abt-199 and Autoimmune-Diseases

Autoimmune cytopenias (AICs) affect 5% to 9% of patients with chronic lymphocytic leukemia (CLL). Targeted drugs-ibrutinib, idelalisib, and venetoclax-have a prominent role in the treatment of CLL, but their impact on CLL-associated AICs is largely unknown. In this study, we evaluated the characteristics and outcome of preexisting AICs and described the incidence, quality, and management of treatment-emergent AICs during therapy with targeted drugs in patients with CLL. We collected data from 572 patients treated with ibrutinib (9% in combination with an anti-CD20 monoclonal antibody), 143 treated with idelalisib-rituximab, and 100 treated with venetoclax (12% in combination with an anti-CD20 monoclonal antibody). A history of preexisting AICs was reported in 104 (13%) of 815 patients. Interestingly, 80% of patients whose AICs had not resolved when treatment with a targeted drug was started experienced an improvement or a resolution during therapy. Treatment-emergent AICs occurred in 1% of patients during ibrutinib therapy, in 0.9% during idelalisib therapy, and in 7% during venetoclax therapy, with an estimated incidence rate of 5, 6, and 69 episodes per 1000 patients per year of exposure in the 3 treatment groups, respectively. The vast majority of patients who developed treatment-emergent AICs had unfavorable biological features such as an unmutated IGHV and a del(17p) and/or TP53 mutation. Notably, despite AICs, 83% of patients were able to continue the targeted drug, in some cases in combination with additional immunosuppressive agents. Overall, treatment with ibrutinib, idelalisib, or venetoclax seems to have a beneficial impact on CLL-associated AICs, inducing an improvement or even a resolution of preexisting AICs in most cases and eliciting treatment-emergent AICs in a negligible portion of patients.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Autoimmune Diseases; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Purines; Quinazolinones; Sulfonamides

Venetoclax is a selective inhibitor of B-cell lymphoma-2, which plays a role in the development of various autoimmune diseases including systemic lupus erythematosus. The aim of these analyses was to quantify the exposure-response relationship for venetoclax effects on B-lymphocyte and total lymphocyte counts as pharmacodynamic markers of efficacy and safety, respectively, in women with systemic lupus erythematosus. The developed modeling framework was also used to evaluate venetoclax effects following cyclic, continuous, or induction/maintenance dosing paradigms as potential dosing alternatives in systemic lupus erythematosus.. Serial pharmacokinetic and lymphocyte count data from 73 women enrolled in a phase I study of venetoclax (single doses of 10-500 mg or two cycles of 30-600 mg or placebo once daily for 7 days followed by a 21-day washout) were analyzed using a sequential population pharmacokinetic/pharmacodynamic modeling approach. Simulations to evaluate changes in B-lymphocyte and total lymphocyte counts following different venetoclax dosing scenarios were conducted.. Venetoclax treatment in women with systemic lupus erythematosus was associated with exposure-dependent reductions in B lymphocytes, and to a lesser extent, total lymphocyte counts. Results from this study support evaluation of B-cell lymphoma-2 inhibitors as potential therapies for the treatment of systemic lupus erythematosus. CLINICALTRIALS.GOV: NCT01686555.

Topics: Adult; Aged; Antineoplastic Agents; Autoimmune Diseases; B-Lymphocytes; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Female; Humans; Lupus Erythematosus, Systemic; Lymphocyte Count; Middle Aged; Models, Theoretical; Placebos; Proto-Oncogene Proteins c-bcl-2; Safety; Sulfonamides; Treatment Outcome

Bruton's tyrosine kinase (BTK) is a Tec family kinase that plays an essential role in B-cell receptor (BCR) signaling as well as Fcγ receptor signaling in leukocytes. Pharmacological inhibition of BTK has been shown to be effective in treating hematological malignancies and is hypothesized to provide an effective strategy for the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. We report the discovery and preclinical properties of JNJ-64264681 (

Topics: Agammaglobulinaemia Tyrosine Kinase; Arthritis, Rheumatoid; Autoimmune Diseases; Humans; Lupus Erythematosus, Systemic; Protein Kinase Inhibitors