Idelalisib modulates CD4+ T cell responses to mitigate rejection of allografts in mice.

Hypothermic machine perfusion (HMP) has been demonstrated to be more effective in mitigating ischemia-reperfusion injury (IRI) of donation after circulatory death (DCD) organs than cold storage (CS), yet the underlying mechanism remains obscure. We aimed to propose a novel therapeutic approach to ameliorate IRI in DCD liver transplantation. Twelve clinical liver samples were randomly assigned to HMP or CS treatment and subsequent transcriptomics analysis was performed. By combining in vivo HMP models, we discovered that HMP attenuated inflammation, oxidative stress, and apoptosis in DCD liver through a SEPRINA3-mediated PI3Kδ/AKT signaling cascade. Moreover, in the hypoxia/reoxygenation (H/R) model of BRL-3A, overexpression of SERPINA3 mitigated H/R-induced apoptosis, while SERPINA3 knockdown exacerbated cell injury. Idelalisib (IDE) treatment also reversed the protective effect of SERPINA3 overexpression. Overall, our research provided new insights into therapeutic strategies and identified potential novel molecular targets for therapeutic intervention against DCD liver.

Time to Next Treatment, Healthcare Resource Utilization, and Healthcare Costs Among Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Following First-Line Ibrutinib

Exposure-Response of Idelalisib Administered in Combination with Bendamustine and Rituximab for the Treatment of Relapsed Chronic Lymphocytic Leukemi

Risk Factors for Grade 3/4 Transaminase Elevation in Patients with Chronic Lymphocytic Leukemia Treated with Idelalisib

The BET Inhibitor GS-626510 Converges with Idelalisib through the Inhibition of Tumor-Macrophage Crosstalk and Cytokine Production in Diffuse Large B-Cell Lymphoma

A Validated Risk Model for Overall Survival in Relapsed/Refractory Chronic Lymphocytic Leukemia Applicable to Patients Treated with Novel Therapies and Standard of Care

External Stimuli Modulate EZH2 Expression in Chronic Lymphocytic Leukemia. Rationale and Evidence for Synergistic Anti-Tumor Effects of B Cell Signaling and EZH2 Inhibitors

Idelalisib (IDEL) is approved as monotherapy in relapsed follicular lymphoma (FL) and with rituximab (IDEL+R) for relapsed chronic lymphocytic leukemia (CLL). Toxic effects can be severe and treatment-limiting. Outcomes in a real-world population are not yet characterized. We compared IDEL treatment outcomes in the clinical setting with outcomes in clinical trial data. This cohort study compared clinical trial participants treated with IDEL, aged 65 years or older, in studies 101-09 and 312-0116 with Medicare beneficiaries treated with IDEL of the same disease state and treatment regimen. Study 101-09 was a phase 2, single-group, open-label trial supporting accelerated approval of IDEL for relapsed or refractory FL. Study 312-0116 was a phase 3, multicenter, randomized, double-blind trial supporting approval of IDEL+R for relapsed CLL. Analyses were conducted between February and December 2018. Treatment duration, on-treatment and overall mortality, and serious and fatal infections were compared between trial participants and Medicare beneficiaries. Cox proportional hazards models quantified differences by cohort. We identified 26 trial participants (mean [SD] age, 73 [4.9] years; 12 [46.2%] women) and 305 Medicare beneficiaries (mean [SD] age, 76 [6.9] years; 103 [54.8%] women) receiving IDEL for FL and 89 trial participants (mean [SD] age, 74 [6.0] years; 30 [33.7%] women) and 294 Medicare beneficiaries (mean age, 76 [6.3] years; 111 [37.8%] women) receiving IDEL+R for CLL. Medicare beneficiaries were older with higher comorbidity; had a shorter median treatment duration for CLL (173 days vs 473 days, P < .001) but not FL (114, days vs 160 days, P = .38); a numerically higher mortality rate (CLL: HR, 1.40; 95% CI, 0.93-2.11; FL: HR, 1.39; 95% CI, 0.69-2.78); and a significantly higher fatal infection rate per 100 person-years for CLL (18.4 vs 9.8, P = .04) and a numerically higher rate for FL (27.6 vs 18.6, P = .54), compared with trial participants. Trial participants had approximately twice as many dose reductions (CLL: 32.6% vs 18.0%; P = .003; FL: 38.5% vs 16.1%; P = .02). Among Medicare beneficiaries, a hospitalized infection within 6 months prior to IDEL initiation was associated with a 2.11-fold increased risk for on-treatment fatal infections (95% CI, 1.44-3.10). Despite a March 2016 recommendation for Pneumocystis jirovecii pneumonia prophylaxis in patients treated with IDEL, prophylaxis rates were low after March 2016 (FL: 25%, CLL: 37%). We observed substantial imbalances in baseline comorbidities and treatment outcomes between Medicare beneficiaries and trial participants aged 65 years or older. Immunosuppression-related toxic effects, including infections, may have been somewhat reduced in trials by more frequent dose reductions and exclusion of patients with ongoing infections. Selective eligibility criteria and closer monitoring of trial patients may be responsible for limited generalizability of trial data to clinical practice.

