Inhibitor Idelalisib Research Articles

Systematic Literature Review of the Clinical Efficacy, Safety, and Patient-Reported Outcomes of Treatments in Patients with Relapsed or Refractory Follicular Lymphoma after Two Prior Therapies

Introduction For patients (pts) with relapsed or refractory follicular lymphoma (r/r FL) beyond front-line therapy, there is no well-defined standard of care (SOC) treatment, especially in the third-line or later (3L+) setting. Treatment decisions for symptomatic patients depend on comorbidities, extent of disease, lines of prior therapy and duration of response to initial anti-CD20 containing treatment. Treatment options for 3L+ may include similar options to the ones in earlier lines, with a preference for non-cross-resistant schemes. Recently, a plethora of new compounds are being studied in clinical trials. A systematic literature review (SLR) was conducted to identify relevant evidence on clinical outcomes in pts with r/r FL, including conventional treatments and emerging compounds, within the 3L+ setting. Methods We performed a SLR on March 17, 2020. Clinical trials and observational studies were searched through Embase, PubMed, and Cochrane Central Register of Controlled Clinical Trials from 1998 to 2020, followed by relevant conference proceedings and regulatory documents. Evidence assessing any intervention as 3L+ FL and published in English language was included. If a study included broader indolent non-Hodgkin's lymphoma (iNHL) pts, only FL data was reported; if a study included pts with fewer than 3L+, 3L+ data was included, with mixed line results excluded. Conventional treatments, defined as approved or clinical guideline recommended treatments, included anti-CD20 monoclonal antibody (mAb)-containing regimen, mAb alone, chemotherapy alone, phosphatidylinositol 3-kinase (PI3K) inhibitors (idelalisib, copanlisib, duvelisib), lenalidomide + rituximab (R2), radio-immunotherapy (RIT) with yttrium-90 (90Y) ibritumomab tiuxetan, tazemetostat, autologous and allogeneic stem cell transplantation (auto- and allo-SCT). Emerging compounds included new treatments that are not approved but were tested in the context of clinical trials (bruton tyrosine kinase inhibitors, bortezomib, polatuzumab vedotin, daratumumab, inotuzumab, bi-specific T-cell engaging CD19 mAb, anti-CD19 chimeric antigen receptor T-cell [CAR-T] therapy). Results Of the 3747 publications identified, 74 studies assessing 26 treatment regimens, including conventional ones like rituximab (R)-containing immunochemotherapy to emerging compounds such as CAR-T therapies, were selected. Across the conventional regimens, 7 studies reported clinical trial data with relatively large 3L+ FL populations (Table 1). With R monotherapy, PI3K inhibitors and tazemetostat, the reported complete response (CR) rates and overall response rates (ORR) ranged from 1-20% and 34-77%, while median duration of response (mDOR) ranged between 7.9-16.3 months. Three clinical trials with PI3K inhibitors reported proportions of pts achieving a response of at least 6 months in duration ranging from 18-30%; median progression-free survival (mPFS) ranging from 8.3-11.2 months. For tazemetostat, mPFS was 11.0 months in EZH2 mutant vs 5.7 months in wild-type FL. With allo-SCT, 2-yr PFS rate was 88% and 57% for pts with CR and PR, respectively. Overall survival (OS) data varied: median overall survival (mOS) was 28-38 months for PI3K inhibitors while mOS was up to 85 months after allo-SCT, despite high non-relapse mortality (NRM) rates with most common causes of death being graft-versus-host disease (GvHD) and infections. Safety profiles were also different across treatments, with most common side effects being hepatotoxicity, diarrhea and infections (PI3K inhibitors) to GvHD (allo-SCT). Three trials presented patient-reported outcomes (PRO) data, all using the Functional Assessment of Cancer Therapy (FACT) questionnaire. Two studies with PI3K inhibitors demonstrated favorable or clinically significant improvement on pts quality of life (QoL), but 1 allo-SCT trial did not show a significant difference between baseline and 2 years post-transplant scores. Conclusion To our knowledge, this is the first SLR focusing on 3L+ treatments of FL. Heterogeneity in study design, patient population, safety profile and reported outcomes make it challenging to identify an optimal treatment regimen for FL in the 3L+ setting. More PRO data are needed considering the important role pt QoL plays in treatment selection. Disclosures Ma: Novartis:Current Employment.Kaur:Novartis:Current Employment.Zhao:Novartis:Current Employment.Zhang:Novartis:Current Employment.Ramos:Novartis:Current Employment.Kumar:Novartis:Current Employment.John:Novartis:Current Employment.Bubuteishvili Pacaud:Novartis:Current Employment.Forcina:Novartis:Current Employment.

Infection Risk in Lymphoproliferative Diseases (LPD) Treated with Targeted Drugs. Geltamo Real-Life Experience

