Date: May 13, 2006
by Chaya Venkat
Sometimes, when luck is running your way and all the stars are in their correct positions in the heavens, everything comes together just so and you can almost taste the sweet juice of the low hanging fruit even before you pluck it and bite into it!
If you did not know this already, here is a simple fact of life with CLL. More CLL patients are hospitalized and die of respiratory illnesses such as pneumonia and even the common annual flu infection gone berserk, than any other single cause. We have covered this topic in detail in earlier articles (Flu Preparedness; Role of Pulmonary Inflammation in CLL) but here are a few highlights.
Cancer. 2003 Nov 1;98(9):1912-7.
Pulmonary complications in chronic lymphocytic leukemia.
Ahmed S, Siddiqui AK, Rossoff L, Sison CP, Rai KR.
Divisions of Hematology and Oncology, Long Island Jewish Medical Center, New Hyde Park, New York 11040, USA.
BACKGROUND: Although pulmonary complications account for significant morbidity and mortality in patients with chronic lymphocytic leukemia (CLL), to the authors' knowledge there are sparse data available in published literature. The authors evaluated pulmonary complications in patients with CLL and identified prognostic variables that predict hospital mortality in these patients.
METHODS: Clinical data were analyzed retrospectively from patients with CLL who required hospitalization for a respiratory illness at a tertiary care institution from January 1993 to December 2001. A logistic regression analysis with a backward elimination procedure was carried out to determine prognostic variables that predict hospital mortality.
RESULTS: There were 110 patients who were admitted on 142 occasions with a pulmonary complication. The median age was 75 years (range, 43-97 years), and the male:female ratio was 1.7:1.0. Among 142 admissions, 68% were high risk according to the Rai criteria, 68% of patients admitted had received prior therapy for CLL, and 35% had received treatment within 3 months of admission. The most common pulmonary complications were pneumonias (75%), malignant pleural effusion/and or lung infiltrate due to CLL (9%), pulmonary leukostasis (4%), Richter transformation or nonsmall cell lung carcinoma (3%), and upper airway obstruction (2%). Forty-four of 110 patients (40%) died. In multivariate analysis, admission absolute neutrophil counts </= 0.5 x 10(9)/L (odds ratio, 4.6; 95% confidence interval [95% CI], 1.3-16.6) and blood urea nitrogen (BUN) levels >/= 20 mg/dL (odds ratio, 3.0; 95% CI, 1.1-8.3) were correlated significantly with mortality.
CONCLUSIONS: Pneumonia was the major pulmonary complication in hospitalized patients with CLL. Severe neutropenia and high BUN levels were correlated significantly with increased mortality.
Copyright 2003 American Cancer Society.
I think most of us know intuitively that pulmonary complications are a big deal for CLL patients. That "anecdotal" impression is now backed by strong statistical evidence, as seen in the abstract above. Dr. Kanti Rai and the CLL team at Long Island Jewish Medical Center are well known and well respected researchers. The statistics are rather impressive, based on 110 CLL patients who were admitted to a hospital with a respiratory disease between 1993 and 2001. There were 142 admissions over that period of time. Pneumonia was the cause of the hospitalization in a whopping 75% of the cases; and 18% of the remaining 25% of the cases were related problems such as lung infiltration, pleural effusion, lung cancer and upper airway blockage. Forty four of these 110 patients died, because of pneumonia and related chest inflammation causes. The take home message is very clear: as a CLL patient, neglecting chest and sinus inflammation problems is really dumb, it carries with it a stiff penalty.
