The efficacy and safety of PI3K and AKT inhibitors for patients with cancer: A systematic review and network meta-analysis.

BACKGROUND: Inhibiting PI3K/AKT pathway activation may hinder the occurrence and progression of cancer. The aim of this study was to evaluate the efficacy and safety of the PI3K/AKT inhibitors and determine the most appropriate inhibitor for different cancer types. METHODS: Electronic databases up to June 2024 were used to examine the efficacy and safety of PI3K inhibitors (alpelisib, copanlisib, duvelisib, and idelalisib) and AKT inhibitors (capivasertib, ipatasertib and MK-2206) for the treatment of cancer. Data was assessed with a random-effect pairwise and network meta-analysis. Randomized controlled trials and retrospective studies were eligible if they compared PI3K or AKT inhibitors with non-PI3K/AKT controls with no restriction. RESULTS: The results were based on 34 studies from 34 published articles and 6 online registration trials (6710 patients). According to pairwise meta-analysis, PI3K/AKT inhibitors showed to be highly effective, especially for treating mutant cancers, but had poor safety profiles. According to our network meta-analysis, PI3K/AKT inhibitors, especially the AKT inhibitor capivasertib, are effective for treating solid cancers such as breast cancer (BC). Moreover, PI3K inhibitors, especially idelalisib, were effective for treating hematologic cancers such as chronic lymphocytic leukemia (CLL). CONCLUSIONS: The PI3K/AKT inhibitors are effective in patients with genetic mutations. For solid cancers such as BC, capivasertib was efficacy and safety. For hematological cancers represented by CLL, idelalisib was efficacy and safety. The above studies can be used when recommending appropriate targeted therapies for patients with different cancer types.

Idelalisib-Induced Pneumonitis in Chronic Lymphocytic Leukemia.

Idelalisib, a phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, effectively treats relapsed chronic lymphocytic leukemia (CLL). While this targeted approach offers a therapeutic edge, particularly in B-cell malignancies, it is associated with complications such as pneumonitis. This report details idelalisib-induced pneumonitis, highlighting the importance of early diagnosis and tailored treatment in achieving a favorable patient outcome.

Pegylated-liposomes increase the efficacy of Idelalisib in lymphoma B-cells.

New drugs and technologies are continuously developed to improve the efficacy and minimize the critical side effects of cancer treatments. The present investigation focuses on the development of a liposomal formulation for Idelalisib, a small-molecule kinase inhibitor approved for the treatment of lymphoid malignancies. Idelalisib is a potent and selective antitumor agent, but it is not indicated nor recommended for first-line treatment due to fatal and serious toxicities. Herein, liposomes are proposed as a delivery tool to improve the therapeutic profile of Idelalisib. Specifically, PEGylated liposomes were prepared, and their physicochemical and technological features were investigated. Light-scattering spectroscopy and cryo-transmission electron microscopy revealed nanosized unilamellar vesicles, which were proved to be stable in storage and in simulated biological fluids. The cytotoxicity of the liposome formulation was investigated in a human non-Hodgkin's lymphoma B cell line. Idelalisib was able to induce death of tumor cells if delivered by the nanocarrier system at increased efficacy. These findings suggest that combining Idelalisib and nanotechnologies may be a powerful strategy to increase the antitumor efficacy of the drug.

Method development and validation for the estimation of gedatolisib in mouse plasma by tandem mass spectrometry and its application to pharmacokinetics studies.

