RITUXAN
Over the past 12+ years with leukemia, I have used the monoclonal antibody drug, Rituxan on four occasions. The first exposure resulted in a near-fatal reaction. It was the only time I was pushed on a stretcher with people running me to ICU. After the completion of that round of treatment, I was covered in a head to toe rash (that itched something fierce) for six weeks. The second and third exposures to Rituxan resulted in a case of pneumonia and need for Red Blood Cell transfusions. My last use of Rituxan was in 2004. I developed five infections associated with that treatment and spent almost two weeks in ICU.
Despite this past history, in my heart and through my research, I believe it remains the safest treatment option for me. To learn more about Rituxan go to: http://www.rituxan.com/lymphoma/hcp/index.m
In addition to receiving this treatment for eight weeks, combined with my long list of supplements, there are a few prescription drugs that will be engaged to boost the effectiveness of this drug and to help prevent reactions.
NEUPOGEN
Most of you are aware that I have been chronically neutropenic since early 2009 (the cause of the serious fungal infections, in my humble opinion). I have been taking Neupogen every 7-10 days in an attempt to maintain a neutrophil count outside of neutropenic levels. This enables my body to fight serious infections, especially life-threatning gram negative infections and septicemia.
Additional benefits of Neupogen have emerged in relation to Rituxan treatments. I will be taking these injections to treat ongoing neutropenia and to help battle ongoing infections. I also will be taking it to prevent Rituxan-induced neutropenia. Review these abstracts to see what potential new benefits might be derived for me as I combine Rituxan with Neupogen.
Phase 3 Study Shows First-Cycle Administration Of Neulasta Significantly Lowers Incidence Of Infection And Hospitalization
Amgen Inc. (Nasdaq:AMGN), the world's largest biotechnology company, today announced data from a Phase 3 study showing that administration of Neulasta(R) (pegfilgrastim) in the first and subsequent cycles of chemotherapy significantly lowers the rate of infection, as manifested by febrile neutropenia (low white blood cell count with fever), hospitalization and the use of intravenous anti-infectives in breast cancer patients receiving moderately myelosuppressive (strong) chemotherapy. The results will be presented by one of the study's lead investigators, Lee Schwartzberg, M.D., medical director of The West Clinic, Memphis, Tenn., in a plenary session tomorrow at the Multinational Association of Supportive Care in Cancer (MASCC) Annual Meeting. (MASCC Abstract #A-52)"This study provides compelling evidence that administering Neulasta in the first and subsequent cycles of moderately myelosuppressive chemotherapy can significantly reduce the risk of potentially life- threatening infections that can result in hospitalizations and require IV antibiotics," said Schwartzberg. "Approximately 600,000 chemotherapy patients are at risk for developing neutropenia, which has traditionally been treated reactively. Doctors usually reserve proactive use of Neulasta for only those patients considered at very high risk of developing chemotherapy-induced neutropenia."Data from the randomized, double-blind, placebo-controlled study of 928 patients show that first and subsequent-cycle administration of Neulasta resulted in a 94 percent reduction in the incidence of febrile neutropenia, a 93 percent reduction in the incidence of hospitalization and an 80 percent reduction in the incidence of intravenous anti-infective use in patients previously considered at moderate risk for neutropenic complications.Specifically, one percent of patients in the Neulasta arm (6/463) developed febrile neutropenia compared with 17 percent of patients in the placebo arm (78/465). Neulasta was also associated with a significantly lower incidence of hospitalizations with one percent of patients (6/463) requiring hospitalization versus 14 percent of patients receiving placebo (64/465). Two percent of patients in the Neulasta arm (7/463) required intravenous anti-infectives versus 10 percent of patients in the placebo arm (48/465). Febrile neutropenia occurred most often in placebo patients during the first cycle of chemotherapy (65 percent). There were two deaths from septic shock on the placebo arm compared to zero in the Neulasta arm."This study may give physicians the evidence they need to help protect cancer patients from chemotherapy-induced neutropenic complications beginning in the first cycle of chemotherapy treatment," added Schwartzberg.Breast cancer patients (Stage 1-4; ECOG performance of 0-2) receiving 100 mg/m2 docetaxel every three weeks for up to four cycles were randomized to receive either 6 mg Neulasta (n=463) or placebo (n=465) once-per-cycle on the day after docetaxel administration for up to four cycles. Docetaxel is associated with an average reported febrile neutropenia incidence of approximately 10 to 20 percent in the absence of growth factor support. Febrile neutropenia was defined as a temperature greater than or equal to 38.2 degrees C and an absolute neutrophil count (ANC) less than 0.5 x 109/L measured the same day or the day after fever was documented.Neulasta was well-tolerated in this study. Bone pain was the most frequently observed adverse event in both arms of the study (31 percent with Neulasta versus 27 percent with placebo). A lower percentage of serious adverse events were reported for Neulasta patients compared with placebo patients (12 percent versus 24 percent); this difference was attributable to the lower percentage of febrile neutropenia events reported in Neulasta patients compared with placebo patients.