Introduction:Recently there has been a renewal of therapeutic tools for the treatment of lymphoid neoplasms to increase the antitumor efficacy and reduce the toxicity generated by conventional chemotherapies, which adds to the intrinsic immunological dysfunction of the disease itself. To date, few data are published about infection risk of these new drugs, and the need for infectious prophylaxis is unknown. The aim of the study is to analyze the infectious complications in patients with LPD treated with monoclonal antibodies (obinutuzumab, ofatumumab, brentuximab, nivolumab and pembrolizumab), BTK inhibitors (ibrutinib, acalabrutinib) and PI3K inhibitors (idelalisib). Methods: Multicenter retrospective study in patients with LPD treated with targeted therapies (single agents or combination) in 18 Hematology centers in Spain, from the time of their commercial availability to March 2020. Patients in clinical trials were excluded as well as patients with active infections at the beginning of treatment. Results:During the study period, 380 patients were included.Baseline characteristics of the entire cohort are shown in Table 1.Median follow-up was 17.3 months (range 0-103), the longest follow-up corresponding to CLL patients (24 months, range 0-98) and the shortest to LBCL (5 months, range 0-25). Median exposure to target drugs was 8 months (range 0-72).Ibrutinib was administered to 219 patients(1 FL, 147 CLL, 27 MCL, 10 DLBCL, 1 TL and 32 WM, 1 HL),Brentuximab to 49(31 HL, 14 TL and 4 DLBCL) andIdelalisibto 35 patients (16 affected by chronic lymphocytic leukemia - CLL, 15 FL and 1 DLBCL, 1 WM, 1MCL, 1HL).Obinutuzumabcombinations were used in 10 (6 CLL, 3 FL, 1 MCL) and 5 HL patients (of which 4/5 underwent previous BMT) receivedNivolumab. A total number of 237 infectious events occurred in 148/380 patients (38.9%), 39% of which were grade 3 and 54/148 (36.4%) experienced 2 or more infective episodes: of those 54, 21 (38%) had underwent 3 or more lines of therapy and 28 (51%) had hypogammaglobulinemia. Hospitalization was required in 59.2% events. A bacterial cause of infection was reported in 40% of cases, and viral in 16%, including 11/237 (4,6%) SARS-CoV-2 infection. Invasive fungal infection (IFI) occurred in 3.3% (8/237). Noteworthy, no case of PJP was identified. Lung was the most frequent site of infection in 24% of cases (57/237) while the upper respiratory tract was involved in 17% of events (41/237). Urinary tract infections were diagnosed in 10% (24/237). Other sites involved were skin and soft tissue 7%, gastrointestinal tract 5,4%, bloodstream infections 3% and catheter related infections 2,5%. Considering drugs individually, 86 patients that receivedIbrutinib(39.2 %)experienced a total of 137 infectious episodes: 30% bacterial, 19% viral, 5% fungal and 45% clinical and image-based infections; the 17(34.6%of those who received Brentuximab, experienced a total of 16 infectious episodes: 56% bacterial, 37.5% viral infections and one catheter-related sepsis. Of those who receivedIdelalisib,18 (51.4%)experienced a total of 28 episodes: 42% bacterial, 14% viral and 7% fungal. Four patients treated withObinutuzumabcombinations (40%) experienced one infection during treatment (25% bacterial and 75% viral). Only one patient treated withNivolumabexperienced more than three infections, he was also under corticosteroid treatment. Focusing on IFI (Table 2): 7/8 infections were identified in CLL patients, 6 out 7 being on ibrutinib treatment and 1/7 on Idelalisib.Aspergilluswas the fungus most frequently isolated. The targeted drug was discontinued temporarily in 4 patients and indefinitely in 3. Twenty three (6%) patients died due to infection in our series. Conclusions: 1. We identified 38.7% infections in our LPD patients treated with targeted drugs, with a median drug-exposure time of 8 months (range 0-72), with a non-negligible incidence of bacterial infections. 2. The highest rates of infection were found in patients treated with with Idelalisib and Ibrutinib (51.4% and 39.2% respectively). 3. IFI (3.3%) occurred with low frequency, mostly in CLL patients during ibrutinib treatment, leading to its temporal discontinuation in most of the cases. 4. No case of PJP was identified in our cohort. 5. An analysis to determine risk factors for infection and the optimal monitoring and prophylaxis for these patients is ongoing. Disclosures Hernandez-Rivas: Janssen:Membership on an entity's Board of Directors or advisory committees;Abbvie:Membership on an entity's Board of Directors or advisory committees;Roche:Membership on an entity's Board of Directors or advisory committees;AstraZeneca:Membership on an entity's Board of Directors or advisory committees;Gilead:Membership on an entity's Board of Directors or advisory committees;Celgene/BMS:Membership on an entity's Board of Directors or advisory committees;Rovi:Membership on an entity's Board of Directors or advisory committees.Lopez-Guillermo:novartis:Consultancy;celgene:Consultancy, Research Funding;roche:Consultancy, Research Funding;gilead:Consultancy, Research Funding.

Combined Genetic Lesions in TP53 and CDKN2A/CDKN2B Drive B Cell Receptor-Dependent/Costimulatory Signal-Independent Proliferation in Richter Syndrome