A simple and a sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of gedatolisib in mouse plasma. The extraction technique involved a simple precipitation method to extract gedatolisib and idelalisib (internal standard) from mouse plasma. A clean chromatographic separation of gedatolisib and the internal standard was achieved on an Atlantis dC18 column using an isocratic mobile phase (10 mm ammonium formate and acetonitrile; 30:70% v/v, both supplemented with 0.1% formic acid) delivered at a flow rate of 0.7 ml/min. The total run time was 2.0 min, and gedatolisib and idelalisib were eluted at 0.80 and 0.95 min, respectively. Gedatolisib was monitored at m/z 616.40 → 488.20 and idelalisib at 416.05 → 176.10. All the required parameters for the method validation were performed as per US Food and Drug Administration guidelines, and the results were within the acceptance criteria. The method was accurate and proved to be precise at a linearity range of 1.33-2667 ng/ml. The accuracy for gedatolisib in mouse plasma was in the ranges 0.99-1.06% (intra-day) and 0.96-1.04% (inter-day). Gedatolisib appeared to be stable in a series of stability conditions. Gedatolisib showed a good intravenous profile when administered through a solution formulation.

Leniolisib: a novel treatment for activated phosphoinositide-3 kinase delta syndrome.

IC50 = 11 nM (PI3Kδ); 244 nM (PI3Kα); 424 nM (PI3Kß), 2,230 nM (PI3Kγ).

Metabolic and toxicological considerations for phosphoinositide 3-kinase delta inhibitors in the treatment of chronic lymphocytic leukemia.

INTRODUCTION: Phosphoinositide 3-kinase delta (PI3Kδ) inhibitors are a class of novel agents that are mainly used to treat B-cell malignancies. They function by inhibiting one or more enzymes which are part of the PI3K/AKT/mTOR pathway. Idelalisib is a first-in-class PI3Kδ inhibitor effective in patients with B-cell lymphoid malignancies. AREAS COVERED: This article reviews the chemical structure, mechanism of action, and metabolic and toxicological properties of PI3Kδ inhibitors and discusses their clinical applications in monotherapy and in combination with other agents for the treatment of chronic lymphocytic leukemia (CLL). A search was conducted of PubMed, Web of Science, and Google Scholar for articles in English. RESULTS/CONCLUSION: PI3Kδ inhibitors hold potential for the treatment of B-cell malignancies, including CLL. However, their use is also associated with severe toxicities, including pneumonia, cytopenias, hepatitis, and rash. Newer drugs are in development to reduce toxicity with novel schedules and/or combinations. EXPERT OPINION: The development of novel PI3Kδ inhibitors might help to reduce toxicity and improve efficacy in patients with CLL and other B-cell lymphoid malignancies.

Aberrant PI3Kδ splice isoform as a potential biomarker and novel therapeutic target for endocrine cancers.

Introduction: PI3K/AKT signaling pathway is upregulated in a broad spectrum of cancers. Among the class I PI3Ks (PI3Kδ/ß/δ isoforms), PI3Kδ has been implicated in hematologic cancers and solid tumors. Alternative splicing is a post-transcriptional process for acquiring proteomic diversity in eukaryotic cells. Emerging evidence has highlighted the involvement of aberrant mRNA splicing in cancer development/progression. Methods: Our previous studies revealed that PIK3CD-S is an oncogenic splice variant that promotes tumor aggressiveness and drug resistance in prostate cancer (PCa). To further evaluate the potential of utilizing PI3Kδ-S (encoded from PIK3CD-S) as a cancer biomarker and/or drug target, comprehensive analyses were performed in a series of patient samples and cell lines derived from endocrine/solid tumors. Specifically, IHC, immunofluorescence, western blot and RT-PCR assay results have demonstrated that PI3Kδ isoforms were highly expressed in endocrine/solid tumor patient specimens and cell lines. Results: Differential PIK3CD-S/PIK3CD-L expression profiles were identified in a panel of endocrine/solid tumor cells. SiRNA knockdown of PIK3CD-L or PIK3CD-S differentially inhibits AKT/mTOR signaling in PCa, breast, colon and lung cancer cell lines. Moreover, siRNA knockdown of PTEN increased PI3Kδ levels and activated AKT/mTOR signaling, while overexpression of PTEN reduced PI3Kδ levels and inhibited AKT/mTOR signaling in cancer cells. Intriguingly, PI3Kδ-S levels remained unchanged upon either siRNA knockdown or overexpression of PTEN. Taken together, these results suggested that PTEN negatively regulates PI3Kδ-L and its downstream AKT/mTOR signaling, while PI3Kδ-S promotes AKT/mTOR signaling without regulation by PTEN. Lastly, PI3Kδ inhibitor Idelalisib and SRPK1/2 inhibitor SRPIN340 were employed to assess their efficacies on inhibiting the PI3Kδ-expressing endocrine/solid tumors. Our results have shown that Idelalisib effectively inhibited PI3Kδ-L (but not PI3Kδ-S) mediated AKT/mTOR signaling. In contrast, SRPIN340 reversed the aberrant mRNA splicing, thereby inhibiting AKT/mTOR signaling. In-vitro functional assays have further demonstrated that a combination of Idelalisib and SRPIN340 achieved a synergistic drug effect (with drastically reduced cell viabilities/growths of tumor spheroids) in inhibiting the advanced tumor cells. Conclusion: In summary, our study has suggested a promising potential of utilizing PI3Kδ-S (an oncogenic isoform conferring drug resistance and exempt from PTEN regulation) as a prognostic biomarker and drug target in advanced endocrine cancers.

