Dose and drug changes in chronic lymphocytic leukemia cell response in vitro: A comparison of standard therapy regimens with two novel cyclin‑dependent kinase inhibitors.

Chronic lymphocytic leukemia (CLL) treatment is improving; however, some patients do not respond to therapy. Due to the high heterogeneity in disease development, there is an urgent need for personalization of therapy. In the present study, the response of leukemic mononuclear cells to anticancer drugs used for CLL treatment (cladribine + mafosfamide; CM or CM combined with rituximab; RCM) was compared with the response to new cyclin‑dependent kinase (CDK) inhibitors: BP14 and BP30.

Bendamustine alone or with rituximab modifies expression of apoptosis-regulating genes and proteins of CLL cells, depending on IGVH mutational status.

We studied whether bendamustine (BENDA) alone or with rituximab (RIT) modifies expression of apoptosis-involved genes and proteins of chronic lymphocytic leukemia (CLL) cells depending on IGVH mutational status. Circulating lymphocytes from 34 untreated patients (18 IGVH-MUT and 16 IGVH-UNMUT) were incubated with above drugs to evaluate proteins expression. Microarray analysis of 93 genes was performed in 14 patients.

Rituximab, cladribine, and cyclophosphamide (RCC) induction with rituximab maintenance in chronic lymphocytic leukemia: PALG - CLL4 (ML21283) trial.

Objectives: PALG CLL4 is the first, randomized, phase IIIb study with rituximab, cladribine, and cyclophosphamide (RCC) induction and subsequent maintenance with rituximab in previously untreated chronic lymphocytic leukemia (CLL) patients.

Methods: The induction treatment consisted of 6 RCC cycles regimen. Patients with complete response (CR) or partial response (PR) after an induction phase were randomized into a maintenance arm with rituximab or an observational arm.

Personalized therapy tests for the monitoring of chronic lymphocytic leukemia development.

There is individual variation in the course of disease development and response to therapy of patients with chronic lymphocytic leukemia (CLL). Novel treatment options for CLL include a new generation of purine analogs, antibodies and inhibitors of specific cell signaling pathways, which typically induce apoptosis or necrosis. A prospective analysis of patient blood samples revealed that a combination of four tests allowed the most appropriate and effective type of treatment to be selected prior to drug administration, and for the analysis of leukemic cell sensitivity to anticancer drug(s) during disease development.

Prognostic value of thymidine kinase activity in patients with chronic lymphocytic leukemia.

Thymidine kinase (TK) activity is a marker of biological activity that allows the indolent and aggressive forms of chronic lymphocytic leukemia (CLL) to be distinguished. The aims of the study were to determine the relationship between TK activity and clinical status and prognosis, as well as to compare its activity with that of other prognostic and predictive factors. TK activity was measured in patient sera at the time of diagnosis using the DiviTum method, with the mean value being 439 Du/L.

Health-related quality of life and patient-reported outcomes of ofatumumab plus fludarabine and cyclophosphamide versus fludarabine and cyclophosphamide in the COMPLEMENT 2 trial of patients with relapsed CLL.

Chronic lymphocytic leukemia (CLL) is an incurable disease. Quality of life during treatment and periods of subsequent remission is therefore vital. Health-related quality of life (HRQoL) was compared in relapsed CLL during and after treatment with ofatumumab combined with fludarabine and cyclophosphamide versus fludarabine and cyclophosphamide alone.

Ofatumumab plus fludarabine and cyclophosphamide in relapsed chronic lymphocytic leukemia: results from the COMPLEMENT 2 trial.

Unlabelled: In this multicenter, open-label, phase III study, patients with relapsed chronic lymphocytic leukemia (CLL) were randomized (1:1) to receive ofatumumab plus fludarabine and cyclophosphamide (OFA + FC) or FC alone; the primary endpoint being progression-free survival (PFS) assessed by an independent review committee (IRC). Between March 2009 and January 2012, 365 patients were randomized (OFA + FC: n = 183; FC: n = 182). Median IRC-assessed PFS was 28.