Leukemia. 2003 Aug;17(8):1658-64.
Treatment of relapsed B-cell non-Hodgkin's lymphoma with a combination of chimeric anti-CD20 monoclonal antibodies (rituximab) and G-CSF: final report on safety and efficacy.
van der Kolk LE, Grillo-Lopez AJ, Baars JW, van Oers MH.Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands.
Antibody-dependent cellular cytotoxicity (ADCC) is one of the possible mechanisms of action of the chimeric CD20 monoclonal antibody IDEC-C2B8 (rituximab). As granulocyte-colony stimulating factor (G-CSF) greatly enhances the cytotoxicity of neutrophils in ADCC, the efficacy of rituximab might be enhanced by the addition of G-CSF. In a phase I/II clinical trial, we investigated the safety and efficacy of the combination of rituximab and G-CSF (5 microg/kg/day, administered for 3 days, starting 2 days before each infusion) in 26 relapsed low-grade lymphoma patients. Adverse events occurred in 25/26 patients and mainly consisted of (grade I/II) fever (29%) and allergic reactions (19%). In phases I and II (375 mg/m(2) rituximab+G-CSF), 19 patients were evaluable for efficacy. The response rate was 42% (8/19; 95% CI 20-67%), with 16% (3/19) complete remissions and 26% (5/19) partial remissions. The median duration of response was 18 months, the median time to progression was 24 months. We conclude that the combination of rituximab and G-CSF is well tolerated. Although the overall response rate seems comparable to that reported for rituximab monotherapy, remission duration in this pilot phase II study is remarkably long. Randomized comparison with rituximab monotherapy should substantiate this promising finding.
PMID: 12886256
Clin Cancer Res. 2003 Dec 1;9(16 Pt 1):5866-73.
Neutrophils contribute to the biological antitumor activity of rituximab in a non-Hodgkin's lymphoma severe combined immunodeficiency mouse model.
Hernandez-Ilizaliturri FJ, Jupudy V, Ostberg J, Oflazoglu E, Huberman A, Repasky E, Czuczman MS.Department of Medicine, Roswell Park Cancer Institute Buffalo, New York 14263,
PURPOSE: Rituximab is a chimeric antibody (Ab) directed against the cluster designated (CD) 20 antigen found on normal and malignant B cells. Rituximab activity has been associated with complement-mediated cytotoxicity, Ab-dependent cellular cytotoxicity (ADCC), and induction of apoptosis. Recent studies performed in severe combined immunodeficiency (SCID) mouse models suggest that in vivo rituximab-associated ADCC is mediated via the FcgammaRIII receptor on effector cells. Despite low level expression of FcgammaRIII, neutrophils are also known to induce ADCC primarily via FcgammaRI receptor (CD64). The purpose of this work was to study the effect(s) of neutrophils on the in vivo antitumor activity of rituximab.
EXPERIMENTAL DESIGN: To better characterize the biological activity of rituximab, we used a human non-Hodgkin's lymphoma animal model by injecting Raji cells i.v. into natural killer (NK) cell-depleted SCID mice. Disseminated disease involving liver, lung, and central nervous system developed, with subsequent death occurring approximately 3 weeks after tumor inoculation. Specifically, 6-8-week-old NK cell-depleted SCID mice were inoculated by tail vein injection with 1 x 10(6) Raji cells on day 0. The animals then were divided into three cohorts: (a) group A received placebo (PBS); (b) group B received rituximab administered via tail vein injection at 10 mg/kg on days 3, 5, 7, and 11; and (c) group C consisted of neutrophil-depleted SCID mice treated with rituximab at 10 mg/kg on the same schedule. Neutrophils were depleted by i.p. administration of 80 microg of rat antimouse Ly-6G (Gr-1) Ab (BD PharMingen, Inc.) on days -1, 4, 9, and 14. The end point of the study was survival. Differences in outcome between treatment groups were analyzed by Kaplan-Meier methodology.
RESULTS: Neutrophil- and NK cell-depleted SCID mice (group C) did not respond to rituximab, and the mean survival time was not significantly different from that of control mice. NK cell-depleted SCID mice with intact neutrophil function (group B) responded to rituximab, and 66% remained alive and appeared healthy after a mean follow-up period of 246 days. Overall, NK cell-depleted SCID mice with intact neutrophil function treated with rituximab had statistically longer mean survival as compared with mice in neutrophil-depleted and control groups (161 days versus 28 days versus 22 days, P=0.003).