Combination strategies to overcome drug resistance in FLT+ acute myeloid leukaemia.

BACKGROUND: Acute myeloid leukaemia (AML) remains difficult to treat despite the development of novel formulations and targeted therapies. Activating mutations in the FLT3 gene are common among patients and make the tumour susceptible to FLT3 inhibitors, but resistance to such inhibitors develops quickly. METHODS: We examined combination therapies aimed at FLT3+-AML, and studied the development of resistance using a newly developed protocol. Combinations of FLT3, CDK4/6 and PI3K inhibitors were tested for synergism. RESULTS: We show that AML cells express CDK4 and that the CDK4/6 inhibitors palbociclib and abemaciclib inhibit cellular growth. PI3K inhibitors were also effective in inhibiting the growth of AML cell lines that express FLT3-ITD. Whereas resistance to quizartinib develops quickly, the combinations overcome such resistance. CONCLUSIONS: This study suggests that a multi-targeted intervention involving a CDK4/6 inhibitor with a FLT3 inhibitor or a pan-PI3K inhibitor might be a valuable therapeutic strategy for AML to overcome drug resistance. Moreover, many patients cannot tolerate high doses of the drugs that were studied (quizartinib, palbociclib and PI3K inhibitors) for longer periods, and it is therefore of high significance that the drugs act synergistically and lower doses can be used.

Phosphatidylinositol 3 kinase inhibitor-related pneumonitis: a systematic review and meta-analysis.

INTRODUCTION: Serious phosphatidylinositol 3 kinase (PI3K) inhibitor-related pneumonitis has raised clinical concerns, and integrated data for this condition are lacking. METHODS: Randomized controlled trials (RCTs) comparing PI3K inhibitor therapy with control treatments from electronic databases and registrations were searched from inception to 1 April 20231 April 2023seven1 April 2023. The outcomes of our study were the incidence and risk of all-grade and grade ≥ 3 PI3K inhibitor-associated pneumonitis compared with controls. RESULTS: The meta-analysis included 13 studies comprising 3916 patients. The incidence of all-grade and grade ≥ 3 pneumonitis was 3.7% (82/2210) and 3.0% (35/1162) in patients treated with PI3K inhibitors. PI3K inhibitors significantly increased the risk of all-grade and grade ≥ 3 pneumonitis compared with controls (RR 5.63, 95% CI [2.97, 10.65], P < 0.00001; RR 6.85, 95% CI [2.45, 19.11], P = 0.0002, respectively) with no significant heterogeneity across studies. In terms of different PI3K inhibitors, copanlisib and idelalisib significantly increased the risk of pneumonitis compared to controls (RR 4.99, 95% CI [1.19, 21.01], P = 0.03; RR 5.53, 95% CI [2.35, 13.01], P < 0.0001, respectively). CONCLUSION: PI3K inhibitors significantly increased the risk of pneumonitis compared with controls, and most cases are severe or even life-threatening. PROSPERO REGISTRATION NUMBER: CRD42022318878.

