Acadesine (Acadra‘) for Patients with Resistant/Relapsed Chronic B-Cell Lymphocytic Leukemia (B-CLL): A Multicentre Phase I/II Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4405-4405
Author(s):  
Eric W Van Den Neste ◽  
Eva Gonzalez-Barca ◽  
Ann Janssens ◽  
Bruno Cazin ◽  
J. Pérez de Oteyza ◽  
...  
Keyword(s):  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
B Cell ◽  
Dose Escalation ◽  
Safety Profile ◽  
Whole Blood ◽  
Lymphocytic Leukemia ◽  
Pharmacokinetic Data ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Abstract 4405 Acadesine (Acadra‘) is a nucleoside that induces cell death in B-cell chronic lymphocytic leukemia (B-CLL) cells ex vivo in a dose-dependent manner over the concentration range 50 mM to 1 mM. Acadesine enters B-cells and is phosphorylated to its active metabolite, ZMP, which induces apoptosis independently of ATM or p53. It is active against B-CLL cells from patients who have not responded to prior treatment with fludarabine and/or chlorambucil (Campas et al, 2003). Based on this pre-clinical data, a Phase I/II clinical study was designed to determine the safety and tolerability of acadesine given intravenously as a 4-hour infusion to patients with B-CLL. This is an open-label dose escalation study of acadesine with two parts. In Part I, the dose escalation part of the study, patients receive a single dose of acadesine on Day 1 and are followed up to Day 22. In Part II, patients will receive up to 5 doses of acadesine at the maximum tolerated dose (MTD) identified in Part I over a period of up to 20 days starting on Day 1. The patient population includes B-CLL patients with refractory or relapsed disease who have received one or more (≥ 1) prior lines of treatment which must have included either a fludarabine or an alkylator based regimen. Primary endpoints of the study evaluate the safety and tolerability of acadesine. Secondary endpoints evaluate the pharmacokinetics of acadesine in plasma, its metabolite ZMP in whole blood, and changes in peripheral blood B-cell and T-cell counts as efficacy biomarkers. Optimal Biological Dose (OBD) is defined as the minimal acadesine dose that gives a maximum Cmax for ZMP in whole blood with a good safety profile. Twelve patients (6 males and 6 females) have been administered acadesine to date in 3 cohorts in Part I. Acadesine has an excellent safety profile to date. The principal safety finding was asymptomatic acadesine-related hyperuricaemia of short duration in four patients. Prophylactic allopurinol has significantly reduced the incidence of hyperuricaemia. Pharmacokinetic data showed acadesine rapidly disappears from plasma to be converted into ZMP inside blood cells. The OBD has not been reached yet and maximum dose administered to date is 139.5 mg/kg. The next cohort will receive 210 mg/kg. Additional safety, pharmacokinetics and efficacy data will be presented at the meeting. Disclosures: Off Label Use: Acadesine (AcadraTM): nucleoside that induces cell death in B-cell chronic lymphocytic leukemia.. Auton:BTG Limited: Consultancy; Advancell Technologies Inc.: Consultancy. Saunders:BTG limited: Consultancy; Advancell Technologies: Consultancy. Campas:Advancecell Technologies Inc: Employment, Equity Ownership.

scholarly journals Interferon gamma inhibits apoptotic cell death in B cell chronic lymphocytic leukemia.

1993 ◽  
Vol 177 (1) ◽  
pp. 213-218 ◽  
Author(s):  
M Buschle ◽  
D Campana ◽  
S R Carding ◽  
C Richard ◽  
A V Hoffbrand ◽  
...  
Keyword(s):  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Programmed Cell Death ◽  
B Cell ◽  
Interferon Gamma ◽  
Lymphocytic Leukemia ◽  
Malignant Cells ◽  
Ifn Gamma ◽  
Cell Chronic Lymphocytic Leukemia

The malignant, CD5+ B lymphocytes of B cell chronic lymphocytic leukemia (B-CLL) die by apoptosis in vitro. This is in contrast to the prolonged life span of the leukemic cells in vivo and likely reflects the lack of essential growth factors in the tissue culture medium. We found that interferon gamma (IFN-gamma) inhibits programmed cell death and promotes survival of B-CLL cells in culture. This effect may also be important in vivo: increased serum levels of IFN-gamma, ranging from 60 to > 2,200 pg/ml, were found in 7 of 10 B-CLL samples tested, whereas the sera of 10 healthy individuals did not contain detectable levels of this cytokine (< 20 pg/ml). High levels of IFN-gamma message were detected in RNA from T cell-depleted B-CLL peripheral blood samples by Northern blot analysis. Synthesis of IFN-gamma by B-CLL lymphocytes was confirmed by in situ hybridization and flow cytometry. The majority of B-CLL cells (74-82%) expressed detectable levels of IFN-gamma mRNA, and CD19+ B-CLL cells were labeled with anti-IFN-gamma monoclonal antibodies. These results show that IFN-gamma inhibits programmed cell death in B-CLL cells and suggest that the malignant cells are able to synthesize this cytokine. By delaying apoptosis, IFN-gamma may extend the life span of the malignant cells and thereby contribute to their clonal accumulation.

