Date: July 5, 2006
by Chaya Venkat
Did you know Epstein-Barr Virus (EBV) is a type of Herpes virus? To be specific, it is a gamma-herpesvirus-4, and close to 90% of the western world’s adult population has it. Chances are good you have been exposed to this virus as a kid or young adult. In most cases the infection goes unnoticed. In a small percentage of people, the viral infection exacerbates enough to become infectious mononucleosis (“mono”). This is also called “glandular fever” since mono is accompanied by swollen lymph nodes, fever, and extreme fatigue. Mono is generally self-limiting and not considered life-threatening in healthy people.
Humans are the only known reservoir of EBV. This virus is most commonly is transmitted through saliva and hence the nickname “the kissing disease” for infectious mono. After initial exposure, the virus replicates and spreads to the salivary glands and lymph nodes around your throat and neck and down the road to the liver, spleen, and the rest of the lymphoid system. EBV establishes a lifelong stealth presence in your B-cells. In most cases, the virus is kept under check by T-cells and the number of infected B-cells in your body will remain stable over the years. The status quo can change dramatically and with disastrous consequences for you as the host if your T-cells responsible for controlling the EBV go AWOL in a big way due to disease (as in AIDS patients, for example) or your T-cell function is gravely damaged due to immunosuppressive therapy.
I think you can guess where I am going with this, why it is important for us to be aware of EBV infections. As CLL patients we are, by definition, playing with less than a full deck when it comes to proper immune function — and that includes T-cell function. To make matters worse, some of the drugs we need to fight the CLL are very damaging to T-cell function. After T-cell damaging therapy, some CLL patients are not that much better off than HIV patients in the EBV-fighting ability of their T-cells. Why is this important? Consider this: EBV is also a tumor virus, the first one that has been identified as responsible for a variety of cancers, such as Hodgkin’s disease, Burkitt lymphoma and head-and-neck cancers. Recently it has been linked to invasive breast cancer, as well as poor-prognosis multiple sclerosis. A little closer to home, EBV reactivation has now been linked to the morphing of CLL to the much more dangerous Richter’s transformation, a type of aggressive lymphoma where median survival is measured in months and weeks, not years.
Here is a very interesting article from M. D. Anderson. Thirty two CLL patients were compared to “normal” people for tell-tale signs of EBV. Viral RNA (EBVR) was detected in the bone marrow of 38% of CLL patients, but 0% of the normal people. There was also a clear link between EBVR detection and stage of the CLL: only 20% of early Rai stage 0-1 patients expressed EBVR versus 66% of later Rai stage 2-4 patients. Just to make the statistics in-your-face, your chances of 10 year survival become less than half of what they would be, from 58% to 22%, if you are one of the guys with high level of EBV markers.
Leuk Lymphoma. 2006 May;47(5):827-36.
Epstein-Barr virus in patients with chronic lymphocytic leukemia: A pilot study.
Tsimberidou AM, Keating MJ, Bueso-Ramos CE, Kurzrock R.
Phase I Program and Department of Leukemia, Division of Cancer Medicine, the University of Texas M. D. Anderson Cancer Center, Houston, TX.
The objective of this study was to assess the incidence and the clinical significance of Epstein-Barr virus (EBV) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients with CLL/SLL who presented at The University of Texas M. D. Anderson Cancer Center over a 2-year period and had available marrow paraffin blocks were studied for evidence of EBV infection using a highly specific in-situ hybridization assay for detection of EBV encoded RNA (EBERs). Results were analysed in relation to other presenting characteristics and outcome. Thirty-two patients were examined. EBERs were detected in the bone marrow of 12 of 32 (38%) CLL/SLL marrows vs 0 of 20 normal marrows (p = 0.002). EBERs were observed in sporadic granulocytes alone or in addition to its presence in lymphocytes in nine of the 12 EBV-positive patients. EBERs were detected less frequently in patients with Rai stage 0 - 1 disease (20%) compared with Rai stage 2 - 4 (66%; p = 0.008). EBER-positive patients tended to have higher lactate dehydrogenase levels (p = 0.053). The 10-year survival rate was 22% vs 58% for patients with and without discernible EBERs (log-rank, p = 0.08). Evidence of EBV infection was found in 38% of patients with CLL/SLL. Despite the small number of patients tested, discernable EBERs were significantly more common in individuals with more advanced Rai stage and there was a trend toward shorter survival in patients in whom EBV EBERs were discerned. Larger studies are needed to determine the prognostic value and role of EBV infection in patients with CLL/SLL.
