public. We investigated the common immune-mediated, infectious, hepatic, and dermatological toxicities of the three PI3KI, idelalisib, copanlisib, and duvelisib for the years 2018 to March 2021. Umbralisib has not much-reported data in FAERS. Results: The data regarding various adverse effects are summarized in Table 1. Idelalisib has the most reported data. Diarrhea is reported to be most common with duvelisib (21.83% of total AE). Though diarrhea is common, colitis is uncommon and least reported with copanlisib (1.15%). Among the patients with colitis, death occurred in 27.2% with idelalisib, 15.3% with duvelisib and 50% with copanlisib. Pneumonitis is most reported with copanlisib (3.45%). Among the patients with pneumonitis, death occurred in 34.7% with idelalisib, none with duvelisib and 50% with copanlisib. Rash is most reported with copanlisib (6.32%) and the incidence of serious dermatological toxicity is uncommon in all the 3 drugs. Rates of neutropenia and thrombocytopenia are overall similar between the drugs except for a slightly higher rate in copanlisib including febrile neutropenia. Infections including pneumonia, urinary tract infection, PJP pneumonia, and CMV reactivation are overall comparable between the 3 drugs. Among the patients with various infections, death occurred in 24.1% with idelalisib, 14.5% with duvelisib and 16.9% with copanlisib. The rate of hepatotoxicity is also comparable between the drugs. Among the patients with hepatic failure, death occurred in 33.3% with idelalisib, 100% with duvelisib and copanlisib. Conclusion: The overall rates of serious adverse effects are comparable between the 3 PI3KI, though diarrhea is most common with duvelisib, pneumonitis, and rash with copanlisib. As these drugs are mainly used in the relapsed refractory setting, many more years of follow-up are needed to get a better idea of real-world data as we have more experience with these drugs. Figure 1 Figure 1. Disclosures Master: Blue Bird Bio: Current holder of individual stocks in a privately-held company.

scholarly journals Managing toxicities of phosphatidylinositol-3-kinase (PI3K) inhibitors

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 346-356
Author(s):  
Ashley Hanlon ◽  
Danielle M. Brander
Keyword(s):  
Late Onset ◽  
Pi3k Pathway ◽  
Lymphocytic Leukemia ◽  
Phosphatidylinositol 3 Kinase ◽  
Small Lymphocytic Lymphoma ◽  
Pi3k Inhibitors ◽  
Novel Treatment ◽  
Immune Mediated ◽  
The Common ◽  
Phosphatidylinositol 3

Abstract Despite the proven effective approach to targeting the phosphatidylinositol-3-kinase (PI3K) pathway in B-cell malignancies, the approved PI3K inhibitors idelalisib and duvelisib have been less commonly selected for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), given the availability of other more tolerable agents. However, patients with CLL/SLL can experience a disease course that is multiply relapsed, refractory, or intolerant to treatment, and PI3K inhibitors can achieve meaningful responses. This article reviews the common early- and late-onset (considered immune-mediated) toxicities with PI3K inhibitors, including infections, hepatotoxicity, diarrhea and/or colitis, and pneumonitis. Data on pretreatment considerations, toxicity management, and drug rechallenge are presented. In addition, next-generation PI3K inhibitors and novel treatment approaches with PI3K inhibitors, including combinations, time-limited treatments, and intermittent dosing, are highlighted.

scholarly journals The dual PI3Kδ/CK1ε inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells

2020 ◽  
Vol 4 (13) ◽  
pp. 3072-3084 ◽  
Author(s):  
Kamira Maharaj ◽  
John J. Powers ◽  
Alex Achille ◽  
Melanie Mediavilla-Varela ◽  
Wael Gamal ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Adverse Events ◽  
Safety Profile ◽  
Lymphocytic Leukemia ◽  
Casein Kinase 1 ◽  
Pi3k Inhibitors ◽  
Treg Number ◽  
Immune Mediated ◽  
And Function

Abstract The in-clinic phosphatidylinositol 3-kinase (PI3K) inhibitors idelalisib (CAL-101) and duvelisib (IPI-145) have demonstrated high rates of response and progression-free survival in clinical trials of B-cell malignancies, such as chronic lymphocytic leukemia (CLL). However, a high incidence of adverse events has led to frequent discontinuations, limiting the clinical development of these inhibitors. By contrast, the dual PI3Kδ/casein kinase-1-ε (CK1ε) inhibitor umbralisib (TGR-1202) also shows high rates of response in clinical trials but has an improved safety profile with fewer severe adverse events. Toxicities typical of this class of PI3K inhibitors are largely thought to be immune mediated, but they are poorly characterized. Here, we report the effects of idelalisib, duvelisib, and umbralisib on regulatory T cells (Tregs) on normal human T cells, T cells from CLL patients, and T cells in an Eμ-TCL1 adoptive transfer mouse CLL model. Ex vivo studies revealed differential effects of these PI3K inhibitors; only umbralisib treatment sustained normal and CLL-associated FoxP3+ human Tregs. Further, although all 3 inhibitors exhibit antitumor efficacy in the Eμ-TCL1 CLL model, idelalisib- or duvelisib-treated mice displayed increased immune-mediated toxicities, impaired function, and reduced numbers of Tregs, whereas Treg number and function were preserved in umbralisib-treated CLL-bearing mice. Finally, our studies demonstrate that inhibition of CK1ε can improve CLL Treg number and function. Interestingly, CK1ε inhibition mitigated impairment of CLL Tregs by PI3K inhibitors in combination treatment. These results suggest that the improved safety profile of umbralisib is due to its role as a dual PI3Kδ/CK1ε inhibitor that preserves Treg number and function.