Impact of Idelalisib Treatment Interruption with or without Dose Reduction on Outcomes in Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Discontinuation Patterns in Patients Receiving Novel Oral Agents for Chronic Lymphocytic Leukemia in the Veterans Health Administration

Primary Analysis of Anti-CD19 Tafasitamab (MOR208) Treatment in Combination with Idelalisib or Venetoclax in R/R CLL Patients Who Failed Prior BTK Inhibitor Therapy (COSMOS Trial)

Efficacy of Therapies Following Venetoclax Discontinuation in CLL: Focus on B-Cell Receptor Signal Transduction Inhibitors and Cellular Therapies

The phosphatidyl-inositol 3 kinase (PI3K) δ inhibitor, idelalisib (IDE), is a potent inhibitor of the B-cell receptor pathway and a novel and highly effective agent for the treatment of chronic lymphocytic leukemia (CLL). We evaluated the activities of IDE in comparison to bendamusine (BEN), a commonly used alkylating agent, in primary CLL cells ex vivo. In contrast to BEN, IDE was cytotoxic to cells from extensively-treated patients, including those with a deletion (del)17p. Cross-resistance was not observed between BEN and IDE, confirming their different modes of cytotoxicity. Marked synergy was seen between BEN and IDE, even in cases that were resistant to BEN or IDE individually, and those with deletion (del) 17p. CD40L/interleukin 4 (IL4) co-treatment mimicking the CLL microenvironment increased resistance to IDE, but synergy was retained. PI3Kδ-deficient murine splenic B cells were more resistant to IDE and showed reduced synergy with BEN, thus confirming the importance of functional PI3Kδ protein. Although IDE was observed to induce γH2AX, IDE did not enhance activation of the DNA damage response nor DNA repair activity. Interestingly, IDE decreased global RNA synthesis and was antagonistic with 5,6-Dichlorobenzimidazole 1-b-D-ribofuranoside (DRB), an inhibitor of transcription. These findings add to the increasingly complex cellular effects of IDE, and B cell receptor (BCR) inhibitors in general, in CLL.