In vitro antileukemic activity of novel adenosine derivatives bearing boron cluster modification.

A series of adenosine derivatives bearing a boron cluster were synthesized and evaluated for their cytotoxicity against primary peripheral mononuclear cells from the blood of 17 patients with leukemias (16 CLL and 1 very rare PLL), as well as from 5 healthy donors used as a control. Among the tested agents, two, i.e.

Antibody therapy alone and in combination with targeted drugs in chronic lymphocytic leukemia.

The development of non-chemotherapeutic agents, including monoclonal antibodies (mAbs) and other targeted drugs, makes chemotherapy-free treatment an attractive option for chronic lymphocytic leukemia (CLL). The classical mAb, rituximab, has been authorized for use in both first-line and second-line therapy for CLL. New mAbs directed against CD20, ofatumumab, and obinutuzumab (GA-101) have also been approved for the treatment of this disease.

Relationship between in vitro drug sensitivity and clinical response of patients to treatment in chronic lymphocytic leukemia.

To improve the efficacy of therapeutic options in chronic lymphocytic leukemia (CLL) an in vitro system to determine the response of mononuclear blood cells from blood of patients was elaborated. The study combines four approaches, i.e.

Cytotoxic and apoptosis-inducing effects of bendamustine used alone and in combination with rituximab on chronic lymphocytic leukemia cells in vitro.

Aim: The aim of our study was to compare the cytotoxic effects of bendamustine (BENDA) and rituximab (RIT) used either alone or in combination and to evaluate the influence of the above mentioned drugs on apoptosis measured as changes in mitochondrial transmembrane potential (Δψm), expression of caspases and selected apoptosis-regulating proteins in freshly isolated peripheral blood mononuclear cells of chronic lymphocytic leukemia (CLL) patients.

Materials/methods: Cytotoxic effect of tested drugs, as well as induction of apoptosis, drop in Δψm and expression of selected proteins involved in regulation of apoptosis were assessed in 48 hour cultures containing autologous serum (AS) using flow cytometry. BENDA was used at the concentration of 40 μg/ml and RIT at the concentration of 10 μg/ml.

Clonal evolution in CLL patients as detected by FISH versus chromosome banding analysis, and its clinical significance.

The acquisition of new aberrations during the course of chronic lymphocytic leukemia (CLL) named clonal evolution (CE) is usually detected by one of the two methods: chromosome banding analysis (CBA) and interphase fluorescence in situ hybridization (I-FISH). The purpose of this study was to compare the usefulness of FISH and CBA for detecting CE and to evaluate its influence on clinical outcome. FISH and CBA were performed at two time points: baseline and follow-up.

In vivo and ex vivo responses of CLL cells to purine analogs combined with alkylating agent.

Background: The heterogeneity of chronic lymphocytic leukemia (CLL) is thought to be due to differences in the expression of factors that regulate apoptosis and cell cycle, giving rise to diverse apoptotic disturbances and tumor properties. Therefore, the primary goal in CLL treatment is to overcome resistance to apoptosis and efficiently trigger this process in leukemic cells.

Methods: Mononuclear cells were obtained from the blood of CLL patients by Histopaque-1077 sedimentation.

Long-term results of the Polish Adult Leukemia Group PALG-CLL2 phase III randomized study comparing cladribine-based combinations in chronic lymphocytic leukemia.

Long-term outcomes following newer therapies for chronic lymphocytic leukemia (CLL) have rarely been reported. This article presents the results of the final analysis of the Polish Adult Leukemia Group PALG-CLL2 study performed 10 years from final patient enrollment. With the extended follow-up time, it was found that cladribine (2-CdA)-based combinations CMC (2-CdA, cyclophosphamide, mitoxantrone) and CC (2-CdA, cyclophosphamide) administered as first-line treatment of progressive CLL resulted in significantly longer progression-free survival, but similar overall survival compared to 2-CdA monotherapy.

Immune thrombocytopenia in patients with chronic lymphocytic leukemia treated with cladribine-based regiments or chlorambucil--follow-up of PALG-CLL randomized trials.

