“Managing” high risk CLL

Sometimes I get hate mail.  The latest was from a patient who is totally against any kind of modern medicine. She lucked out in the lottery and got very indolent “smoldering” variety of CLL. She is convinced that her particular brand of snake oil “cured” her cancer and cannot forgive “Chemo Nazis” like me; three pages of vitriolic self reassurance at my expense. 

Duh!  If like her you are lucky enough to have all the good prognostic indicators lined up in your favor, you will trundle along just fine even if you don’t twist yourself into a pretzel with the crazy stuff.  Just thank your lucky stars and please try to be kind and not rub it in – not every CLL patient is as lucky.

It is the folks at the other end of the spectrum that we need to worry about, guys who are in the high risk Bucket C  right from the get go. These guys contribute most heavily to the scary mortality statistics. By now we know what to look for, the tell-tale pattern of high risk disease. Patients with unmutated IgVH gene status, and / or unfavorable FISH results (deletions in the important 11q or 17p chromosomal regions) have more aggressive disease that does not respond well to many of the available therapy choices. These patients have a shorter fuse between diagnosis and time to first treatment, their remissions are shorter and they have to go back into therapy again and again in an attempt to keep a lid on their high risk CLL, eventually becoming refractory cases with few choices remaining.

If we can develop low toxicity chemoprevention techniques for these high risk patients that nevertheless keep their disease under control we would have a gone a long way to making CLL a more manageable cancer.

Modern day chemoimmunotherapy combos such as FCR are now the most commonly used front-line treatment. In spite of high overall and complete response rates obtained with these combinations, all patients eventually relapse and develop resistance to therapy. Bottom line, most standard chemotherapy drugs are immune suppressive, often they are mutagenic and toxic to varying degrees. The million dollar question is how to control high risk CLL without causing more damage to the patients’ already fragile immune system, possibly encouraging more chromosomal damage and clonal evolution to higher risk status.

Today I would like to tell you about such an approach that is rapidly gaining more support from some of our best experts. Surprisingly enough, it is not a brand new drug but one that has been in the news quite a bit in recent years. The difference is that as researchers are learning more about how it works, why it works, they are developing better ways of using it. The name of the drug? It is Revlimid(lenalidomide). Surprised? I must confess I was – pleasantly so.

CLL and Chemoprevention

CLL behaves differently from most solid cancers and this difference may give us a window of opportunity to manage high risk CLL, convert it to a more indolent form. Chemoprevention is not a cure, not in the English sense of the word. But if this approach means our Bucket C guys live longer, live with better quality of life, get fewer infections and require fewer hospitalizations, I am sure all of us can appreciate the value of such an approach. But before we embrace new approaches it is important that we understand what is going on, get a sense of the lay of the land. I will make this as easy to understand as I can, but you must do your bit and come up the learning curve.

Most cancers grow by each malignant cell having too many babies too quickly. When cancer cells multiply faster than normal cells it gives them a tremendous advantage in taking over available eco niches, grabbing available nutrient resources and becoming the dominant players when competing with healthy law-abiding normal cells.

The thing that sets apart CLL is that it is not really all that aggressive in terms of having more and more baby CLL cells. The reason why CLL cells gradually accumulate and increase in numbers is that they have forgotten how to die. All healthy cells have programmed into them a finite life span. Normal cells go about their business, live out their allotted life spans and then die obediently when it is time for them to die. CLL cells have managed to forget this crucial trick of how to die when it is their time. Since they don’t die when they should, even at the slow rate of their proliferation their numbers gradually increase over time and become huge armies.

Research has shown that CLL cells gain this important survival advantage by manipulating their environment. They have learned how to surround themselves with enablers (among them, “nurse-like cells” – a term coined at UCSD) which constantly feed the CLL cells encouraging survival signals (“survival cytokines”). Altering how neighboring cells behave and subverting the cytokine messages around them is how CLL cells resist death. In addition to manipulating their environment CLL cells can also produce and secrete growth factors such as VEGF(vascular endothelial growth factor. As an interesting aside, the claim to fame of EGCG the green tea extract is thought to be its ability to block this important growth factor). Pro-survival cytokines and growth factors such as VEGF directly influence the ability of CLL cells to grow, avoid cell death and develop resistance to therapy.

Revlimid Method of Action

While the home grown terrorists (CLL cells) are gradually increasing their numbers, what do you think is happening at the police departments and law enforcement agencies (immune system) sworn to protect and defend the land (your body)?   Gradual process of corruption, my friends - that is what is happening.  The terrorists have too many contacts within the police and Feds.  Since the terrorists were once part of the police force (immune system) they know all the tricks necessary to  fool their erstwhile comrades. They still hang out at the same donut shops (lymph nodes).    Heck, they look just like ordinary law enforcement officers, no signs of dangerous activities at all!  (CLL cells decrease the immune recognition proteins called the co-stimulatory molecules that are usually present on their surface). 