Why does a relatively tame little virus that does little harm in 90% of the people out there suddenly become a killer in CLL patients? The answer is actually very simple: it is a case of criminals running amok when the police force is on strike. The delicate balance between the virus and the immune surveillance that keeps it in check is out of kilter in CLL patients. As the abstract above showed, the further along you are in your CLL, the more likely that your immune system is playing a losing battle against EBV. Mice will play when the cat is away. As the EBV grows unchecked, it can cause further cancerous mutations in the B-cells it inhabits. Remember, EBV has clearly been shown to be a mutagenic virus, rewriting the DNA of its host cells to the point where the cell becomes cancerous. In the case of CLL patients, there is now a clear link between EBV and increased incidence of Richter’s transformation. Response rates to therapy for patients with Richter's Syndrome (RS) are low and the survival statistics are grim: 5-8 months on average.
Semin Oncol. 2006 Apr;33(2):250-6.
Richter's transformation in chronic lymphocytic leukemia.
Tsimberidou AM, Keating MJ.
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Richter's syndrome (RS) is characterized by the development of high-grade non-Hodgkin's lymphoma (NHL) in a patient with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma. At The University of Texas M.D. Anderson Cancer Center the incidence of RS is 3.9%. The large cells of RS may arise through transformation of the original CLL clone or represent a new neoplasm. RS may be triggered by viral infections, such as Epstein-Barr virus (EBV). Trisomy 12 and chromosome 11 abnormalities, as well as multiple genetic defects, have been described in patients with RS. These abnormalities may cause CLL cells to proliferate and, by facilitating the acquisition of new genetic abnormalities, to transform into RS cells. The therapeutic strategies for RS typically include therapies developed for NHL or acute lymphoblastic leukemia. The reported response rates with these therapies are 5% to 43%, and the median survival duration ranges from 5 to 8 months. The median overall survival duration at our institution of patients with RS is 9.1 months (95% confidence interval, 7.8 to 11 months), and the median failure-free survival duration is 7.1 months (95% confidence interval, 5.1 to 10.4 months). Patients appear to benefit from cytoreductive therapy consisting of chemotherapy and immunotherapy, followed by allogeneic stem cell transplantation, as postremission therapy. As part of a program aiming to cure RS, we are currently conducting a clinical trial of oxaliplatin, fludarabine, and cytarabine in combination with rituximab and recommend postremission therapy, including allogeneic stem cell transplantation in patients with available donors.
Am J Hematol. 1999 Feb;60(2):99-104.
Epstein-Barr virus infection in Richter's transformation.
Ansell SM, Li CY, Lloyd RV, Phyliky RL.
Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota.
