The single biggest killer of CLL patients is uncontrolled infection – most often, pneumonia. Adding insult to injury, routine vaccinations do not work very well for our patient group. Secondary cancers such as skin cancer could also be due to inadequate immune protection. Getting a clear understanding of immune dysfunction baked into the cake for our guys is the first step in perhaps protecting yourself better. In this context, this review could easily be the most important one I have / will ever publish. New information and a brand new, exciting clinical trial has prompted me to do this review. I have tried to take much of the jargon and intimidation out of it. But there is no way of making a sound bite of this topic and only you can do the heavy lifting of actually reading this admittedly long review carefully and deciding for yourself whether you agree with the logic. I promise you the effort is worth it.
Many things contribute to poor immune defenses in our patients. Before we get to the main course of this article, let us count the many different ways we are vulnerable to infections – especially viral infections. You cannot fight an enemy you do not understand.
First and foremost, CLL is a cancer of the very immune system that is supposed to protect us – a case of a corrupt police department that allows criminals to flourish unchecked. True, CLL is a cancer of the B-cells and that is only one part of the immune system. But there is so much interaction between the various arms of the immune system that given enough time the corruption spreads far and wide. This is particularly true of B-cells and T-cells, comrades in arms with many interactions. Net result is that many CLL patients have deeply compromised immune function across all aspects of their immune defenses. This is particularly true of advanced cases and / or those that have already been through immune suppressive chemotherapy regimens.
Age is an important contributing factor. There is no denying the majority of our patients are in their sixties, seventies or older. One of the consequences of aging is drop in both the number and diversity of T-cells. Since T-cells are the most important front-line troops as far as viral infections are concerned, this means older patients are more at risk of viral attack. As we age, and T-cell counts drop, so too do their ability to secrete very important proteins called cytokines. In particular, two specific ones called interleukin -2 and interferon gamma (IL-2, IFN-gamma). Low levels of these two cytokines is the hallmark of the frail elderly, prone to infections.
No matter how fit you are or how young you look, there are some aspects of aging that are unavoidable. One of them is the health of your thymus. This little gland is located just behind the sternum, below your thyroid gland. At birth it is about 5 cm long and reaches its maximum weight (20-40 grams) by the time of puberty. The thymus is at its most active during pre-adolescent period. By the early teens, the thymus has already started to shrink (“atrophy”). By the time you reach 75 years, it is a mere shadow of its former self, weighing only 6 grams. Why is this important? A healthy thymus is not just important but pretty damn near critical to the health of your T-cells. You see, newly minted T-cells are not very smart. They have no idea what to attack, how to tell the difference between friend and foe. They get their education and become “smart troops” at only one location in the body: your thymus. In fact, these cells are named “T“-cells because they get their marching orders during their stay in the Thymus (get it, T for thymus). As the thymus decays, so too does the ability of this glad to train new generations of T-cells. It is no coincidence that as people get older, they are more prone to viral infections, autoimmune disease, even cancer – all of which are a direct consequence of poor T-cell function.
Can drugs take over where our bodies and T-cells fail us? Not when the infections are due to viral invaders. Unlike bacterial infections, viral infections are harder to treat. We have available to us a huge line-up of broad spectrum antibiotics and with the exception of a few multi-drug resistant bacteria (MRSA and NDM-1 are good examples) it is possible to hit bacterial infections with a heavy duty shotgun approach that is quite effective. Not so if the infection is caused by a virus. PLEASE understand antibiotics do NOT work on viral infections. As of today, we have only a few very specific anti-viral drugs. None of them are truly broad spectrum and more often than we would wish it is impossible to even identify the real viral culprit soon enough to treat the patient. Nothing we have invented by way of drug discovery comes close to the job that a large and well educated army of T-cells can do.
One of the most important methods of defending against viral infections is active vaccinations. Basically, a small and de-fanged (meaning not dangerous) piece of the virus in question (say, the annual flu virus) is introduced into our bodies. The hope is that seeing this dangerous looking bit of a virus our bodes go on high red alert mode, beefing up resources to fight the actual virus should it ever invade our bodies. This is what is meant by the phrase “mounting a response to vaccination”. Unfortunately, older people and especially immune compromised folks like our guys are unable to respond sufficiently to vaccinations and mount robust response. We just don’t have what it takes by way of T-cells (among others) to get the ball rolling! It is now well understood that CLL patients have less than effective response to annual flu shots or periodic pneumonia shots, especially if the patient has already undergone chemotherapy. We have discussed these and similar concepts at length in several earlier articles – please browse through them if you want to refresh your memory. ( Improving routine immunizations “Jab & Dab” Killer T-cells )
Last but not least, some of the most potent drugs in our arsenal to fight CLL are also the most dangerous to T-cell health. Fludarabine and Campath (alemtuzumab) are both justly infamous for killing off T-cells. In the case of Campath, it has been clearly documented that T-cell numbers and their diversity take a huge hit that is not reversed any time soon. T-cell counts are less than 25% of their former levels as much as 9 months after completion of Campath therapy. Is it any wonder that viral infections and viral reactivations are so much more common after Campath and/or fludarabine therapy?
