Cytokine-Release Syndrome in Patients With B-Cell Chronic Lymphocytic Leukemia and High Lymphocyte Counts After Treatment With an Anti-CD20 Monoclonal Antibody (Rituximab, IDEC-C2B8)

Blood ◽  
1999 ◽  
Vol 94 (7) ◽  
pp. 2217-2224 ◽  
Author(s):  
U. Winkler ◽  
M. Jensen ◽  
O. Manzke ◽  
H. Schulz ◽  
V. Diehl ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
B Cell ◽  
Tumor Cells ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Anti Cd20 ◽  
Cell Chronic Lymphocytic Leukemia

Eleven patients with relapsed fludarabine-resistant B-cell chronic lymphocytic leukemia (CLL) or leukemic variants of low-grade B-cell non-Hodgkin’s lymphoma (NHL) were treated with the chimeric monoclonal anti-CD20 antibody rituximab (IDEC-C2B8). Peripheral lymphocyte counts at baseline varied from 0.2 to 294.3 × 109/L. During the first rituximab infusion, patients with lymphocyte counts exceeding 50.0 × 109/L experienced a severe cytokine-release syndrome. Ninety minutes after onset of the infusion, serum levels of tumor necrosis factor- (TNF-) and interleukin-6 (IL-6) peaked in all patients. Elevated cytokine levels during treatment were associated with clinical symptoms, including fever, chills, nausea, vomiting, hypotension, and dyspnea. Lymphocyte and platelet counts dropped to 50% to 75% of baseline values within 12 hours after the onset of the infusion. Simultaneously, there was a 5-fold to 10-fold increase of liver enzymes, d-dimers, and lactate dehydrogenase (LDH), as well as a prolongation of the prothrombin time. Frequency and severity of first-dose adverse events were dependent on the number of circulating tumor cells at baseline: patients with lymphocyte counts greater than 50.0 × 109/L experienced significantly more adverse events of National Cancer Institute (NCI) grade III/IV toxicity than patients with less than 50.0 × 109/L peripheral tumor cells (P= .0017). Due to massive side effects in the first patient treated with 375 mg/m2 in 1 day, a fractionated dosing schedule was used in all subsequent patients with application of 50 mg rituximab on day 1, 150 mg on day 2, and the rest of the 375 mg/m2 dose on day 3. While the patient with the leukemic variant of the mantle-cell NHL achieved a complete remission (9 months+) after treatment with 4 × 375 mg/m2 rituximab, efficacy in patients with relapsed fludarabine-resistant B-CLL was poor: 1 partial remission, 7 cases of stable disease, and 1 progressive disease were observed in 9 evaluable patients with CLL. On the basis of these data, different infusion schedules and/or combination regimens with chemotherapeutic drugs to reduce tumor burden before treatment with rituximab will have to be evaluated.

Pharmacokinetic Study of Single Doses of Oral Fludarabine Phosphate in Patients With “Low-Grade” Non-Hodgkin's Lymphoma and B-Cell Chronic Lymphocytic Leukemia

1999 ◽  
Vol 17 (5) ◽  
pp. 1574-1574 ◽  
Author(s):  
James M. Foran ◽  
David Oscier ◽  
Jennifer Orchard ◽  
Stephen A. Johnson ◽  
Mary Tighe ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Intravenous Administration ◽  
Pharmacokinetic Study ◽  
Lymphocytic Leukemia ◽  
Hodgkin's Lymphoma ◽  
Low Grade ◽  
Fludarabine Phosphate ◽  
Non Hodgkin's Lymphoma ◽  
Cell Chronic Lymphocytic Leukemia

PURPOSE: Fludarabine phosphate (F-AMP), a purine analog, requires daily intravenous administration. A pharmacokinetic study of an oral formulation (10 mg immediate-release tablet) was undertaken in patients with “low-grade” non-Hodgkin's lymphoma and B-cell chronic lymphocytic leukemia. PATIENTS AND METHODS: Oral F-AMP was incorporated into the “conventional” treatment schedule. Single oral trial doses of 50, 70, and 90 mg of F-AMP were given on the first day of three cycles of treatment; a comparative 50-mg intravenous trial dose was given on the first day of the fourth cycle. Intravenous F-AMP (25 mg/m2) was given on days 2 to 5 at 4-week intervals. Pharmacokinetic samples taken after each trial dose were analyzed for plasma 2-fluoro-arabinofuranosyl-adenine (2F-ara-A) concentration (its main metabolite); area under the curve 0 to 24 hours (AUC(0-24h)) and maximum concentration (Cmax) were calculated. Eighteen patients received all three oral trial doses, and bioavailability was determined in 15 patients who completed four courses of therapy. RESULTS: Oral administration of F-AMP resulted in a dose-dependent increase in Cmax and AUC(0-24h) of 2F-ara-A and achieved an AUC(0-24h) similar to intravenous administration, although at a lower Cmax. The linear increase in mean AUC(0-24h) by factors of 1.36 ± 0.22 (mean ± SD) and 1.72 ± 0.31 corresponded well with the increase in oral dose from 50 to 70 mg (factor of 1.4) and 90 mg (factor of 1.8), respectively. Bioavailability (approximately 55%, with low intraindividual variation) and time to Cmax were dose independent. CONCLUSION: Oral doses of F-AMP can achieve an AUC(0-24h) of 2F-ara-A similar to intravenous administration, with dose-independent bioavailability. The tablet will greatly enhance the use of F-AMP in a palliative setting.