Chronic lymphocytic leukemia (CLL) may convert to a diffuse large cell lymphoma (Richter's syndrome) over time. In occasional cases of Richter's transformation, Epstein-Barr virus (EBV) has been identified in the lymphoma cells. To evaluate the association of EBV infection with Richter's syndrome, the biopsy specimens and clinical records of 25 patients who were seen at the Mayo Clinic between 1984-1996 were retrospectively evaluated for the presence of EBV by immunoperoxidase staining for expression of EBV latent membrane protein (LMP), as well as the expression of EBV RNA and DNA in the cells by in situ hybridization. Four of the 25 patients showed evidence of EBV in the diffuse large cell lymphoma cells-three patients with a B-cell phenotype were positive for LMP, EBV DNA, and RNA; and one patient with a T-cell phenotype had positive EBV RNA in the large cell lymphoma cells. The Richter's syndrome was treated with combination chemotherapy in 15 patients, three received radiotherapy, three were followed without further therapy after a splenectomy, two died before treatment could be started, and one patient had insufficient follow-up. One patient with evidence of EBV in large cell lymphoma cells was treated with acyclovir as initial therapy. The median survival of EBV-positive patients was three months compared with nine months for EBV-negative patients, but this difference was not statistically significant (P = 0.385). Evidence for EBV infection related to Richter's transformation was present in 16% of the patients in this study and may be associated with a poorer outcome. Primary therapy with acyclovir in one patient did not seem to be beneficial and other therapeutic modalities in patients with EBV-positive Richter's transformation need to be explored.
There is not a whole heck of a lot you can do about the EBV infection you picked up a long time ago, perhaps in high school kissing your sweetheart. The little present you did not know you were getting (would you have cared back then, even if you had known?) is going to be with you for the rest of your life. The best you can hope to do is not give aid and comfort to this enemy within and factor its role in the therapy decisions you make in the future.
T-cells are the brave viral fighters in your body, the frontline troops that keep EBV and other dormant infections under control. It goes without saying, anything that you do to hurt and decrease the effectiveness of your T-cells is going to make life that much easier for the viral enemies. As we have reported in several prior articles, two of the most T-cell damaging drugs are fludarabine and Campath. (Fludarabine belongs to a class of drugs called purine analogs. The other two members of the class are pentostatin and cladrabine. I believe there is not much to chose between the three purine analogs, as far as T-cell damage is concerned).
Br J Haematol. 2005 Apr;129(2):199-205.
Hodgkin's disease variant of Richter's syndrome in chronic lymphocytic leukaemia patients previously treated with fludarabine.
Fong D, Kaiser A, Spizzo G, Gastl G, Tzankov A.
Division of Haematology and Oncology, Innsbruck Medical University, Innsbruck, Austria.
The transformation of chronic lymphocytic leukaemia (CLL) into large-cell lymphoma (Richter's syndrome, RS) is a well-documented phenomenon. Only rarely does CLL transform into Hodgkin's lymphoma (HL). To further analyse the clinico-pathological and genetic findings in the HL variant of RS, we performed a single-institution study in four patients, who developed HL within a mean of 107 months after diagnosis of CLL. All were treated with fludarabine. Three cases were Epstein-Barr virus (EBV)-associated mixed cellularity (MC) HL, the fourth was nodular sclerosis (NS) HL without EBV association. The sites involved by HL included supra- and infradiaphragmal lymph nodes and the tonsils; stage IV disease was also documented. All patients presented with CLL treatment-resistant lymphadenopathies and B-symptoms. In two of the MC cases, molecular analysis performed on CLL samples and microdissected Hodgkin and Reed-Sternberg cells (HRSC) suggested a clonal relationship, while in NS no indication of a clonal relationship was detected. In summary, HL can occur in CLL patients at any site, up to 17 years after initial diagnosis, especially after treatment with fludarabine. The majority present with B-symptoms and CLL treatment-resistant lymphadenopathy, are of the MC type, clonally related to CLL and might be triggered by an EBV infection.
Leuk Res. 2005 Apr;29(4):389-95.
Richter's transformation of chronic lymphocytic leukemia. The possible role of fludarabine and the Epstein-Barr virus in its pathogenesis.
Thornton PD, Bellas C, Santon A, Shah G, Pocock C, Wotherspoon AC, Matutes E, Catovsky D.
Section of Haemato-Oncology, Institute of Cancer Research, The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.