So what can we do about all this? There is no fountain of youth that can turn us back into healthy youngsters with a hefty thymus doing its job of training hordes of new T-cells (or may be there is!? Read on). We don’t really have much control over new viral drug development. True, we can use more commonsense and try to avoid viral infections by practicing “social distancing”. Anything else? Are there any drugs out there that will make vaccinations work better for us? CLL Topics sponsored and funded a clinical trial that explored one such approach, in our “Jab & Dab” clinical trial. Unfortunately, this trial has not gone anywhere and there are no clear results one way or another.
Here is a new approach that may succeed – a new clinical trial that has pulled together a lot of stuff that I have been pondering for quite some time. It has strong research backing and may succeed where “Jab & Dab” failed. In the real world of medical research, pedigree and funding matter.
This clinical trial is hot off the presses, just announced on May 10, 2011. It is not yet open for recruitment, but that just means you can keep your powder dry and explore this option as soon as they start recruiting. The NCI (National Cancer Institute) and Ohio State University Hospital are collaborating on this one – high pedigree indeed. I am sorry to see that OSU is the only location where it will be offered.
In a nut-shell, the study involves giving CLL patients pneumonia vaccination shots (PCV13 vaccine) concurrently with low dose lenalidomide therapy. Say what? Low dose Revlimid along with pneumonia shots? How does that compute? Please click on the clinical trial link to read all the details of exactly how the trial is designed, who is eligible to participate, contact information and so on. I want to focus on the logic behind this trial, why there may be hope that this approach will allow our patients to be better protected by pneumonia vaccinations.
Senility and the immune system
Lenalidomide (Brand name “Revlimid”) belongs to a class of drugs called imids – meaning immune modulating drugs. Its mode of action is very different from that of standard chemotherapy drugs. We are only now beginning to understand how different.
A research team at the University of California (SF) led by Dr. Edward Goetzl discovered that low doses of lenalidomide can improve immune function in the elderly: increasing their ability to migrate throughout the body, more efficient patrolling activity and longer survival after a pitched battle against pathogen invaders.
They studied a group of 50 elderly adults through the National Institute on Aging and discovered there were two important cytokines (Interleukin -2 and Interferon gamma) that controlled good immune function. When these cytokine levels were adequately high, elderly patients were healthy. When these levels were low, the patients were sickly and prone to infections. Dropping levels of these important cytokines is a crucial part of poor immune function in the elderly. The technical name for it is “immunosenescence” – senility of the immune system. I will give you one guess as to which immune system cell line is responsible for secreting these two important cytokines: you got it, T-cells and their sidekicks, NK cells. Even if you are a feisty young CLL patient, your cancer may make your immune system behave as if it is senile!
The team found that low levels of lenalidomide administered daily increased IL-2 production by as much as 120 fold!! Interferon gamma levels increased by six fold. You can read more about Dr. Goetzl’s work in this UCSF newsletter article appropriately titled Fountain of Youth. His work has also been reported in the lay press as well as interviews by MIT, Wall Street Journal etc. For those of you who prefer your science undiluted, the professional article abstract in “Clinical Immunology” is given below. Please pay attention to the last sentence of this abstract. Dr. Goetzl is saying low dose lenalidomide therapy may be a way of improving senility of the immune system in the elderly.
Clin Immunol. 2011 Feb;138(2):201-11. Epub 2010 Dec 3.
Preferential enhancement of older human T cell cytokine generation, chemotaxis, proliferation and survival by lenalidomide.
Huang MC, Greig NH, Luo W, Tweedie D, Schwartz JB, Longo DL, Ferrucci L, Ershler WB, Goetzl EJ.
Department of Medicine, University of California, San Francisco, CA, USA.