Acadesine for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL): A Multicentre Phase I/II Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4625-4625
Author(s):  
Eric Van den Neste ◽  
Bruno Cazin ◽  
Ann Janssens ◽  
Eva González-Barca ◽  
María José Terol ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Partial Response ◽  
Phase I ◽  
B Cell ◽  
Cell Count ◽  
Lymphocytic Leukemia ◽  
Pharmacokinetic Data ◽  
Dependent Manner ◽  
Refractory Disease ◽  
Grade 3

Abstract Abstract 4625 CLL - Therapy, excluding Transplantation Acadesine induces cell death in B-cell chronic lymphocytic leukemia (CLL) cells in a dose-dependent manner. Acadesine enters B-cells where it is phosphorylated to ZMP, which induces apoptosis independently of ATM or p53. It is active in vitro against CLL cells from patients who have not responded to prior treatment with fludarabine and/or chlorambucil. A phase I/II open-labeled clinical study was designed to determine the safety and tolerability of acadesine given intravenously as a 4-hour infusion to patients with CLL. Part I is the dose escalation part of the study where patients receive a single dose of acadesine on Day 1 and are followed up to Day 22. In Part II, patients will receive up to 5 doses of acadesine at the maximum tolerated dose (MTD) identified in Part I over a period of up to 20 days. Patient population includes CLL patients with relapsed/refractory disease who have received one or more prior lines of treatment including either a fludarabine or an alkylator-based regimen. A patient is defined as having refractory disease if they fail to achieve less than a partial response (PR) according to the NCI working group guidelines, or relapse within the first 6 months after treatment after achieving at least partial response. Primary endpoints of the study evaluate the safety and tolerability of acadesine. Secondary endpoints evaluate the pharmacokinetics of acadesine and ZMP, and B and T-cell counts in peripheral blood as efficacy biomarkers. Twenty-one patients have been included to date, eighteen in Part I at doses of 50, 83.5, 139.5, 210 or 315 mg/kg, and three in Part II, with two doses at 210 mg/kg at days 1 and 4. Pharmacokinetic data showed acadesine is rapidly converted into ZMP inside blood cells. In part I, at single acadesine dose, the Cmax levels for ZMP in whole blood obtained at 315 mg/kg were similar to the ones obtained at the previous dose (210 mg/kg), suggesting that the saturation plateau was reached, which was confirmed by the PK modeling. In 5 patients treated with acadesine at 210 mg/kg and 315 mg/kg a decrease in absolute B cell count was observed, ranging from 6% to 54% with respect to the B cell count prior to acadesine administration. Reversible asymptomatic hyperuricaemia was observed in four patients in cohorts 1 to 3, probably due the metabolism of acadesine to ZMP and uric acid. Prophylactic allopurinol was used in cohorts 4 and 5 and it has significantly reduced the incidence of hyperuricaemia. Acadesine 315 mg/kg was the dose limiting toxicity (DLT) dose with 2 of 3 patients having DLTs-Tumour Lysis Syndrome (TLS) and clinically significant acute renal failure (CTCAE V3.0 Grade 3-chronic dialysis not indicated). We started Part II of the study, with two consecutive doses at 210 mg/kg (Optimal Biological Dose). Three patients have been included to date. No DLT nor grade 3 or 4 Adverse Events related to acadesine were observed, and in all of treated patients a decrease in absolute B cell count was observed ranging from 6% to 35% with respect to the B cell count prior to acadesine administration. In the following cohort, we will administer 5 consecutive doses of acadesine at 210 mg/kg, at days 1, 4, 8, 11 and 15. In conclusion, a MTD was found at one single acadesine dose. Two consecutive doses have already been tested without safety concerns and 5 consecutive doses are currently planned in part II of this ongoing study. Results for this cohort and additional safety, pharmacokinetics and efficacy data will be presented at the meeting. Disclosures: Saunders: Advancell: Consultancy. de Frias:Advancell: Employment. Campàs:Advancell: Employment.

Mevalonate pathway inhibitors in the treatment of B-cell chronic lymphocytic leukemia.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6561-6561
Author(s):  
Ravi Kiran Bobba ◽  
Indira Benakanakere ◽  
Smitha Bearelly ◽  
Monica Arya ◽  
Richard Sleigtholm ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Viability ◽  
B Cell ◽  
Combination Treatment ◽  
Mevalonate Pathway ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Cell Chronic Lymphocytic Leukemia