Transformation of CLL into a large cell lymphoma has an incidence of 3-5%. We have studied 101 cases of CLL treated with fludarabine over a 10-year period (1990-2000) and observed a 12% incidence of transformation. In six of 12 patients, transformation was documented within 4 months following treatment with fludarabine. Pathological material, available in nine cases, was investigated for latent EBV by staining for LMP-1 by immunohistochemistry and EBERs-1 and 2 by in situ hybridisation. LMP-1 and EBERs were demonstrated in three of the nine samples. In two cases there was a different pattern of immunoglobulin gene rearrangement in the transformed cells assessed by PCR (FR3 fragment) compared to the original CLL clone. One of these two cases showed evidence of latent EBV. The other seven cases, of which two were EBV positive, showed identical pattern of Ig gene rearrangement in both the CLL and the transformed cells. We suggest that the relatively high incidence of transformation in this series may be due to immunosuppression mainly related to fludarabine, although other agents and prior therapies may have also contributed.
Combination chemotherapy regimens are all the rage these days. The idea is that by attacking the tumor from many different angles, by putting the cancer cells in the cross hairs of multiple drugs, we will get higher killing power and therefore better response rates. As long as the patient can handle the “non-overlapping toxicites” and “maximum tolerated dose” of the drugs used, this premise of aggressive therapy makes sense for aggressive cancers. Recently, thoughtful researchers are beginning to question the validity of this approach when it comes to indolent cancers like CLL. Does it make sense to go for a “Shock and Awe” approach to control CLL - a no-holds-barred strategy that may leave the patient's immune system worse off than when he started? We discussed some of these issues in a recent article (Winning the Battle but Losing the War). As far back as 1999 (abstract below), the role of increasingly immunosuppressive therapies (in this case fludarabine, cyclophosphamide and the corticosteroid drug dexamethasone) on depleting T-cell control of viruses such as EBV was well understood.
Br J Haematol. 1999 Dec;107(4):877-82.
The immunosuppression and potential for EBV reactivation of fludarabine combined with cyclophosphamide and dexamethasone in patients with lymphoproliferative disorders.
Lazzarino M, Orlandi E, Baldanti F, Furione M, Pagnucco G, Astori C, Arcaini L, Viglio A, Paulli M, Gerna G, Bernasconi C.
Institute of Haematology, University of Pavia, Division of Haematology, IRCCS Policlinico S. Matteo, Pavia, Italy.
Fludarabine is effective in chronic lymphocytic leukaemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). A major side-effect of this purine analogue is immunosuppression which may favour opportunistic infections. Additionally, impairment of immunosurveillance might promote Epstein-Barr virus (EBV) reactivation and possibly favour transformation to high-grade malignancy. The aim of this study was to evaluate the immunosuppression-related effects of the fludarabine-based combination Flucyd in advanced low-grade NHL or CLL by serially monitoring T-lymphocyte subsets, opportunistic infections, EBV-reactivation, and histologic transformation. 24 patients with advanced NHL (n = 21) or CLL (n = 3) received fludarabine 25 mg/m2/d + cyclophosphamide 350 mg/m2/d + dexamethasone 20 mg/d in 3 d courses for a maximum of six courses. The overall response rate was 79% (eight CR, 11 PR, five failures); 11 patients relapsed or progressed between 3 and 19 months from response, and eight are in CR or PR at 3-27 months. The CD4+ T-lymphocyte counts decreased significantly during therapy from a median of 484/microliter pre-treatment (range 142-1865) to a median of 198/microliter (71-367). In 19 responders monitored off therapy every 3 months until relapse/progression, CD4+ T-cell counts were persistently low with minimal recovery over time. During treatment, 16 infections occurred in 11/24 patients. No delayed opportunistic infections occurred in responders while off therapy. The circulating EBV DNA load serially measured in 19 patients by a quantitative PCR assay showed an increase in four patients during treatment. A lymph node biopsy performed in two of these was PCR positive for EBV DNA, whereas LMP1 and EBERs were negative. Six NHL patients evolved into high-grade B-cell NHL. In conclusion, fludarabine combined with cyclophosphamide and dexamethasone is an effective therapy for recurrent indolent lymphoma. This combination produces prolonged T-lymphocytopenia and has the potential to reactivate a latent EBV infection. T-cell dysfunction, however, is not associated with higher incidence of clinical opportunistic infections and does not adversely influence clinical outcome.
