Date: July 6, 2004
by Chaya Venkat
Below is a press release of a Phase III, randomized, double-blinded and placebo controlled study of cancer patients going through moderately myelosuppressive therapy. The study found that administering patients Neulasta (a longer lasting form of Neupogen, I am told the major difference is that you need less frequent injections. Otherwise both Neupogen and Neulasta work in the same way) in a pre-emptive fashion reduced febrile neutropenia by 94%, hospitalizations by 93% and need for intravenous antibiotics for opportunistic infections by 80%. These are mind-blowingly high numbers, and remember, the study design is about as rigorous as it gets: Phase 3, randomized, double-blinded and placebo controlled. It does not get any more credible than that, in terms of clinical trial design. A huge cohort of 928 patients participated in this trial.
True, this trial was with reference to breast cancer. But the researchers point out the same logic holds for any cancer therapy that puts the patient at risk of developing neutropenia. It might surprise you to know that even Rituxan therapy causes a transient dip in neutrophil counts. If your neutrophils are low to begin with, even before therapy starts, then the logic of adding Neupogen is a slam dunk. That is, unless you like being admitted to the hospital and being waited on hand and foot by (hopefully) pretty nurses.
Several of you have written about the difficulties you are having in convincing your local oncologists to add Neupogen (G-CSF, granulocyte colony stimulating factor) to Rituxan therapy. Here is some ammunition that I think might help you make your case. Frankly, the evidence is now mounting up to the level where it is just about irrefutable.
Phase 3 Study Shows First-Cycle Administration Of Neulasta Significantly Lowers Incidence Of Infection And Hospitalization 6/24/2004 (Source: Amgen)
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.
The above clinical trial data (I will get the scientific paper as soon as it is published - for now we have to make-do with the company press release) make it clear that one of the advantages of preemptive administration of Neupogen ahead of chemotherapy or even immunotherapy is an increased numbers of neutrophils and therefore avoiding all the problems of potential development of neutropenia. Below are some other advantages, many of these we have discussed already. But some of the abstracts below are hot off the presses, and they add weight to prior articles we cited. As always, write to us if you want to know how to get hold of the full text articles.
Below are abstracts of several recent articles from the most prestigious peer-reviewed journals, by some of the best known Rituxan experts, that pulls together all these considerations, all of them addressing the important topic of how to make Rituxan therapy more effective. Taken together, they make a strong case that immune system modulators such as G-CSF ("Neupogen", Neulasta") and GM-CSF ("Leukine") as well as others such as IL-12 may give Rituxan mono-therapy a much desired boost.
Comment: Below is the abstract of a must-read article for the individual who wants to know how Rituxan works, and the role of immune system modulators such as Neupogen and Leukine. Figure 4 of this article puts all the pieces together nicely. Write to us if you want to know how to get the full text of this important review article, hot off the presses.
Blood. 2004 Jun 29 [Epub ahead of print]
From the bench to the bedside: ways to improve rituximab efficacy.
Cartron G, Watier H, Golay J, Solal-Celigny P.
Universite Francois Rabelais, UPRES-EA Immuno-Pharmaco-Genetique des Anticorps therapeutiques (IPGA), Tours, France; CHRU Bretonneau, Oncologie Medicale et Maladies du Sang, Tours, France; Canceropole Grand Ouest, France.
Rituximab is a chimeric IgG1 monoclonal antibody that specifically targets the CD20 surface antigen expressed on normal and neoplastic B lymphoid cells. Rituximab is currently used in the treatment of both follicular and aggressive B-cell non-Hodgkin's lymphomas. Despite its demonstrated clinical effectiveness, its in vivo mechanisms of action remain unknown and could differ by subtype of lymphoma. Rituximab has been shown to induce apoptosis, complement-mediated lysis (CDC) and antibody-dependent cellular cytotoxicity (ADCC) in vitro and there is some evidence pointing towards an involvement of these mechanisms in vivo. Rituximab also has a delayed therapeutic effect as well as a potential "vaccinal" effect. Here, we review the current understanding of the mechanism of action of rituximab and discuss approaches that could increase its clinical activity. A better understanding of how rituximab acts in vivo should make it possible to develop new and more effective therapeutic strategies.
