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Patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) whose treatment failed with a Bruton's tyrosine kinase inhibitor have poor outcomes. We investigated tafasitamab plus idelalisib (cohort A) or venetoclax (cohort B) in this patient population in a phase II study (NCT02639910). In total, 24 patients were enrolled (cohort A: n = 11, median time on study, 7.4 months; cohort B: n = 13, median time on study, 15.6 months). The most common treatment-emergent adverse event (TEAE) in cohort A was anemia (63.6%) and in cohort B was infusion-related reaction (53.8%). The most common severe TEAE was neutropenia (cohort A: 45.5%; cohort B: 46.2%). The best overall response rate was 90.9% (cohort A) and 76.9% (cohort B). Undetectable minimal residual disease in peripheral blood was achieved in 2/8 patients (cohort A) and 6/7 patients (cohort B). Overall, these results suggest that anti-CD19 antibody-based combinations may be important in the treatment of patients with CLL. [ABSTRACT FROM AUTHOR]

Idelalisib is associated with increased occurrence of immune-related adverse events (irAEs). Clinical observations suggest a correlation between immune checkpoint inhibitor–induced irAEs and survival outcomes in patients with solid tumors; however, this relationship in hematologic malignancies is not well understood. In a post hoc analysis of 3 registrational trials, we explored the relationship between Grade ≥3 diarrhea/colitis and alanine/aspartate transaminase (ALT/AST) elevation incidences and efficacy endpoints in patients with indolent non-Hodgkin lymphoma (iNHL), follicular lymphoma (FL), and chronic lymphocytic leukemia treated with idelalisib. Grade ≥3 diarrhea/colitis was associated with higher overall response rate (ORR) and longer progression-free survival (PFS) for all subgroups. Grade ≥3 ALT/AST elevations were associated with improved duration of response and overall survival for all subgroups and improved ORR and PFS for patients with FL or iNHL. Our analysis in hematologic malignancies showed a trend correlating idelalisib-induced Grade ≥3 irAEs with improved efficacy. [ABSTRACT FROM AUTHOR]

Idelalisib is a first-in-class selective, oral, phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor approved for the treatment of several types of blood cancer. Idelalisib has demonstrated significant efficacy and a tolerable safety profile in clinical trials. However, the US prescribing information contains a black box warning for fatal and/or severe diarrhea or colitis, hepatotoxicity, pneumonitis and intestinal perforation. An expert panel was convened to review the pathology of these treatment-emergent adverse events (TEAEs) to propose key management tools for patients receiving idelalisib therapy. This article provides an overview of idelalisib TEAEs reported in clinical trials, and a summary of the panel's recommendations for identification and management of idelalisib treatment-emergent diarrhea or colitis as well as a discussion of transaminitis and pneumonitis. For idelalisib-related diarrhea or colitis (including unresolved grade 2 and grade ≥ 3), after exclusion of infectious causes, the panel recommends individualized treatment with budesonide or oral or intravenous steroid therapy.

Molecular targets of tyrosine kinase inhibitors are not restricted to the B-cell compartment but also regulate functions in the tumor microenvironment. Increasing evidence suggests that B-cell receptor-associated kinases like protein kinase C (PKC)-β is essential for the formation of a microenvironment supporting leukemic growth. Here we describe the effect of Idelalisib on the PKCβ/NF-κB and Notch pathway in stromal cells upon contact to primary chronic lymphocytic leukemia cells (CLL). There is no Idelalisib-dependent regulation of the Notch expression in stromal cells, whereas Idelalisib induces PKCβ expression and activates the canonical NF-κB pathway. Idelalisib deregulates important immune-modulatory proteins in activated stromal cells, which might provoke the patient's side effects. Additionally, we established a 3D-stroma/leukemia model, that can give us a more defined look into the communication between tumor and stromal cells than standard cell cultures. This opens up the possibility to improve therapies, especially in the context of minimal-residual disease. [ABSTRACT FROM AUTHOR]

The phase 2 study of idelalisib monotherapy for indolent non-Hodgkin lymphomas (iNHLs) was completed in 2018; final efficacy and safety data with up to 6.7 years long-term follow-up are reported. Patients with iNHL refractory to both rituximab and an alkylating agent were enrolled and received 150 mg idelalisib twice daily (N = 125). Idelalisib resulted in an overall response rate of 57.6% with 34.4% continuing therapy for ≥12 months. The median progression-free survival and duration of response were 11.0 and 11.8 months for follicular lymphoma, 22.2 and 20.4 months for lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (LPL/WM), and 6.6 and 18.4 months for marginal zone lymphoma (MZL). Median overall survival after extended follow-up was 48.6 (95% CI 33.9, 71.7) months. Long-term follow-up did not reveal new safety concerns. These data indicate beneficial outcomes with longer follow-up after idelalisib for treatment of iNHL including in patients with LPL/WM and MZL. [ABSTRACT FROM AUTHOR]

Phosphoinositide-3-kinase (PI3K) inhibitors have efficacy in lymphoid malignancies; however, inflammatory and infectious toxicities can compromise the treatment course. An improved understanding of these toxicities will guide clinical use and further development. We evaluated the occurrence of treatment-related adverse events (AEs) in a retrospective review of 79 patients treated in standard fashion with PI3K inhibitor monotherapy or with anti-CD20 monoclonal antibodies or as part of a novel combination regimen. Patients treated with a novel combination were at a higher risk of developing a severe AE compared to those treated with standard therapy (HR 1.89, 95% CI 1.02, 3.49; p =.04). Additionally, previously untreated patients were at higher risk of developing a severe AE compared to previously treated patients (HR 3.19, 95% CI 1.48, 6.84; p =.003). These results caution against the use of untested PI3K inhibitor combinations in routine practice and suggest that early phase clinical trials should utilize conservative treatment schemas. [ABSTRACT FROM AUTHOR]