Since just about all of us are infected with EBV, it is a level playing field, right? Wrong.
If you are one of those people that had a full blown attack of mono as a kid or young adult, you are much more at risk. Below is the abstract of a brand-new paper that makes it clear that ex-mono patients carry a life-long T-cell defect and this is not quite the case with those of us who never even knew we have picked up this viral hitchhiker. In other words, if you had a massive dose of EBV, a heavy enough viral load to precipitate a clinically diagnosed case of infectious mononucleosis, you are much more at risk of T-cell defects even after many years. This plenary paper in the latest issue of “Blood” certainly got my attention and prompted me to write this article. If you want to read the full text version for yourself, please don’t hesitate to write to us for help in locating a copy.
Blood. 2006 Jul 1;108(1):11-8. Epub 2006 Mar 16.
EBV-associated mononucleosis leads to long-term global deficit in T-cell responsiveness to IL-15.
Sauce D, Larsen M, Curnow SJ, Leese AM, Moss PA, Hislop AD, Salmon M, Rickinson AB.
CRUK Institute for Cancer Studies, University of Birmingham, Vincent Drive, Edgbaston Birmingham B15 2TT, United Kingdom.
In mice, interleukin-7 (IL-7) and IL-15 are involved in T-cell homeostasis and the maintenance of immunologic memory. Here, we follow virus-induced responses in infectious mononucleosis (IM) patients from primary Epstein-Barr virus (EBV) infection into long-term virus carriage, monitoring IL-7 and IL-15 receptor (IL-R) expression by antibody staining and cytokine responsiveness by STAT5 phosphorylation and in vitro proliferation. Expression of IL-7Ralpha was lost from all CD8(+) T cells, including EBV epitope-specific populations, during acute IM. Thereafter, expression recovered quickly on total CD8(+) cells but slowly and incompletely on EBV-specific memory cells. Expression of IL-15Ralpha was also lost in acute IM and remained undetectable thereafter not just on EBV-specific CD8(+) populations but on the whole peripheral T- and natural killer (NK)-cell pool. This deficit, correlating with defective IL-15 responsiveness in vitro, was consistently observed in patients up to 14 years after IM but not in patients after cytomegalovirus (CMV)-associated mononucleosis, or in healthy EBV carriers with no history of IM, or in EBV-naive individuals. By permanently scarring the immune system, symptomatic primary EBV infection provides a unique cohort of patients through which to study the effects of impaired IL-15 signaling on human lymphocyte functions in vitro and in vivo. (Blood. 2006;108:11-18).
If you are one of the unlucky ones who have had infectious mononucleosis (IM) in your past, it is very likely that you have been left with permanent T-cell defects. Interleukin 7 and 15 are important in triggering memory T-cells as well as CTLs (cytotoxic T-lymphocytes) and NK (natural killer) cells to proliferate and go about their task of attacking viral invaders. This important paper says the receptors for these interleukins are missing on T-cell populations after an attack of mono. In other words, if you have had mono, your T-cells are not able to respond to warning signals that EBV (or perhaps other viral enemies as well) is on the warpath and it is time to get the troops mobilized. T-cells that are deaf to interleukin signals because they do not have the right receptors to get the message are not very good at doing their job. The mono patients were followed for 14 years and the researchers define the “scarring of the immune system” as “permanent”.
I don’t know about you, but that last sentence in the abstract sent a shiver down my back. It also raised an interesting question in my mind - tell me if you think the logic holds together:
Most of us baby boomers who are struggling with a little extra weight and high cholesterol are all too familiar with the word “statin”. These are the ubiquitous drugs that everyone seems to be taking these days in their efforts to decrease overall cholesterol numbers and decrease risk of cardiac disease. One of the most famous members of this family is simvastatin (trade name: Zocor). I understand simvastatin has just come off patent and that the FDA has approved a generic version of it. Soon we will be able to buy this drug for a fraction of the cost we paid for it while it was under patent protection.