Comment: Below is the abstract of a well-documented paper, with clinical trial details of dosage, timing and sequence of administration of the Rituxan and Neupogen. Must-have article if you wish to implement the same approach yourself. Write to us if you want to know how to get hold of the full text article.
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.
Comment: Too bad the abstract below is only a mouse study. Does anyone have bright ideas how we can get the research community to actually do a clinical trial for CLL patients, using Rituxan + G-CSF (or GM-CSF) with EGCG chaser? There are many "Harvey" wannabees out there...
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 .
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.
Comment: The abstract below explains some of the reasons why Neupogen-induced neutrophils are more effective in ADCC cell kill mechanisms, because of up regulated FcGamma receptors. In this case the monoclonal antibody that is being helped by Neupogen goosed neutrophils is Nd2, effective in pancreatic cancer. Don't be confused by the term "poly-morphonuclear neutrophils" or "PMNs". Just different names, but they mean the same thing as regular neutrophils.
Once again, these results are tantalizing, close but no cigar; pancreatic cancer cell lines and a different monoclonal antibody, not Rituxan. The study adds to the credibility of the general principle, that neutrophils are important for ADCC based cancer cell kill in monoclonal therapy, and neutrophils do this job better when they are activated by G-CSF (Neupogen).
Int J Oncol. 2002 Sep;21(3):649-54.
Granulocyte-colony stimulating factor enhances chimeric antibody Nd2 dependent cytotoxicity against pancreatic cancer mediated by polymorphonuclear neutrophils.
Tamamori Y, Sawada T, Nishihara T, Yamashita Y, Ohira M, Ho JJ, Kim YS, Hirakawa-Y S Chung K.
Department of Surgical Oncology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
Nd2 is a monoclonal antibody against pancreatic cancer. We have previously reported that human/mouse chimeric antibody Nd2 (c-Nd2) can induce antibody-dependent cell-mediated cytotoxicity (ADCC) with peripheral blood mononuclear cells (PBMs) as effectors. In this study, we investigated whether c-Nd2 can induce ADCC with poly-morphonuclear neutrophils (PMNs) as effector cells and the effects of granulocyte-colony stimulating factor (G-CSF) in enhancing this cytotoxicity. Cytotoxicities for pancreatic cancer cell line, SW1990 were dose-dependently increased by c-Nd2 during co-culture with PMNs and these cytotoxicities were significantly suppressed by the addition of neutralizing antibodies against CD16, which is Fcgamma receptor expressed on PMN membranes. PMNs treated with G-CSF significantly enhanced in vitro ADCC activity against SW1990 induced by c-Nd2. The in vivo growth of subcutaneously transplanted SW1990 tumor in nude mouse was significantly inhibited by i.p. administration of c-Nd2 compared to control (non-specific IgG1). In addition, this inhibitory effect was enhanced by the combination of c-Nd2 and G-CSF. Immunohistochemical study with anti-mouse neutrophil elastase antibody demonstrated strong infiltrations of PMNs into and around the transplanted tumor, treated with c-Nd2 and G-CSF. These results suggest that PMNs play an important role in c-Nd2 inducing ADCC and that combination immunotherapy of c-Nd2 with G-CSF may have clinical applications in the treatment of patients with pancreatic cancer by enhancing ADCC.
Comment: Dr. Eva Kimby is on the frontlines of developing better responses to Rituxan therapy by adding immune system enhancers like G-CSF. This is one of the original review papers that kicked off the whole debate. More power to this lady! Want to read the whole text of this article? Write to us.
Semin Oncol. 2002 Apr;29(2 Suppl 6):7-10.
Beyond immunochemotherapy: combinations of rituximab with cytokines interferon-alpha2a and granulocyte colony stimulating factor
Department of Hematology, Karolinska Institute at Huddinge University Hospital, Stockholm, Sweden.