The CLL-IPI is a risk-weighted prognostic model for previously untreated patients with chronic lymphocytic leukemia (CLL), but has not been evaluated in patients with relapsed CLL or on novel therapies. We evaluated the CLL-IPI in 897 patients with relapsed/refractory CLL in 3 randomized trials testing idelalisib (PI3Kδ inhibitor). The CLL-IPI identified patients as low (2.2%), intermediate (12.8%), high (48.7%), and very high (36.2%) risk and was prognostic for survival (log-rank p <.0001; C-statistic 0.706). Of CLL-IPI factors, age >65, β2-microglobulin >3.5mg/L, unmutated immunoglobulin heavy chain variable region gene, and deletion 17p/TP53 mutation were independently prognostic, but Rai I-IV or Binet B/C was not. The CLL-IPI is prognostic for survival in relapsed CLL and with idelalisib therapy. However, low/intermediate risk is uncommon, and regression parameters of individual factors in this risk-weighted model appear different in relapsed CLL. Reassessment of the weighting of the individual variables might optimize the model in this setting. [ABSTRACT FROM AUTHOR]

The lymph node and bone marrow microenvironments promote the survival and proliferation of CLL cells. Defining the immunophenotype of CLL cells from the tumor microenvironment may help to better understand the mechanisms of action of current therapies and identify novel drug targets. Significant changes in the levels of 25 CD antigens were identified using the DotScan™ antibody microarray following CLL-cell culture with CD40L-expressing fibroblasts. Ibrutinib or idelalisib countered the change in expression of 11 of these antigens (CD23, CD27, CD53, CD58, CD71, CD80, CD84, CD97, CD126, CD150, and FMC7), which have known roles in cell activation and adhesion. The immunophenotypic changes identified may provide further insight into the mechanisms by which CLL cells interact with the tumor microenvironment and better define how ibrutinib and idelalisib release CLL cells from the lymph nodes and bone marrow. [ABSTRACT FROM AUTHOR]

Ibrutinib and idelalisib, B-cell receptor (BCR) signaling pathway inhibitors, have been recently approved for use against relapsed/refractory chronic lymphocytic leukemia (CLL). To assess the efficacy and safety of BCR pathway inhibitors in relapsed/refractory CLL, we conducted a systematic review and meta-analysis of five randomized controlled trials (1866 patients). Our study demonstrated that BCR pathway inhibitors significantly prolonged progression-free survival (PFS; pooled HR = 0.24; 95% CI: 0.19-0.30) and overall survival (HR = 0.58; 0.46-0.73) compared with control treatment. BCR pathway inhibitors increased the probability of response (RR = 3.54; 95% CI: 1.69-7.41) and decreased the risk of progression (RR = 0.21, 95% CI: 0.13-0.34). However, BCR pathway inhibitors increased the risk of grade 3 and 4 adverse events (AEs; RR = 1.25; 95% CI: 1.08-1.44) and serious AEs (RR = 1.32; 95% CI: 1.17-1.50). AEs causing discontinuation (RR = 1.26; 95% CI: 0.88-1.81) or death (RR = 1.06; 95% CI: 0.72-1.57) were not significantly increased. No statistically significant difference in any aspect of meta-analysis was noted between ibrutinib and idelalisib. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is a neoplastic disorder of mature B lymphocytes. While traditionally treated with combinations of chemoimmunotherapy, the therapeutic options for CLL have expanded in recent years with the emergence of novel oral agents, such as the Bruton tyrosine kinase inhibitor ibrutinib, that are well tolerated and highly efficacious. The role of novel agents in the first-line setting is now being investigated in head-to-head clinical trials. In this discussion paper, we consider the role of novel agents in the up-front setting, using three case studies of treatment-naive patients to highlight how choice of therapy may be individualized depending on the characteristics of the patient and the disease, as well as patient preferences. [ABSTRACT FROM PUBLISHER]

Over the last 20 years there have been sustained and dramatic improvements in the therapy of chronic lymphocytic leukemia (CLL). Until 1990, therapy for CLL was based on alkylating agents, chlorambucil and cyclophosphamide, which did not impact meaningfully on overall survival. The more recent therapeutic regimens, built on combination chemoimmunotherapy, achieve complete responses in 40–50% of cases. However, these regimens are limited in their applicability mostly to the treatment of younger and physically fit patients due to their associated toxicity. Furthermore, since disease progression and drug resistance are considered inevitable, CLL remains incurable. Fortunately, significant progress in the understanding of CLL biology has enabled the development of new molecular drugs targeting the B-cell receptor signaling pathway, such as ibrutinib and idelalisib, which have shown impressive results in patients with relapsed/refractory disease or withTP53mutation/deletion. Furthermore, obinutuzumab, a type II anti-CD20 antibody, which results in direct cell death and antibody-dependent cell-mediated cytotoxicity, also has proven efficacy when used in combination with chlorambucil in previously untreated and unfit patients. All these three new drugs have recently received FDA approval for the treatment of CLL. This review focuses on the role of ibrutinib, idelalisib and obinutuzumab in therapy of CLL. [ABSTRACT FROM AUTHOR]