scholarly journals bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia

Blood ◽  
1993 ◽  
Vol 82 (6) ◽  
pp. 1820-1828 ◽  
Author(s):  
M Hanada ◽  
D Delia ◽  
A Aiello ◽  
E Stadtmauer ◽  
JC Reed
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Lines ◽  
Methylation Status ◽  
Peripheral Blood Lymphocytes ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Gene Rearrangements ◽  
Normal Peripheral Blood ◽  
Cell Chronic Lymphocytic Leukemia

Abstract The bcl-2 gene becomes transcriptionally deregulated in the majority of low-grade non-Hodgkin lymphomas as a result of t(14;18) translocations that place the bcl-2 gene at 18q21 into juxtaposition with the Ig heavy- chain locus at 14q32. This chromosomal translocation or similar bcl-2 gene rearrangements involving the Ig light-chain genes have been reported to occur in some cases of B-cell chronic lymphocytic leukemia (B-CLL). We analyzed the structure, methylation, and expression of the bcl-2 gene in 20 cases of B-CLL or closely related variants of this lymphoproliferative disorder, including at least 16 typical examples of CD5+ B-CLL. None of the 20 specimens had evidence of bcl-2 gene rearrangements, based on Southern blot analysis using three different bcl-2 probes. However, immunoblot analysis using antibodies specific for the Bcl-2 protein showed that 14 of 20 cases (70%) contained levels of p26-Bcl-2 that were equal to or greater than those found in a t(14;18)-bearing lymphoma cell line. Furthermore, in 19 of 20 cases (95%), the Bcl-2 protein was present at levels that were 1.7- to 25- fold higher than in normal peripheral blood lymphocytes. These differences in the relative levels of Bcl-2 protein among cases of B- CLL appeared to be functionally significant, in that a preliminary analysis of 3 representative cases showed that CLL cells with higher levels of Bcl-2 protein survived longer in culture and were delayed in their onset of DNA degradation relative to CLL cells with lower Bcl-2 protein levels. Evaluation of the methylation status of the bcl-2 gene using the isoschizomers Msp I and Hpa II, and a probe corresponding to the first major exon of the gene showed complete demethylation of both copies of the bcl-2 gene in a region corresponding to a 2.4-kb Msp I fragment in all 20 cases of B-CLL. In contrast, analysis of 6 of 6 B- cell lines that harbor a t(14;18) was consistent with hypomethylation of only one of the two bcl-2 alleles. Neither copy of the bcl-2 gene was demethylated in this region in 5 of 5 lymphoid cell lines that lack this translocation. However, hypomethylation of the bcl-2 gene did not necessarily correlate with the relative levels of Bcl-2 protein present in the B-CLL cells, suggesting that additional mechanisms for regulating bcl-2 expression are involved.(ABSTRACT TRUNCATED AT 400 WORDS)

Anti-CD20 monoclonal antibody rituximab for the treatment of B-cell chronic lymphocytic leukemia-associated pure red cell aplasia

2004 ◽  
Vol 5 (6) ◽  
pp. 546-547 ◽  
Author(s):  
Despina Pantelidou ◽  
Costas Tsatalas ◽  
Dimitris Margaritis ◽  
Vasiliki Kaloutsi ◽  
Emmanuel Spanoudakis ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Pure Red Cell Aplasia ◽  
Lymphocytic Leukemia ◽  
Red Cell ◽  
Red Cell Aplasia ◽  
Anti Cd20 ◽  
Cell Chronic Lymphocytic Leukemia

The chimeric anti-CD20 antibody rituximab induces apoptosis in B-cell chronic lymphocytic leukemia cells through a p38 mitogen activated protein–kinase–dependent mechanism