Annual flu vaccinations and pneumonia vaccinations every 5 years or so are pretty well known, and for “normal” people they do a pretty good job of protecting people. How do these vaccinations work? To put a very complex field into a very small nutshell, vaccinations are little more than injecting small snippets of the offending pathogen just under the skin. In the case of the annual flu shot, since the influenza virus changes its spots every year, a new vaccination recipe has to be concocted to battle the new version of the bug each year. When a properly constructed flu vaccine is injected under the skin, these snippets of the flu pathogen are most often picked up by specialized cells called dendritic cells. Dendritic cells are messenger cells, couriers that carry interesting bits and pieces of pathogens that they come across in their random travels through the blood circulation. They carry these bits and pieces to the nearest lymph node, prime location where T-cells hang out. T-cells are the “smart” killer troops of our immune system, but they are trained to act only when they are presented with an officially approved target. T-cells are such powerful killers, it would not be safe to have them go on a rampage without proper controls, killing the wrong targets or our own perfectly good cells. One of the necessary steps before T-cells can get their act together is that they must have the target antigen presented to them by an officially certified “antigen presenting cell”. Dendritic cells are among the best of the best antigen presenting cells. Antigen presentation by dendritic cells is one of the safety switches our bodies use, to make sure only appropriate pathogens are targeted by T-cells.
In fact, our normal response to vaccinations is miserable! Here is a startling report that describes exactly how bad the situation is when it comes to protecting our patients by means of vaccinations. This particular abstract deals with flu and pneumonia vaccinations, but I have read others reports where the same observations have been made with reference to vaccinations such as tetanus.
Eur J Intern Med. 2001 Sep;12(5):420-424.
Influenza virus vaccination and booster in B-cell chronic lymphocytic leukaemia patients.
van der Velden AM, Mulder AH, Hartkamp A, Diepersloot RJ, van Velzen-Blad H, Biesma DH.
Department of Internal Medicine, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands
Background: Influenza vaccination is recommended for patients with B-cell chronic lymphocytic leukaemia (CLL). Because response rates are often low, we decided to evaluate antibody response to single and booster vaccinations with influenza A and B virus vaccine in these patients. Methods: Twenty patients with B-CLL received two subunit virus vaccine injections 21 days apart. Antibody titres were determined before and 21 days after the single and booster vaccinations. The serological response was expressed using the following criteria: (1) response rate, i.e. the proportion of subjects with at least a 4-fold titre increase; (2) the protection rate, i.e. the proportion of subjects exceeding the threshold of 100 (influenza A) or 200 (influenza B); and (3) the mean fold increase (MFI), i.e. the difference between the log-adjusted geometric mean titres of pre- and post-vaccination sera. Results: Response rates were 5% for influenza A and 15% for B after the single vaccination and 15% for A and 30% for B after the booster vaccination. Protection rates were 0% for influenza A and 25% for B after the single vaccination; they were 5% (H1N1) and 10% (H3N2) for influenza A and 30% for B after the booster. The MFI+/-S.D. (range) after the booster vaccination was 0.26+/-0.33 (0-1.00), 0.17+/-0.34 (0-1.00) and 0.35+/-0.34 (0-1.20) for H1N1, H3N2 and influenza B, respectively. Conclusion: In this study with B-CLL patients, immune response to influenza vaccination was poor. Thus, single and booster vaccinations with influenza virus vaccine do not appear to be of great value to patients with B-cell CLL.
That’s right folks. A mere 5% of CLL patients respond to vaccinations for influenza type A. Type B flu bug vaccination gets a little better response rate, around 15%. But if you look at the actual protection rates, the story gets even bleaker. The percent of CLL patients who are protected against Type A influenza by means of a single jab of usual vaccination is zero, zip, none, nada! The abstract below re-enforces the message, with the added bit of wisdom that CLL patients in later stages of disease are even worse off, it is important to get your pneumonia shot sooner rather than later after you are diagnosed.
Antibody responses to pneumococcal and haemophilus vaccinations in patients with B-cell chronic lymphocytic leukaemia.
Hartkamp A, Mulder AH, Rijkers GT, van Velzen-Blad H, Biesma DH.
Vaccine. 2001 Feb 8;19(13-14):1671-7.
Department of Internal Medicine, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands.
