Search

Highlights • Patient similarity network (PSN) is a new approach for patient stratification. • PSN clusters patients based on their similarities in various features. • PSN supports heterogeneous data (demographic/laboratory/clinical data, genomics). • PSN has excellent model interpretability utilizing selections of relevant features. • PSN is suited for precision medicine. Abstract Background Better risk-stratification of patients with chronic lymphocytic leukemia (CLL) and identification of subsets of ultra-high-risk (HR)-CLL patients are crucial in the contemporary era of an expanded therapeutic armamentarium for CLL. Methods A multivariate patient similarity network and clustering was applied to assess the prognostic values of routine genetic, laboratory, and clinical factors and to identify subsets of ultra-HR-CLL patients. The study cohort consisted of 116 HR-CLL patients (F/M 36/80, median age 63 yrs) carrying del(11q), del(17p)/ TP53 mutations and/or complex karyotype (CK) at the time of diagnosis. Results Three major subsets based on the presence of key prognostic variables as genetic aberrations, bulky lymphadenopathy, splenomegaly, and gender: profile (P)-I (n = 34, men/women with CK + no del(17p)/ TP53 mutations), P-II (n = 47, predominantly men with del(11q) + no CK + no del(17p)/ TP53 mutations), and P-III (n = 35, men/women with del(17p)/ TP53 mutations, with/without del(11q) and CK) were revealed. Subanalysis of major subsets identified three ultra-HR-CLL groups: men with TP53 disruption with/without CK, women with TP53 disruption with CK and men/women with CK + del(11q) with poor short-term outcomes (25% deaths/12 mo). Besides confirming the combinations of known risk-factors, the used patient similarity network added further refinement of subsets of HR-CLL patients who may profit from different targeted drugs. Conclusions This study showed for the first time in hemato-oncology the usefulness of the multivariate patient similarity networks for stratification of HR-CLL patients. This approach shows the potential for clinical implementation of precision medicine, which is especially important in view of an armamentarium of novel targeted drugs. [ABSTRACT FROM AUTHOR]

Highlights • Ibrutinib influences the expression of HLA-DR on CLL cells. • Ibrutinib gradually increases HLA-DR levels on circulating monocyte subsets. • Immunomodulatory effect of ibrutinib on CLL, T cells, monocytes is time-dependent. Abstract There is the first evidence of changes in the kinetics of B cell antigen receptor (BCR) internalisation of neoplastic cells in chronic lymphocytic leukemia (CLL) after the short-term and long-term administration of ibrutinib. We aimed to assess the influence of short-term and long-term ibrutinib treatment on the HLA-DR expression on CLL cells, T cells and monocytes. The immunophenotyping of CLL and immune cells in peripheral blood was performed on 16 high-risk CLL patients treated with ibrutinib. After early ibrutinib administration, the HLA-DR expression on CLL cells reduced ( P = 0.032), accompanied by an increase in CLL cell counts in peripheral blood ( P = 0.001). In vitro culturing of CLL cells with ibrutinib also revealed the reduction in the HLA-DR expression at protein and mRNA levels ( P < 0.01). The decrease in HLA-DR on CLL cells after the first month was followed by the gradual increase of its expression by the 12th month ( P = 0.001). A one-month follow-up resulted in elevated absolute counts of CD4+ ( P = 0.002) and CD8+ ( P < 0.001) T cells as well as CD4+ and CD8+ cells bearing HLA-DR ( P < 0.01). The long-term administration of ibrutinib was associated with the increased numbers of CD4+ bearing HLA-DR ( P = 0.006) and elevation of HLA-DR expression on all monocyte subsets ( P ≤ 0.004). Our results provide the first evidence of the time-dependent immunomodulatory effect of ibrutinib on CLL and T cells and monocytes. The clinical consequences of time-dependent changes in HLA-DR expression in ibrutinib treated patients deserve further investigation. [ABSTRACT FROM AUTHOR]

• Complex karyotype affects clinical and treatment decision-making in the diagnosis of chronic lymphocytic leukemia. • Complex karyotype is a marker of poor prognosis and short overal survival. • Complex karyotype has adverse prognosis with or without aberrations of TP53 and ATM. A complex karyotype (CK) is considered a poor prognostic marker in chronic lymphocytic leukemia (CLL). The study analyzed 644 untreated CLL patients (pts) using conventional/molecular cytogenetics to reveal the presence of a CK and its composition and to assess its predictive value. The mutational status of TP53 was detected by next generation sequencing. A CK was detected in 79 pts (12.3%). Patients with a CK showed shorter overall survival (OS) compared to those without a CK (77 months vs. 115 months, p < 0.0001). Chromosomes most frequently included in a CK were 13, 11, 17, 8, 2, and 6. The most common aberrations in a CK were translocations, numerical changes and dicentric chromosomes (with no effect on OS). Patients with aberrations of TP53 and ATM were shown to have adverse prognosis comparable to patients with a CK without these abnormalities. A stronger impact of a CK on OS of female and older CLL patients was observed. The determining of the presence of a CK is essential in modern clinical CLL practice. According to recent studies, the presence of a CK affects clinical and treatment decision-making. [ABSTRACT FROM AUTHOR]