Blood ◽  
2002 ◽  
Vol 99 (4) ◽  
pp. 1314-1319 ◽  
Author(s):  
Irene Munk Pedersen ◽  
Anne Mette Buhl ◽  
Pia Klausen ◽  
Christian H. Geisler ◽  
Jesper Jurlander
Keyword(s):  
Protein Kinase ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphocytic Leukemia ◽  
Cross Linking ◽  
Mitogen Activated Protein ◽  
Cd20 Antibody ◽  
Induction Of Apoptosis ◽  
Anti Cd20 ◽  
Cell Chronic Lymphocytic Leukemia

Antibodies against CD20 can activate complement and induce antibody-dependent cellular cytotoxicity (ADCC) in B lymphocytes. In B-cell lines, such antibodies also induce apoptosis. In this study, the expression and function of CD20 on B-cell chronic lymphocytic leukemia (B-CLL) cells were analyzed. Flow cytometric analysis demonstrated that B-CLL cells express CD20 with a fluorescence intensity that is significantly weaker than that of normal CD5+ and CD5− B cells and that of malignant CD5− low-grade non-Hodgkin lymphoma cells. A small population of cells from healthy donors that have an expression pattern of CD5 and CD20 identical to that of B-CLL cells were identified, and this population was confirmed to be of T lineage, not B lineage. Culture of freshly isolated B-CLL cells in the presence of the chimeric anti-CD20 antibody rituximab and a cross-linking F(ab)2 fragment, resulted in dose- and time-dependent induction of apoptosis. The induction of apoptosis occurred under conditions in which the influence of complement activation and ADCC was negligible. Cross-linking of rituximab induced strong and sustained phosphorylation of the 3 mitogen activated protein (MAP) kinases c-Jun NH2-terminal protein kinase, extracellular signal–regulated kinase, and p38. Introduction of the p38 inhibitor SB203580 into the system completely blocked signaling downstream of p38, as evidenced by the absence of MAPKAP K2 activity, and significantly reduced the degree of anti-CD20–induced apoptosis. These results demonstrate that cross-linking of rituximab bound to CD20 on freshly isolated B-CLL cells induces apoptosis through a signaling pathway that is dependent on p38 MAP-kinase activation.

scholarly journals bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia

Blood ◽  
1993 ◽  
Vol 82 (6) ◽  
pp. 1820-1828 ◽  
Author(s):  
M Hanada ◽  
D Delia ◽  
A Aiello ◽  
E Stadtmauer ◽  
JC Reed
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Lines ◽  
Methylation Status ◽  
Peripheral Blood Lymphocytes ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Gene Rearrangements ◽  
Normal Peripheral Blood ◽  
Cell Chronic Lymphocytic Leukemia

The bcl-2 gene becomes transcriptionally deregulated in the majority of low-grade non-Hodgkin lymphomas as a result of t(14;18) translocations that place the bcl-2 gene at 18q21 into juxtaposition with the Ig heavy- chain locus at 14q32. This chromosomal translocation or similar bcl-2 gene rearrangements involving the Ig light-chain genes have been reported to occur in some cases of B-cell chronic lymphocytic leukemia (B-CLL). We analyzed the structure, methylation, and expression of the bcl-2 gene in 20 cases of B-CLL or closely related variants of this lymphoproliferative disorder, including at least 16 typical examples of CD5+ B-CLL. None of the 20 specimens had evidence of bcl-2 gene rearrangements, based on Southern blot analysis using three different bcl-2 probes. However, immunoblot analysis using antibodies specific for the Bcl-2 protein showed that 14 of 20 cases (70%) contained levels of p26-Bcl-2 that were equal to or greater than those found in a t(14;18)-bearing lymphoma cell line. Furthermore, in 19 of 20 cases (95%), the Bcl-2 protein was present at levels that were 1.7- to 25- fold higher than in normal peripheral blood lymphocytes. These differences in the relative levels of Bcl-2 protein among cases of B- CLL appeared to be functionally significant, in that a preliminary analysis of 3 representative cases showed that CLL cells with higher levels of Bcl-2 protein survived longer in culture and were delayed in their onset of DNA degradation relative to CLL cells with lower Bcl-2 protein levels. Evaluation of the methylation status of the bcl-2 gene using the isoschizomers Msp I and Hpa II, and a probe corresponding to the first major exon of the gene showed complete demethylation of both copies of the bcl-2 gene in a region corresponding to a 2.4-kb Msp I fragment in all 20 cases of B-CLL. In contrast, analysis of 6 of 6 B- cell lines that harbor a t(14;18) was consistent with hypomethylation of only one of the two bcl-2 alleles. Neither copy of the bcl-2 gene was demethylated in this region in 5 of 5 lymphoid cell lines that lack this translocation. However, hypomethylation of the bcl-2 gene did not necessarily correlate with the relative levels of Bcl-2 protein present in the B-CLL cells, suggesting that additional mechanisms for regulating bcl-2 expression are involved.(ABSTRACT TRUNCATED AT 400 WORDS)

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