Learning From Experience of Others
Experts often use case histories as a way of illustrating their points in CME (continuing medical education) seminars for physicians. Abstract concepts are a lot easier to understand when presented in the format of a concrete case history. I think the approach works very well for patients too. For starters, it is hard to concentrate and learn much of anything when you are personally in the cross hairs. It is a lot easier to absorb the information and understand the nuances, when it is not so personal. Learn now, use later.
In this article I would like to present the case history of a recently relapsed CLL patient. We will go through her medical background, concerns, choices, risks and rewards. I will present my personal take on her best option(s), with the full expectation that many of you will have other opinions and perspectives. In fact, I am counting on it to generate a vibrant discussion! We learn best when we get personally involved in the discussion.
Meet Sarah
Sarah (not her real name, of course – but the details of her case history are entirely true-to-life) is one of my most cherished CLL friends. She is a bright and vivacious lady with a lot to live for. Her 65th birthday is around the corner.
Sarah was diagnosed with CLL in the summer of 2000, when she was 54 years old. She has pretty good prognostics, mutated IgVH and 13q deletion (what used to be single allele deletion has recently evolved into deletion of 13q on both alleles).
Sarah’s Frontline Therapy
After four years of watch and wait, Sarah opted to participate in the PCR (pentostatin, cyclophosphamide and Rituxan) clinical trial. (Thank you, Sarah!) As most of you know, PCR is very similar to the present day gold standard FCR, with the difference that the purine analog used in PCR is pentostatin versus fludarabine. Pentostatin is thought to be kinder and gentler by some experts. I am not so sure I buy into that. You can read our earlier review comparing the two regimens.
Sarah got a long remission, just about 6 years. It was not entirely worry free remission since Sarah developed significant pulmonary problems after the PCR. Looking at this slender woman who led an active life, played tennis etc earlier on, it shocked me how out of breath she was just climbing stairs or even talking animatedly on the phone. There is some literature suggesting that one of the less lovely side effects of pentostatin is lung injury. Zillions of tests and visits to experts did not really resolve her problems. Physical therapy seemed to help some.
Relapse!
All chemotherapy induced remissions end eventually and Sarah’s 6 year long remission is now history. Her white blood count is increasing, but not galloping at any great pace and there do not seem to be any obvious swollen lymph nodes, yet. At this stage of the game, it is reasonable to expect her tumor load is still quite low. Platelet counts have dropped a little bit, possibly indicating increase in bone marrow infiltration with CLL cells. But the most worrisome aspect of her relapse is the frequency of various infections over the last 4-6 months, in spite of her taking every possible precaution to avoid getting infected. Regularly scheduled IVIG (intravenous immunoglobulin) infusions seem to help somewhat.
Family History
Sarah’s mother was also a CLL patient, diagnosed when she was 85 years old. I am not sure she was ever treated for her CLL. But a few years later she was also diagnosed with a second cancer, ovarian cancer. She died at the ripe old age of 92, in 2005.
There is a concept called “anticipation” in family clusters of CLL. It seems that CLL shows its ugly face earlier in life and it may be a more aggressive variety in succeeding generations. As far as Sarah and her mother are concerned, that certainly seems to be the case. Sarah’s diagnosis was a full three decades sooner than her mother’s. While her mother lived out her natural life span (even with a second cancer!) without needing treatment for the CLL, Sarah has already been through PCR therapy, relapsed, and now looking at her best salvage options.
Cancer does seem to be a common theme in Sarah’s family. Her father had skin cancer and eventually died of brain cancer. Her grandmother died of stomach cancer.
Two Additional Complications
There are a couple of other interesting points about Sarah’s background. First, Sarah is of Ashkenazi Jewish background. Second, at the age of 18 she was clinically diagnosed with full fledged mononucleosis (Glandular Fever, for our British readers). And oh, by the way, continuing the family tradition Sarah’s daughter too had mononucleosis as a youngster.
Why are these two relevant to our discussion? If down the road Sarah wants to consider a mini-allo transplant, chances of finding a suitably well matched unrelated donor are not certain by any means. The stem cell donor banks are under-represented in all ethnic minorities. Compared to the higher incidence of CLL in Ashkenazi Jewish people, this low representation becomes a double whammy, something I wrote about a while back in an earlier article: “Does Ethnicity Matter?”
What About Her Bout of “Mono” as a Teenager?
As we have pointed out in several articles, once a person is infected with EBV (Epstein-Barr) virus, traces of the virus linger in the body for the rest of the life of the patient. Vast majority of our population are carriers of this virus. It is passed from person to person through saliva. But not everyone who has been infected with EBV goes on to develop full fledged, clinically diagnosed mononucleosis. That distinction is important to remember.
Researchers at M. D. Anderson reported that patients who have had full blown, clinically diagnosed mononucleosis in their youth are more likely to have reactivation of EBV infection. This is all the more likely in patients who have been through immune suppressive chemotherapy. More recently, M. D. Anderson also reported EBV reactivation might increase risk of Richter’s transformation. “Richter’s transformation occurs in approx 5% of CLL patients and may be associated with infection with Epstein-Barr virus (EBV).”
Given Sarah’s recent history of infections, it is obvious that her immune system is not quite able to nip potential infections in the bud, before they become dangerous. Viral reactivation is one of the hallmarks of reduced T-cell and NK cell function. In this context her medical history of mononucleosis becomes relevant. Is she at increased risk of EBV reactivation if the immune suppression becomes even more pronounced?
You can learn more about EBV by visiting our flagship website CLL Topics and browsing through our review article “EBV: the enemy within”
Life After PCR: Similar to Life After FCR?
We discussed “Life after FCR” in a prior article. In general, patients who have relapsed after FCR have few good options. Salvage therapy is not all that effective and remissions are short lived. With the exception of mini-allo transplant, the survival statistics for post FCR relapse patients are bleak at best.
But does relapse after PCR signal the same kind of response to salvage therapy? The plain answer is that we do not know. The statistics are just not detailed enough for us to peer into the crystal ball. Since fludarabine and pentostatin are both purine analogs and have very similar methods of action, it might be reasonable to guess that therapy options after PCR relapse are similar to options after FCR relapse – but that is just an assumption. Also, patients who get reasonably long remissions after FCR seem to fare better in salvage therapy as well. Sarah got a very satisfactory 6 year remission from PCR, significantly longer than the average PCR patient. I hope this signals her response to salvage therapy in future will be equally robust, compared to the averages.
Sarah’s Concerns
- Given her family history, Sarah worries about secondary cancers and would therefore like to avoid heavy duty chemotherapy, if she can. Alkylating agents such as chlorambucil and cyclophosphamide have long been known to be “genotoxic” (toxic to the genome) and therefore present increased risk of secondary cancers.
- With all the infections she had to deal with in the recent past, and her history of mononucleosis as a teenager, she is reluctant to take on additional hits on her T-cell and NK cell function. That might rule out Campath containing therapy, since this monoclonal is justly infamous for destroying T-cell populations for many months. Viral reactivation is of real concern in patients undergoing regimens containing Campath.
- Sarah is very fair skinned, and with the history of her father’s skin cancer as a wake-up call, she does not take skin cancer lightly. Many experts think that immune surveillance by effective T-cell and NK-cell troops is one of the ways the body protects itself from skin cancer, killing off micro clusters of skin cancer cells before they get a chance to grow and establish themselves as full fledged cancers. One more reason why therapy options that kill of T-cells and NK-cells may not be in her best interest.