Objectives: The relationship between treatments of chronic lymphocytic leukemia (CLL) with cladribine (2-CdA) or chlorambucil and immune thrombocytopenia (IT) has not been yet determined.

Methods: The records of 777 patients in two randomized Polish Adult Leukemia Group (PALG)-CLL programs treated with these agents were retrospectively analyzed.

Results: Immune thrombocytopenia occurred in 55 of 777 (7.

Promising anti-leukemic activity of atorvastatin.

There is a current need for novel therapeutic strategies for the treatment of chronic lymphocytic leukemia (CLL), a still incurable hematological cancer involving mainly deregulated apoptosis. The purpose of the present study was to determine ex vivo the effect of the synthetic statin, atorvastatin, a known cholesterol-lowering drug, on peripheral blood mononuclear cells obtained from CLL patients. Using flow cytometry, we investigated the viability and induction of apoptosis in leukemic cells exposed to statin by the Vybrant apoptosis assay kit #4, compared with untreated control cells.

Toward personalized therapy for chronic lymphocytic leukemia: DSC and cDNA microarray assessment of two cases.

The differences in clinical course of chronic lymphocytic leukemia could have an impact on variations in a patient's response to therapy. Our published results revealed that thermal transition (95 ± 5°C) in differential scanning calorimetry profiles appear to be characteristic for the advanced stage of CLL. Moreover, a decrease/loss of this transition in nuclei from leukemic cells exposed to drugs ex vivo could indicate their diverse efficacy.

Apoptotic gene expression under influence of fludarabine and cladribine in chronic lymphocytic leukemia-microarray study.

Background: A deep insight into gene expression profiling (GEP) is a key to understanding the background of disease. It can lead to identification of diagnostic and prognostic factors and then to a selection of the most appropriate therapy. The aim of this study was to evaluate differences in apoptotic gene expression in chronic lymphocytic leukemia (CLL) cells influenced by fludarabine (FA) or cladribine (2-CdA).

Changes in the apoptotic gene expression profile in CLL patients treated with rituximab combined with cladribine and cyclophosphamide-preliminary results.

The study was aimed to investigate modifications of apoptotic gene expression profile by microarray technique in 10 patients with chronic lymphocytic leukemia by treatment with rituximab, cladribine and cyclophosphamide (RCC) according to IGHV mutational status. The TaqMan Low Density Array for 96 gene transcripts was used. Those modifications followed two distinctive patterns largely overlapping the IGHV mutational status.

Can ex vivo evaluation (testing) predict the sensitivity of CLL cells to therapy with purine analogs in conjunction with an alkylating agent? A comparison of in vivo and ex vivo responses to treatment.

Malfunctions in the regulation of apoptosis cause the accumulation of malignant, long-lived B CD19+/CD5+ cells in chronic lymphocytic leukemia (CLL). The primary goal in CLL therapy is to overcome resistance to apoptosis and efficiently trigger programmed cell death in leukemic cells. This study demonstrated that the in vivo responses of malignant cells from CLL patients after administration of purine analogs (cladribine/fludarabine) with cyclophosphamide vary significantly.

Chromosomal aberrations in chronic lymphocytic leukemia detected by conventional cytogenetics with DSP30 as a single agent: comparison with FISH.

The aim of our study was to estimate the usefulness for conventional cytogenetics (CC) of DSP30 as a single agent (CC-DSP30) for detecting the most important chromosomal aberrations revealed in CLL by FISH and to find other abnormalities possibly existing but undetected by FISH with standard probes. Using CC-DSP30, the metaphases suitable for analysis were obtained in 90% of patients. CC-DSP30 and FISH were similarly efficacious for detecting del(11)(q22) and trisomy 12, whereas FISH was more sensitive for del(13)(q14).

Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study).

PURPOSE Little is known about comparison of the activity of different purine nucleoside analogs in chronic lymphocytic leukemia (CLL). We conducted a randomized phase III trial to compare efficacy and safety of cladribine and fludarabine, each combined with cyclophosphamide, in previously untreated progressive CLL. PATIENTS AND METHODS Patients received cladribine at 0.