It turns out statins in general, and simvastatin in particular, have other interesting properties beyond their demonstrated ability to lower cholesterol. Did you know simvastatin kills CLL cells? The role of simvastatin in killing cancer cells is sufficiently well documented it seems that some researchers are combining this statin in human clinical trials for lymphoma patients. The clinical trial is for the purpose of establishing maximum tolerated dose of simvastatin, used in combination with other chemotherapy drugs. Please be aware the dosages they use in this trial are much higher than the dosages you and I would be prescribed for handling cholesterol. Please DO NOT self-medicate yourself with these high dose levels of Zocor, it would be dangerous to do so without medical supervision.
Exp Hematol. 2003 Sep;31(9):779-83.
Simvastatin induces apoptosis of B-CLL cells by activation of mitochondrial caspase 9.
Chapman-Shimshoni D, Yuklea M, Radnay J, Shapiro H, Lishner M.
Oncogenetic Laboratory, Meir Hospital, Kfar-Saba, Israel.
BACKGROUND AND OBJECTIVES: Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. Despite several advances in therapeutic options, the disease remains incurable. Recently, it was repeatedly demonstrated that statins, competitive inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, have antineoplastic effects. Therefore we aimed to study the effects of simvastatin (Sim) on malignant B cells derived from patients with CLL and mechanisms of action of the drug.
METHODS AND RESULTS: Purified B-CLL cells from 15 patients were cultured either alone or with Sim at concentrations of 10, 50, and 100 microM. Viability, measured by the activity of mitochondrial dehydrogenases, was reduced significantly in the cells treated with Sim at 50 and 100 microM for 24 hours (p<0.005). The level of apoptosis, as measured by annexin binding to exposed phosphatidylserine moieties, increased significantly in the treated cells at concentrations higher than 50 microM for 24 hours (p<0.003). The level of necrosis, as measured by propidium iodide internalization, increased significantly after 24 hours exposure to Sim at 50 microM (p<0.01). The apoptotic cascade was studied by immunoblot analysis of caspases following Sim treatment. These showed cleavage of caspases 9, 8, and 3. Addition of the caspase inhibitor Z-VAD.fmk inhibited caspase 8 and 3 significantly but did not affect caspase 9.
CONCLUSION: Exposure of clonal B lymphocytes from patients with CLL to simvastatin decreases viability significantly by the induction of apoptosis. The apoptosis induced by Sim is probably initiated by the mitochondrial caspase 9, which indirectly leads to activation of caspase 3 and 8.
Haematologica. 2006 Apr;91(4):542-5.
Dose-finding study of high-dose simvastatin combined with standard chemotherapy in patients with relapsed or refractory myeloma or lymphoma.
van der Spek E, Bloem AC, van de Donk NW, Bogers LH, van der Griend R, Kramer MH, de Weerdt O, Wittebol S, Lokhorst HM.
Department of Hematology and Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands.
In vitro statins induce apoptosis in myeloma and lymphoma cells in a dose-and time-dependent way. In combination with dexamethasone and doxorubicin, statins have a chemo-sensitizing effect. Twenty-eight patients with relapsed myeloma or lymphoma were treated with a dose-escalating regimen of simvastatin for 7 days followed by VAD in myeloma patients and CHOP in lymphoma patients. The maximum tolerated dose was 15 mg/kg/day simvastatin. The most frequently reported side-effects were fatigue, gastrointestinal CTC grade 1-2 and neutropenic fever. The dose-limiting toxicity was neutropenic sepsis and grade 3 gastrointestinal side effects. High-dose simvastatin given immediately prior to chemotherapy is safe and tolerable up to a dose of 15 mg/kg/day.