- Will additional doses of purine analogs (most likely fludarabine) cause further pulmonary issues? In fact, there is strong guidance that patients should not use pentostatin and fludarabine concurrently. No such guidance about using them 6 years apart, however.
- What about a mini-allo transplant? It would be a very tough call for her to opt for a transplant right now. After all, her relapse is just a few months old, her counts are still very low – and she has four wonderful grand kids she wants to play with! In any case, given her ethnicity it is not going to be all that easy finding a well matched and unrelated donor.
- The other side of the transplant coin, if she decides against a transplant right now and opts instead for a salvage therapy that gives her a good second remission of say, 3-4 years, she will be a lot closer to 70 years the next time she has to consider a mini-allo transplant. True, the age restrictions for mini-allo transplants are a lot less strict than they used to be, but age does influence outcome – especially if there are complicating co-morbidities, such as Sarah’s poor lung function.
As you can see, Sarah’s list of concerns put a big red warning flag on just about all chemotherapy agents out there, as well as Campath. If this is not the time for a mini-allo transplant, what are her remaining choices?
Sarah’s Options Going Forward
Here is are the game-plans that Sarah and her doctors can consider:
- Do nothing right now, wait for better choices to become available down the road. After all, she has relapsed only a few months ago and her counts are still pretty low. No lymph adenopathy by physical examination. What is the rush?
- But her history of frequent infections in recent months is a real worry. Remember, majority of CLL patients die from infections. Especially pulmonary infections. Can Sarah afford to wait while her CLL continues to grow and her immune function gets progressively worse? Her pulmonary function is already compromised.
- The other approach is to treat the CLL before the tumor load gets large. If I were in her shoes, this would be my preference. Without huge armies of cancer cells to deal with, Sarah may have the option of lower dose chemoimmunotherapy combinations such as FCR Lite. Lower dosage of chemotherapy drugs may translate into lower toxicity, we hope.
But my best advice to her is to avoid chemotherapy all together, use only immunotherapy drugs instead.
Immunotherapy, as Maintenance
Aha. I bet that got your attention. I cannot claim to be the inventor of this concept. In a recent article on chemoprevention we discussed some of the background of this new think. The latest issue of “Blood” has an excellent editorial by John Gribben on the subject of immunotherapy. Here is the link, you can read the full editorial for free by clicking on it. Here is what Dr. Gribben had to say, translated into plain English.
- Response rates are increasing using modern drug cocktails such as FCR. But the few CLL cells that survive are likely to be drug resistant clones, and they are the ones that grow back during relapse. This makes treating post relapse patients difficult.
- Immune suppression is also increased in relapsed patients.
- Mini-allo transplants have the ability to really CURE patients because we can harness the power of graft-versus-leukemia (GVL) effect. This is immunotherapy, plain and simple. When everything goes right, the newly grafted immune system cells go after the CLL cells and kill them.
- Expanding immunotherapy options should help us find new ways of CURING CLL and other cancers.
I like the sound of that!
Why is it that immune systems of cancer patients cannot fight off the cancer by themselves? Because in CLL patients their immune system is defective, that is why they got CLL in the first place. For starters, CLL cells develop “stealth technology”, whereby they can slink around and not be “seen” by the immune system cells. Second, some of the most powerful troops whose job it is to provide constant surveillance as well as killing of potentially cancerous cells – T-cells and NK cells – are either in short supply or asleep on the job. Anything we can do to paint a big red bull’s-eye on CLL cells, and increase the number and effectiveness of T-cells and NK cells is going to be helpful.
Standard chemotherapy drugs are a lot more blunt in how they work. Many of them mash up the DNA of the cell to the point where the cell’s own internal mechanisms take over and cause the cell to die. Problem is that in cancerous cells these internal mechanisms may not always work the way they should and then the result is an even more mangled cell that continues to live and reproduce! In patients with 17p deletion, the crucial p53 gene is missing. This gene is necessary for most of the cell death mechanisms. That is why standard chemotherapy does not work very well in patients with this FISH deletion. The percentage of patients with defective p53 function goes up sharply after they have relapsed following chemotherapy.
Rituxan is perhaps the most famous of our modern immunotherapy drugs. It does very little direct damage to the cell by itself. Most of what it does is attach itself to the CD20 marker on CLL cells (all mature B-cells express some level of CD20 marker). With enough Rituxan molecules tagged on, the CLL cell can no longer hide, it looses its “stealth” ability as it were. Immune system cells (such as T-cells, NK-cells) can no longer ignore this monstrosity and therefore the CLL cell is killed. Unfortunately for us, CLL cells do not express a lot of CD20 markers. The relatively sparse tagging of CLL cells means many of them can still escape death. Another problem is that without adequate T-cells and NK-cells to do the actual killing, response is going to be poor. That is why single agent Rituxan does not work very well, especially in previously treated patients with poor T-cell and NK cell function.
The more recent ofatumumab (Arzerra, Humax-CD20) adds a little extra oomph (we think), because it is also able to use another part of the immune system to deliver the death blow, namely complement.
Immunotherapy as Maintenance Regimen
Now we come to the exciting development, the reason why I pounded away on my laptop writing this very long review. Lenalidomide (Revlimid) seems to be able to achieve both parts of the immunotherapy game. As we pointed out in our earlier Chemoprevention article, it increases the visibility of CLL cells. Revlimid takes away their stealth advantage by increased expression of CD154, a danger marker for the immune system. Second, it heals some of the defects in T-cell function, increases the numbers of T-cells and NK cells needed to do the job of hunting and killing CLL cells.
Revlimid is not an easy drug – there is no disputing that. In patients with bulky lymph adenopathy, with heavy tumor load, it is very important to start Revlimid therapy gradually, at low doses and build up slowly to higher doses. Otherwise, the swelling of the lymph nodes –what is called “tumor flare” – can be very painful and downright dangerous. Most experts now agree that extra precautions should be taken in treating patients with high tumor load with Revlimid. Starting dosages can be as low as 2.5mg per day in such cases. Jumping right in with high doses of Revlimid in patients with heavy tumor load can be dangerous.
Many experts are beginning to think that Revlimid therapy is best initiated in patients with low tumor burden, when the troops of the enemy are still small. Tumor flare is likely to be less of a problem in such patients. Hopefully the increased T-cell and NK-cell function as a result of Revlimid therapy will bring about an effective response, effective cell kill. Hopefully the low tumor load means the immune system troops are not overwhelmed by very large armies of the enemy. Unlike standard chemotherapy drugs, there is no mashing up of DNA of the target cells and therefore less chance of secondary cancers – we hope.
While immune suppression in terms of destruction of T-cells and NK-cells does not happen with Revlimid therapy, it is important to remember that a very large majority of patietns treated with Revlimid develop neutropenia. Monitoring and controlling neutropenia with drugs such as Neupogen and Neulasta is an important thing to remember while on Revlimid therapy.
A couple of unanswered questions that I find very interesting are these: does the improved effectiveness of T-cell and NK-cell function due to Revlimid therapy also result in increased ability to fight general viral infections and reactivations? Does it also protect patients from micro clusters of secondary cancers (think skin cancer spots) from gaining a foothold and becoming full fledged monsters?
Many clinical trials are going on to see if the ability of Revlimid to increase T-cell and NK-cell function means it can give Rituxan or Arzerra a more effective helping hand. Remember, we said both Rituxan and Arzerra depend on the immune system to do the actual cell kill of CLL cells. They do the tagging, Revlimid supplies the T-cell and NK-cell troops to do the actual killing. Sweet concept, I hope it proves to be the case.