Lenalidomide, an analog of thalidomide, modified responses of stimulated T cells from healthy young (ages 21-40 years) and old (≥ age 65 years) subjects. At 0.03 μM to 1 μM, lenalidomide enhanced generation of IL-2 and IFN-γ by T cell receptor-stimulated T cells of young subjects up to respective maximum increases of 17-fold and three-fold, but at 0.3 μM and 1 μM suppressed IL-17 generation. The same concentrations of lenalidomide enhanced IL-2 and IFN-γ generation by stimulated T cells of old subjects more, with greater respective maximal increases of up to 120-fold and six-fold, without suppressing IL-17 generation. Lenalidomide enhanced proliferation and suppressed apoptosis of stimulated T cells from old subjects, by IL-2-dependent mechanisms, and restored diminished T cell chemotactic responses to CCL21 and sphingosine 1-phosphate. The reversal of T cell abnormalities of immunosenescence by low concentrations of lenalidomide suggest a potential for improvement of immunity in the elderly.
“No one’s really talking about longevity and lifespan now, but about ‘health span,’” said Goetzl, director of UCSF Allergy and Immunology Research, which focuses on developing new diagnostics and treatments for allergic and immunological diseases.
“If, at age 50, your cytokine levels are the same as they were at 25, you’ll probably stay healthy as you age,” he said. “But if they’re heading downhill, we need to do something about it. If you could take a low-dosage pill with no side effects, wouldn’t you do it?”
So, if low dose Revlimid therapy can increase T-cell function and their ability to secrete IL-2 and IFN-gamma in the elderly, can it also do the same job in immune compromised patients such as CLL patients? Dr. Goetzl intends to find out.
Response to Vaccinations
As we discussed above, one of the major complications associated with immune compromised patients is that they do not mount sufficient response to routine vaccinations. Talk about a double whammy. They are most at risk of getting annual flu and perhaps having that escalate into full blown pneumonia – and they are also the least protected by routine vaccinations. It is all part of the same picture – an immune system that is not doing what it is supposed to do. If low dose lenalidomide can reverse some of the effects of aging on immune system function, can it also improve the response to vaccinations in patients with blood cancers?
The abstract below was presented at ASH2010. In this two arm study, patients in the experimental arm (Cohort B) were given shots of Prevnar (Brand name for pneumonia vaccination) while they were also getting low dose Revlimid therapy. The control group (Cohort A) got their pneumonia shots prior to start of lenalidomide therapy. All patients were relapsed multiple myeloma patients who had not had Revlimid before. Both groups also got booster shots of the pneumonia vaccination. Here is the punch line: “ the most potent immune response was observed when both prime and boost vaccines were administered while receiving lenalidomide”.
2772 The Immunomodulatory Role of Lenalidomide on Prevnar® Responses in Patients with Relapsed Multiple Myeloma: A Comprehensive Analysis of the Immune Response
Kimberly Ann Noonan, MPH, BS1*, Anna Ferguson, RN1*, Carol A. Huff, MD2, Amy Emerling1*, Stephanie Mgebroff1*, Rose Wilson1*, Robert D. Knight, MD3 and Ivan M. Borrello, MD4*
Johns Hopkins University, Baltimore, MD; Celgene Corporation, Summit, NJ
Aim: Pre-clinical data suggest that lenalidomide imparts an immunomodulatory effect. This clinical trial in relapsed myeloma patients examined the ability of lenalidomide to augment both endogenous as well as vaccine-specific immune responses in vivo.
Methods: Relapsed, lenalidomide naïve, patients treated with 3 or less prior regimens were eligible for the study. Prevnar®, a pneumococcal vaccine, was given either before or during administration of lenalidomide in two cohorts of patients. Cohort A received their first vaccination prior to administration of drug, and the second vaccine on cycle 2, day 15 of lenalidomide. Cohort B were first vaccinated on cycle 2, day 15 and then cycle 4, day 15. Patients were treated with 25mg of lenalidomide daily days 1-21 every 28 days for 6 cycles. Pneumococcal serotypetitres as well as CRM-197 T cell responses quantified the B and T cell responses, respectively, to Prevnar vaccination and were correlated with lenalidomide administration. Systemic immune responsiveness was determined by delayed type hypersensitivity (DTH) responses toCandida and tetanus and quantification of cytokines in the peripheral blood (PBL) serum and bone marrow (BM) plasma.
