Individual features of the pharmacokinetics of fludarabin phosphate in the treatment of patients with chronic lymphocytic leukemia

Fludarabine is a purine antimetabolite with a pronounced immunosuppressive effect. The inhibitory effect of fludarabine depends on its concentration in blood plasma. In addition, the phenotypic characteristics of patients affect the pharmacokinetic and pharmacodynamic profile of the drug, which necessitates a personalized approach to the dosage regimen. The chromatography-mass spectrometric method for the quantitative determination of 2-fluorine in blood plasma was developed for studying the individual parameters of pharmacokinetics of the international non-proprietary name (INN) fludarabine in patients with B-cell chronic lymphocytic leukemia during the standard course. Such method for the quantitative determination of 2-fluorine in blood plasma was developed and validated in accordance with international requirements. Significant individual variability of the main pharmacokinetic parameters in patients with B-cell chronic lymphocytic leukemia with a single oral administration of the drug with INN fludarabine at a dose of 40 mg/m2 was established, so the coefficient of variability Cmax was 42 %, Tmax — 92 %, AUC0-t — 45 %, Kel — 23 %, T1/2 — 26 %. It should be noted that there is a high interindividual variability of fludarabine, for example, 24 hours after taking the study drug, the maximum and minimum plasma concentrations of the fludarabine metabolite 2-fluoro-ara-A in different in patients with B-cell chronic lymphocytic leukemia differed 9 times. Individual variability of pharmacokinetic parameters characterizing absorption (Cmax/AUC0-t) and total clearance of the active metabolite of fludarabine is statistically significantly associated with a combination of gender and anthropometric factors.

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More on the determination of Ki-67 as a novel potential prognostic marker in B-cell chronic lymphocytic leukemia

Leukemia Research ◽

10.1016/j.leukres.2010.07.036 ◽

2010 ◽

Vol 34 (12) ◽

pp. e326-e328 ◽

Cited By ~ 1

Author(s):

Fortunato Morabito ◽

Giovanna Cutrona ◽

Massimo Gentile ◽

Fabrizio Loiacono ◽

Serena Matis ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Prognostic Marker ◽

Lymphocytic Leukemia ◽

Ki 67 ◽

Cell Chronic Lymphocytic Leukemia

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T cells in B-cell chronic lymphocytic leukemia: quantitative assessment of cytotoxic and interleukin-2-producing lymphocyte precursors by limiting dilution analysis

Blood ◽

10.1182/blood.v73.6.1622.bloodjournal7361622 ◽

1989 ◽

Vol 73 (6) ◽

pp. 1622-1626

Author(s):

O Janssen ◽

C Nerl ◽

D Kabelitz

Keyword(s):

T Cells ◽

B Cells ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Cytotoxic T Cells ◽

Interleukin 2 ◽

Lymphocytic Leukemia ◽

Limiting Dilution ◽

Cell Chronic Lymphocytic Leukemia

Controversy exists as to the functional capacity of T lymphocytes in patients with B-cell chronic lymphocytic leukemia (CLL). We have used a limiting dilution (LD) culture approach to quantitatively assess frequencies of proliferating lymphocyte precursors (PLP), cytotoxic lymphocyte precursors (CLP), and interleukin-2 (IL-2)-producing helper lymphocyte precursors (HLP). Unseparated mononuclear cells (MNC) or purified T cells (E+) and leukemic B cells (E-) were cocultured under LD conditions with irradiated OKT3 hybridoma cells in the absence (determination of HLP) or presence of recombinant IL-2 (determination of PLP and CLP). Under these conditions, low frequencies of PLP, HLP, and CLP (f = 1/65 to 1/4600) were measured in unseparated MNC of CLL patients. In contrast, purified T cells (50% to 92% CD3+) contained precursors of proliferating, IL-2-producing and cytotoxic T cells in similar frequency as did T cells from healthy control donors (f = 1/4 to 1/24). Leukemic B cells rigorously depleted of T cells did not give rise to measurable frequencies of PLP, HLP, or CLP (f less than 1/50.000) except in one CLL patient where a significant frequency (f = 1/1700) of HLP was consistently present in E- cells, despite the absence of growth-inducible PLP and CLP. Taken together, these results indicate that comparable numbers of IL-2-producing helper T cells and cytotoxic T cells are present in B-CLL patients and healthy controls, respectively. The data are discussed with respect to reported T cell abnormalities in B-CLL.