Idelalisib (PI3Kδ inhibitor) therapy for patients with relapsed/refractory chronic lymphocytic leukemia: A Swedish nation-wide real-world report on consecutively identified patients.

OBJECTIVES: We examined the efficacy and toxicity of the PI3Kδ inhibitor idelalisib in combination with rituximab salvage therapy in consecutively identified Swedish patients with chronic lymphocytic leukemia (CLL). METHODS AND RESULTS: Thirty-seven patients with relapsed/refractory disease were included. The median number of prior lines of therapy was 3 (range 1-11); the median age was 69 years (range 50-89); 22% had Cumulative Illness Rating Scale (CIRS) >6 and 51% had del(17p)/TP53 mutation. The overall response rate was 65% (all but one was partial response [PR]). The median duration of therapy was 9.8 months (range 0.9-44.8). The median progression-free survival was 16.4 months (95% CI: 10.4-26.3) and median overall survival had not been reached (75% remained alive at 24 months of follow-up). The most common reason for cessation of therapy was colitis (n = 8, of which seven patients experienced grade ≥3 colitis). The most common serious adverse event was grade ≥3 infection, which occurred in 24 patients (65%). CONCLUSIONS: Our real-world results suggest that idelalisib is an effective and relatively safe treatment for patients with advanced-stage CLL when no other therapies exist. Alternative dosing regimens and new PI3K inhibitors should be explored, particularly in patients who are double-refractory to inhibitors of BTK and Bcl-2.

Treatment with idelalisib in patients with chronic lymphocytic leukemia - real world data from the registry of the German CLL Study Group.

Idelalisib in combination with rituximab is an efficacious treatment for patients suffering from chronic lymphocytic leukemia (CLL) with known limitations due to toxicities. However, the benefit after prior Bruton tyrosine kinase inhibitor (BTKi) therapy remains unclear. For this analysis, 81 patients included in a non-interventional registry study of the German CLL study group (registered at www.clinicaltrials.gov as # NCT02863692) meeting the predefined criteria of a confirmed diagnosis of CLL and being treated with idelalisib containing regimens outside clinical trials were considered. 11 patients were treatment naïve (13.6%) and 70 patients (86.4%) pretreated. Patients had median of one prior therapy line (range 0-11). Median treatment duration with idelalisib was 5.1 months (range 0-55.0 months). Of 58 patients with documented treatment outcome, 39 responded to idelalisib containing therapy (67.2%). Patients treated with the BTKi ibrutinib as last prior treatment prior to idelalisib responded in 71.4% compared to a response rate of 61.9% in patients without prior ibrutinib. Median event free survival (EFS) was 15.9 months with a 16 versus 14 months EFS in patients with ibrutinib as last prior treatment or not, respectively. Median overall survival was 46.6 months. In conclusion, treatment with idelalisib appears to have a valuable impact in patients being refractory to prior ibrutinib therapy even though there are limitations in our analysis due to the low number of patients included.

Management of Gastro-Intestinal Toxicity of the Pi3 Kinase Inhibitor: Optimizing Future Dosing Strategies.

The phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in cancer progression and in host immunity. Idelalisib was the first of this class to be approved with the second-generation Pi3 kinase inhibitors copanlisib, duvelisib and umbralisib, subsequently being approved in the United States. Real-world data are lacking, however, in relation to the incidence and toxicity of Pi3 kinase inhibitor-induced colitis. We here review, in the first instance, the general landscape of the Pi3K inhibitors in the context of hematological malignancies, with a focus on the adverse gastrointestinal side effects reported by various clinical trials. We further review the available worldwide pharmacovigilance data in relation to these drugs. Finally, we describe our own real-world experience with idelalisib-induced colitis management in our center and in a national setting.