So, that is my advice to Sarah; that she should talk to her doctors about low dose Revlimid therapy, either by itself or in combination with Rituxan (or Arzerra). And that she should consider starting sooner rather than later, in order to possibly avoid massive tumor flare reactions. Unlike Campath and fludarabine which will further demolish her T-cells and NK-cells, Revlimid may actually build up these immune defenses, give her additional protection against opportunistic infections, especially viral infections. The neutropenia that seems to be built into the cake with Revlimid therapy can be controlled with prudent use of Neupogen or Neulasta shots. Staying away from standard chemotherapy drugs may also increase her chances of avoiding secondary cancers.
What say you?
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56 comments on "Case History of a Relapsed CLL Patient"
First, I hope everyone is having a good Easter Sunday…even for those of you who don’t celebrate it.
Ah! PCR…my brand of treatment! And a very appropriate “pounding” on your computer as well Chaya! My doctor and I had a very similar discussion at my last appointment two weeks ago, as I was concerned if my CLL was sneaking back unnoticed, since it’s been over two years now since my PCR with the Campath chaser.
My lymph count has never gone above 500 since then (with the NK cells staying around 40), and my platelets have been slowly dropping (still above 120, but we think that this may be due to the green tea extract…I stopped it for two months and my platelets began climbing again…I’m back on 650 mg of EGCG daily and we’ll see what the platelets look like in my blood draw scheduled for this week)
Everything else has been normal…I feel great, working as hard as ever…maybe harder than I have in the past 5 years, feel normal and healthy (except for allergy problems, which I have had for 30 years and just learned to live with ) , and have had no infections…not even a cold. Had intraocular lens surgery in December, and that went without a hitch as well. And now I can see again!
It was good to hear that Sarah went 6 years after her PCR. Maybe that’ll help me to stop worrying for awhile since I have had no change in my symptoms (no lymph node involvement since then…they all measured normal at my last CT scan a few weeks ago), or at least until something shows up to indicating it’s coming back.
So, how soon should something like Revlimid be considered for maintenance therapy. Has anyone determined that very low doses taken earlier be of any benefit…even when there is not yet any sign of the CLL…while I’m still strong and relatively healthy (I’m 67 now and am still in pretty good shape…exercise regularly, for example) ?
Since we know that it will be coming back someday, I would think that the earlier we start, with the lowest possible doses, the better the remission may be…which is the hope I’m placing on the backs of the extra vitamin D and the EGCG I’m taking now in addition to the anti virals and anti bactrerials.
How should I present this idea to my doctor…or doesn’t earlier intervention at this stage really make any difference in the long run?
Now, break time is over…back to cleaning winter out of my yard!
Harley
Harley:
You are still in official remission. I am willing to bet no oncologist would agree to treat you with Revlimid before you have relapsed! I could be wrong. There may be some acceptance of prolonging the remission with judicious use of low dose maintenance Revlimid therapy.
Whether to start Revlimid style chemoprevention sooner rather than later (but after the patient has relapsed from prior chemoimmunotherapy) is the million dollar question. We discussed some of the pros and cons. In your case, you are not infection prone; you do not seem to have reasons to worry about secondary cancers. Compared to Sarah you might have more room to wait for a while, even after you relapse.
Chaya, the clarity and seeming simplicity of this article leaves me breathless. It says so much that I’ve had difficulty understanding, mostly because even the best doctors seem to use terms that just don’t allow for a smooth, even flow of patient-level information. I thank you, since I am just the kind of patient you speak about— currently in a 6-year remission as a result of chemo + a bio agent. I also find your venture into the EBV connection very interesting and worthwhile.
One question: Why haven’t you included anything about CAL-101? Is it simply that it’s not available yet? Still even so, I wonder if you could say something about it’s possible use in the context of this article. Thanks.
-Ellen Diamond
I would like to know a bit more. As a familial CLL, she is almost certainly a mutated Ig heavy chain, good news. Are her chromosomes still reading normal on the FISH panel? PCR probably means Ohio State, so there might be the chance to get in on a trial but until I know more I would not be willing to suggest revlimid. I am all for increasing the immune system and have not given up on cord blood transplants.
As an aside, I would like to see some clinical trials that compare single unit transplants (if appropriate, stringent matching is used). IMO cord blood was rushed onto the stage without the same level of examiation based on some early sensational results. You get a new immune system if it takes without the fighting that goes on with pooled cord blood samples. Graft vs tumor is good, but I don’t think it is better in concept, than a new baby’s working immune system.
I am not yet sure I understand how well CAL-101 works. There is usually a lot of ‘buzz’ associated with very early phase clinical trials, but only a very small percentage of the new drugs stand the test of time. The vast majority are no more than flashes in the pan, soon forgotten.
Let’s hope CAL-101 is one of the winners. Right now there is very little published information about it – barring company press releases and anecdotal patient testimonials. When I have something worth writing about, I will.
Happy Easter to all. This is another thought provoking, informative review . I think that waiting would be a good idea, except for the increased tendency to infection. Especially in this day and age of “Super Bugs” that are causing problems for people with healthy immune systems. I agree that boosting the immune system would be beneficial.There are times when it feels as if the number of choices are overwhelming, resulting in confused decision making.I have a question about green tea extract. Harley implys that it affects platelet counts. Is this true or proven? My husband is the CLL patient and he takes Green tea Extract. Thank you Chaya for your work.
For those interested, David Arenson, Chaya’s neighbor in Sedona, is undergoing combination therapy using Revlimid and Humax. He is posting his experience on his blog:
http://clldiary.blogspot.com/
What do you think about (newly-approved) Bendamustine with Rituxan/Arzerra as a post-relapse treatment in this case?
Chaya:
Thank you for the very insightful and thought provoking article. It is a harsh reminder of reality for me (and I am certain many others who subscribe to your web site).
I am (unfortunately) one of the “poster children” for CLL. I am of Ashkenazi Jewish decent. When I was younger, I was diagnosed with “mono” twice!! – which I know is highly unusual. The first time was when I was 19 years old and in college. The second time was when I was 25 years old. The second time, I was very ill (with high fevers) and needed to be hospitalized (with IV’s) for many days.
Throughout my life, I have always been prone to either: upper or lower respiratory infections (i.e. sinus, pneumonia, bronchitis, etc).
When I was 56 years old (I am now 60), I was diagnosed with stage 4 (the Rai staging system) CLL. To say the least, I was very ill at that time. As I have previously communicated, I was fortunate that locally (in Pittsburgh) I was able to get enrolled in the FCR-Lite study/protocol at UPMC. Although, I did have a rough time with the FCR-Lite regimen – including several hospitalizations – even though the protocol/treatment was to be “lite”!
Due to severe reactions to Rituxan (including becoming neutropenic and hospitalized after treatments), I could not continue on the maintenance dose/treatment of Rituxan for the 2 years following the 6 month FCR-Lite treatment.
Also, as my immune system (igg, iga, igm) was severely depressed/effected, I have been receiving ongoing IVIG treatments – generally every 4 to 6 weeks during the past 3 + years – with no end in sight.
I fully realize that each and every day that I am in remission is a true gift (it has been nearly 3 ½ years now!), given that there is no cure for CLL. I also fully realize that it is not “if” the CLL will return, but “when” the CLL will return that is the reality! (just like Sarah and I am sure many others).
If, or when, the CLL returns, I hope and pray that there will be many viable options and alternatives for me to consider – as you have so eloquently outlined in this/your most recent article/update. Hopefully, with a little luck: I will continue to be in remission for many years to come; and that there will continue to be successful research on alternative treatments – especially for patients (such as Sarah, me and many others) who relapse.