B cell receptor (BCR) signals play a critical role in the pathogenesis of chronic lymphocytic leukemia (CLL), but their role in regulating CLL cell proliferation has still not been firmly established. Unlike normal B cells, CLL cells do not proliferate in vitro upon engagement of the BCR, suggesting that CLL cell proliferation is regulated by other signals from the microenvironment, such as those provided by Toll-like receptor (TLR) ligands or T cells. However, the rapid reduction in the percentage of proliferating CLL cells in patients treated with a BTK or SYK inhibitor suggests that the BCR may be more directly involved, at least in a subset of cases. To further address this issue, we investigated the expression of cell cycle regulatory proteins in human and Eμ-TCL1-derived murine CLL cells stimulated with immobilized anti-IgM or cognate antigen, respectively. In both cases, BCR stimulation induced the expression of the positive cell cycle regulators MYC, CCND1, CCND2 and CDK4, consistent with G1 cell cycle entry, but also induced the expression of the negative regulators CDKN1A, CDKN2A and CDKN2B, which block cell cycle progression. Since combined deficiency of these negative regulators occurs in approximately one quarter of Richter syndrome cases because of deletion of the CDKN2A/CDKN2B locus and inactivating genetic lesions of the CDKN1A regulator TP53, we introduced these defects by CRISPR/Cas9 in autoreactive murine Eμ-TCL1 leukemia cells and investigated the effects on leukemia behavior. Adoptive transfer experiments showed that combined targeting of TP53, CDKN2A and CDKN2B results in accelerated leukemia growth and morphological changes consistent with Richter's transformation, including more diffuse infiltration, larger and more pleomorphic cells, and a higher proliferation rate. Moreover, in vitro experiments showed that cells with combined TP53/CDKN2A/2B deficiency had acquired the capacity for spontaneous proliferation, in contrast to control, TP53- or CDKN2A/2B-targeted cells which died after a couple of weeks in culture. Nucleotide sequencing of the TP53/CDKN2A/2B-targeted cells showed complete disappearance of the wild type alleles, suggesting that biallelic loss of all three genes is required for spontaneous growth in vitro. Combined disruption of TP53, CDKN2A and CDKN2B in two other autoreactive Eμ-TCL1 leukemias yielded the same results. To determine whether the spontaneous in vitro proliferation is dependent on BCR signals, the TP53/CDKN2A/2B-deficient cells were transfected with Cas9 ribonucleoprotein complexes targeting the IgM heavy chain constant region (IGHM) gene or were treated with the BCR inhibitors ibrutinib, idelalisib and fostamatinib. Disruption of the IGHM gene or treatment with a BCR inhibitor resulted in almost complete block of proliferation. In contrast, knockdown of the TLR-adaptor protein MyD88 had no effect. Considering that T cells were not present in the culture conditions, these experiments establish that proliferation of Eμ-TCL1 leukemia cells with biallelic TP53/CDKN2A/2B disruption is BCR-dependent but independent of costimulatory signals. To validate these findings in a human setting, we performed experiments with two recently established Richter syndrome patient-derived xenografts, one with biallelic inactivation/deletion of TP53, CDKN2A and CDKN2B (RS9737), and one with wild type TP53, CDKN2A and CDKN2B (RS1316). BrdU incorporation experiments showed that only RS9737 cells proliferate in vitro following BCR stimulation, whereas both RS9737 and RS1316 cells proliferate following stimulation with CpG + IL-15 or CD40L + IL-4 + IL-21. Finally, we tested the activity of combined treatment with a BCR inhibitor and the CDK4/6 inhibitor palbociclib against the murine and human TP53/CDKN2A/2B-deficient Richter syndrome models. Combined treatment showed synergistic activity in vitro and significantly prolonged mouse survival in vivo compared to single agent treatment (n = 10 mice/group, P<0.001). In conclusion, these data provide evidence that BCR signals are directly involved in regulating CLL cell proliferation and suggest that frequently co-occurring genetic lesions in TP53 and CDKN2A/2B contribute to Richter transformation by allowing for BCR dependent/costimulatory signal independent proliferation, which can be therapeutically targeted with a BCR and CDK4/6 inhibitor combination. Disclosures Deaglio: Verastem: Research Funding; Heidelberg Pharma: Research Funding. Laurenti:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees. Efremov:Janssen-Cilag International: Speakers Bureau.

Efficacy of Idelalisib and Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Treated Outside of Clinical Trial. a Report of the Gimema Group

Efficacy of Idelalisib and Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Treated Outside of Clinical Trial. a Report of the Gimema Group

Tazemetostat Is Associated with Lower Risk for Safety Outcomes Versus the PI3-Kinases Idelalisib, Duvelisib and Copanlisib, in Patients with Relapsed/Refractory Follicular Lymphoma Who Have Received at Least 2 Prior Systemic Treatments: A Matching-Adjusted Indirect Comparison of Single-Arm Trials