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Free and bound forms of sialic acid in blood plasma of patients with chronic lymphocytic leukemia

Visnyk of Dnipropetrovsk University Biology medicine ◽

10.15421/021520 ◽

2015 ◽

Vol 6 (2) ◽

pp. 108-112 ◽

Cited By ~ 1

Author(s):

O. V. Netronina

Keyword(s):

Sialic Acid ◽

Chronic Lymphocytic Leukemia ◽

Blood Plasma ◽

Sialic Acids ◽

Lymphocytic Leukemia ◽

General Level ◽

Control Group ◽

Free Sialic Acid ◽

In Blood Plasma

The level of free and bound forms of sialic acids (SА) was investigated in chronic lymphocytic leukemia (CLL) and at different stages of receiving chemotherapy. Determination of sialic acid in blood plasma of patients with CLL before treatment were carried out on the first day and 2 months after taking chemotherapy drugs for combination schemes. Hematologically healthy donors represented the control group. Determination of SA was conducted by thiobarbituric method using trichloroacetic acid for distribution of total sialic acids onto free, protein bound sialic acid, and oligo bound sialic acid. Levelof free sialic acid in serum in chronic lymphocytic leukemia was equal to 43.2% compared to the total number of plasma. On the first day of chemotherapy on background of the general level of oligo bound sialic acids we observed increase in free sialic acid by 24.2% compared to patients not receiving treatment. The level of sialic acids increased 2.6 times compared to norm and featured no significant changes at different stages of treatment. The concentration of sialic acids bound to proteins at 73.4% was lower compared to the control group. After receiving chemotherapy on the first day there was a decline of this indicator to 56.2% compared to groups of patients before treatment. Two months after the treatment the level of all parameters under study returned back to the values obtained at the start of treatment. This data can serve as an additional efficiency criterion of the chemotherapy.

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T cells in B-cell chronic lymphocytic leukemia: quantitative assessment of cytotoxic and interleukin-2-producing lymphocyte precursors by limiting dilution analysis

Blood ◽

10.1182/blood.v73.6.1622.1622 ◽

1989 ◽

Vol 73 (6) ◽

pp. 1622-1626 ◽

Cited By ~ 9

Author(s):

O Janssen ◽

C Nerl ◽

D Kabelitz

Keyword(s):

T Cells ◽

B Cells ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Cytotoxic T Cells ◽

Interleukin 2 ◽

Lymphocytic Leukemia ◽

Limiting Dilution ◽

Cell Chronic Lymphocytic Leukemia

Abstract Controversy exists as to the functional capacity of T lymphocytes in patients with B-cell chronic lymphocytic leukemia (CLL). We have used a limiting dilution (LD) culture approach to quantitatively assess frequencies of proliferating lymphocyte precursors (PLP), cytotoxic lymphocyte precursors (CLP), and interleukin-2 (IL-2)-producing helper lymphocyte precursors (HLP). Unseparated mononuclear cells (MNC) or purified T cells (E+) and leukemic B cells (E-) were cocultured under LD conditions with irradiated OKT3 hybridoma cells in the absence (determination of HLP) or presence of recombinant IL-2 (determination of PLP and CLP). Under these conditions, low frequencies of PLP, HLP, and CLP (f = 1/65 to 1/4600) were measured in unseparated MNC of CLL patients. In contrast, purified T cells (50% to 92% CD3+) contained precursors of proliferating, IL-2-producing and cytotoxic T cells in similar frequency as did T cells from healthy control donors (f = 1/4 to 1/24). Leukemic B cells rigorously depleted of T cells did not give rise to measurable frequencies of PLP, HLP, or CLP (f less than 1/50.000) except in one CLL patient where a significant frequency (f = 1/1700) of HLP was consistently present in E- cells, despite the absence of growth-inducible PLP and CLP. Taken together, these results indicate that comparable numbers of IL-2-producing helper T cells and cytotoxic T cells are present in B-CLL patients and healthy controls, respectively. The data are discussed with respect to reported T cell abnormalities in B-CLL.

