Bone marrow stroma-induced resistance of chronic lymphocytic leukemia cells to arsenic trioxide involves Mcl-1 upregulation and is overcome by inhibiting the PI3Kδ or PKCβ signaling pathways

CLL remains an incurable disease in spite of the many new compounds being studied. Arsenic trioxide (ATO) induces apoptosis in all CLL cell types and could constitute an efficient therapy. To further explore this, we have studied the influence of stromal cells, key components of the CLL microenvironment, on the response of CLL cells to ATO. Bone marrow stromal cells induced CLL cell resistance to 2 μM ATO and led to activation of Lyn, ERK, PI3K and PKC, as well as NF-κB and STAT3. Mcl-1, Bcl-xL, and Bfl-1 were also upregulated after the co-culture. Inhibition experiments indicated that PI3K and PKC were involved in the resistance to ATO induced by stroma. Moreover, idelalisib and sotrastaurin, specific inhibitors for PI3Kδ and PKCβ, respectively, inhibited Akt phosphorylation, NF-κB/STAT3 activation and Mcl-1 upregulation, and rendered cells sensitive to ATO. Mcl-1 was central to the mechanism of resistance to ATO, since: 1) Mcl-1 levels correlated with the CLL cell response to ATO, and 2) blocking Mcl-1 expression or function with specific siRNAs or inhibitors overcame the protecting effect of stroma. We have therefore identified the mechanism involved in the CLL cell resistance to ATO induced by bone marrow stroma and show that idelalisib or sotrastaurin block this mechanism and restore sensibility to ATO. Combination of ATO with these inhibitors may thus constitute an efficient treatment for CLL.     

Cost‐utility analysis of idelalisib in combination with rituximab in relapsed or refractory chronic lymphocytic leukaemia

Objective

To evaluate the incremental cost‐utility ratio (ICUR) of idelalisib in combination with rituximab (IR) versus rituximab monotherapy (R) in the treatment of patients with relapsed or refractory (R/R) chronic lymphocytic leukaemia (CLL), from the Spanish National Health System (NHS) perspective.

Methods

A partitioned survival Markov model for a lifetime horizon (30 years) was developed to estimate costs (€, 2016) and quality‐adjusted life years (QALY) with IR and R. Initial cohort included patients with CLL receiving a second or subsequent line (2L) of treatment with IR or R. Survival data were based on CLL clinical trial. Drug, administration, monitoring, adverse events and clinical management of CLL costs were included in the model. Costs and outcomes were discounted using a 3% annually. Deterministic and probabilistic sensitivity analyses (PSA) were performed.

Results

Compared to R, 2L IR treatment resulted in QALY gain of 3.147 (4.965 versus 1.818). Total costs were €118 254 for IR versus €23 874 for R. ICUR was €29 990/QALY gained with IR versus R. In the PSA, IR was cost‐effective in 78% of iterations using a threshold of €45 000/QALY.

Conclusion

IR can be considered a cost‐effective treatment compared to R, in the treatment of R/R CLL patients for the Spanish NHS.     

Indirect Treatment Comparisons of Ibrutinib Versus Physician’s Choice and Idelalisib Plus Ofatumumab in Patients With Previously Treated Chronic Lymphocytic Leukemia

Purpose

Treatment options for patients with relapsed or refractory chronic lymphocytic leukemia (R/R CLL) are limited. Until recently, few effective treatment options existed, and even with the advent of new agents, studies evaluating comparative efficacy are scarce. In the Ibrutinib Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (RESONATE) Phase III study, ibrutinib, an oral, once-a-day, first-in-class covalent Bruton tyrosine kinase inhibitor, improved progression-free survival (PFS) and overall survival (OS) compared with ofatumumab (PFS hazard ratio [HR] = 0.106 and OS HR = 0.369 [adjusted for crossover] at a median of 16 months’ follow-up). We sought to establish the relative efficacy of ibrutinib versus other treatment options for patients with R/R CLL using indirect comparison methods.

Novel synthetic drugs currently in clinical development for chronic lymphocytic leukemia

Introduction: Over the last few years, several new synthetic drugs, particularly Bruton’s tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K) and BCL-2 inhibitors have been developed and investigated in chronic lymphocytic leukemia (CLL).