Results: A median two-fold increase in antibody responses to Prevnar was observed in cohort B, whereas cohort A demonstrated an 80% decrease in antibody titres. Antibody responses in the bone marrow were more pronounced than in blood and were greatest in Cohort B. 1.8% of the total T cell population proliferated to CRM-197 in Cohort B vs. 0% in Cohort A. Increases in DTH responses were seen in 50% of patients post lenalidomide. Luminex was utilized to measure cytokine levels pre and post lenalidomide. Globally, IL-6 levels were greatly reduced in both the BM (88% reduction) and PBL (77% reduction) samples. Both IFNγ and IL-17 were undetectable in the PBL samples, but were elevated and unchanged respectively in BM samples. Levels of IL-10 peaked in both cohorts after the first vaccination but were ultimately reduced with the administration of lenalidomide, and overall the levels were higher in the BM than PBL samples. MCP-1 and MIP-1β levels showed an overall decrease over the course of the trial. There was no alteration of IL2, IL-4, IL-5, TNFα, IL-7, IL-1 β, IL-12, IL-13, G-CSF or GM-CSF levels with the administration of lenalidomide.
Conclusions: This is the first comprehensive examination of the immunomodulatory effect of lenalidomide on global and vaccine specific in vivo immune responses. We show that the most potent immune response was observed when both prime and boost vaccines were administered while receiving lenalidomide. Immune enhancement by lenalidomide was seen in both the blood and BM compartments. Of note, the serologic titres were greater in the BM than blood and the T cell responses (when observed) appeared greater in the BM. These data provide evidence of the important role of bone marrow niche in the maintenance of immune memory responses. The increased DTH response to both Candida and tetanus provides in vivo evidence of lenalidomide-mediated immune enhancement. Taken together, these data demonstrate that lenalidomide augments in vivo immune responses in patients with advanced/relapsed multiple myeloma. This study provides the rationale for utilizing this drug in combination with cancer vaccines to augment anti-tumor efficacy or with infectious vaccines.
That was in multiple myeloma patients. How about CLL folks? Thought you would never ask. That is the point of this whole article folks. The just announced clinical trial we highlighted earlier (NCT01351896 ) does just that. It too is a double arm study. Both groups get low dose lenalidomide. The experimental group gets their pneumonia shot and booster on days 78 and 134, when they are nicely dosed up with Revlimid. The control group will get their pneumonia shot and booster on days 1 and 78. Notice the control group is getting their first (and major) pneumonia shot on day 1, before they have been on the daily low dose lenalidomide. The hope is that the response to vaccination will be better in the experimental group. As I said, this clinical trial is not yet recruiting. Only 48 people will be recruited and the only location is Ohio State University. That might make it difficult to get in. But both lenalidomide and PCV13 pneumonia vaccination are commercially available drugs. Both drugs are perfectly legitimate for use in CLL patients. If your oncologist agrees with the logic of this clinical trial, there is nothing preventing him from following the same protocol outside of the clinical trial. Worth discussing? You tell me.
Thinking outside the box
This is not the first time we discussed lenalidomide as an unusual drug for the treatment of CLL. Some of you may have read an earlier article I wrote on the subject of Chemoprevention . This clinical trial at Roswell Park ( NCT01003821 ) looks to treat high risk but chemo-naive patients with low dose lenalidomide, sooner than they would normally be treated. Once again the logic is very similar. The hope is that lenalidomide improves the patient’s own immune function so that it does a better job of keeping the CLL under control. If we can find ways of keeping high risk patients from progressing rapidly, that is a goal very worth achieving. If in the process of doing that we also make them less at risk of infections, who is going to complain?
This is the kind of research we need, ways of working with our own immune systems to gradually make CLL a “managed” cancer. A day may come when we can cure CLL patients with no fuss or risks associated with stem cell transplants. In the meanwhile, I would be delighted if we can slow it down, make it less dangerous in terms of infection risk. Improved quality of life and increased overall survival – the two goals that actually matter to patients and their families. Many different groups are working in this area, coming at the problem from different directions.
OK, a lot of people seem to be interested in the immune modulating properties of Revlimid and that is good. Here are some of the concepts making the rounds, concepts we discussed above.
