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.

Diagnostic Utility of CD200 and CD43 Co-Expression by Flow Cytometry In Differentiating Chronic Lymphocytic Lymphoma From Other of Mature B Cell Non Hodgkin's Lymphoma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4615-4615
Author(s):  
Papagudi Ganesan Subramanian ◽  
Vijaya Siddharth Gadage ◽  
Ashok Kumar ◽  
Yajamanam Badrinath ◽  
Sitaram Ghogale ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Peripheral Blood ◽  
Hodgkin’S Lymphoma ◽  
Lymphocytic Leukemia ◽  
Hodgkin's Lymphoma ◽  
Low Grade ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma

Abstract Abstract 4615 Diagnosis and subtyping of mature B cell Non-Hodgkin's lymphoma (NHL) in the bone marrow (BM) and peripheral blood in a leukemic phase may be challenging due to overlapping cell morphology and immunophenotypic features. This study aims to investigate the utility of CD200 and CD43 co-expression on lymphoid cells in differential diagnosis of mature B cell Non-Hodgkin's lymphoma by flow cytometry (FCM). CD200, known as OX-2 protein was first purified in 1982 as a type I membrane glycoprotein membrane of the Ig superfamily is postulated to play an immunoregulatory role in tumors. A prospective study of staging and diagnostic BM aspirates or peripheral blood samples for immunophenotyping from all consecutive cases of suspected Lymphomas referred to our center over a period of 3 months was done. Co-expression was determined by 3 color FCM. An additional tube with Fluorescein Isothiocyanate conjugated anti CD43, Phycoerythrin conjugated anti CD200 and Phycoerythrin cyanine5 conjugated CD19 was added to the routine panel of antibodies used for immunophenotyping in all the samples. Diagnostic utility of CD200 and CD43 co-expression was determined by comparison with Gold standard diagnosis made out of a combination of clinical features, morphology of tissue biopsies, FCM, immunohistochemistry and cytogenetics using Fluorescent insitu Hybridisation (FISH) for translocations involving IgH gene. Total 116 patients of suspected cases of Lymphomas were referred to our laboratory during the period of study. In addition to Bone marrow and peripheral blood FCM evaluation was done in ascitic fluid (n=1) and pleural fluid (n=3) and FNAC of lymph node (n=1) and retro-orbital mass FNAC (n=1). Out of these, 60 patients showed involvement by mature B cell NHL. Age range of the patients was 26 years to 86 years (Male:Female = 48:12). Chronic Lymphocytic Leukemia (CLL) was the commonest subtype (43.3%, 26/60) followed by follicular lymphoma (16.6%, 10/60), Diffuse Large B-cell Lymphoma (DLBCL) (13.3%, 8/60), Mantle cell lymphoma (MCL) (8.3%, 5/60), Splenic Marginal Zone Lymphoma (SMZL) (5.0%, 3/60), Hairy cell leukemia variant (HCLv) and Waldenstrom's Macroglobulinemia (3.3%, 2/60 each), one patient each (3.3%, 1/60) of Chronic Lymphocytic Leukemia/Prolymphocytic leukemia (CLL/PL), Prolymphocytic leukemia (PL) and Burkitt's Lymphoma. One patient was of unclassifiable low grade B-cell NHL presenting with splenomegaly and pancytopenia with bone marrow involvement and no lymphadenopathy and absence of any trans locations involving IgH gene.This patient had the immunophenotype of CD19, CD22, CD23, CD25, CD79b, CD200 and Kappa positive, with CD20 dim+ and CD5, CD11c, CD103, CD123 and CD43 negative. Annexin A1 was negative in the bone marrow biopsy. The detailed distribution of expression of CD200 and CD43 is given in Table 1.Table 1DiagnosisCD200 pos CD43 posCD200 pos CD43 negCD200 neg CD43 negCD200 neg CD43 posTOTALCLL2600026CLL/PL10001Follicular Lymphoma027110Splenic Marginal Zone Lymphoma02103Hairy cell leukemia variant00202Diffuse large B Cell Lymphoma12328Burkitts Lymphoma00101Small cell/Low grade B Cell Non-Hodgkins Lymphoma01001Mantle Cell Lymphoma00415Prolymphocytic Lymphoma10001Waldenstrom's macroglobulinemia02002Total29918460 Amongst all, CD200 and CD43 co-expression was noted in all cases of CLL, CLL/PL, PLL and only one case of DLBCL. This case of DLBCL was negative for CD5. The truth table for same is given in Table 2.Table 2CD43 and CD200CLL and related NHLNon CLL NHLTotalCoexpression present28129Coexpression absent03131Total283260 The sensitivity specificity data is given in Table 3.Table 3Specificity96.88%Sensitivity100%Positive predictive value96.55%Negative predictive value100% Conclusion: 1. Absence of CD200 and CD43 co-expression strongly rules out a diagnosis of chronic lymphocytic leukemia and related neoplasms. 2. In the differential diagnosis CD5 positive NHL, CD200 positivity strongly suggests the diagnosis of CLL/PLL or PLL. Disclosures: No relevant conflicts of interest to declare.

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.

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