As always, thank you for your very insightful and informative update – even if it is a dose of reality and a harsh reminder of reality for me!
Thanks very much!
Pittsburgh. PA
P.S. I hope that your move/relocation “back east” was smooth and uneventful and that you are now settled
mbperniz:
There have been significant number of patients reporting drop in platelet counts after initiating EGCG (green tea) therapy. Mayo thinks this is a real effect. Fortunately, the effect seems reversible and the platelet counts go back up when EGCG is discontinued.
Grifj:
Bendamustine is pretty old fashioned chemotherapy drug (been around since pre second world war days, was first used in East Germany) and therefore carries all the usual adverse effect risks. I would expect bendamustine + Arzerra (or Rituxan) would be similar to FCR. Bendamustine can be classified as an alkylating agent and therefore carries the risk of genotoxicity – which in turn increses the risk of secondary cancers.
CLL:
Indeed, you are the poster child for difficult CLL. I could easily have written this case history about you. No, I have not moved east yet. I am still in Sedona, surrounded by half-filled packing cartons. This move is proving to be very time consuming and I will be glad when I am finnaly settled in my new home – around the first week of May.
Chaya,
Thanks. You present the clear and present dilemma all of us will face when we begin to relapse. I am there now myself.
BTW, here is part of a note I got from Dr Neil Kay out of Mayo when my platelets were falling and I had just started on OTC green tea extract.
“Brian, we do not see any evidence of fall in platelets with EGCG but we have to remember we do not know what is in the OTC drugs most folks are taking.”
He thought I had ITP again and he was right.
Concerning Sarah:
Before Sarah made any difficult decisions. I would want to know that her FISH studies were up to date, and less critically, but still helpful, the amount of CLL in her marrow. If she has 11q del, I would also want a CT of her abdomen.
A low resolution search for a donor might also help. Knowing that you have zero or 20 possible matches could make a big difference in your plans.
That said, I would likely wait and watch longer, but now too much longer. Ah that is the rub. If her disease is starting to ramp up, or her BMB already shows extensive disease bring on the lenolidamide + R. If not, bide your time. Lenolidamide is such a new med, and we are learning more and more about it all the time. So many drugs are great when they are new and then down the line, we discover their dark underbellies.
Does F cause the same pulmonary issues as P? SHe is very likely to get a good second remission with FCR or BR or Weirda’s new combo trial with B if she wants to wait even longer and the disease burden has grown too much for L+R.
A transplant is a huge decision. A perfect donor makes it more tempting, especially with the work Miklos is doing with no chemo, only ATG and TLI. very new stuff, but very low numbers for GVHD and good PFS stats
Still, I would wait, and watch closely. (Unless the marrow was packed)
Be well
Brian, 58 yr family doc & father of 4, dx 9/05 del 11q unmutated, CD38+, ITP 9/06 failed steroids, IVIG , Rituxan and splenectomy controlled w cyclosporin A & Rituxan combo. RIC MUD HSCT July 1/08 was CR w BMB MRD neg. – lost graft w growing nodes at 6 months 2.8% BM involvement and ITP again at 13 months, now 5-10% in the marrow at 20 months, but ITP still controlled w IVIG
Like Sarah I had pretty good prognostics when diagnosed in ’89 at age 48. Any nodes have always been teensy and few, and my spleen has always been well behaved. RELAPSE, however has been my game. I have had many. I frankly don’t know how I keep ticking. This wonderful article, and the Revlimid warning about high tumor load may have saved me lots of grief, as that is likely my next stop. This article spawns lots of thought for me. Thanks Chaya. To go back, I started on chlorambucil in ’93 due to very high whites and absolute lymphs, infections and sweats. Next was fludarabin in ’98. Then the FCR trial in ’01 with Dr. Keating. FCR completely cleaned me up. Dr. Keating was thinking “cure” it looked so good. I strated relapsing in early’04. After failing to respond to Rituxan, Cytoxin and Campath, I did a stem cell transplant April ’05. I went into it risky as my marrow was loaded with CLL at the time. Had two DLIs (3/06 & 2/07). The transplant looked good at first, but the CLL came out of hiding with a vengeance for another aggressive relapse. To my pleasant surprise I responded to a heavy Campath regimen June ’07 to Nov ’07. Granted I had a few bouts of chest and bronchial flareups, but for over a year I felt the most energetic I can remember. In early ’09 I needed tx again. I was approved for the CAL-101 trial at Dana Farber, but some “issues” bounced me out of it, so I did subQ Campath 4/09 to 8/09. Again, I’ve had a good response and have been feeling great, save some occasional bronchial flareups. My Neuts have stubbornly hovered in the critical range. Getting off Bactrim fixed that problem. As I’m typing this, I am at the tail end of a few days of flu like symptoms…. dang this compromised immunity!
Again Chaya, thanks for this great topic. It is close to my heart. Through all my responses, especially these last two from Campath, my marrow is still loaded with CLL. My numbers are all holding well at the moment, but I believe I am headed to Revlimid next. While I don’t have bulky lymph adenopathy, it seems my packed marrow is reason to go slowly with Revlimid, don’t you think?
Bob Larkin
North Branford, CT
Chaya:
Good luck with your upcoming move. At least the weather in the “east” is much better now than it was a few months ago when there was 3+ feet of snow on the ground!
Even though there are some similarities, the current big difference between Sarah and me is that I am currently/still in remission (cr) – but i fully realize that it is only now 3 1/2 years. I hope and pray that I remain in remission and do not “cross that bridge” for several more years to come!
I hope that you keep on writing all of “us” during your move/transition and that your move/transition goes smoothly.
Take care and thanks!
Chaya,
You are my angel, sent by God. Thank you, thank you!
If I understand this latest information, it seems there may be treatment for those of us who are watch and wait. My symptoms so far are fatigue, some sweats, and ongoing upper respitory problems. My lymph nodes are increasing in size, although not large enough for the FCR yet. I’m wondering if the Revlimid treatment might save me from progression of this disease. My next visit with the doctor is scheduled for July. I’m thinking a phone call with this information in hand might speed things up a little? I’m stage 2.
Thank you, thank you.
Becky J.
Chaya,
This was a most interesting and relavent article. Is Revlimid in the class of drugs known as immune modulators? Are there any othhers besides Revlimid? For lst line tx, would it make sense to use an immune modulator with a MAB to avoid the toxicity and risk of further chromosome damage assoc. with the FCR type regimans?
Happy Easter to all who celebrate,
Chris R.
Famial CLL, you bet…Dad died of it’s complications at age 80. He was diagnosed 2-3 years prior to he death. I’m of Ashkenazi Jewish descent and was diagnosed three years ago at age 65. I also have Type II diabetes, Idiopathic thrombocytopenic purpura, loads of skin cancers, wet macular degeration, (caused by low platelets, e.g. the ITP), and very severe skin rashes.
Two sets of Rituxan infusions put the CLL and ITP “to sleep”. The rashes continue but are helped by Prednisone and immununotherapy by way of Cyclosporin.
Chaya, do you think the Cyclosporin will also benefit the other immuno issues as well? As always thanks for the great work.
Thank you Chaya!
Bob, thanks for writing your history. It’s inspiring to hear you’ve been kicking some CLL butt.
Sarah’s story is similar to mine and my mother’s.
I hate to ask this question because I fear the answer. Alas, knowledge is power and so I will ask. Are there any cases of mini-allo transplants that have been successful with a forever cure of CLL? Or does the CLL always reappear a few years down the road?