Background: Tazemetostat, a first-in-class, oral enhancer of zeste homolog 2 (EZH2) inhibitor was recently approved by the US Food and Drug Administration in patients with relapsed/refractory (R/R) follicular lymphoma (FL) after demonstrating single-agent, antitumor activity in patients with wild-type (WT) or mutant (MT) EZH2. The PI3K inhibitors idelalisib, duvelisib, and copanlisib are indicated for third-line or later (3L+) treatment of R/R FL, but they are associated with safety concerns, and clinical studies with these agents did not include grade 3B or transformed FL. However, tazemetostat idelalisib, duvelisib, and copanlisib were all approved based on single-arm studies and have not been compared in head-to-head randomized trials for the treatment of 3L+ R/R FL. Here, we present an indirect treatment comparison (ITC) of tazemetostat with idelalisib, duvelisib, and copanlisib for the treatment of 3L+ R/R FL. Methods: A systematic literature review identified clinical trial publications for idelalisib (DELTA), duvelisib (DYNAMO), and copanlisib (CHRONOS-1 Part B) for use in an ITC with tazemetostat for 3L+ treatment of R/R FL. Matching-adjusted indirect comparison (MAIC) methodology was selected as all comparator trials were single-arm and individual patient data (IPD) were available for the tazemetostat E7438-G000-101 trial (n=99). Three MAIC analyses were conducted by weighting individual patients treated with tazemetostat to baseline characteristics reported from each comparator trial. FL subpopulation baseline characteristics and outcomes data were available for matching idelalisib (n=72); full trial mixed-NHL populations were reported for duvelisib (n=129, 64% FL) and copanlisib (n=142, 73% FL). Baseline characteristics for matching-adjustment were chosen using clinical advice, an evaluation of prognostic factors associated with outcomes, and published data availability. Characteristics included: age, ECOG performance status, disease stage, histology (tumor grade, transformed FL), number of prior lines of treatment, prior stem cell therapy, and refractory status (to last therapy). Only the tazemetostat trial included patients with grade 3b or transformed FL, or recorded EZH2 mutation status. Safety and efficacy outcome definitions were similar across trials. Primary safety outcomes included risk of any grade ≥3 treatment-emergent adverse event (TEAE), any treatment-emergent serious adverse event (TESAE), and TEAEs leading to dose reduction, drug discontinuation, or interruption. The primary efficacy outcome was objective response rate (ORR), reported across all trials. Rates of individual grade ≥3 TEAEs also were compared. Limitations of such indirect methods include inability to account for any unmeasured covariates that may be effect modifiers, and reductions in the effective sample size. Results: After matching, all baseline characteristics were successfully balanced. Matched patients treated with tazemetostat had lower relative risk for all safety outcomes compared with all treatments, including any grade ≥3 TEAE (vs idelalisib: RR=0.45; vs duvelisib: RR=0.35; vs copanlisib: RR=0.37; all, P<0.001), any TESAE, and any TEAE leading to dose reduction, drug discontinuation, or interruption. These results were statistically significant (where comparator data were reported) for all but 2 safety outcomes (Figure). Several grade ≥3 TEAEs occurred at a significantly lower incidence with tazemetostat compared with matched patients treated with idelalisib, duvelisib, or copanlisib, including neutropenia (vs idelalisib: 3% vs 22%; vs duvelisib: 3% vs 25%; vs copanlisib: 4% vs 24%; all, P<0.05). The ORR was similar after matching for tazemetostat versus all treatments, with no statistically significant difference between therapies (vs idelalisib: 43% vs 56%, P=0.16; vs duvelisib: 48% vs 47%, P=0.91; vs copanlisib: 49% vs 61%, P=0.11). Conclusion: More tolerable treatment options are needed for 3L+ treatment of R/R FL because patients in this setting are often elderly and have exhausted multiple prior lines of treatment. Results from this ITC indicate that, after adjusting for baseline population differences, tazemetostat addresses this unmet need, as it is associated with lower relative risk for safety outcomes versus idelalisib, duvelisib, or copanlisib while achieving similar efficacy outcomes. Disclosures Proudman: Analysis Group, Inc.: Consultancy. Nellesen:Analysis Group, Inc.: Consultancy. Gupta:Analysis Group, Inc.: Consultancy. Adib:Epizyme, Inc.: Consultancy; Alacrita: Current Employment. Yang:Epizyme, Inc.: Current Employment. Keith:Epizyme: Current Employment, Current equity holder in publicly-traded company. Mamlouk:Epizyme: Current Employment, Current equity holder in publicly-traded company.

Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancies.

The approval of BTK and PI3K inhibitors (ibrutinib, idelalisib) represents a revolution in the therapy of B cell malignancies such as chronic lymphocytic leukemia (CLL), mantle-cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), or Waldenström’s macroglobulinemia (WM). However, these “BCR inhibitors” function by interfering with B cell pathophysiology in a more complex way than anticipated, and resistance develops through multiple mechanisms. In ibrutinib treated patients, the most commonly described resistance-mechanism is a mutation in BTK itself, which prevents the covalent binding of ibrutinib, or a mutation in PLCG2, which acts to bypass the dependency on BTK at the BCR signalosome. However, additional genetic aberrations leading to resistance are being described (such as mutations in the CARD11, CCND1, BIRC3, TRAF2, TRAF3, TNFAIP3, loss of chromosomal region 6q or 8p, a gain of Toll-like receptor (TLR)/MYD88 signaling or gain of 2p chromosomal region). Furthermore, relative resistance to BTK inhibitors can be caused by non-genetic adaptive mechanisms leading to compensatory pro-survival pathway activation. For instance, PI3K/mTOR/Akt, NFkB and MAPK activation, BCL2, MYC, and XPO1 upregulation or PTEN downregulation lead to B cell survival despite BTK inhibition. Resistance could also arise from activating microenvironmental pathways such as chemokine or integrin signaling via CXCR4 or VLA4 upregulation, respectively. Defining these compensatory pro-survival mechanisms can help to develop novel therapeutic combinations of BTK inhibitors with other inhibitors (such as BH3-mimetic venetoclax, XPO1 inhibitor selinexor, mTOR, or MEK inhibitors). The mechanisms of resistance to PI3K inhibitors remain relatively unclear, but some studies point to MAPK signaling upregulation via both genetic and non-genetic changes, which could be co-targeted therapeutically. Alternatively, drugs mimicking the BTK/PI3K inhibition effect can be used to prevent adhesion and/or malignant B cell migration (chemokine and integrin inhibitors) or to block the pro-proliferative T cell signals in the microenvironment (such as IL4/STAT signaling inhibitors). Here we review the genetic and non-genetic mechanisms of resistance and adaptation to the first generation of BTK and PI3K inhibitors (ibrutinib and idelalisib, respectively), and discuss possible combinatorial therapeutic strategies to overcome resistance or to increase clinical efficacy.