Synergistic Effects of PI3K Inhibition on Arsenic Trioxide Cytotoxicity in Acute Promyelocytic Leukemia Cells: A New Portrait of Idelalisib as an Adjuvant Therapy.

The advent of small-molecule inhibitors targeting the components of oncogenic signaling pathways has revolutionized cancer treatment, where the pharmacological approaches have gone from an era of non-specific chemotherapeutic drugs to the golden age of targeted therapies. In the present study, we evaluated the therapeutic value of an isoform-specific inhibitor of PI3K (Idelalisib) in potentiating the anti-leukemic effects of arsenic trioxide (ATO), an eminent drug used in the treatment of acute promyelocytic leukemia (APL). We found that the abrogation of the PI3K axis profoundly reinforced the anti-leukemic effects of the lower concentrations of ATO, as revealed by the superior reduction in the viability, cell number, and metabolic activity of APL-derived NB4 cells as compared to either agent alone. The cytotoxic effect of Idelalisib in combination with ATO was probably mediated through suppression of c-Myc that was coupled with the elevation in the intracellular level of reactive oxygen species and induction of caspase-3-dependent apoptosis. Notably, our results showed that the suppression of autophagy reinforced the ability of the drugs in eradicating the leukemic cells, suggesting that the compensatory activation of this system may probably overshadow the success of Idelalisib-plus-ATO in APL cells. All in all and given the significant efficacy of Idelalisib against NB4 cells, we proposed the application of this PI3K inhibitor as a foreseeable approach with a safe profile in the treatment of APL.

Idelalisib plus rituximab versus ibrutinib in the treatment of relapsed/refractory chronic lymphocytic leukaemia: A real-world analysis from the Chronic Lymphocytic Leukemia Patients Registry (CLLEAR).

Idelalisib (idela), a phosphatidylinositol 3-kinase inhibitor, and ibrutinib, a Bruton tyrosine kinase inhibitor, were the first oral targeted agents approved for relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL). However, no randomised trials of idelalisib plus rituximab (R-idela) versus ibrutinib have been conducted. Therefore, we performed a real-world retrospective analysis of patients with R/R CLL treated with R-idela (n = 171) or ibrutinib (n = 244). The median age was 70 versus 69 years, with a median of two previous lines. There was a trend towards higher tumour protein p53 (TP53) aberrations and complex karyotype in the R-idela group (53% vs. 44%, p = 0.093; 57% vs. 46%, p = 0.083). The median progression-free survival (PFS) was significantly longer with ibrutinib (40.5 vs. 22.0 months; p < 0.001); similarly to overall survival (OS; median 54.4 vs. 37.7 months, p = 0.04). In multivariate analysis, only PFS but not OS remained significantly different between the two agents. The most common reasons for treatment discontinuation included toxicity (R-idela, 39.8%; ibrutinib, 22.5%) and CLL progression (27.5% vs. 11.1%). In conclusion, our data show significantly better efficacy and tolerability of ibrutinib over R-idela in patients with R/R CLL treated in routine practice. The R-idela regimen may still be considered a reasonable option in highly selected patients without a suitable treatment alternative.

Molecular Insight into Drug Resistance Mechanism Conferred by Aberrant PIK3CD Splice Variant in African American Prostate Cancer.