CONCLUSIONS: In the absence of neutrophils, rituximab was less effective in controlling lymphoma cell growth or prolonging survival in our B-cell lymphoma SCID mouse model. Neutrophil-induced ADCC appears to contribute to the in vivo antitumor activity of rituximab. Strategies that improve the function of neutrophils, such as granulocyte-macrophage colony-stimulating factor or G-CSF priming, may increase the antitumor effects of rituximab. Additional in vivo animal studies are warranted.PMID: 14676108
SINGULAIR
Singulair is used by asthma patients, including me. This research impressively demonstrates that it might have value to leukemia patients.
The Leukotriene Receptor CysLT1 Is Involved in Migration and Survival of Chronic Lymphocytic Leukemia (CLL) Cells: Potential Role of CysLT1Antagonists in the treatment of CLL
Andreas M. Boehmler, Gabriele Seitz, Tina Wiesner, Lothar Kanz, Robert Mhle Department of Medicine II, University of Tbingen, Tbingen, Germany
G protein-coupled receptors (GPR) mediate chemotactic and proliferative effects in both normal and malignant hematopoietic cells. CysLT1, a GPR for a subgroup of lipid mediators (cysteinyl-leukotrienes), is involved in inflammatory reactions such as allergic asthma, but its ligands are also released in the bone marrow by stromal and endothelial cells similar to the chemokine SDF-1. In RT-PCR analyses, we now demonstrate expression of CysLT1 in the CLL cell lines EHEB and MEC-1, as well as in CD19+ cells isolated immunomagnetically from the peripheral blood of patients with B-CLL. Stimulation of CLL cells with the natural CysLT1 ligand cysteinyl leukotriene D4 (LTD4) resulted in a sustained effect on the cytoskeleton with a 37.8% increase in the concentration of filamentous actin. In transmigration experiments throughfenestrated polycarbonate membranes (pore size: 5 M), CLL cells responded positively chemotactic to LTD4, with an increase in the total number of transmigrated cells of up to 6-fold as compared to carrier alone. In addition, the CysLT1 receptor antagonist MK-571 drastically decreased the in vitro survival of primary CLL cells as well as of CLL cell lines. Interestingly, antiproliferative effects were seen at receptor antagonist concentrations (low micromolar), which could potentially be achieved by oral treatment in vivo. We conclude that expression of CysLT1 may contribute to bone marrow tropism of CLL cells and their maintenance in the hematopoietic microenvironment. More important, the highly antiproliferative effect of CysLT1 receptor antagonists, which are currently used only in asthma therapy, might offer a new approach in the therapy of CLL.
CIMETIDINE
Cimetidine is a multi-tasking drug. I take it to help control reflux disease. In turn, my treating the reflux, my asthma improved. Then we discovered through consultations with allergists that Cimetidine is an h-2 antagonist and can help to prevent drug reactions. Clinical research has now demonstrated that Cimetidine can improve Natural Killer Cell activity in leukemia patients. And all for a $5.00 co-pay. This might be the deal of the century.
Cimetidine modulates natural killer cell function of patients with chronic lymphocytic leukemia.
Allen JI, Syropoulos HJ, Grant B, Eagon JC, Kay NE.
Peripheral blood natural killer (NK) activity in patients with B-cell chronic lymphocytic leukemia (B-CLL) is frequently low or absent. Because cimetidine (a histamine-2 antagonist) has been shown to alter human lymphocyte function in vitro, we decided to study cimetidine's effect on peripheral blood NK activity of patients with B-CLL and controls. We administered cimetidine orally (1.2 gm per day) to seven patients with B-CLL and 12 controls for up to 28 days. Peripheral blood NK activity of patients with B-CLL rose from a pretreatment level of 0.7 +/- 0.5 (mean +/- SEM) lytic units/10(6) cells (LU) to 8.7 +/- 2.4 LU (P less than 0.05) at day 28. Peripheral blood NK activity of controls decreased after 14 days of cimetidine treatment but returned to pretreatment levels by day 28. When peripheral blood cells from controls were exposed to cimetidine during in vitro incubation (10 micrograms/ml), mean NK activity was increased at 48 hours (54% +/- 22% increase over controls, n = 5, P less than 0.05). Single cell cytotoxicity assays revealed increased killing of target cells (but not effector-target conjugation) with cimetidine-exposed effector cells. These data suggest that cimetidine may be useful to augment peripheral blood NK activity for patients with B-CLL.
PMID: 349331
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