Abstract 4439: BR101801 triggers anti-tumor immunity and enhances efficacy of immune checkpoint antibodies in syngeneic model

Abstract Introduction: BR101801 received U.S. FDA approval of Phase Ia/Ib clinical trial as an anti-cancer drug candidate. PI3K γ / δ and DNA-PK inhibitory potency of BR101801 exerts anti-cancer efficacy as a target anticancer agent in hematologic malignancies. Recent studies have reported anti-cancer immunity by use of PI3K-δ inhibitor (Idelalisib), PI3K-γ inhibitor (IPI-549) and DNA-PK inhibitor (NU7441). Considering triple inhibitory activity of the BR101801. First, we investigated the anti-cancer efficacy of monotherapy by BR101801 in syngeneic model. Second, synergistic efficacy was confirmed through the combination of BR101801 with anti-PD1 or anti-PDL1, which are known as anti-tumor immunotherapeutics. Finally, immune cell response by BR101801 in human PBMC was tested. Overall, This study aims to demonstrate efficacy of the BR101801 as a potent immunocancer drug. Methods: The enzymatic potency of the PI3K isotype and DNA-PK was analyzed by Eurofin. Proliferation of 4T1(breast cancer) and CT26(colon cancer) cells following a 4 h treatment with the indicated BR101801, WST-8 staining after 72 h culture. Mice bearing syngeneic 4T1 or CT-26 cell lines were treated with vehicle, BR101801, anti-PD1, anti-PD1 + BR101801, anti-PDL1, anti-PDL1 + BR101801. Tumor volumes were measured by caliper. Tregs and CD8+ T cells were quantified by flow cytometry from mice bearing spleen. In addition, CD3 + cells were isolated from human PBMCs and stimulated with CD3/CD28 and analyzed for immunofluorescence by FACS for expression of PD-1, TIM3, LAG3 and TIGIT in Tregs and CD8. Results: In vitro selectivity and target potency of BR101801 on different PI3K subtypes including DNA-PK were studied in cell-free system. The biochemical IC50 values of BR101801 for PI3K-α, -β, -γ, -δ and DNA-PK were 106 nM, 171 nM, 15 nM, 2 nM and 6 nM. 50% growth inhibition in 4T1 and CT26 cell lines was measured above 10 uM. BR101801 showed tumor inhibitor efficacy in 4T1 and CT26 syngeneic models. In 4T1 or CT-26 bearing mouse spleens, Tregs decreased and CD8 + T cells increased. Strong anti-tumor efficacy was observed with about 70% reduction in tumor growth when using BR101801 with anti-PD1 or anti-PDL1 in 4T1 and CT26 syngeneic models. Finally, Tregs decreased and anticancer effects were increased by decreasing the expression of PD1, LAG3, TIM3 and TIGIT of CD8+ T cells. Conclusions: The immunosuppressive effect of BR101801 changing the tumor microenvironment was verified without cancer cells. It is demonstrated that anticancer immunity by decreasing Tregs and increasing CD8. Anti-tumor immunity was enhanced by decreasing the expression of PD1, TIM3, LAG3 and TIGIT in CD8 + cells. In this study, In addition to monotherapy of BR101801, It's synergistic effects with PD-1 or PDL1 have been proposed. This data supports the evidence that it is applicable not only to blood cancer but also to various cancer patients. Citation Format: Seungho Wang, Mi kwon Son, Bo Ram Lee, Byeongwook Jeon, Soo Jung Kim, Eunhui Yang, Min Park, Joo Han Lee, Jayhyuk Myung. BR101801 triggers anti-tumor immunity and enhances efficacy of immune checkpoint antibodies in syngeneic model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4439.

Combination of the PI3K inhibitor Idelalisib with the conventional cytostatics cytarabine and dexamethasone leads to changes in pathway activation that induce anti-proliferative effects in B lymphoblastic leukaemia cell lines

BackgroundThe introduction of combined conventional cytostatics and pathway-specific inhibitors has opened new treatment options for several cancer types including hematologic neoplasia such as leukaemias. As the detailed understanding of the combination-induced molecular effects is often lacking, the identification of combination-induced molecular mechanisms bears significant value for the further development of interventional approaches.MethodsCombined application of conventional cytostatic agents (cytarabine and dexamethasone) with the PI3K-inhibitor Idelalisib was analysed on cell-biologic parameters in two acute pro-B lymphoblastic leukaemia (B-ALL) cell lines. In particular, for comparative characterisation of the molecular signatures induced by the combined and mono application, whole transcriptome sequencing was performed. Emphasis was placed on pathways and genes exclusively regulated by drug combinations.ResultsIdelalisib + cytostatics combinations changed pathway activation for, e.g., “Retinoblastoma in cancer”, “TGF-b signalling”, “Cell cycle” and “DNA-damage response” to a greater extent than the two cytostatics alone. Analyses of the top-20 regulated genes revealed that both combinations induce characteristic gene expression changes.ConclusionA specific set of genes was exclusively deregulated by the drug combinations, matching the combination-specific anti-proliferative cell-biologic effects. The addition of Idelalisib suggests minor synergistic effects which are rather to be classified as additive.