What is important to remember is that in the early stages of the national security crisis (early stage CLL) there are still loyal and honest troops (T-cells, NK cells)  around, if only we can galvanize them into action, get them to root out the corrupt officers that have gone over to the dark side. Equally important, we must find ways of tricking the corrupt cops into betraying their identity so that they can be targeted effectively. 

Unfortunately, T-cells and NK Cells are killed in droves by many of the standard chemotherapy drugs. Campath and fludarabine are most infamous in this regard, T cell and NK cell populations are destroyed by both of these drugs.

Unlike conventional chemotherapy drugs, Revlimid does not directly kill cancer cells. Recent work has shown that Revlimid works by activating the patient’s own immune system.That is why it is classified as an immune modulating (“imid”)  drug. It is able to harness the potent cancer cell killing powers of home grown T-cells and NK cells – provided there are enough of these effector cells around and the cancer has not grown too big to fight. One other thing it seems to do is make the cancer cells more “visible” to the rest of the immune system.

With a Little Help From Our T and NK Cells

Putting all this in a nutshell, we must meet four important criteria before our own immune systems can do an adequate job of controlling aggressive CLL.

  1. Patients must be relatively early stage so that the tumor load has not yet grown into gigantic proportions. If the T-cells and NK cells are outnumbered by huge armies of CLL cells, chances are the war is lost right then and there.
  2. Patients must be chemo naïve so that their T-cell and NK-cell populations have not been destroyed by exposure to chemotherapy.
  3. We must find a way of waking up the effector cells so that they take on the job of killing CLL cells with gusto.
  4. We must find a way of making the CLL cells more visible to the effector cells, find a way of pinning a “kill me” sign on theie backsides, as it were.

Recruiting high risk but early stage and chemo-naïve  patients takes care of items 1 and 2 above. What makes Revlimid interesting is that it seems to accomplish items 3 and 4. Below is the abstract of a recent and to my mind very important paper published in Blood by Ohio State group. Send me a personal email if you want to read the full text of this paper. It helps explain why we think chemoprevention by Revlimid has a chance of succeeding.

Blood. 2009 Nov 24.

Lenalidomide treatment promotes CD154 expression on CLL cells and enhances production of antibodies by normal B Cells through a PI3-kinase dependent pathway.

Lapalombella R, Andritsos L, Liu Q, May SE, Browning R, Pham LV, Blum KA, Blum W, Ramanunni A, Raymond CA, Smith LL, Lehman A, Mo X, Jarjoura D, Chen CS, Ford R Jr, Rader C, Muthusamy N, Johnson AJ, Byrd JC.

Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio;

Chronic lymphocytic leukemia (CLL) has a profound humoral immune defect and tumor-specific humoral tolerance that contributes directly to the disease morbidity and mortality. While CD154 gene therapy has demonstrated the ability reverse this immune defect, attempts to do this pharmacologically have been unsuccessful. Lenalidomide is an immune modulating agent with clinical activity in CLL whose mechanism of action is not clearly understood. We demonstrate that clinically relevant lenalidomide concentrations induce surface expression of functional CD154 antigen on CLL cells, via enhanced transcription mediated by a NFATc1/NF-kappaB complex to the CD154 promoter and also through down-stream mRNA stabilization that is dependent upon activation of the PI3-kinase pathway. Importantly, CD154-positive CLL cells promote co-stimulatory activation of normal B cells to produce antibodies, up-regulate BID, DR5, and p73, and become sensitized to TRAIL-mediated apoptosis. Similar evidence of CD154 activation is observed in vivo among patients receiving lenalidomide, including the induction of BID, DR5, and p73 in vivo and also development of a ROR1 anti-tumor directed antibody. Our data demonstrate that lenalidomide promotes CD154 expression on CLL cells and may reverse the humoral immune defect observed in this disease. This study is registered at http://clinicaltrials.gov as NCT00466895.

PMID: 19965642

“Gene Therapy”, “Vaccine Therapy”

Back in 2001- 2002 when I was first blundering my way around the CLL landscape, there was a lot of excitement about an early phase “gene therapy” approach at UCSD. Later on the same approach with some modifications came to be known as the ISF35 “vaccine therapy”. Patients are still being recruited for this trial at UCSD and M. D. Anderson.

The concept was to collect CLL cells from the patient, treat the cells in the lab with a very high tech method to make them express CD154. The process involved using an adenovirus as a Trojan horse to deliver the CD154 package to the CLL cells. Not to worry, the adenovirus had its fangs pulled ahead of time. On the whole, think of this as an amazingly high tech method of pinning a “kill me” sign on the CLL cells.

Once modified to express CD154 the CLL cells were injected back into the patient. The researchers were able to show that many of the surrounding ‘by-stander’ CLL cells and normal B-cells also took their cue from the lab modified cells and began expressing CD154 on their surface. All of these cells expressing CD154 attracted the lethal attention of T-cells and NK-cells and got killed. The concept worked.

Unfortunately, we came close - but no cigar.