6561 Background: B-cell chronic lymphocytic leukemia (CLL) cells are arrested in G0/G1 phase of the cell cycle and are resistant to programmed cell death, hypothesized to contribute to the resistance of CLL cells to standard chemotherapy with curative intent. Methods: Mec-2 cells and Wac-3 cells are CLL cells that have been shown to be resistant to fludarabine and rituximab. We tested a novel enzyme inhibitor’s ability to render CLL cells sensitive to fludarabine and rituximab. Results: BIBB515, a lanosterol synthase inhibitor, at a concentration of 10μM, was able to reduce the cell viability from 82% in controls to 65% after 72 hours. Fludarabine 10μM alone did not reduce the cell viability, 82 % in controls compared to 80%. BIBB515+ fludarabine treatment for 72 hours, at the dose of 10μM each decreased the cell viability to 37%. Cell proliferation by MTT assay was 0.66±0.010 in control compared to 0.37±0.01 in BIBB515+fludarbine and 0.21±0.01 in BIBB515+ fludarabine+ rituximab. There is a 68% down-regulation of cell proliferation using this treatment. There was a two fold induction of CD 20 with combination treatment, and BIBB515 treatment. The mechanism of cell death in the combination treatment of BIBB515 and fludarabine may be due to the up regulation of cell surface marker CD-20. WAC-3 is another CLL cell line that is sensitive to fludarabine, and resistant to rituximab. BIBB515 sensitizes WAC-3 cells to CD 20 antibody rituximab. There is a 68.7% decrease in cell proliferation with combination treatment of BIBB515 and rituximab. Proliferation of Mec-2 cells were inhibited by 60µM and 30µM terbinafine. Ro-48-8071, showed dose-dependent activity, alone or in combination to fludarabine was seen to induce cell death in Mec-2 cells. Fludarabine alone did not have any effect on these cells. Conclusions: Inhibitors of the mevalonate pathway make resistant CLL cells sensitive to current chemotherapeutic agents. Exploiting this mechanism could alter the current treatment regimens, leading to control of the disease in advanced stages by either inducing the leukemic cells to be static or to regress. This strategy may also limit the toxicities involved with chemotherapy.

Phase I study of a novel pro-apoptotic drug R-etodolac in patients with B-cell chronic lymphocytic leukemia

2007 ◽  
Vol 26 (2) ◽  
pp. 139-149 ◽  
Author(s):  
Markus Jensen ◽  
Andreas Engert ◽  
Florian Weissinger ◽  
Wolfgang Knauf ◽  
Eva Kimby ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
Lymphocytic Leukemia ◽  
Cell Chronic Lymphocytic Leukemia

Immunophenotyping of B-cell chronic lymphocytic leukemia on whole blood sample

1992 ◽  
Vol 76 (2) ◽  
pp. 280-280
Author(s):  
Robillard Nelly ◽  
Garreau Yves ◽  
Garand Richard ◽  
Bataille Régis
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Blood Sample ◽  
Whole Blood ◽  
Lymphocytic Leukemia ◽  
Whole Blood Sample ◽  
Cell Chronic Lymphocytic Leukemia

Characterization of Interleukin-10 Receptor Expression on B-Cell Chronic Lymphocytic Leukemia Cells

Blood ◽  
1997 ◽  
Vol 89 (11) ◽  
pp. 4146-4152 ◽  
Author(s):  
Jesper Jurlander ◽  
Chun-Fai Lai ◽  
Jimmy Tan ◽  
Chuan-Chu Chou ◽  
Christian H. Geisler ◽  
...  
Keyword(s):  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Interleukin 10 ◽  
Receptor Activation ◽  
Lymphocytic Leukemia ◽  
Receptor Expression ◽  
Interferon Α ◽  
Ifn Γ ◽  
Cell Chronic Lymphocytic Leukemia

Abstract B-cell chronic lymphocytic leukemia (B-CLL) cells accumulate in vivo in the G0/G1 phase of the cell cycle, suggesting that their malignant expansion is due, at least in part, to a delay in cell death. However, the cellular or molecular factors responsible for a delay in B-CLL cell death are unknown. B-CLL cells do express receptors for interferon-α (IFN-α) and IFN-γ, and activation of both has been shown to promote B-CLL survival in vitro by preventing apoptosis. The interleukin-10 (IL-10) receptor is another member of the IFN receptor family, but its ligand, IL-10, has been reported to induce apoptosis in B-CLL cells. In the current study, we undertook a biochemical analysis of IL-10 receptor expression on freshly isolated B-CLL cells and characterized the functional responsiveness of IL-10 binding to its constitutively expressed receptor. We show that B-CLL cells bind IL-10 with significant specificity and express between 47 and 127 IL-10 receptor sites per cell, with a dissociation constant in the range of 168 to 426 × 10−12 mol/L. Ligand binding and activation of the IL-10 receptor expressed on B-CLL cells results in the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 proteins. This pattern of STAT protein phosphorylation is identical to IL-10 receptor activation on normal cells and similar to IFN-α (STAT1 and STAT3) and IFN-γ (STAT1) receptor activation in CLL. Further, in consecutive samples of fresh blood obtained from patients with B-CLL cells, the addition of IL-10 inhibited B-CLL proliferation, enhanced B-CLL differentiation, but did not induce apoptosis. Indeed, IL-10, like IFN-γ, was able to significantly reduce the amount of B-CLL cell death caused by hydrocortisone-induced apoptosis. We conclude that cytokines, which signal through the interferon family of receptors, have comparable functional effects on B-CLL cells.

Sign in / Sign up

Export Citation Format

Share Document