Current diagnosis and treatment of chronic lymphocytic leukaemia

Two major advances were made in the treatment of chronic lymphocytic leukaemia (CLL): the addition of the antibody rituximab to chemotherapy two decades ago and the introduction of the targeted agents during the last few years. Four targeted drugs with different mechanisms of action were added to the armamentarium of CLL treatment: the anti-CD20 antibody obinutuzumab, the two kinase inhibitors ibrutinib and idelalisib, which target the Bruton tyrosine kinase (BTK) and Phosphatidylinositiol-3-Kinase (PI3K) respectively in the B-cell receptor signalling pathway, as well as the Bcl2-antagonist venetoclax.Recently, the combination of venetoclax/obinutuzumab was approved for the first-line treatment of all CLL patients based on a phase-III trial in elderly unfit patients. This combination was shown to be clearly superior to chlorambucil/obinutuzumab and should become the preferred first-line treatment for the so called "slow-go" patients. Other options for these elderly, unfit patients are continuous ibrutinib or chlorambucil/obinutuzumab. Although data from phase-III studies are not yet available, venetoclax/obintuzumab may also be offered to younger, fit patients. Established therapeutic options for these so called "go go" patients are ibrutinib, fludarabin/cyclophosphamide/rituximab or bendemustine/rituximab (if > 65 years). Patients with the high-risk parameters deletion 17p or TP53mutation are known to poorly respond to chemo(immuno)therapy and should receive either ibrutinib or venetoclax/obinutuzumab.Thus, a choice has to be made between a continuous monotherapy with ibrutinib or a time-limited combination with either venetoclax/obinutuzumab (12 months) or chemoimmunotherapy (usually 6 months). In addition to disease-related factors (e. g. presence of deletion 17p/TP53 mutation, IgHV mutational status, prior therapies), comorbidities, co-medication and the specific side effects of the CLL therapies (myelosuppression, infections and secondary malignancies for chemoimmunotherapy; cardiac toxicity, bleeding and autoimmune disease for ibrutinib; tumour-lysis syndromes and infections for venetoclax) the patient's expectations need to be considered.

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

AbstractThe 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.

Aspartic Aminopeptidase Is a Novel Biomarker of Aggressive Chronic Lymphocytic Leukemia.

Treatment of chronic lymphocytic leukemia has advanced substantially as our understanding of the kinase signal transduction pathways driven by the B cell receptor (BcR) has developed. Particularly, understanding the role of Bruton tyrosine kinase and phosphatidyl inositol 3 kinase delta in driving prosurvival signal transduction in chronic lymphocytic leukemia (CLL) cells and their targeting with pharmacological inhibitors (ibrutinib and idelalisib, respectively) has improved patient outcomes significantly. The kinase signaling pathway induced by the BcR is highly complex and has multiple interconnecting branches mediated by tyrosine and serine/threonine kinases activated downstream of the BcR. There is a high level of redundancy in the biological responses, with several BcR-signaling kinases driving nuclear factor kappa B activation or inducing antiapoptotic Bcl-2 genes. Accordingly, common gene targets of BcR-signaling kinases may serve as biomarkers indicating enhanced BCR-signaling and aggressive disease progression. This study used a gene expression correlation analysis of malignant B cell lines and primary CLL cells to identify genes whose expression correlated with BCR-signaling kinases overexpressed and/or overactivated in CLL, namely: AKT1, AKT2, BTK, MAPK1, MAPK3, PI3KCD and ZAP70. The analysis identified a 32-gene signature with a strong prognostic potential and DNPEP, the gene coding for aspartic aminopeptidase, as a predictor of aggressive CLL. DNPEP gene expression correlated with MAPK3, PI3KCD, and ZAP70 expression and, in the primary CLL test dataset, showed a strong prognostic potential. The inhibition of DNPEP with a pharmacological inhibitor enhanced the cytotoxic potential of idelalisib and ibrutinib, indicating a biological functionality of DNPEP in CLL. DNPEP, as an aminopeptidase, contributes to the maintenance of the free amino acid pool in CLL cells found to be an essential process for the survival of many cancer cell types, and thus, these results warrant further research into the exploitation of aminopeptidase inhibitors in the treatment of drug-resistant CLL.

Inhibition of PI3K by copanlisib exerts potent antitumor effects on Merkel cell carcinoma cell lines and mouse xenografts

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer with steadily increasing incidence and poor prognosis. Despite recent success with immunotherapy, 50% of patients still succumb to their diseases. To date, there is no Food and Drug Administration-approved targeted therapy for advanced MCC. Aberrant activation of phosphatidylinositide-3-kinase (PI3K)/AKT/mTOR pathway is frequently detected in MCC, making it an attractive therapeutic target. We previously found PI3K pathway activation in human MCC cell lines and tumors and demonstrated complete clinical response in a Stage IV MCC patient treated with PI3K inhibitor idelalisib. Here, we found that both PI3K-α and -δ isoforms are abundantly expressed in our MCC cell lines and clinical samples; we therefore examined antitumor efficacy across a panel of five PI3K inhibitors with distinctive isoform-specificities, including idelalisib (PI3K-δ), copanlisib (PI3K-α/δ), duvelisib (PI3K-γ/δ), alpelisib (PI3K-α), and AZD8186 (PI3K-β/δ). Of these, copanlisib exerts the most potent antitumor effects, markedly inhibiting cell proliferation, survival, and tumor growth by suppressing PI3K/mTOR/Akt activities in mouse models generated from MCC cell xenografts and patient-derived tumor xenografts. These results provide compelling preclinical evidence for application of copanlisib in advanced MCC with aberrant PI3K activation for which immunotherapy is insufficient, or patients who are unsuitable for immunotherapy.