Areas covered: This review highlights key aspects of BTK, PI3K and BCL-2 inhibitors that are currently at various stages of preclinical and clinical development in CLL. A literature review of the MEDLINE database for articles in English concerning CLL, B-cell receptor, BCL-2 antagonists, BTK inhibitors and PI3K inhibitors, was conducted via PubMed. Publications from 2000 through July 2017 were scrutinized. The search terms used were acalabrutinib, ACP-196, BGB-3111, ONO-4059, GS-4059, duvelisib, IPI-145, TGR-1202, copanlisib, Bay 80–6946, buparlisib, BKM-120, BCL-2 inhibitors, venetoclax, ABT-263, navitoclax, CDK inhibitors, alvocidib, flavopiridol, dinaciclib, SCH 727,965, palbociclib, PD-0332991, in conjunction with CLL. Conference proceedings from the previous five years of the ASH and EHA Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles.

Expert opinion: The use of new synthetic drugs is a promising strategy for the treatment of CLL. Data from ongoing and future clinical trials will aid in better defining the status of new drugs in the treatment of CLL.     

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.     

Idelalisib for optimized CD19-specific chimeric antigen receptor T cells in chronic lymphocytic leukemia patients

Despite encouraging results with chimeric antigen receptor T (CART) cells, outcome can still be improved by optimization of the CART cell generation process. The proportion of less-differentiated T cells within the transfused product is linked to enhanced in vivo CART cell expansion and long-term persistence. The clinically approved PI3Kδ inhibitor idelalisib is well established in the treatment of B cell malignancies. Besides B cell receptor pathway inhibition, idelalisib can modulate T cell differentiation and function. Here, detailed longitudinal analysis of idelalisib-induced effects on T cell phenotype and function was performed during CART cell production. A third generation CD19.CAR.CD28.CD137zeta CAR vector system was used. CART cells were generated from peripheral blood mononuclear cells of healthy donors (HDs) and chronic lymphocytic leukemia (CLL) patients. Idelalisib-based CART cell generation resulted in an enrichment of less-differentiated naïve-like T cells (CD45RA+CCR7+), decreased expression of the exhaustion markers PD-1 and Tim-3, as well as upregulation of the lymph node homing marker CD62L. Idelalisib increased transduction efficiency, but did not impair viability and cell expansion. Strikingly, CD4:CD8 ratios that were altered in CART cells from CLL patients were approximated to ratios in HDs by idelalisib. Furthermore, in vivo efficacy of idelalisib-treated CART cells was validated in a xenograft mouse model. Intracellular TNF-α and IFN-γ production decreased in presence of idelalisib. This effect was reversible after resting CART cells without idelalisib. In summary, PI3Kδ inhibition with idelalisib can improve CART cell products, particularly when derived from CLL patients. Further studies with idelalisib-based CART cell generation protocols are warranted.     

Approved and emerging PI3K inhibitors for the treatment of chronic lymphocytic leukemia and non-Hodgkin lymphoma

ABSTRACT

Introduction

PI3K inhibition with idelalisib (at that time CAL-101) was at the forefront of the development of molecularly targeted therapies in Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Leukemia (SLL) and follicular lymphoma. However, after initial approval, subsequent trials identified specific immune-mediated and infectious toxicity that led to a reduced use and stopped the further development of this agent. PI3K inhibition as a treatment paradigm fell out of favor compared to other developments such as BTK or BCL2 inhibitors.     

Management of adverse events associated with idelalisib treatment in chronic lymphocytic leukemia and follicular lymphoma: A multidisciplinary position paper

The introduction of new therapeutic agents in chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL), including the new kinase inhibitor idelalisib, has changed the therapeutic landscape of these diseases. However, the use of idelalisib is associated with a peculiar profile of side effects, which require an optimization of the current approach to prophylaxis and supportive treatment. Moving from the recognition that the abovementioned issue represents an unmet need in CLL and FL, a multidisciplinary panel of experts was convened to produce a consensus document aiming to provide practical recommendations for the management of the side effects during idelalisib therapy for CLL and FL. The present publication represents a consensus document from a series of meetings held during 2017. The Panel generated clinical key questions using the criterion of clinical relevance through a Delphi process and explored 4 domains, ie, diarrhea/colitis, transaminitis, pneumonitis, and infectious complications. Using the consensus method, the Panel was able to shape recommendations which may assist hematologist to minimize adverse events and guarantee adherence to treatment in patients with CLL and FL candidate to receive idelalisib.