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Abnormal Intracellular Level of Bax in CD3 + Cells from Untreated B-Cell Chronic Lymphocytic Leukemia Patients

Laboratory Hematology ◽

10.1532/lh96.06020 ◽

2006 ◽

Vol 12 (4) ◽

pp. 187-192

Author(s):

F. Scamardella ◽

M. Maconi ◽

L. Albertazzi ◽

B. Gamberi ◽

L. Gugliotta ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Lymphocytic Leukemia ◽

Intracellular Level ◽

Cell Chronic Lymphocytic Leukemia

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Cutaneous leukocytoclastic vasculitis in B-cell chronic lymphocytic leukemia patients

Giornale Italiano di Dermatologia e Venereologia ◽

10.23736/s0392-0488.18.05916-3 ◽

2019 ◽

Vol 154 (5) ◽

Cited By ~ 2

Author(s):

Alessandro Pileri ◽

Carlotta Baraldi ◽

Alessandro Broccoli ◽

Roberto Maglie ◽

Annalisa Patrizi ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Leukocytoclastic Vasculitis ◽

Lymphocytic Leukemia ◽

Cell Chronic Lymphocytic Leukemia

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Faculty Opinions recommendation of The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1005104.59404 ◽

2002 ◽

Author(s):

Guy Laurent

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Tumor Cell ◽

B Cell ◽

Lymphocytic Leukemia ◽

Apoptosis Induction ◽

Caspase Activation ◽

Cell Clearance ◽

Cell Chronic Lymphocytic Leukemia

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Faculty Opinions recommendation of MicroRNA as biomarkers and regulators in B-cell chronic lymphocytic leukemia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.11671956.12741054 ◽

2011 ◽

Author(s):

Varsha Gandhi ◽

Kumudha Balakrishnan

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Lymphocytic Leukemia ◽

Cell Chronic Lymphocytic Leukemia

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Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia

Journal of Experimental Medicine ◽

10.1084/jem.194.11.1639 ◽

2001 ◽

Vol 194 (11) ◽

pp. 1639-1648 ◽

Cited By ~ 766

Author(s):

Andreas Rosenwald ◽

Ash A. Alizadeh ◽

George Widhopf ◽

Richard Simon ◽

R. Eric Davis ◽

...

Keyword(s):

Gene Expression ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Germ Line ◽

Gene Expression Signature ◽

Lymphocytic Leukemia ◽

Common Mechanism ◽

Human Leukemia ◽

Mutational Status ◽

Cell Chronic Lymphocytic Leukemia

The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malignancy of mature B cells with a characteristic clinical presentation but a variable clinical course. The rearranged immunoglobulin (Ig) genes of CLL cells may be either germ-line in sequence or somatically mutated. Lack of Ig mutations defined a distinctly worse prognostic group of CLL patients raising the possibility that CLL comprises two distinct diseases. Using genomic-scale gene expression profiling, we show that CLL is characterized by a common gene expression “signature,” irrespective of Ig mutational status, suggesting that CLL cases share a common mechanism of transformation and/or cell of origin. Nonetheless, the expression of hundreds of other genes correlated with the Ig mutational status, including many genes that are modulated in expression during mitogenic B cell receptor signaling. These genes were used to build a CLL subtype predictor that may help in the clinical classification of patients with this disease.

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