Novel approaches in marginal zone lymphoma: Systematic review.

e20089 Background: Marginal zone lymphoma represents no more than 17% of NHLs and there is no standard of care. We reviewed the efficacy of novel drugs with main focus on ORR and PFS/OS (when available). Methods: Literature search was performed based on PRISMA guidelines in PubMed, Cochrane, EMBASE, Clinicaltrials.gov. Studies which did not give separate results for MZL were excluded. Results: 23 trials (n = 1491 patients) were included. 57% were refractory to previous line of therapy. 9 studies were conducted specifically in MZL (n = 440). The most common intervention was Rituximab and its combinations. PFS and OS were inconsistently reported. 1. Monotherapy in untreated MZL: In a phase III study, ORR was reported at 82.8% vs 81.3% with PFS of 75% vs 78% at 3 years in Obinutuzumab vs Rituximab. In Phase II Ibritumumumab tiuxetan showed 100% ORR in 11 patients with 5-year PFS of 82%. Most common grade 3-4 AE were hematological. Lenalidomide was studied in 18 EMZL patients, with 60% being untreated. In this study, ORR was reported at 61% with CR 33%. 2. Combination therapy in untreated MZL: Lenalidomide+Rituximab showed 93% ORR and median PFS 59.8 months with manageable toxicities. Ibrutinib in combination with Rituximab and Lenalidomide produced ORR of 90% with CR 60%. The addition of Bendamustine to Rituximab showed ORR and CR of 91% and 73% with 3-year PFS of 93% in a study of only SMZL (n = 56). 3. Monotherapy in R/R MZL: Ibrutinib demonstrated ORR of 50%, 54% and 41% in EMZL, SMZL and NMZL, respectively with median PFS of 14.2 months. Less hematologic toxicity was seen in MZL patients receiving Ibrutinib monotherapy compared to other regimens. In 30 patients receiving Everolimus, ORR was reported at 25%. Bortezomib has significant activity in EMZL with ORR of 48%. PI3Kδ inhibitors Idelalisib, Copanlisib and Duvelisib showed clinical activity. Umbrelisib and Ofatumumab demonstrated ORR > 50%. Vorinostat demonstrated an ORR of 22%. 4. Combination therapy in R/R MZL: Rituximab+Lenalidomide had a higher ORR (39.4 vs. 14.1%) and higher PFS (58 vs. 36% at 2-year) compared to Rituximab monotherapy. Combination of Tirabrutinib and Entospletinib showed 20% ORR in a small group of MZL patients. Addition of Idelalisib to Tirabrutinib demonstrated ORR 40%. Ibrutinib and Venetoclax combination demonstrated ORR > 50%. Ublituximab and Umbralisib showed clinical activity. Conclusions: With expanding armamentarium of targeted agents, our review has demonstrated positive results especially in terms of ORR in patients with MZL. Further studies are required to explore the role of these drugs and their impact on survival.

Reaserch Advance on Inhibitor Targeting at the B-Cell Receptor Pathway in Chronic Lymphocytic Leukemia --Review

Abstract Disregulated BCR signaling pathway plays an important role in the occurence and progress of chronic lymphocytic leukemia (CLL). As key kinases of BCR pathway, the Bruton tyrosine kinase (BTK), phosphoinositide 3-kinase (PI3K) and spleen tyrosine kinase (SYK) have become the focus of CLL targeted therapy. Over the past decade, drugs targeting of BCR pathway for CLL treatment have been continuously developed, including BTK inhibitors, PI3K inhibitors and SYK inhibitors. To date, the BTK inhibitor Ibrutinib, PI3K inhibitors Idelalisib and Duvelisib have been approved for CLL treatment, and some novel inhibitors are still in clinical trials. These targeted drugs are much less toxic than chemoimmunotherapy and show better efficacy in certain high-risk patients such as del 17P. These inhibitors targeted BCR pathway are increasingly prominent in CLL treatment and gradually replace traditional chemoimmunotherapy.

Design, Synthesis, and Biological Evaluation of Quinazolin-4-one-Based Hydroxamic Acids as Dual PI3K/HDAC Inhibitors.

A series of quinazolin-4-one based hydroxamic acids was rationally designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating an HDAC pharmacophore into a PI3K inhibitor (Idelalisib) via an optimized linker. Several of these dual inhibitors were highly potent (IC50 < 10 nM) and selective against PI3Kγ, δ and HDAC6 enzymes and exhibited good antiproliferative activity against multiple cancer cell lines. The lead compound 48c, induced necrosis in several mutant and FLT3-resistant AML cell lines and primary blasts from AML patients, while showing no cytotoxicity against normal PBMCs, NIH3T3, and HEK293 cells. Target engagement of PI3Kδ and HDAC6 by 48c was demonstrated in MV411 cells using the cellular thermal shift assay (CETSA). Compound 48c showed good pharmacokinetics properties in mice via intraperitoneal (ip) administration and provides a means to examine the biological effects of inhibiting these two important enzymes with a single molecule, either in vitro or in vivo.

Management of psoriasis-like rash associated with idelalisib monotherapy in a patient with refractory follicular lymphoma: a\xa0case report

BackgroundFollicular lymphoma is an indolent non-Hodgkin lymphoma that is most commonly diagnosed in elderly individuals. The majority of patients with follicular lymphoma present with advanced disease. Despite the recent advances in treatment, there remains a substantial unmet need for effective treatments for patients with relapsed/refractory follicular lymphoma. The PI3Kδ inhibitor idelalisib was approved by the European Medicines Agency in 2014 as a monotherapy for the treatment of adult patients with follicular lymphoma that is refractory to two prior lines of treatment. Real-world evidence from patients with follicular lymphoma treated with idelalisib indicates its utility in these patients.Case presentationThis case report describes an 82-year-old, retired, white, female patient with refractory follicular lymphoma who achieved a partial response with idelalisib treatment. Despite experiencing two incidences of a psoriasis-like rash during idelalisib treatment that required effective management with topical steroids, the patient was able to restart treatment successfully and maintain a continued partial response.ConclusionsThe clinical relevance of the effective management of adverse events in this case demonstrates the opportunity to enable patients to remain on therapy, thereby maintaining long-term response and improving overall outcomes.