Targeting PI3Kδ has emerged as a promising therapy for hematologic and non-hematologic malignancies. Previously, we identified an oncogenic splice variant, PIK3CD-S, conferring Idelalisib resistance in African American (AA) prostate cancer (PCa). In the current study, we employed a comprehensive analysis combining molecular biology, biochemistry, histology, in silico simulation, and in vitro functional assays to investigate the PIK3CD-S expression profiles in PCa samples and to elucidate the drug resistance mechanism mediated by PI3Kδ-S (encoded by PIK3CD-S). The immunohistochemistry, RT-PCR, and Western blot assays first confirmed that PI3Kδ-S is highly expressed in AA PCa. Compared with PCa expressing the full-length PI3Kδ-L, PCa expressing PI3Kδ-S exhibits enhanced drug resistance properties, including a higher cell viability, more antiapoptotic and invasive capacities, and constitutively activated PI3K/AKT signaling, in the presence of PI3Kδ/PI3K inhibitors (Idelalisib, Seletalisib, Wortmannin, and Dactolisib). Molecular docking, ATP-competitive assays, and PI3 kinase assays have further indicated a drastically reduced affinity of PI3Kδ inhibitors with PI3Kδ-S vs. PI3Kδ-L, attributed to the lack of core binding residues in the PI3Kδ-S catalytic domain. Additionally, SRSF2 has been identified as a critical splicing factor mediating exon 20 skipping in PIK3CD pre-mRNA. The inhibition of the SRSF2 activity by SRPIN340 successfully sensitizes AA PCa cells to PI3Kδ inhibitors, suggesting a novel therapeutic option for Idelalisib-resistant tumors.

Combined BCL-2 and PI3K/AKT Pathway Inhibition in KMT2A-Rearranged Acute B-Lymphoblastic Leukemia Cells.

Numerous hematologic neoplasms, including acute B-lymphoblastic leukemia (B-ALL), are characterized by overexpression of anti-apoptotic BCL-2 family proteins. Despite the high clinical efficacy of the specific BCL-2 inhibitor venetoclax in acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL), dose limitation and resistance argue for the early exploration of rational combination strategies. Recent data indicated that BCL-2 inhibition in B-ALL with KMT2A rearrangements is a promising intervention option; however, combinatorial approaches have not been in focus so far. The PI3K/AKT pathway has emerged as a possible target structure due to multiple interactions with the apoptosis cascade as well as relevant dysregulation in B-ALL. Herein, we demonstrate for the first time that combined BCL-2 and PI3K/AKT inhibition has synergistic anti-proliferative effects on B-ALL cell lines. Of note, all tested combinations (venetoclax + PI3K inhibitors idelalisib or BKM-120, as well as AKT inhibitors MK-2206 or perifosine) achieved comparable anti-leukemic effects. In a detailed analysis of apoptotic processes, among the PI3K/AKT inhibitors only perifosine resulted in an increased rate of apoptotic cells. Furthermore, the combination of venetoclax and perifosine synergistically enhanced the activity of the intrinsic apoptosis pathway. Subsequent gene expression studies identified the pro-apoptotic gene BBC3 as a possible player in synergistic action. All combinatorial approaches additionally modulated extrinsic apoptosis pathway genes. The present study provides rational combination strategies involving selective BCL-2 and PI3K/AKT inhibition in B-ALL cell lines. Furthermore, we identified a potential mechanistic background of the synergistic activity of combined venetoclax and perifosine application.

High risk of infection in 'real-world' patients receiving ibrutinib, idelalisib or venetoclax for mature B-cell leukaemia/lymphoma.

OBJECTIVE: The infection risk in patients receiving ibrutinib, idelalisib or venetoclax for chronic lymphocytic leukaemia (CLL) or B-cell lymphoma treated outside of clinical trials is incompletely defined. We sought to identify the severe infection rate and associated risk factors in a 'real-world' cohort. METHODS: We conducted a retrospective cohort study of adult patients with CLL or lymphoma treated with ibrutinib, idelalisib or venetoclax. RESULTS: Of 67 patients identified (ibrutinib n = 53, idelalisib n = 8 and venetoclax n = 6), 32 (48%) experienced severe infection. Severe infection occurred at a rate of 65 infections per 100 person-years, with a median of 17.8 months of therapy. Median time to first infection (IQR) was 5.4 months (1.4-15.9). Poor baseline Eastern Cooperative Oncology Group (ECOG) performance status and high Charlson Comorbidity Index (CCI) score associated with increased risk of severe infection [hazard ratios (95% CI) 1.57 (1.07-2.31, p = .018) and 1.3 (1.05-1.62, p = .016) respectively]. CONCLUSION: The severe infection rate for patients receiving ibrutinib, idelalisib or venetoclax for lymphoma and CLL exceeded those reported in clinical trials. Patients with poor ECOG or high CCI should be closely monitored for early signs of infection and prevention strategies actively pursued. Further prospective research is required to define optimal antimicrobial prophylaxis recommendations.