scholarly journals AIHA and Pancytopenia as Complications of Pembrolizumab Therapy for Metastatic Melanoma: A Case Report

2019 ◽  
Vol 12 (2) ◽  
pp. 456-465 ◽  
Author(s):  
Dan Ni ◽  
Fatmah AlZahrani ◽  
Michael Smylie
Keyword(s):  
Case Report ◽  
Adverse Effects ◽  
Metastatic Melanoma ◽  
Death Receptor ◽  
Tumour Response ◽  
Lymphocytic Leukemia ◽  
Immune Checkpoints ◽  
Immune Mediated ◽  
Successful Recovery ◽  
Increased Risk

Immunotherapy has been an emerging treatment for metastatic melanoma and several other malignancies since 2015. Hematological immune-mediated adverse effects from immunotherapy are rarely reported but they can cause serious harm to patients. Antibodies such as ipilimumab, nivolumab and pembrolizumab target different immune checkpoints to promote T cell anti-tumour response. In particular, pembrolizumab is an antibody that inhibits programmed cell death receptor 1 (PD-1) to upregulate tumour suppression. In this report, we present a case of pembrolizumab-induced autoimmune hemolytic anemia and pancytopenia in a patient who was receiving pembrolizumab treatment for metastatic melanoma. This patient has a history of chronic lymphocytic leukemia and was diagnosed with metastatic melanoma in 2017. He developed symptomatic AIHA and pancytopenia after receiving 8 cycles of pembrolizumab in 2018. Pembrolizumab treatment was discontinued and he was treated with blood transfusion and prednisone. After 5 months of tapering prednisone treatment, his anemia and pancytopenia have improved toward successful recovery. Cancer patients already face an increased risk of immunosuppression with conventional chemotherapy. This case report also summarized all reported cases of PD-1 inhibitor hematological adverse effects in the treatment of oncological diseases. These incidents reflect the risk of immune-mediated hematologic adverse effects, which should be considered in all patients using immunotherapy.

scholarly journals The role of phosphatidylinositol 3-kinase-δ in the immunomodulatory effects of lenalidomide in chronic lymphocytic leukemia

Blood ◽  
2011 ◽  
Vol 117 (16) ◽  
pp. 4323-4327 ◽  
Author(s):  
Sarah E. M. Herman ◽  
Rosa Lapalombella ◽  
Amber L. Gordon ◽  
Asha Ramanunni ◽  
Kristie A. Blum ◽  
...  
Keyword(s):  
B Cells ◽  
Growth Factor ◽  
Chronic Lymphocytic Leukemia ◽  
Immune Modulation ◽  
Cell Activation ◽  
Costimulatory Molecule ◽  
Immunoglobulin M ◽  
Lymphocytic Leukemia ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

Abstract In patients with chronic lymphocytic leukemia (CLL), lenalidomide can promote humoral immune responses but also induces a distinct disease-specific toxicity of tumor flare and cytokine release. These CLL-specific events result from increased expression of costimulatory molecules on B cells. Here we demonstrate that lenalidomide activation of CLL cells depends on the phosphatidylinositol 3-kinase p110δ (PI3K-δ) pathway. Inhibition of PI3K-δ signaling by the PI3K-δ-inhibiting drug, CAL-101, or by siRNA knockdown of p110δ, abrogates CLL cell activation, costimulatory molecule expression, and vascular endothelial growth factor and basic fibroblast growth factor gene expression that is induced by lenalidomide. In addition, CAL-101 attenuates lenalidomide-mediated increases in immunoglobulin M production by normal B cells. Collectively, these data demonstrate the importance of PI3K-δ signaling for lenalidomide immune modulation. These findings may guide development of strategies for the treatment of CLL that combine lenalidomide with CAL-101, with other inhibitors of the PI3K-δ pathway, or with other agents that target downstream kinases of this signaling pathway.

scholarly journals B cell receptor antigen receptor expression and phosphatidylinositol 3-kinase signaling regulate genesis and maintenance of mouse chronic lymphocytic leukemia