As for Sarah’s choices….to treat or to wait? I think it’s important to know how Sarah feels today? How is her quality of life today? If it’s good, then I say wait. And if it’s not so good, then I say look into treatment. I wish she had better options.
Wishing everyone a healthy and happy April.
doggeedoc
I am glad you asked your question because the answer is a resounding YES!!!! mini-allo transplants do actually CURE a significant portion of the patients who undergo the procedure. CURE in the English sense of the word, as in gone forever, none of the medical jargon double-speak. Please read the series of articles on transplants I wrote last year on Updates for some of the details.
Relapse after a mini-allo transplant happens more frequently when the patient goes into the transplant with a large tumor burden and the trasnplant pre-conditioning is not able to clear most of it prior to the new graft coming in. Think of it as out-numbered armies of good guys. Too many CLL cells to kill right away, before the new graft has a chance to establish itself and go to work. We also discussed some of these concepts in an article titled “The only cure” on our website http://www.clltopics.org .
Another important article titled “Catch-22” (also on http://www.clltopics.org) discusses the process of deciding WHEN to initiate a transplant. That article featured another case history of a CLL patient we called “Richard”. I am deeply saddened to report “Richard” died a couple of weeks ago, two years after his transplant due to GVHD complications. I met Richard and his wife at my home in Sedona, soon after my own husband died. His loss is deeply felt by this patient advocate. Sincere condolences to his wife and family.
Azzy, Brian:
You asked about Sarah’s recent FISH status. I would not dream of writing a case history of this type without such important information! She started with single allele 13q deletion, then graduated to double alled 13q deletions. And I did report that in the article.
Brian, the concern with FCR or bendamustine type of chemo regimens is exacerbating her already vulnerable ability to fight infections. Especially pulmonary infections.
Chaya,
Thanks for the detail on Revlimid. It is helpful in making decisions that are coming up for me. Readers may want to know there are Revlimid trials currently at UCSD (Dr.Tom Kipps) and I believe at a few research centers back east. Does it make sense to use Rituxan/Hu-Max20 to lower tumor burden and then begin low dose Revlimid? Is there good information regarding the method in which Revlimid actually “builds” the reserves of T and NK cells?
Thank you for you time and best wishes with all the packing….I hate that part. Wendy
yesmar:
The Gribben editorial in Blood (I gave a link to it above in the article) as well as the John Byrd article in the same issue of Blood (we referred to that article and provided a link to it in my earlier review on chemoprevention) provide the theoretical underpinnings for this approach. There is really no way for me to simplify the complex science in this case without losing the sense of it all together, so I suggest you read the original articles if you wish to learn.
Should Rituxan be used ahead of time to reduce tumor load prior to start of Revlimid? I can see how this might make sense in someone with heavy tumor burden, in order to reduce the load and possibly reduce risk of tumor flare reaction. However, the interesting thing is that Revlimid might make Rituxan work better, so using both drugs concurrently might be a good idea. Only time will tell. A number of centers (including OSU, UCSD, MDA, Roswell Park, NCI and others) are conducting Revlimid based clinical trials. It has been a while since I have seen this level of excitement in the researcher community.
The article certainly underlines the need for one’s oncologist to give a serious ear to one’s views and plans for treatment as the options become more complex. For me, a “top down” directive, in which my own thoughts were swept aside because I am not “the doctor”, would be most disconcerting. I hope they keep making progress by the time I need to consider the chemotherapy option. Thanks for the article Chaya-your efforts are a great comfort and support in this bewildering morass! :)
I would agree with trying Revlimid/Azerra…..I have reported this before but for the sake of this discussion…..Tom’s IgA/IgM/IgG levels are all very low and his T cells are also very low. He was in the Revlimid/Rituximab trial for relapsed patient’s at MDACC…He made it 10 months before being taken off trial for not responding. He had many problems on Revlimid consisting of possible RTransformation, possible SJ Syndrome, horrible fatigue, feeling much malaise. He stayed on it as long as MDACC allowed him to. Researcher’s say that they do not know how Lenalidomide modulates the immune system. They just believe that it does. Could it be possible that in some patient’s it modulates it in a negative way? Tom also had nerve damage in his lips and chin during treatment with Revlimid. It left after one month off Revlimid to only be replaced by treatment with Azerra. Azerra and Revlimid may prove a great choice for many, but both have the ability to cause peripheral neuropathy. (Fingers and lips for my Tom.) Dr. Keating is studying this neuropathy with both drugs as he has other patients presenting with it. He did state that if you are prone to getting numb fingers, etc., when it is cold outside that you would be more likely to be affected with neuropathy from these drugs. This is only his idea right now because his patients who show neuropathy while taking Revlimid or Azerra have this common denominator. (Not quite scientific). Tom is now in what MDACC calls the “band-aid” treatment. Tom’s lungs are compromised from either treatment or CLL plus asthma and I feel an STC would not be a good idea right now. That is one of his options.
Tom also is double aelle 13q-deleted and 17p deleted, unmutated using the VH3.21 gene, CD38+, Zap70+ Dx at age 50 in 2004.
Good Stuff, Chaya.
Thank you again,
Jlou
For the discussion about this “case”, I agree with what Brian wrote. I would look to see how many possible matches there might be. While doing that I would wait. I think most of the issues with tumor flare are when the nodes are larger. Based on your case, you can’t find any swollen nodes yet, so I would wait until there was some enlargement.
I’m also interested on what you think Chaya in terms of Lupner9’s question. Every opinion I’ve been given from doctors on 1st line treatment has been FCR. I’m curious if there are less toxic choices that might not do as much initial chromosomal damage. Does something like HDMP+R (highly immune suppressive) which gives you a shorter remission give you more options later? If not, would something like Revlimid and Humax for 1st line have other concerns that would limit treatment options later?
I forgot to include on my above post that all of your work is greatly appreciated and I look forward to each of your articles.
I just finished reading the link you supplied to the blood article and found one interesting point that correlates to my question above.
The study showed that in “one patient, development of polyclonal hypergammaglobulinemia with increasing titers of the CLL-specific antibody ROR1” AND “The authors suggest that the reason only a single case report identified recovery of immunoglobulins and development of ROR1 tumor-specific antibodies was that all the other patients received prior rituximab, which depletes normal B cells as well as malignant cells”
Now to me… and I may be wrong. This is saying that one person started to produce CLL anitbodies. I would think that your body producing CLL antibodies *could* lead to a cure. Now if I believe the author of the studies assumption (which I do) that rituximab by depleting the normal B cells has now stopped the ability of the body to produce CLL antibodies with the use of Revlimid then I wonder if using Revlimid first might be a better choice.
Ugh… the puzzle pieces just don’t fit nicely.
Great article, thank you for sharing. I too am concerned with the familial aspect as my mother has CLL. My grandmother and great aunt also had CLL. And my great-grandmother died of Leukemia, we believe it was CLL,but prior to the time it was known as such.
Secondly, in regards to Rituxan. I understand it benefits, but I would weigh it heavily against it’s potential bad side effects. My mother has gone blind, has terrible hallucinations, can no longer walk, and much more because she has PML, Progressive multifocal leukoencephalopathy a rare inflammatory disorder that causes damage to the material (myelin) that covers nerves. It will soon take her life. The FDA stated on it’s recent approval of Rituxan for CLL, that PML is “generally” fatal, do not believe it, it IS fatal, research it elsewhere please.