- Chemoprevention or slowing down the rate of progression by early treatment of aggressive CLL with low dose Revlimid (NCT01003821)
- Improved T-cell function and higher levels cytokines IL-2 and interferon gamma, therefore better resistance to infections (“Fountain of Youth“)
- Improved T-cell based responses to routine vaccinations (NCT01351896)
You know me, I can’t resist stretching the boundaries just a bit. I like all of these concepts just fine, I think these researchers are truly thinking outside the box and we are grateful. But there is one more angle where T-cells (or lack thereof) has huge significance for CLL patients. I am talking about secondary cancers, especially skin cancer. Did you know that T-cells play a very important role in controlling actinic keratosis, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)? It seems all of us – even healthy folks with no CLL – have microscopic clusters of cancerous cells scattered around on our skin. This is more likely as we age and accumulate decades worth of skin damage due to UV exposure. In healthy folks, these tiny clusters of cancer cells most often do not grow to become full fledged BCC or SCC or more dangerous malignant melanoma. That is because when T-cells are doing their job of immune surveillance, these malignant cells are quickly identified and killed, long before they become they can even be detected.
But that is precisely the problem with CLL patients. Our guys do not have sufficient T-cell surveillance to catch these incipient cancers before they can become full blown problems. That may be the reason why CLL patients are at increased risk of secondary cancers, especially skin cancer.
That brings us to the million dollar question: can low dose Revlimid therapy kill two (or many more!) birds at one stroke? In addition to all the other good stuff discussed above, can low dose Revlimid therapy also help reduce the risk of skin cancers in CLL patients? Below is a letter I sent to one of my friends who is also a CLL expert. It is pretty self explanatory. I will leave it up to you to judge its potential value of this hypothesis – please be aware it is only a hypothesis at this point.
In just the last month I lost two members / dear friends to aggressive skin cancer. Ironically, both had just undergone therapy (one had FR, the other PCR) to control their CLL and had done very well. Now I am in the middle of advising three different patients looking to make frontline therapy decisions. One has 17p deletion, one has 11q, and one has all the good prognostic indicators. The common theme between all of them is a long history of BCC and SCC.
• the guy with the good prognostics is told FCR is the gold standard, that is what he should get.
• The man with 17p deletion is told Campath is one of very few drugs that works on 17p deleted patients and that is what he should do.
• The 11q deleted patient has had massive increase in abdominal adenopathy – and at the same time he is also fighting a case of squamous cell carcinoma that invaded subcutaneous layers and needed very extensive Moh’s surgery to dig it out of his forehead. Based on the recent excellent European study comparing FC versus FCR, he is told he should get FCR since that levels the playing field for 11q patients.
Here is my problem in a nutshell: I do not want to lose any more friends to aggressive skin cancer while they are trying to do the “right thing” by their CLL – if I can find a way of finessing the problem. Whether or not FCR and Campath get these guys a good CLL remission, both of these options will destroy their T-cell and NK-cell counts – which may be just what is needed to kick their frequent bouts of BCC / SCC into high gear.
There seems to be consensus that Revlimid therapy increases the numbers and efficiency of T-cells and NK-cells. If you believe the recent article out of OSU on Revlimid, it also increases antibody production! A 2006 case history reported by Mike Keating suggests the improved cellular immunity can help clear refractory skin infections (relapsed FCR patient, bad case of mycobacterium marinum infection, Revlimid therapy demonstrably increased T-cell counts and cleared the skin infection as well as did a good job on the patient’s CLL).
To make a long story short, I have searched high and low to see if anyone has used Revlimid therapy to control BCC and SCC and prevent them getting out of control in immune compromised patients. I could not find any references. I discussed this concept with several CLL experts – using low dose Revlimid as a therapy option in early stage CLL patients at risk of aggressive skin cancer – as a way of keeping a lid on both the CLL and skin cancer issues. With a little bit of luck, I hope this pet project of mine may find a home in some clinical trial. I sure hope so. All I have at this point is a hypothesis, that Revlimid may help control skin cancer as well as CLL. That and ten cents will get me a dime. Nothing would please me more than see this concept explored.
Please feel free to send it on to whoever you think might be interested. The worst that can happen is a few of them might get a chuckle out of my naiveté about the complex issues of immunology.
Don’t get me wrong. If you were a perfectly healthy person, never heard of CLL and not immune compromised in any way, you would be plain nuts to consider Revlimid therapy, low dose or otherwise! We have discussed the adverse effects of Revlimid therapy in earlier articles. Among them, the infamous tumor flare reaction, increased risk of blood clots etc. And let us not forget the $$$ cost of this drug! I wonder how long it will take before the generic and much lower cost version of the drug presently available from India will get FDA approval. But that is the subject of another article.
But if you are an immune compromised CLL patient, you don’t get much joy from routine vaccinations and of late you have been prone to frequent infections – especially pneumonia, and you get more than your share of BCC or SCC patches on your scalp or else where that need to be frozen off or dug out, this review may give you something to think about. And something to discuss with your doctors.