But the abstracts that really got my attention are given below. Both of these abstracts are from the National Institute of Health and both talk about the benefits of statins in delaying the development of EBV-driven lymphomas, as well as treating such lymphomas after they happen. Just to remind you, the earlier abstracts we reviewed in this paper linked EBV to Richter’s transformation, a case of EBV-driven aggressive lymphoma. The message seems to be, statins may help prevent / delay the risk of this happening in high risk patients!
If you have had infectious mononucleosis in your youth and have been treated with T-cell depleting drugs for your CLL, I think these two papers are sufficient cause to have a serious discussion with your oncologist. You may or may not need statins for cholesterol, but it may well be that taking daily simvastatin may give you a little bit of insurance against the risk of your CLL morphing into the much more dangerous aggressive lymphoma (Richter’s transformation). I wonder how many of our local healthcare providers are aware of this precious nugget of information? The second abstract below was published in the prestigious Proceedings of the National Academy of Sciences and a full text copy of the paper is free to all comers, something they do when they want wide circulation of the paper. Just click on the link provided above the abstract.
Br J Cancer. 2005 May 9;92(9):1593-8.
HMG CoA reductase inhibitors (statins) to treat Epstein-Barr virus-driven lymphoma.
Laboratory of Clinical Infectious Diseases, Medical Virology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 10; Rm. 11N228, 10 Center Drive, MSC 1888, Bethesda, MD
While statins have been highly effective for lowering serum cholesterol and reducing the incidence of coronary events, they have multiple other effects. Certain statins block the interaction of adhesion molecules that are important for cell-cell interactions including those between EBV-transformed B cells. These same statins inhibit NF-kappaB activation in the cells and induce apoptosis of transformed B cells. Studies in severe combined immunodeficiency mice show that simvastatin delays the development of EBV-lymphomas in these animals. These statins might be considered for the treatment of EBV-lymphomas in selected patients.
Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4960-5. Epub 2004 Mar 23.
Simvastatin induces apoptosis of Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines and delays development of EBV lymphomas.
Katano H, Pesnicak L, Cohen JI.
Medical Virology Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
Simvastatin and pravastatin are inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase, and are used as antihypercholesterolemia drugs. Simvastatin, but not pravastatin, binds to the inserted domain of leukocyte function antigen (LFA)-1 and inhibits the function of LFA-1, including adhesion and costimulation of lymphocytes. Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) express high levels of LFA-1 on their surface and grow in tight clumps. Here we show that simvastatin (2 microM) inhibits clump formation and induces apoptosis of EBV-transformed LCLs. The apoptosis-inducing effect of simvastatin depends on binding to the inserted domain of LFA-1. Simvastatin, but not pravastatin, dissociates EBV latent membrane protein 1 from lipid rafts of LCLs, resulting in down-regulation of nuclear factor kappaB activity and induction of apoptosis. Analysis of multiple EBV-positive and -negative cell lines indicated that both LFA-1 and EBV latent membrane protein 1 expression were required for simvastatin's effects. Administration of simvastatin to severe combined immunodeficiency mice followed by inoculation with LCLs resulted in delayed development of EBV lymphomas and prolonged survival of animals. To our knowledge, this is the first report in which a drug that targets LFA-1 has been used to treat B cell lymphoma. These data suggest that simvastatin may have promise for treatment or prevention of EBV-associated lymphomas that occur in immunocompromised persons.
The topic of viral drivers in CLL has been one that I have been thinking about for several years now. If you fall into the high risk EBV category (prior clinically diagnosed infectious mononucleosis) I would like to hear from you. Have you had fludarabine or Campath therapy, with or without steroids? Have you had more than your share of other viral infections such as shingles, oral herpes, chronic sinus problems? Have you been hospitalized for pneumonia or other pulmonary infections? Do you have frequent recurrences of basal cell and squamous cell carcinoma? The common theme in all of these is impaired T-cell function. Having a better understanding of the root cause of the problems may help you and your doctors make better treatment choices.
Editor's Note: For those interested in reading our past articles on related topics here is a reading list.
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