Although vaccination against Streptococcus pneumoniae (S. pneumoniae) and Haemophilus influenzae type b (Hib) is recommended for immunocompromised patients, such as patients with B-cell chronic lymphocytic leukaemia (B-CLL), its protective effect is questionable. We studied antibody responses to pneumococcal polysaccharide vaccine (Pneumovax-23) and to conjugated H. influenzae type b-vaccine (Act-Hib) in 25 patients with B-CLL. After vaccination, the number of patients with antibody levels in the protective range against pneumococcal serotypes and H. influenzae b increased from 9 (38%) to 12 (50%) of 24 patients and from 8 (35%) to 11 (48%) of 23 patients, respectively. The patients with adequate antibody response to Pneumovax-23 and Act-Hib had significantly less advanced stages of B-CLL, higher gammaglobulin levels, total IgG-levels and IgG-subclasses 2 and 4 levels, and lower levels of soluble CD23. Consequently, vaccination with these vaccines should be given as soon as the diagnosis of B-CLL is made, early in the course of the disease with determination of post-vaccination antibody levels.
Since CLL is a cancer of the very immune system that is supposed to protect us from all the nasty bugs out there, it is sort of obvious that we are working with less than a full deck here. Viral defense falls mostly on the elite killer T-cells (“CTLs”, cytotoxic T-lymphocytes). Unfortunately, over and beyond the CLL itself, many of the therapies used to treat CLL are not very friendly to T-cells. Among the major culprits are famous chemotherapy agents such as fludarabine, and monoclonal antibody drugs such as Campath. Both of these drugs wipe out much of the T-cell repertoire, and you are well advised to consider this aspect of therapy prior to initiating it. Discuss with your doctor and make sure you are protected from the more common varieties of viral dangers such as oral herpes, shingles, CMV, Epstein-Barr, etc.
But even in newly diagnosed or relatively chemo-naïve CLL patients, in whom the T-cells have not yet been hurt by T-cell damaging therapy or disease progression, there is another angle to the problem. It has been suggested that dendritic cells are compromised and corrupted in CLL patients. Without these precious messengers to do the proper presentation of pathogen snippets to the T-cells, nothing much happens after vaccination. T-cells cannot attack what they do not recognize as legitimate targets and only officially-sanctioned antigen presenting cells such as dendritic cells can take care of this little safety switch.
Funny you should ask. As it turns out, chances are there is something we can do to improve matters.
There is this drug on the market (it's been around for a few years) called imiquimod (trade name is Aldara, made by 3M). It is called an immune system modulator. It has been approved by the FDA for use in treating early stages of skin cancer, such as basal cell carcinoma, squamous cell carcinoma and actinic keratosis. It is also approved to treat warts, especially genital warts, caused by papilloma virus. There is an avalanche of research papers on the subject of imiquimod, and many clinical trials are looking at how best to use this drug. Aldara is sold as an ointment, in these itsy bitsy foil sachets. If you are a glutton for technical detail, I suggest you type in the word “imiquimod” or “toll-like receptors” or “TLR” into search engines such as PubMed, and you can stay busy for the next couple of weeks or months reading the fun stuff. Believe me, I have been there and done that. I have selected the abstracts below as relevant to our purpose.
Clin Exp Dermatol. 2002 Oct;27(7):571-7.
Imiquimod and the imidazoquinolones: mechanism of action and therapeutic potential.
University of Cambridge, Department of Pathology, Tennis Court Road, Cambridge CB2 1QP, UK.