Chaya, The very best for your move; moves are always trying! Speake from personal experince as first 40 years of own life was spent moving rather frequently. You are moving to be closer to those you love; makes it worth while.
Thanks for all the beautifully “digested” articles; so clear and useful. Must admit that they often have confirmed suspicions felt/formed but difficult to formulate, thanks! It is not easy to navigte papers which tether between “real” patient-benefitting research and pecuniary induced juggeling; if you understand…..
I believe there are all sorts of ideas in the wind pt re. CLL, personally I have a “thing” about the need to always “inform” people of potentially very dangerous conditions even long beforethere is any need, as seen from the potential “sufferer’s” point of view. Difficult!
Keep well!
Delise–
The first trials, (phase I) of Revlimid/Rituximab were where they were given together all the time. That is where the b-cell depletion happened. The MDAnderson trial was a phase II trial and tweaked the protocol by giving Rituximab for 3 days the month prior to starting Revlimid and then just one day a month thereafter did they infuse Rituximab. The rest of the month, every day, Revlimid was taken orally. They believe that this synergy keeps the b-cell depletion from happening and therefore, reboosts the immune system. Revlimid alone does not work as well as with Rituximab. Synergy is what works the best when treating CLL—at least in the present time.
Chaya:
Thank you, again, for explaining the nuances of cell and drug behavior to us laypeople. Every time we read an article, we gain a better understanding, which empowers us to choose what is right for us. What a comfort not to be completely in the dark! So far so good on our end but we know we need to keep up with the curve. Don’t want to be cramming last minute in a panic. We advise all CLL patients with less aggressive disease not to be complacent. The game can change and you want to be ready if it does. Don’t forget to exercise and take care of your body every way you can.
Barb + Blair
Thank you Chaya for a great article.
Monique
Hello jlou
Thanks for the feedback, but I think you missed my point. I wasn’t talking about the Revlimid/Rituximab study, which also shows promise. I was talking about the other study which you can see fully here:
This one does a study of Revlimid for relapsed and refractory patients. Take a look the article was very interesting. The most interesting part was the index patient who never had Rituximab. Her body started making an antibody against the CLL. I couldn’t tell from the article, but I think they are trying her on maintenance Revlimid because she keeps getting better every month.
They believe that the reason her system created the antibody was because she still had plenty of healthy B cells. Remember that Rituximab attaches to CD-20 to make them visible to the body for destruction. CD-20 is on both CLL and healthy B cells. I believe once the healthy cells are destroyed, it takes quite a while for them to come back.
For untreated patients with CLL, these two comments from article were very interesting.
“application of lenalidomide
early in the course of the disease in combination with targeted
therapies that spare normal immune cells may be warranted to
optimize lenalidomide-induced tumor humoral response
”
“to fully appreciate the benefit of this application, new strategies of
lenalidomide administration and combination strategies that build
upon previously reported observations with CD154 gene therapy based
approaches14,38 will be required
”
I understand that combination therapy is what is working great right now, but I believe the intention of Chaya’s article was to point out the Immunotherapy as Maintenance which as the last quote shows, if you can get Revlimid to build up immunity and make the CLL only cells visible to the immune system and combine that with some other immune enhancer like LDN maybe or some other non toxic drug to fight the CLL, we may have a winner for newly diagnosed patients. But these articles also show that Revlimid has great use for refractory patients. I believe that same article mentioned that Revlimid with fludarabine worked on patients without p53!
Now I have to go find the studies on Revlimid on un-treated patients from MD…
Tom
Chaya;
A good friend of mine has recently started her third round of treatments for CLL– Rituxan and Treanda. Her first treatment was FCR, giving her a 1 and 1/2 year remission. Next, Campath, with about a six month remission following completion. Her doctors feel she could be a candidate for a BMT (although not the mini-allo), but I think she is feeling that the risks are not worth it. My question– Would Revlimid still be a possibility in the future after all these other treatments?
RozGrant:
Sounds like your friend has pretty aggressive variety of CLL, given the short length of remission(s). Making the decision to go for a transplant is very complex and only the patient herself can make the call. But I would strongly advice her not to write off this option without checking it out thoroughly.
The interesting thing about Revlimid is that it does not seem to care whether the patient is 17p deleted (FISH test). It seems to work by mechanisms that are different from other drugs and yes, I think Revlimid is still a possibility in her case, even after all her prior treatments. She really should discuss this therapy option with her doctors – my comments above are based on very minimal information and in any case I am not a doctor. Best wishes to her. She is a lucky lady to have a caring friend like you to watch out for her.
Ellen-
My husband has been on CAL 101 for a month. He’s 11Q deleted and unmutated. He’s more SLL than CLL (much appreciation for the great articles on SLL, Chaya). His first course of treatment was FCR because of bulky mesentery lymph nodes (>15 cm.); his lymphocyte count has always been normal but his marrow was 95% packed at diagnosis. The FCR reduced the nodes and significantly reduced the CLL/SLL in the marrow, but he relapsed less than 6 months after completion of FCR. We made the decision to go to a MUD but needed to reduce the nodes further to improve the success of the transplant. To prepare for the MUD, his second course of treatment was HDMP + R. While this further reduced the bulky lymph nodes in his mesentery, the nodes were still not less than 10 cm. in the aggregate, though the mass had started to break up into individual nodes. The general rule seems to be that you don’t want any node greater than 5 cm and the less of those the better. We then looked at other treatments to get him ready for the transplant. One of the advantages of the HDMP not succeeding was that a 10/10 match was found at this time – if the HDMP had succeeded then he would have gone to transplant with a 9/10 (always look for the silver lining!). Revlimid, CAL 101, OFAR, and flavopiridol were some of the many treatments we considered. We decided to go with CAL 101 at Dana Farber because of its high success rate with nodes, during its limited history, and it’s apparent lack of side effects. My husband has had no noticeable side effects while being on CAL 101. The results of his CT, after being on CAL 101 for a month, showed that his nodes had been reduced 29-55%. We’re expecting that he’ll stay on it for another couple of months and then probably go to transplant in July, feeling in very good shape (as opposed to the battered feeling after FCR and HDMP). We’ve heard that one side effect of CAL 101 can be an increase in the lymphocyte count in the circulating blood, which count diminishes gradually over time. He has not experienced this – his count has stayed the same and this may be attributed to the fact that his marrow is relatively clean. We looked at the 51st ASH publication on CAL 101, as well as two papers written by J. Brown (Dana Farber), J. Byrd (Ohio State), R. Furman (Weill Cornell), I. Flinn (Sarah Cannon), S. Coutre (Stanford) and other authors. CAL 101 is in phase 1 clinical trials and, we understand, has about 90 patients participating. It’s made by Calistoga Pharmaceuticals and you can go to their web site. Will it be a flash in the pan? Who knows at this point but it looks like it has debulked with minimal side effects and that’s encouraging.
ANNETTE
Chaya,
We have a syaing that every change is for the best, so good luck, you will feel much better after you move.
My husband’s symptoms so far are fatigue, some sweats in the early evening,SCC and BCC operated 3 yimes already and his lymph nodes are increasing in size. His oncologist ordered a new PET-CT scan in order to consider a first treatment. I’m wondering if the Revlimid treatment might be considered instead of the golden FCR for first treatment ? He is 65, last FISH was normal, but ZAP70+ 80% and CD38+ 90%- bad prognosis.
agail:
Thanks for the information about CAL-101. I will look more closely into it.