Targeted therapies in CLL/SLL and the cumulative incidence of infection: A systematic review and meta-analysis.

Background: Patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) are prone to infections. Aims: Provide a pooled estimate of the cumulative incidence for infections that fulfilled the criteria associated with severe infectious adverse events for grade 3 or higher (including pneumonia, febrile neutropenia and sepsis) in patients who receive targeted therapies. Methods: We searched PubMed and EMBASE for randomized controlled trials (RCT) that included patients with CLL/SLL who received targeted therapies and performed a random-effects meta-analysis to estimate the cumulative incidence of infections. Results: Of 2,914 studies screened, we retrieved 31 which evaluated 11,660 patients. The pooled cumulative incidence of infections for patients who received treatment regimens based on a BTK inhibitors was 19.86%. For patients who received treatment based on rituximab and second generation anti-CD20 monoclonal antibodies, the pooled cumulative incidence of infections was 19.85 and 13.46%, respectively. Regarding PI3K inhibitor-based regimens the cumulative incidence of severe infections was 30.89%. BCL-2 inhibitors had a cumulative incidence of infections of 17.49% while lenalidomide and alemtuzumab had an incidence of 13.33 and 45.09%, respectively. The cumulative incidence of pneumonia ranged from 3.01 to 8.45% while febrile neutropenia ranged from 2.68 to 10.80%. Regarding sepsis, the cumulative incidence ranged from 0.9 to 4.48%. Conclusion: Patients with CLL/SLL who receive targeted therapies may develop severe infections at significant rates that, in addition to disease stage and other complications, depend on the mechanism of action of the used drug. Surveillance for infections and development of effective prophylactic strategies are critical for patients with CLL/SLL who receive targeted therapies. Systematic Review Registration: [https://systematicreview.gov/], identifier [registration number].

Real-life efficacy and safety of idelalisib in 55 double-refractory follicular lymphoma patients.

Idelalisib, a reversible inhibitor of PI3Kδ (phosphoinositide-3 kinase delta), showed remarkable activity in the phase II DELTA trial, leading to its approval by the European Medicines Agency (EMA) in patients with relapsed/refractory (R/R) follicular lymphoma (FL). However, real-life data on idelalisib are scarce. We treated 55 double-refractory FL patients with idelalisib in a real-life setting. With a median exposure to idelalisib of 10 months (range 1-43), overall response rate was 73%, the highest ever reported. Non-haematological toxicities were mild and manageable. At 12 months, 80% of patients were alive, and 72% disease-free. The efficacy and safety of idelalisib was confirmed in a real-life setting.

Prospects of targeting PI3K/AKT/mTOR pathway in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses among all malignancies. PI3K/AKT/mTOR signaling pathway, a main downstream effector of KRAS is involved in the regulation of key hallmarks of cancer. We here report that whole-genome analyses demonstrate the frequent involvement of aberrant activations of PI3K/AKT/mTOR pathway components in PDAC patients and critically evaluate preclinical and clinical evidence on the application of PI3K/AKT/mTOR pathway targeting agents. Combinations of these agents with chemotherapeutics or other targeted therapies, including the modulators of cyclin-dependent kinases, receptor tyrosine kinases and RAF/MEK/ERK pathway are also examined. Although human genetic studies and preclinical pharmacological investigations have provided strong evidence on the role of PI3K/AKT/mTOR pathway in PDAC, clinical studies in general have not been as promising. Patient stratification seems to be the key missing point and with the advent of biomarker-guided clinical trials, targeting PI3K/AKT/mTOR pathway could provide valuable assets for treatment of pancreatic cancer patients.