A central development of the past decade has been in our understanding of the interactions between, and interdependence of, the innate and adaptive immune responses. Innate immunity recognizes 'danger' signals and activates adaptive immunity in a targeted, appropriate and effective response. Dendritic cells and macrophages have a central role in this process, and pharmacological agents that modulate the functions of these cells could have therapeutic value. The imidazoquinolone compounds, of which imiquimod, formulated as Aldara trade mark, is the best characterized to date, are such molecules. Imiquimod and its homologues act by activating macrophages and other cells via binding to cell surface receptors, such as Toll receptor 7, thereby inducing secretion of pro-inflammatory cytokines, predominantly interferon (IFN)-alpha, tumour necrosis factor (TNF)-alpha and interleukin (IL)-12. This locally generated cytokine milieu biases towards a Th1 cell mediated immune response with the generation of cytotoxic effectors, and this has been exploited clinically in the treatment of viral infections (human papillomavirus, herpes simplex virus, molluscum contagiosum) and nonmelanoma skin cancer. Imiquimod has been shown to be significantly more effective than placebo in clearing genital warts, and mechanism of action studies indicate that this is related to the ability to generate proinflammatory cytokines and a Th1 response. Intra-epithelial neoplasms of cutaneous and mucosal surfaces are associated with human papillomavirus infection and there is some evidence that immune response modifiers may have therapeutic value for these lesions. Topical immunotherapy with immunomodulators shows potential for effective and patient-friendly treatment of cutaneous viral infections. These compounds also have adjuvant properties that could significantly enhance conventional vaccine strategies.
J Immunol. 2005 Mar 1;174(5):2476-80.
Cutting edge: priming of CTL by transcutaneous peptide immunization with imiquimod.
Rechtsteiner G, Warger T, Osterloh P, Schild H, Radsak MP.
Institute for Immunology, Johannes Gutenberg-University, Mainz, Germany.
CTL are important in combating cancer and viruses. Therefore, triggering the complete potential of CTL effector functions by new vaccination strategies will not only improve prophylaxis of tumor or virus-related diseases, but also open opportunities for effective therapeutic immunizations. Using transcutaneous immunization, we show that epicutaneous (e.c.)(4) application of an ointment containing a CTL epitope and the TLR7 ligand imiquimod is highly effective in activating T cells in mice using TCR-transgenic CTL or in wild-type mice. Transcutaneous immunization-activated CTL mount a full-blown immune response against the target epitope characterized by proliferation, cytolytic activity, and the production of IFN-gamma that is completely restricted to the epitope used for vaccination. Our results obtained by simple e.c. application of an ointment, without further skin irritating procedures, provide the basis for the development of new, easy to use vaccines against cancer or virus-associated diseases.
Blood. 2006 Mar 14; [Epub ahead of print]
Synergistic activation of dendritic cells by combined Toll-like receptor ligation induces superior CTL responses in vivo.
Warger T, Osterloh P, Rechtsteiner G, Fassbender M, Heib V, Schmid B, Schmitt E, Schild H, Radsak MP.
Institute for Immunology, Johannes Gutenberg-University, Mainz, Germany.
Toll like receptors (TLR) are able to interact with pathogen-derived products and their signals induce the coordinated activation of innate and adaptive immune mechanisms. Dendritic cells (DC) play a central role in these events. As the different TLR are able to trigger MyD88/TRIF-dependent and independent signalling pathways, we wondered if the simultaneous activation of these signalling cascades would synergize with respect to DC activation and induce superior CTL activity in vivo. We observed that indeed the combined activation of MyD88-dependent and independent signalling induced by TLR7 and TLR3 ligands provoked a more rapid and more sustained BMDC activation with regard to the secretion of pro-inflammatory cytokines, like IL-6 and IL-12p70 and the expression of costimulatory molecules like CD40, CD70 and CD86. Furthermore, in the presence of combined TLR ligand stimulated DC, CD4(+) and CD8(+) T cells were insensitive towards the inhibitory effects of regulatory T cells. Most importantly, peptide-loaded BMDC stimulated by TLR ligand combinations resulted in a marked increase of CTL effector functions in wild-type mice in vivo. Thus, our results provide evidence that unlocking the full potential of DC by advanced activation protocols will boost their immunogenic potential and improve DC-based vaccination strategies.
For those of you who have short attention spans for technical detail, here is the sound-byte to remember: imiquimod has the ability to wake up the dendritic cells, make them do a better job of presenting viral snippets in the vaccination, so that T-cells in turn get turned on and go about killing the real virus when and if the real virus shows up in your body.