Annette:
I have no way of telling if Revlimid is an option for your husband. But this much I can say without stepping over the line – you should explore the option by talking to your doctors about it. With the bulky lymph nodes tumor flare is something to keep in mind. Perhaps they would want to treat first with Rituxan to decrease the size of the nodes and then start him on Revlimid. These are medical details for a specific patient, only you and your doctors can make these calls.
Sorry, I too missed the clinical parameters, although I guessed correctly mutated. There are many good ideas suggested. I might go for the green tea while waiting. Let me explain my single cord idea a bit more for the clinicians who (mostly) silently read this board. Cord Blood has been used to treat many people with cancers considered more “difficult” than CLL but has not caught on in CLL to the same degree because clinicians like the idea of graft vs tumor seen in MUD (matched unrelated donors). From the comments here, the rumors of cures seem to be much more common than testimonials of cures. A single unit of cord blood cells has been used to treat children for a long time, but adults get pooled because the dogma says the single unit has too few cells to catch before the adult immune system wipes them out. Pooled cord blood has been known to provoke unwanted complications . But, here is the good catch 22, CLL is famous for compromised immune systems! The single unit may not be wiped out before it takes. I have experience with cord blood banking. There is a huge variability in cells per cord. Some units have 2-3 times the average number of cells and could be used in these types of trials. It is a curative strategy. I admire the advances in medicine tweaking, but they all stall what is known to be inevitable.
The discussions for real cures, no matter how far fetched they seem to the “experts”, needs to expand in CLL, imo.
Chaya,
Your articles are ALWAYS good, but this is one of your best! One of main problems faced by CLL patients such as myself is to sieve the gold out of the dirt, so to speak. This article is a BIG help in that regard. I have an appointment with my haematologist in 2 weeks’ time so will discuss this. Anything that gives hope before the need for hope becomes urgent is particularly welcome!
Lawrence
(UK patient in remission 18 months after FCR treatment)
In terms of ‘cure’ rate for transplants, I asked my consultant here in London UK and she said there have been 10 bone marrow transplants done for CLL at Barts Hospital. 15% died because of the treatment, but 6 are still surviving. Not bad odds when faced with the alternative – incurable.
Chaya, the news about alternative treatments to chemo seem very encouraging. The thought of having to go through that again without even the hope of a total remission next time was really bothering me. Thanks for these life lines.
Chaya,
What do you think about insulin potentiation therapy. From what I have read, it seems to have great benefits without being too hard on the patient.
Do you know if it is covered by Medicare?
My husband is 81 in stage 4 CLL and is still in “watch and wait.” He is also a 43 year type 1 diabetic which complicates the picture as well.
Thanks much for all you do. Best of luck with your move.
Donna Ryan
Deder:
I am not aware of any peer-reviewed journal publications dealing with “insulin potentiation” as legitimate CLL therapy.
Our focus at CLL Topics and Updates in entirely on evidence based medicine and I am upfront in acknowledging that hard nosed bias. If you are aware of clinical trial data reporting insulin potentiation for CLL, do bring it to my attention. Otherwise, I am afraid I am the wrong person to ask about it. Sorry.
I was reading more of the research that was cited in the immunotherapy Blood article and found that it looks like Revlimid and Rituxan do NOT work well together. It seems that Revlimid decreases the amount of CD20 expressed on a CLL cell. Without that expression, Rituxan is unable to mark it.
Tom
Tom:
We reported that finding (from Ohio State University hospital, John Byrd et al) as well. And it is a concern. But I have not been able to find any other center that confirmed that finding or seems to worry about it in terms of combining Rituxan + Revlimid. Go figure. Only time will tell how this immunomodulating drug (Revlimid) is best used. It took many years before experts sorted out exactly how to administer Campath, what to watch out for etc.
Chayn,
Yes, I see that there are some trials going on with that combination. Continuing my research on Revlimid I remembered that David from CLLDiary was just starting Revlimid with some bad reactions. I thought I would re-read his entries and lo and behold he is on a trial for ofatumumab (another CD20 antagonist) and lenalidomide(Revlimid).
I pray for the best in these trials!
Chaya,
Thanks for another thought provoking article and your wonderfully ‘plain english’ translation of medical jargon.
I’ve a few similarities to Sarah, a parent with CLL in their later years, my CLL diagnosed in my early 50’s, Mono as a teenager..
I had 6 cycles of FCR in 2006 and have been in CR since, however I’ve been experiencing several more colds and respiratory infections in the past year and after questioning my local onco doc, they’ve been collecting Immunoglobulin levels during my quarterly local onco visits as well as at my annual CLL specialist’s visits. And levels of IgA, IgM, and IgG have all been dropping and are now all in the basement.
At last months annual visit to my specialist, we decided to start IVIg infusions. Still too early to see what benefit this will bring, but my questions and concerns are are more for long term.
Are there any articles on whether IVig treatments will ‘jump start’ an immune system? Is there hope that mine will come back to function without these regular infusions boosting it?
I’m also wondering if the 6 cycles of FCR is the cause of this, if I should have stopped at 3 when my local onco said I should, or have completed the 6 as the specialist recommended. Did I cause this with my siding with the CLL specialist?
We’re currently awaiting BMA results to see if there is any MRD and if I qualify for a Bevlimid study..
Where else should I be looking to educate myself?
Thanks for your time, energy, and concern. You are a shining light in my world.
My 44 year old husband, Sami, recently relapsed after about a 4 1/2 year remission with FCR. He was treated in a new clinical trial with TRU-016. He completed treatment in December, 2009. The results appear to be very good, with a good remission (BMB showed minimal residual disease) and virtually no side effects. Time will tell how well this therapy has worked and how long the remission lasts. Sami’s doctor strongly recommended this trial because he said this therapy does not affect the T-cells (as campath does) and early results are looking very promising. Thank you, Chaya, for your well written, insightful article! We’ll keep everybody updated!!
Karen
MicheleB;
Reduced immmunoglobulin levels (“hypogammaglobulinemia”) are very common in CLL patients, even if they have never been treated with chemotherapy. Basically, immunoglobulins are produced by plasma cells. Mature B-cells become plasma cells down the road. You see the connection. Lack of healthy mature B-cells means fewer plasma cells, which in turn means low immunoglobulins. CLL cells are not very good at producing immunoglobulins and in any case they do not produce the wide repertoire of immunoglobulins we need to fight the mind-bendingly large number of pathogens out there. This is why CLL patients are likely to have low Ig, even if they are chemo-naive (untreated).
Rituxan therapy too has an impact on immunoglobulin levels. Since Rituxan targets CD20, the marker carried by all mature B-cells (healthy B-cells too, not just CLL cells), effective Rituxan therapy is automatically going to lead to fewer mature B-cells, therefore plasma cell deficiency down the road, therefore reduced production of immunoglobulins.
Intravenous immunoglobulin infusion (IVIG) is one of the ways to correct hypogammaglobulinemia. We discussed some of the issues involed in an earlier article on our CLL Topics website. http://www.clltopics.org/tchoices/IVIgBenefits.htm and I urge you to read it. IVIG therapy is expensive and always in short supply, so you are likely to find resistance to its prescription by doctors and insurance companies. But be aware that CLL is one of very few diseases for which IVIG therapy has been formally approved by the FDA. In earlier times IVIG therapy was associated with risk of viral transmission etc, since it is made from pooled blood supply from thousands of donors. Modern immunoglobulin preparations are much safer and the standards are much stricter. However, there is always some level of risk in using any blood product and you should be aware of that.