Please indicate where the abstract has been published before: ASH Abstract‐Blood 2018 132:5924.Background:Idelalisib (IDELA), a PI3K‐delta inhibitor, is indicated for the treatment of adult patients (pts) with chronic lymphocytic leukemia (CLL) and for pts with follicular lymphoma refractory to two prior lines of treatment. Its clinical efficacy and safety profile have been established in clinical trials, however, there is a paucity of real‐word data regarding its use. This study was initiated to describe pts who started IDELA treatment during the French EAP.Aims:The aims of this retrospective multicenter study were to describe the effectiveness, adverse events (AE), adverse drug reaction (ADR), serious ADR (SADR), AE of special interest (AESI: diarrhea/colitis, pneumonitis, liver enzyme elevation, neutropenia, infection, and rash), and IDELA use in adult pts previously enrolled in the EAP between June and October 2014 for CLL or iNHL.Methods:Physicians who enrolled at least one patient in the EAP were contacted to participate in this study. For each patient, 12 months follow up data were collected and monitored by the Lymphoma Academic Research Organization (LYSARC). The primary endpoint was the overall response rate (ORR) at 6 months. Statistical analysis was descriptiveResults:Seventy‐five pts were included, 41 in CLL group (39 in third‐line or later line and 2 in first‐line with del(17p)/TP53m unsuitable for chemo‐immunotherapy and 34 in iNHL group, all refractory after two prior lines of treatment (table 1). In CLL/iNHL groups respectively, median IDELA treatment duration was 25.1 weeks/18.9 weeks, ORR was 82.8%/56.5% at 6 months (data reported in 29 pts/23 pts), median PFS was not reached (NR)/ 6.7 months, median time to next treatment (TTNT) defined as the time between the date of the last IDELA intake and the start of next treatment after progression of disease (PD) was NR/11.6 months, median OS was NR in both groups and OS estimate at 12 months was 69.9%/67.6% (table 2). In CLL/iNHL groups respectively, at least one ADR related to IDELA was reported during the study in 35 pts (85.4%)/26 pts (76.5%) and SADR related to IDELA in 23 pts (56.1%)/15 pts (44.1%), most frequently reported AEs were: infections and infestations 61.0%/50.0% [Pneumocystis jirovecii pneumonia (PJP) 2.4%/5.9%], gastrointestinal disorders 56.1%/35.3% (diarrhea 41.5%/29.4%), blood and lymphatic system disorders 41.5%/41.2% (neutropenia 17.1%/23.5%) and lab investigation 43.9%/47.1% (hepatic enzyme increase 19.5%/14.7%). 24 pts (58.5%)/15 pts (44.1%) interrupted IDELA temporarily for AE, 6 pts (14.6%)/8 pts (23.5%) discontinued permanently for AE, 38 pts (92.7%)/25 pts (73.5%) had at least one AESI and 3 pts (7.3%)/6 pts (17.6%) permanently discontinued IDELA for AESI. Deaths were reported during the study in 13 pts (31.7%)/11 pts (32.4%), due to PD (46.2%/72.7%).Summary/Conclusion:The results of this study of heavily pretreated CLL and iNHL population indicate that IDELA is an effective treatment in routine clinical practice with an acceptable safety profile. ORR at 6 months was 83%/56.5% in CLL/iNHL mirroring those of clinical trials (Furman NEJM 2014, Gopal NEJM 2014). The pattern of AEs corresponds to that reported in previous clinical studies and might be improved by specific management of AESI.image

Background:Idelalisib (IDELA) and duvelisib (DUVA), both oral agents, and copanlisib (COPA), an IV agent, are PI3K inhibitors approved as monotherapy for relapsed / refractory (R/R) follicular lymphoma (FL). IDELA and DUVA are also listed in the National Comprehensive Cancer Network (NCCN) guidelines as monotherapy for R/R CLL. All agents target PI3Kδ while DUVA also targets PI3Kγ and COPA also targets PI3Kα. These drugs display comparable efficacy; therefore, anticipated treatment emergent adverse events (TEAEs) may guide selection of PI3Kδ inhibitor therapy.Aims:To compare safety profiles for IDELA vs. COPA and IDELA vs. DUVA and to evaluate the effect of preexisting conditions on IDELA‐induced TEAEs.Methods:AEs for evaluation were identified in the “Highlights of Prescribing Information” in each drug's United States Package Insert (USPI). Using the Safety Analysis Set (SAS) for IDELA‐treated patients (pts) with R/R iNHL (N = 163, median duration of treatment [mDoT] 27 weeks) and TEAEs reported for COPA‐treated pts with FL and other hematologic malignancies (Aliqopa® USPI [N = 168, mDoT 22 weeks], Dreyling et al., J. Clin. Oncol. 2017 [N = 142, mDoT 22 weeks], and Dreyling et al., Blood. 2017 [N = 142, mDoT 26 weeks]) or the SAS for IDELA‐treated pts with R/R iNHL or CLL (N = 261, mDOT 28.1 weeks) and TEAEs reported for DUVA‐treated pts with hematologic malignancies (Copiktra™ USPI, N = 442, mDOT 39.1 weeks), we compared the incidence of all grade (aGr), grade 3/4 (Gr3/4, for IDELA vs. COPA) or grade ≥3 (Gr≥3, for IDELA vs. DUVA) TEAEs and the effect of preexisting comorbidities on selected IDELA‐mediated AEs. TEAE incidences were compared by estimating the difference in proportions with p‐values based on Fisher's exact test.Results:IDELA‐treated pts demonstrated significantly increased incidences of aGr and Gr3/4 AST and ALT elevation and diarrhea compared to COPA‐treated pts. In contrast, COPA‐treated pts showed significantly increased aGr and Gr3/4 hyperglycemia and hypertension relative to IDELA (Table 1A). IDELA‐treated pts experienced significantly more Gr≥3, but not aGr, AST and ALT elevation than DUVA‐treated pts. DUVA‐treated pts experienced significantly higher aGr and Gr≥3 diarrhea + colitis, lower respiratory tract infection, anemia, and neutropenia; aGr mucositis, musculoskeletal pain, and thrombocytopenia; and Gr≥3 rash and fatigue than IDELA‐treated pts (Table 1B).We evaluated the effect of co‐morbidities in IDELA‐treated patients on emergence of Gr3/4 or Gr≥3 TEAEs observed more commonly in COPA‐treated (hyperglycemia and hypertension) and DUVA‐treated (diarrhea + colitis and rash) pts, respectively. IDELA‐treated pts with pre‐existing diabetes mellitus or hyperglycemia experienced more Gr3/4 hyperglycemia; however, pre‐existing hypertension had no impact on the frequency of aGr or Gr3/4 hypertension seen with IDELA. Concomitant systemic steroids also did not increase hyperglycemia or hypertension in IDELA‐treated pts. A history of or predisposition to diarrhea did not increase the incidence of diarrhea + colitis and a history of rash or eczema did not increase rash in IDELA‐treated pts.Summary/Conclusion:Although the approved PI3Kδ inhibitors may be perceived to be associated with synonymous AE profiles (“class effect”), this intra‐class comparison highlights specific AE risks associated with each compound. The potential emergence of specific AEs associated with each agent should be considered when selecting a PI3Kδ inhibitor, though drug exposure differences and major limitations of cross‐trial comparisons should be noted.image