Structurally novel PI3Kδ/γ dual inhibitors characterized by a seven-membered spirocyclic spacer: The SARs investigation and PK evaluation

Herein, we communicate our recent medicinal chemistry efforts which have culminated in a series of PI3Kδ/γ dual inhibitors structurally featuring a seven-membered spirocyclic spacer. Compound 26, the most potent one among them, exhibited superior PI3Kδ inhibitory activity (IC50 = 1.0 nM) to that of the approved PI3Kδ inhibitor Idelalisib. Besides, it exerted remarkable anti-proliferative efficacy against human malignant B-cell line SU-DHL-6 with GI50 value of 33 nM. The biochemical assay against the other three class I PI3K isoforms identified compound 26 as a potent PI3Kδ/γ dual inhibitor with considerable selectivity over PI3Kα and PI3Kβ. In SU-DHL-6 cells, a dramatic down-regulation of PI3K signaling was observed following compound 26-treatment at the concentration as low as 10 nM. Inspiringly, the pharmacokinetic (PK) study in Sprague-Dawley (SD) rats revealed it was orally available with a favorable bioavailability (F = 87.5%). Overall, compound 26, a promising PI3Kδ/γ dual inhibitor, has the potential to emerge as a clinical candidate for the treatment of leukocyte-mediated malignancies after extensive functional investigation.

Hyperkeratotic Skin Adverse Events Induced by Anticancer Treatments: A Comprehensive Review.

Hyperkeratotic skin adverse events are a group of toxic effects, characterized by the disruption of epidermal homeostasis and interaction with keratinocyte proliferation/differentiation or keratinocyte survival, and frequently reported with systemic anticancer treatments. These types of reactions include hand-foot skin reaction or palmoplantar keratoderma, induced psoriasis, keratosis pilaris-like or pityriasis rubra pilaris-like rashes, Grover's disease, and contact hyperkeratosis. Cutaneous squamoproliferative lesions are also described because of the presence of abnormal keratinocyte proliferation. They are usually observed with tyrosine kinase inhibitors but have also been described in association with cytotoxic chemotherapeutic agents. Their pathogenesis is related mainly to the disruption of epidermal homeostasis and interaction with keratinocyte proliferation/differentiation or keratinocyte survival caused by anticancer treatment. Early recognition and adequate management are critical to prevent exacerbation of the lesions, to limit treatment interruption, and to minimize impairment of quality of life. This review summarizes the current knowledge concerning the presentation, pathogenesis, and management of secondary hyperkeratotic reactions to anticancer therapies. It also includes hyperkeratotic reactions that have been more recently described with newly approved targeted therapies or immune checkpoint inhibitors, such as keratosis pilaris-like exanthema with second-generation BCR-ABL inhibitors, lamellar ichthyosis-like lesions with ponatinib, pityriasis rubra pilaris with the newly approved selective phosphoinositide 3 kinase inhibitor idelalisib, or psoriasis with anti-programmed death-1 and programmed death ligand-1.

Homeostatic and pathogenic roles of PI3Kδ in the human immune system.

Phosphoinositide 3-kinase delta (PI3Kδ) mediates signaling transduction downstream of diverse immune receptors, including the T cell receptor (TCR), the B cell receptor (BCR), costimulatory molecules and cytokine receptors. Our understanding of the role of PI3Kδ in the immune system comes primarily from mice, and especially from the consequences of pharmacological inhibition of PI3Kδ in mouse models of human disease as well as the consequences of genetic manipulation, resulting in hyperactivation or loss of PI3Kδ function. In case of humans, in vitro studies with PI3Kδ-specific inhibitors, the consequences of treatment of hematologic malignancies with the PI3Kδ-specific inhibitor idelalisib and primary immunodeficiency disorders due to germline variants hyper- or underactivating PI3Kδ provide most of our knowledge on the role of PI3Kδ in immunity and immune regulation. In this review, we summarize the physiological and pathophysiological roles of PI3Kδ in the human immune system, focusing on immunodeficiency due to defects in PI3Kδ signaling and especially on the recently reported cases with mutations resulting in loss of PI3Kδ activity.

Enhanced Sensitivity of Idelalisib and Ibrutinib-Resistant Cell Lines to Anti-CD38 Antibodies

BCR pathway inhibitors idelalisib and ibrutinib were the first small molecule targeted agents for B-cell malignancies. In spite of encouraging response rates in various forms of B cell diseases, patients will eventually develop relapse due to the emergence of resistant cells. To better identify the possible mechanisms of resistance we developed and characterized idelalisib- and ibrutinib-resistant variants of the human non Hodgkin’s lymphoma cell lines DoHH2 and Daudi. These resistant variants displayed a cross-resistance profile limited to PI3K inhibitors, BTK inhibitors and a SYK inhibitor but not to unrelated agents. A number of alterations were observed in the resistant lines, including a strong reduction of BLINK and the AKT3. A new SNP in PLCgamma2 (Leu848Phe) closely related to a previously reported SNP associated to ibrutinib resistance (Leu845Phe) was observed in both DAUDI-based resistant cell lines but was absent in wild type cells. Resistant lines tended to express larger amounts of CD38 and were found to display enhanced sensitivity to anti-CD38 antibodies. These results identify potential novel mechanisms of resistance to idelalisib and ibrutinib and raise the possibility that cells resistant to BCR pathway inhibitors might possess enhanced sensitivity to anti-CD38 antibodies.