Haematologica ◽  
2022 ◽  
Author(s):  
Vera Kristin Schmid ◽  
Ahmad Khadour ◽  
Nabil Ahmed ◽  
Carolin Brandl ◽  
Lars Nitschke ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Antigen Receptor ◽  
Lymphocytic Leukemia ◽  
Regulatory Function ◽  
Phosphatidylinositol 3 Kinase ◽  
Expression Levels ◽  
Bcr Signaling ◽  
Phosphatidylinositol 3

Chronic lymphocytic leukemia (CLL) is a frequent lymphoproliferative disorder of B cells. Although inhibitors targeting signal proteins involved in B cell antigen receptor (BCR) signaling constitute an important part of the current therapeutic protocols for CLL patients, the exact role of BCR signaling, as compared to genetic aberration, in the development and progression of CLL is controversial. To investigate whether BCR expression per se is pivotal for the development and maintenance of CLL B cells, we used the TCL1 mouse model. By ablating the BCR in CLL cells from TCL1 transgenic mice, we show that CLL cells cannot survive without BCR signaling and are lost within eight weeks in diseased mice. Furthermore, we tested whether mutations augmenting B cell signaling influence the course of CLL development and its severity. The Phosphatidylinositol-3-kinase (PI3K) signaling pathway is an integral part of the BCR signaling machinery and its activity is indispensable for B cell survival. It is negatively regulated by the lipid phosphatase PTEN, whose loss mimics PI3K pathway activation. Herein, we show that PTEN has a key regulatory function in the development of CLL, as deletion of the Pten gene resulted in greatly accelerated onset of the disease. By contrast, deletion of the gene TP53, which encodes the tumor suppressor p53 and is highly mutated in CLL, did not accelerate disease development, confirming that development of CLL was specifically triggered by augmented PI3K activity through loss of PTEN and suggesting that CLL driver consequences most likely affect BCR signaling. Moreover, we could show that in human CLL patient samples, 64% and 81% of CLL patients with a mutated and unmutated IgH VH, respectively, show downregulated PTEN protein expression in CLL B cells if compared to healthy donor B cells. Importantly, we found that B cells derived from CLL patients had higher expression levels of the miRNA-21 and miRNA-29, which suppresses PTEN translation, compared to healthy donors. The high levels of miRNA-29 might be induced by increased PAX5 expression of the B-CLL cells. We hypothesize that downregulation of PTEN by increased expression levels of miR-21, PAX5 and miR-29 could be a novel mechanism of CLL tumorigenesis that is not established yet. Together, our study demonstrates the pivotal role for BCR signaling in CLL development and deepens our understanding of the molecular mechanisms underlying the genesis of CLL and for the development of new treatment strategies.

Albumin activates the AKT signaling pathway and protects B-chronic lymphocytic leukemia cells from chlorambucil- and radiation-induced apoptosis

Blood ◽  
2003 ◽  
Vol 101 (8) ◽  
pp. 3174-3180 ◽  
Author(s):  
Dylan T. Jones ◽  
Kanagasabai Ganeshaguru ◽  
Robert J. Anderson ◽  
Trevor R. Jackson ◽  
K. Richard Bruckdorfer ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Kinase Inhibitor ◽  
Protective Action ◽  
Cellular Systems ◽  
Lymphocytic Leukemia ◽  
Phosphatidylinositol 3 Kinase ◽  
Akt Activation ◽  
Radiation Induced ◽  
Induced Apoptosis ◽  
Phosphatidylinositol 3

Abstract Activation of the phosphatidylinositol 3- kinase/AKT pathway antagonizes apoptosis in diverse cellular systems. We previously showed that human plasma activated AKT and potently blocked the ability of chlorambucil or gamma radiation to induce apoptosis of B-chronic lymphocytic leukemia (CLL) cells. Here we report experiments that identify albumin as the major component of plasma that blocks CLL cell killing by chlorambucil or radiation. Intact plasma depleted of albumin by chromatography on Cibacron blue–Sepharose or plasma from a subject with analbuminemia failed either to activate AKT or to protect CLL cells from chlorambucil-induced apoptosis. Both functions were restored by re-addition of albumin. The protective action of albumin as well as AKT activation was compromised by the binding of lipids. Fluorescence-activated cell sorter (FACScan) analysis demonstrated the uptake of fluoresceinated albumin by CLL cells. Accumulation of albumin in intracellular vesicles was also shown by confocal microscopy. Indirect inhibition of AKT activation by the phosphatidylinositol 3-kinase inhibitor LY294002 reversed the blockade of chlorambucil-induced killing by plasma albumin. The data suggest that activation of AKT consequent to binding of albumin by CLL cells blocks chlorambucil- and radiation-induced apoptosis. Strategies designed to block albumin-induced antiapoptotic signaling may, therefore, be of value in enhancing cytotoxic drug action on CLL cells.

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