Monotherapy with the human-mouse chimeric anti-CD20 monoclonal antibody rituximab is effective and well tolerated in the treatment of indolent non-Hodgkin's lymphoma, but the majority of patients relapse. The combination of chemotherapeutic agents with rituximab results in greater efficacy, but at the cost of the increased toxicity associated with chemotherapy. To increase the efficacy of rituximab without compromising tolerability, the cytokines interferon-alpha2a, which has multiple immunomodulatory effects and enhances antibody-dependent cell-mediated cytotoxicity, and the granulocyte-colony stimulating factor, which enhances antibody-dependent cell-mediated cytotoxicity by neutrophils, have been combined with rituximab. In a randomized comparative study in patients with relapsed or untreated indolent non-Hodgkin's lymphoma, the addition of interferon-alpha2a significantly increased responsiveness to a second course of rituximab in patients with a partial response or minor response to an initial course of rituximab monotherapy. In a single-arm study in 20 patients with relapsed disease, the combination of granulocyte-colony stimulating factor with rituximab resulted in a longer duration of response than normally seen with rituximab monotherapy. In both studies, no significant increase in adverse events compared with rituximab monotherapy was reported. Currently available data suggest that the combination of rituximab with immunomodulatory cytokines result in increased efficacy without compromising tolerability.
Copyright 2002, Elsevier Science (USA). All rights reserved.
Comment: This abstract of a paper by Prof. Y. Gazitt is seminal in the sense that it identifies clearly the advantage of mobilizing cancer cells out of the bone marrow and lymph nodes, with cancer specific monoclonal antibodies like Rituxan and Campath waiting just outside to pounce on the cancer cells kicked out into their comfortable homes. Besides being an insightful researcher, Dr. Gazitt also happens to be on my short list of good guys, an expert who actually bothers to reply to technical questions from pushy patient advocates.
Leukemia. 2004 Jan;18(1):1-10.
Homing and mobilization of hematopoietic stem cells and hematopoietic cancer cells are mirror image processes, utilizing similar signaling pathways and occurring concurrently: circulating cancer cells constitute an ideal target for concurrent treatment with chemotherapy and antilineage-specific antibodies.
University of Texas Health Science Center, San Antonio, TX.
Adhesion molecules and stromal cell-derived factor-1 (SDF-1)/CXCR4 signaling play key role in homing and mobilization of hematopoietic progenitor (HPC) and hematopoietic cancer clonogenic cells (HCC). High expression of VLA-4 is required for homing of HPC and HCC, whereas downregulation of these molecules is required for successful mobilization of HPC and HCC. Upregulation and activation of the SDF-1/CXCR4 signaling is required for homing of HPC and HCC, whereas disruption of the SDF-1 signaling is required for mobilization of HPC and HCC. Hence, mobilizations of HPC and HCC occur concurrently. It is proposed that drug resistance evolves as a result of repeated cycles of chemotherapy. Following each cycle of chemotherapy, HCC lose adhesion molecules and SDF-1 signaling. Surviving cells, released from tumor sites, circulate until re-expression of adhesion molecules and CXCR4 occurs, then homing to stroma of distal tissues occurs. Cytokines secreted by cells in the new microenvironment induce proliferation and drug resistance of HCC. This process is amplified in each cycle of chemotherapy resulting in disease progression. A novel model for treatment is proposed in which circulating HCC are the target for clinical intervention, and concurrent treatment with chemotherapy and antilineage-specific antibodies will result in abrogation of the 'vicious cycle' of conventional anticancer therapy.