PURPOSEA randomized, double-blind, phase III study of idelalisib (IDELA) plus rituximab versus placebo plus rituximab in patients with relapsed chronic lymphocytic leukemia (CLL) was terminated early because of superior efficacy of the IDELA-plus-rituximab (IDELA/R) arm. Patients in either arm could then enroll in an extension study to receive IDELA monotherapy. Here, we report the long-term efficacy and safety data for IDELA-treated patients across the primary and extension studies.PATIENTS AND METHODSPatients were randomly assigned to receive rituximab in combination with either IDELA 150 mg twice daily (IDELA/R; n = 110) or placebo (placebo/R; n = 110). Key end points were progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and safety.RESULTSThe long-term efficacy and safety of treatment with IDELA was assessed in 110 patients who received at least one dose of IDELA in the primary study, 75 of whom enrolled in the extension study. The IDELA/R-to-IDELA group had a median PFS of 20.3 months (95% CI, 17.3 to 26.3 months) after a median follow-up time of 18 months (range, 0.3 to 67.6 months). The ORR was 85.5% (94 of 110 patients; n = 1 complete response). The median OS was 40.6 months (95% CI, 28.5 to 57.3 months) and 34.6 months (95% CI, 16.0 months to not reached) for patients randomly assigned to the IDELA/R and placebo/R groups, respectively. Prolonged exposure to IDELA increased the incidence of all-grade, grade 2, and grade 3 or greater diarrhea (46.4%, 17.3%, and 16.4%, respectively), all-grade and grade 3 or greater colitis (10.9% and 8.2%, respectively) and all-grade and grade 3 or greater pneumonitis (10.0% and 6.4%, respectively) but did not increase the incidence of elevated hepatic aminotransferases.CONCLUSIONIDELA improved PFS and OS compared with rituximab alone in patients with relapsed CLL. Long-term IDELA was effective and had an expected safety profile. No new IDELA-related adverse events were identified with longer exposure.

Real-Word Clinical Management of Patients Treated with Idelalisib in France: A Study of 529 Cases of Chronic Lymphocytic Leukemia (CLL) and Follicular Lymphoma (FL)

Idelalisib Plus Anti-CD20 Used Second Line Shows Improved PFS and Comparable Safety Compared to Later Line Therapy of Relapsed CLL

Risk Model for Overall Survival for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Validated for Patients on Ibrutinib, Idelalisib, Venetoclax, or Chemoimmunotherapy