Here is a cheat-sheet of the logic we have discussed thus far:
I suppose we could sit on our hands, wait for someone to sponsor and fund this clinical trial or otherwise actually do something about it. I expect we will have to wait a long time, if we take that route.
Who will stand to gain from this clinical trial, besides us chickens? Chances are that 3M, the company that makes imiquimod, could not care less. We are talking about a single dab of their precious ointment, a very small amount used once a year at most, by a small patient population. They would make no money marketing to this very specialized niche! They would much rather spend their time and resources developing the lucrative market of warts and skin cancer, where patients have to use the imiquimod in copious amounts, several times a day and for many days. Will run-of-the-mill vaccine makers do this little clinical trial for us? I doubt it. As it is, we have few vaccine makers ready and able to supply the annual flu vaccine to the general public and it would be foolish to hope that they will even think about specialized situations like ours.
I think the logic is undeniable. Right now, the only ones who stand to gain from this research are CLL patients. We have the most at stake, we have the most to gain if the research pans out. No one will support this research, if we do not do it ourselves. This project has all the hallmarks of a clinical trial that CLL Topics membership can and must support. We cannot afford to do otherwise.
We are fortunate that we have some one like Dr. Terry Hamblin — a world renowned CLL expert with unimpeachable professional and research credentials — is willing to work with us. I proposed this project a few weeks ago in emails to several of our research contacts that are active in the area of immune modulators as a way of improving vaccination efficiency. I got a lot of feedback that supported the concept and logic, but only one, Dr. Hamblin, took the extra step of agreeing to take the concept and develop it into a full-fledged clinical trial. Dr. Hamblin is now in the process of getting the necessary approvals from regulatory agencies and ethics committees.
CLL is a non-discriminatory cancer, it does not care about geographic or political boundaries, religious or political persuasions. It strikes where it will, and we all share common ground in fighting this awful disease. CLL Topics is an international organization. We have members across the globe. Last time I checked, patients from more than 80 countries visit our website. We at CLL Topics are proud to be sponsoring this clinical trial in the UK. We are also proud to announce that we have been joined in this effort by the UK CLL Support Association (www.cllsupport.org.uk). If all goes according to plan, the trial will be up and running before the flu season this fall.
If the results show that vaccination efficiency improves if done in combination with imiquimod as an immune modulator, that piece of news will save lives of many CLL patients across the globe. That knowledge will belong to all of us, it will benefit all of us. Heck, it might even help other groups of patients with defective immune systems, not just CLL patients.There is no room here for petty jealousies or turf issues. I would dearly like to see this project supported and warmly embraced by all the other Internet CLL groups as well. Even if it does not improve matters one hundred percent, even if only a segment of our patient population actually gets better protection from vaccinations, how can we not celebrate that victory? This is indeed low-hanging fruit — even a small improvement in the response and protection statistics will mean lives saved.
CLL Topics has pledged to support this clinical trial to the tune of $20,000, at a minimum. The actual trial is likely to cost more than that. Time will tell how the difference will be covered. The UK CLL Support Association has agreed to join us in this effort. As a relatively new organization, it will take them time to come up the curve. We appreciate their pledge of $1,000 and we appreciate even more their solidarity with us in this worthwhile effort. PC and I take our hats off to the leadership of this new organization (you can find a description of this new registered charity on our Support Groups page). They were quick to see the value of this project when we suggested it to them during our recent trip to the UK. We appreciate their generous commitment to this project and help in mobilizing patient involvement — after all the trial will be conducted in their neck of the woods!
I hope each and every one of you who reads this article and agrees with our logic will support this effort. CLL Topics is all about patient education, activism and empowerment! Let’s get out there and get the job done! Each little bit helps. Please be generous, to the extent that your finances allow. At the very least, write to us and let us know what you think. We are only as strong as our grassroots support, and your emails supporting the work we do is all the legitimacy and credibility that we have (and need) to keep going. In the weeks to come I will be writing more about the details of this project as they are firmed up. Please keep an eye out for them and be ready with your feedback.
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