The problem was as simple as this. The effect faded quickly over time (often in a few days) and even with protocol changes to include multiple injections of the “vaccine”, it was not possible to sustain the effect. Remissions were transient at best. A close personal friend of mine participated in the early gene therapy trials. I regret she got little joy from it. Lise Rasmussen passed away in 2008 after many subsequent layers of therapy including two mini allo sibling donor transplants. Sweet Lise, I was thinking of you as I wrote this article.

The latest paper from OSU is pretty blunt: gene therapy experiments showed the concept worked, but “attempts to do this pharmacologically have been unsuccessful.”

“The CD154 gene therapy approach for CLL represents an exciting proof of concept to reverse the disease-induced immune defect. However as with other gene therapy approaches, CD154 gene therapy is inefficient, cumbersome and has not produced durable remissions, perhaps due to the inability to administer therapy over an extended period of time. Identifying an alternative pharmacologic strategy that mimics this approach would represent a major therapeutic advance for CLL and other related lymphoproliferative disorders.”

Enter Revlimid, Center Stage

Now we are learning that we may be able to do the same job as the earlier “gene therapy” and present day ISF35 “vaccine therapy” with a lot less fuss, a lot more consistency and for a longer period of time – by giving patients a Revlimid pill each day. Suddenly, many of the problems associated with the gene therapy approach appear to have been removed. Meeting requirements 3 and 4 on our check list of necessary conditions for chemoprevention may be within our reach now: Revlimid up-regulates CD154 (and other co-stimulatory markers) on CLL cells,  the equivalent of pinning “kill me” signs on the nasty little buggers.  And this immune modulating drug surely wakes up the sleeping T-cells and NK-cells.The pesky “tumor flare” associated with Revlimid therapy is not a lot of fun, but it is a clear indication of powerful stimulation of the patient’s own immune system.

Quality of Life, Prevention of Infections

There is one other very intriguing result reported in this paper from OSU that needs a bit of explaining. I was delighted to read this stuff. It may add significantly to the general health and overall quality of life of high risk patients.

Early stage chemo naïve patients still have small percentage of non-cancerous healthy B-cells. Having a supply of healthy B-cells is important because when B-cells finally grow up, they become plasma cells. Think of plasma cells as busy little factories making zillions of copies of immunoglobulins; that is their sole purpose in life. What happens when all the healthy B-cells have died, driven out of hearth and home by hordes of cancerous CLL cells? No healthy B-cells means no more plasma cells, which in turn means no more immunoglobulin production. Now you know why patients with late stage CLL often have low levels of immunoglobulins. Patients with low levels of Ig are more prone to infections.  Intravenous immunoglobulin infusion (IVIG) therapy is the only way of making sure these foks have enough immunoglobulins present to protect them from all kinds of bugs out there in the general community.

It seems Revlimid is capable of stimulating whatever healthy B-cells the patient still has to greater efforts. Byrd et al report that immunoglobulin (Ig) levels improved in chemo naïve patients treated with Revlimid!This effect went away if the patients had been exposed to Rituxan or ofatumumab (Arzerra, Humax-CD20). That is easy to understand, both of these anti-CD20 monoclonal antibody drugs target all CD20 carrying cells – which includes CLL cells as well as healthy B-cells. In other words, to get this beneficial effect of improved Ig levels, Revlimid must be administered while the patient still has sufficient numbers of healthy B-cells and has not been treated with Rituxan or ofatumumab.

The Chemoprevention Clinical Trial

Below is the link to this interesting clinical trial just launched at Roswell Park under the supervision of Dr. Asher Chanan-Khan.

http://clinicaltrials.gov/ct2/show/NCT01003821

Asher is both a good friend and an expert who has pioneered the use of Revlimid in CLL patients. He is some one I depend on a great deal to help patients considering Revlimid therapy. Without his generous and pro-bono help it would not have been possible for my husband PC to go through Revlimid salvage therapy ahead of his cord blood transplant.

As you can see, this trial is looking to recruit only high risk and untreated CLL patients in relatively early stage disease. The size of the trial is not very large - only 25 patients will be recruited. Make a note of the contact information and get in touch with Dr. Chanan Khan if you wish to participate in it.

Be warned: Revlimid is not an easy drug, not something that you can take without precautions. We have discussed “tumor flare” and potential risk of tumor lysis syndrome associated with Revlimid therapy in earlier articles. I was pleased to see the protocol is very clear in mandating Allopurinol as prophylactic preconditioning to protect patients against tumor lysis syndrome.

If you have high risk CLL (unmutated IgVH or high risk FISH – 11q or 17p deletions), chemo naïve, Rai stage 0, 1 or 2 and meet the rest of the inclusion criteria (please do read all the details in the clinicaltrials.gov citation – devil is indeed in the details!), I strongly recommend that you consider participating in this clinical trial. This chemoprevention approach may let you slow down the rate at which your “Bucket C” CLL progresses and as an added benefit it may boost your Ig levels so that you can avoid infections and hospitalizations.

Longer time to disease progression and better overall health and quality of life; you may be helping future generations of CLL patients by becoming a volunteer for this trial; all this under careful monitoring and supervision of your situation. Seriously, what is not to like? Get in line guys. I don’t think the 25 slots will stay open for long once they start recruiting.