More on the determination of Ki-67 as a novel potential prognostic marker in B-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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Individual features of the pharmacokinetics of fludarabin phosphate in the treatment of patients with chronic lymphocytic leukemia

Kachestvennaya klinicheskaya praktika ◽

10.37489/2588-0519-2021-2-67-77 ◽

2021 ◽

pp. 67-77

Author(s):

G. G. Rodionov ◽

I. I. Shantyr ◽

V. B. Vasilyuk ◽

E. A. Kolobova ◽

E. V. Svetkina ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Quantitative Determination ◽

Blood Plasma ◽

B Cell ◽

Individual Variability ◽

Lymphocytic Leukemia ◽

Pharmacokinetic Parameters ◽

Cell Chronic Lymphocytic Leukemia ◽

In Blood Plasma

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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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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