Modeling absolute lymphocyte counts after treatment of chronic lymphocytic leukemia with ibrutinib

Abstract

The objective in this study was to characterize the pattern of the treatment-related lymphocytosis curve in chronic lymphocytic leukemia (CLL) patients treated with ibrutinib, and assess the relationship between the baseline factors and absolute lymphocyte counts (ALC). The PCYC-1102-CA study was a five-arm phase Ib/II open-label, nonrandomized, multicenter study in CLL/SLL. The arms and accruals were 420 and 840 mg/day treatment-naive elderly CLL/SLL (N = 27 and N = 4, respectively), 420 and 840 mg/day relapsed/refractory CLL/SLL (N = 27 and N = 34, respectively), and 420 mg/day high-risk CLL/SLL (N = 24). The results were generated through statistical modeling using data from a clinical trial (PCYC-1102) in five cohorts of treatment-naïve or relapsed/refractory CLL patients treated at 420 and 840 mg daily of ibrutinib. In cases in which the initial increase in ALC doubles by day 28, it takes patients longer to reach their maximum ALC when compared with those with a lower rate of increase. Our models show that all of the cohorts exhibited the same pattern of treatment-related lymphocytosis from ibrutinib, and there are no significant differences between cohorts, including no detectable dose effect. The ALC of the majority of patients return to baseline ALC values by the end of cycle 5.

Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib

“…32,33 Supplemental Table 4 shows the starting and peak absolute lymphocyte counts (ALCs). Of 18 patients (14%) with baseline ALC .100 3 10 9 /L, 4 developed ALC $ 400 3 10 9 /L.…”

Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment

“…del17p and del11q) [169, 171, 173, 174], as well as in previously untreated older patients (>65 years) have been reported [173, 175]. Early lymphocytosis and organomegaly reduction followed by lymphocyte count normalization are typical effects of ibrutinib treatment [176, 177, 178], linked to CLL-cell inhibition of proliferation and induction of cell death in vivo . Mutations in BTK and PLCγ2 were identified through whole-exome sequencing of peripheral blood samples from patients experiencing relapse after ibrutinib treatment, including a cysteine-to-serine mutation at position 481 in BTK (C481S) leading to a protein product with reduced kinase activity, that is only partially inhibited by ibrutinib [179, 180], and three putative gain-of-function mutations in PLCγ2, including arginine-to-tryptophan at position 665 (R665W), leucine to phenylalanine at position 845 (L845F) and serine to tyrosine at position 707 (S707Y) [179].…”

Diagnostic histochemistry and clinical-pathological testings as molecular pathways to pathogenesis and treatment of the ageing neuromuscular system: a personal view

“…Consider using for dysimmune diseases new antilymphocyte drugs, such as ones that look promising for chronic lymphocytic diseases. One currently showing early usefulness for Blymphocyte malignancies is Ibrutinib, an inhibitor of Bruton's tyrosine kinase [102,103].…”