Comment: The abstract below proves once more that there is no free lunch, you really need to look at things very carefully and not jump to conclusions. One of our recent articles on the website discussed the Dark Side of Epoetin. Indeed, the FDA is now taking a second look at a couple of Epoetin drugs, in view of their potential for triggering angiogenesis and therefore facilitating relapse. The abstract below makes the case that this risk is not limited to growth factors dealing with red blood cells, as in epoetin, but may be more pervasive and across the board for all hematopoietic growth factors, including G-CSF. I would expect GM-CSF would have the same problem as well. Using growth factors is a double-edged sword. On the one hand, the lusty effector cells such as neutrophils and macrophages that they create may help Rituxan therapy be more effective. On the other hand, you might want to think about putting a sock in the angiogenesis side effect. The original "Harvey" articles spelled out the logic that our hypothetical patient and Round-Headed Kid employed when he used EGCG (green tea polyphenol) as a backstop against angiogenesis.
Biochem Biophys Res Commun. 2002 Oct 4;297(4):1058-61.
G-CSF stimulates angiogenesis and promotes tumor growth: potential contribution of bone marrow-derived endothelial progenitor cells.
Natori T, Sata M, Washida M, Hirata Y, Nagai R, Makuuchi M.
Department of Surgery, University of Tokyo, Graduate School of Medicine, Tokyo 113-8655, Japan.
Solid tumors require neovascularization for their growth. Recent evidence indicates that bone marrow-derived endothelial progenitor cells (EPCs) contribute to tumor angiogenesis. We show here that granulocyte colony-stimulating factor (G-CSF) markedly promotes growth of the colon cancer inoculated into the subcutaneous space of mice, whereas G-CSF had no effect on cancer cell proliferation in vitro. The accelerated tumor growth was associated with enhancement of neovascularization in the tumor. We found that bone marrow-derived cells participated in new blood vessel formation in tumor. Our findings suggest that G-CSF may have potential to promote tumor growth, at least in part, by stimulating angiogenesis in which bone marrow-derived EPCs play a role.
It is my considered opinion that the information presented in the abstracts above, as well as the hot-of-the-presses Amgen study make for a very strong argument for preemptive administration of Neupogen or similar growth factor to monoclonal therapy with Rituxan or Campath. I know, it is frustrating that the Amgen study is with breast cancer patients, and the articles are with reference to non-Hodgkin's lymphoma (NHL) patients most of the time. Welcome to the real world, CLL is not the biggest cancer out there, companies would rather spend their research money looking at the financially important markets like breast cancer or even NHL.
Do we have enough here to convince the reasonable local oncologist? I think so, the crucial word being "reasonable".
In the summer of 2003 I was sitting in the back seat of a car on the way to Houston airport, listening with rapt attention while two of our biggest CLL Research Consortium ("CRC") experts sitting in the front discussed launching a clinical trial for CLL patients using Rituxan and Leukine (GM-CSF). It was music to my ears, I had been rooting for a such a clinical trial for a couple of years. Indeed, there have been several non-official reports that M. D. Anderson and UCSD have initiated such a clinical trial, and patients have been treated with this combination. However, I have not been able to find any reports that speak to the results of these trials, or even the details of the trial protocols. It would have made therapy decisions for patients so much easier, if we could have public access to the results of this specific clinical trial.
I wish there was some way we can break this logjam in getting clinical trial information out into the public domain. Prestigious institutions like M. D. Anderson and powerful groups such as the CRC should take the lead in setting an example for the rest of the research industry. Here are some guidelines that seem pretty obvious and reasonable:
Disclosure and exposure to pubic scrutiny is an important part of the regulatory process. I know the good doctors are busy, but prompt disclosure of clinical trial results is of such huge importance both to patients and the scientific community that I am surprised there is not more emphasis on it. In the present context of critical review of the clinical trial process and the difficulty faced by some important trials in recruiting the required numbers of participants, it is time researchers took this aspect of their obligations seriously. And it is high time that regulatory agencies such as the NCI strengthened / enforced the guidelines in this respect. If any of you have participated in these rumored clinical trials of Rituxan plus GM-CSF at Anderson or other CRC sites, do write and let us know. We would like to see official and well documented reports of trial results, but we will settle for anecdotal information from the patient community, if that is the best we can do.
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Topic: Rituxan Therapy