Besides the generic IVIG (which contains zillions of different immunoglobulins targeting zillions of different pathogens), exciting work is being done where they select and concentrate specific immunoglobulin molecules that fight specific infections, say CMV (cytomegalovirus) infections. I believe there is also a EBV targeting Ig product. Some of these targeted Ig products are still experimental.
This will probably blow your mind: a recent paper in “Blood” explored the concept of extracting immunoglobulins from the blood of patients who have successfully gone through mini-allo transplants, identifying the particular immunoglobulin that targets CLL cells (bit of a needle in a haystack operation), then making huge number of copies of that particular immunoglobulin to treat other patients. Talk about cutting edge science. Someday we may cure CLL by a CLL targeted Ig infusion, no need for all that complicated transplant stuff.
Dear Chaya,
Thank you for another excellent article. My local doc diagnosed my CLL last October at 67 (4.45% IgVH mutated, CD38 negative, ZAP70 positive (dim), Q13 bialle deletion, WBC 12.0, lympocytes 6.8).
I went to UCSD (Dr. Castro) in November & results were similar except ZAP70 showed negative, WBC 14.0, lymphocytes 9.8. UCSD will work with my local hemotologist/oncologist so I will alternate my 3 month follow ups between UCSD & local doc.
March 09 I saw my local doc and CD38 now positive (dim), CD 45 bright (was moderate) & ZAP70 moderate (was dim), WBC 14.3, lymphocytes 8.3.
So the test results are worrysome (ZAP70, CD38 positive & bialle q13).
I feel well but have less energy than I used to. But I do make every effort to take good care of myself which includes 8-9 hours sleep, exercise, eating sensibly & taking supplements to help boost my immune system (Life Extension EGCG, Meriva curcumin, ReservAge resveratrol & vitamin D3). An excellent source of info is the Life Extension Foundation (MD’s who combine traditional & alternative approaches when possible). They have an excellent website lef.org & publish a monthly magazine. The Vitamin D Council (Dr. Jack Cannell MD) that Chaya has written about is an excellent source of info about vitamin D3.
I now make time for an hour of daily prayer & meditation. I can’t overstate the positive difference in my mental outlook this has made.
Thank you again Chaya for all that you do. You are in my daily prayers.
Patti Kruse
chaya
I am currently participating in a MDA clinical trial for R+R, on my last of 6 cycles. Have a meeting with my Dr. tomorrow and was going to try and discuss the Blood article with him (although getting more than 3 minutes of his time is difficult). While difficult for this lay person to interpret, it seems to indicate that exposing the NK cells to Revlimid prior to Rituxan therapy is better: “NK-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CLL cells is enhanced by preincubation of NK cells with lenalidomide before exposure to rituximab-exposed CLL cells”. But there is also discussions here and you have said yourself that it may be that the two drugs complement one another. I guess not enough is known about Revlimid to have the answer, thus the need for the trials. I hope I can contribute to a better understanding of this potentially helpful drug. Also, can you point me to any information out there on CAL 101. I am not familiar with it.
Chaya,
Sara’s case is indeed a tough one and part of anyone’s decision for relapse therapy will depend on many factors other than the course of the disease or relapse, such as the person’s mental make up- “Are you a gambler?”
For the sake of discussion I would like to offer the consideration of an immunotherapy I have been watching for a couple of years now.
AlloStim is an immunotherapy now offered by Immunovative Therapies Ltd. While I am not medically trained and cannot offer a good examination of this therapy’s potential efficacy, the CONCEPT is very appealing. AlloStim threapy attempts to do all the good from a BMT (Bone Marrow Transplant) or HSCT while eliminating GVHD (Graft Vs Host Disease).
AlloStim Therapy is an infusion of “normal” donor T-cells that have been cultured/activated outside of the body to be infused into the cancer patient. The T-cells are intentionally mismatched (hence the “Allo” part) with the patient and consist of naive CD4 cells cultured on a matrix with anti CD3/CD28 mAbs (antibodies).
Because this approach uses the body’s own immune system and potentially eliminates GVHD it has grabbed my attention. The other potential benefit may come from its wider application in fighting solid tumors as well as hematological cancers. How many of our club are battling multiple cancers beside CLL?! The severely immune compromised CLLer may not respond to AlloStim but I wonder what the risk of trying this therapy might be? It does not appear to burn any bridges but since the trial is classified as a phase I/II and although “treatment” is the primary purpose of a currently recruiting clinical trial, SAFETY must be a considered issue.
Interested: go to ClinicalTrials.gov and enter NCT00558675
Great article,
WWW
Thanks for a great article, Chaya. Good luck with your move–Beth and John Havey still in remission from 3/09
Thanks for your great Articles Chaya. I have followed your writing since diagnosed 1998 age 63. I began treatment 1-2008 at MDA. WC 150
beta 2 microgobulin 5.1, discomfort from enlarged spleen, low energy etc. I am on the revlimid treatment for patients over 65 with no prior treatments. I have never taken over 5mg per day and at times 2.5. My main problems have been diarrhea and body aches. I now control the diarrhea with lomotil. Have been mostly free of infections except sinus,2 hospital stays one with phneumonia, and a viral infection. After the first 8 months i began having neutropenia. I understand only 4 of us in the trial have this problem. I have been having a neulasta shot every 5 to 6 weeks. This has been a concern for me and I was relieved to read in your article this is common and can be controlled this way. My spleen is now very small. WC around 25 Most every thing else a little out of the normal range but not significant. My last trip to MDA they started me on 5mg four days a week to see if I can go longer without the neulasta. So far there hasn’t been any change. Should really be able to tell within the next 2 or 3 weeks. All in all I would say I feel better on the reduced dosage. Has helped some with the Diarrhea and generally fell better. Considering I have been on this 2 years and 3 months I am pleased I made this choice for treatment. I will read up on the ECGC. I keep thinking there is something I can do to help myself improve the neutopenia. I excersise and eat a healthy diet. I am also diabetic diet controlled. Thanks again for all you hard work and research. Charlcia
Annette
HunterCG,
Do I understand right ? Your first treatment is Revlimid as single drug ? No additional drugs ?
My husband is going to start tratment soon for the first time, but he has bulky lymph nodes and an enlarged spleen and they say that Revlimd can cause tumor flare so you have to decrease the size of the nodes with Rituxan and then start Revlimid.
So although you had enlarged nodes you did not get anything else but Revlimid ?
This is very interesting.
Awaiting your reply
My lymph nodes were not enlarged very much. But my Spleen was quite enlarged and giving me discomfort. No I did not receive any other drugs untill about the 9th month when I started having Neulasta shots about every 5th or sixth week because of low neutrophils. They consider me stable. In Feb they cut back on the revlimid to 4 days a week seeing if I can maintain and not have the Neulasta shots as often. I am just now finishing my first complete cycle at 4 days a week and next wednesday will be my 5th week. So this will be interesting. Usually by the 5th or 6th week Neutrophils are getting close to the .5. Below .5 I have to come off the revlimid hence the neulasta shots. The Study I’m in was started 10-97. I began 1-98. I understand they may have started another study since then with the Rituxan?? Any other questions I will try to answer.
I am a type 1 diabetic and keep my glucose level pretty good. Last year I was bitten by something (spider, tick) don’t know and the doctors wouldn’t commit to what it was. I did get lyme’s and 2 months later was told I had cll stage 0. I don’t know what the two disease’s will do. I was wondering if anyone else with cll was diabetic also, and what if any were the effects of this. I am male, 56
Franco I’m type 2 diabetic and as far as I can tell the cll has not effected the diabetes. I am not on any medications. controlled by diet and excersise
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