“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.
- 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.
- Patients must be chemo naïve so that their T-cell and NK-cell populations have not been destroyed by exposure to chemotherapy.
- We must find a way of waking up the effector cells so that they take on the job of killing CLL cells with gusto.
- 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.
39 comments on "“Chemoprevention” Approach to High Risk CLL"
Dear Chaya,
With a recent visit to M. D. Anderson, I was offered to have my t-cells removed and expanded. Then given FCR. After the chemo, the expanded t-cells would be infused back into me. Then Revlimid was to be used as the imunomodulator. Keating told me it would improve the killing effect, and also tell the cll cells to die thru the removal of the survival cytokines. I have trisomy 12 not the worse but has progressed enough to have two rounds of rituxan prednosone treatments.
It looks like FCR is in the very near future reguardless, so adding Revlimid seems logical. I will see them again in March as the free lunches are running out!!
With Kindest Regards!!
Raymond Parker
Dear Chaya,
I have an appt with Dr CHanan-Khan this Monday, we have been discussing this approach, I will keep you updated if he decides to go this route and let everyone know how it has helped me.
Thanks
Bo Larssen
Dear Chaya,
I read the information on Revlimid with great interest. I am extremely lucky in that I have a 13q single deletion and although I have had CLL for nearly 7 years now, having started at the age of 57, I only have ‘exhausted days’, occasional night sweats and a few swollen lympth nodes. I cannot understand why anyone should object to the info on chemotherapy you give, you state the facts clearly and consisely and leave us to make up our own minds. I know that I don’t need any of it at the moment, but if and when I do, at least I will have had the benefit of all the information you have supplied so that I will be able to make the best decision, whatever that might be. Might I say that this lucky ‘smouldering’ person is extremely grateful to you.
Many thanks
Sandy (UK)
Chaya,
Do you think they see this treatment with Revalimid being available to all groups of CLL patients to slow down the disease?
Thanks!
Doug C.
Coted:
I think the logic works in all groups of patients. But since this is the first of its kind clinical trial, they will only recruit high risk patients since this is the group that really needs the help most in slowing down their disease. “Do no harm” is a very important concept when it comes to designing good clinical trials.
Another and more practical reason is this: since good prognosis patients “smolder” at a very slow rate anyway, how can the researchers tell if they had any impact with this chemoprevention approach? The cohort of Bucket C folks will give an answer quickly – one way or another.
A member asked me via personal email how this approach of single agent Revlimid in chemo naive patients compares with combination therapy with Revlimid + Rituxan.
I can see two differences. First, combination of Revlimid + Rituxan is likely to be more potent, give deeper remissions in patients who are no longer chemo naive and likely to have developed some degree of resistance.
But, following the logic of the Byrd paper we quoted, treatment with Rituxan will surely destroy normal B-cells as well as CLL cells. In the absence of normal B-cells it is unlikely there will be any improvement in immunoglobulin levels. We discussed the logic in our article.
It seems to me the chemoprevention method is a slow and steady way of whittling away at the CLL, keep it under control more or less. The R + R approach is more like conventional therapy to try and get the CLL tumor load to come down as much as possible and as quickly as possible. Chemoprevention versus chemotreatment.
Thank you, Chaya, for this update on Revlimid.
I can only speak about my husband, Tom’s, experience on the MDACC trial of Revlimid/Rituximab for relapsed patient’s. Tom is bucket C and has been treated numerous times….the first was in 2004–he was one of the 300 CLLer’s to first go on trial with FCR. After relapsing, he did a year and a half of Rituxan and solumedrol. A bandaid approach as we waited for the next trial. Then, he started the Revlimid/Rituximab trail in Jan. 2009. Not only was fatigue a major factor in quality of life, but Tom was one of the few who are allergic to Revlimid and was very close to JS Syndrome. He was stopped numerous times for chronic high eosinophil absolute counts, a horrible rash over his body and finally a severe lung infection which he still is being treated for. Yes, he was multi-treated with low T-cell counts. I have spoken with another patient who is in a Revlimid trial for first line at MDACC and after one year of treatment and constant, albeit rare, tumor flare, his counts are coming back up and his disease is trying to progress. He is only taking 5mg of Revlimid daily and is at this time trying to up the dosage. I have heard from Dr. Keating that out of the 40 or so previously treated patient’s at MDACC on the Revlimid trial that many are doing very well. Tom was only the second person to have to be dropped from the trial. Dr. Keating finally believed that Revlimid was not working for Tom.
Tom is now on Ofatumumab/solumedrol weekly and has been told that this is another “band-aid” approach as we wait for a brand new genetic trial due at MDACC sometime later this year.
I hope that we see some great results with this Bucket C non treated group. It sure would change the landscape!!!!!!
My thanks to all who volunteer for this and other trials. I believe with all my heart that our children will never have to face this cancer as incurable……and it is because of out brave patient’s joining trials to help our dreams of a cure see fruition.
Jenny Lou Park
ayurvedic, Chinese herbal and allopathic, for to destroy the immune system and not to rebuild it through adjunct therapies is to leave one open to vulnerabilities and side effects which may prove to be fatal.
Kind regards,
R. Worldie
Note the above posting did not take here it is again:
Dear Chaya,
Regrets that the person who laid their trip on you about your good and kind work does not see the efficacy of the chemo treatments, indolence in this disease sometimes creates indolence in intelligence.
I avoid snake oil treatments and the hope that comes along with them with religious zeal, however we must weed through the bogus adjunct therapies to find those with merit.
Having Richter’s and CLL is no picnic, nonetheless your article on Let Them Eat Yogurt, as well as other extensive research on other mythologies has seemingly been beneficial in my case as far as one can ascertain.
Since chemo destroys T Helper, B lymphocytes and NK cells I have been following Dr. C. K. Wong’s therapy to boost these cells using an extract from mushrooms known as Polysaccharide Peptide. As well as the yogurt treatment and I have my FCR mixed with Dextrose 5% not saline after a 12 hour fast (making the cancer cells {hungry”} as cancer is dependent on sugars. There are a number of other nutritional supplements used as well including EGCG, NAC, Alpha Lipoic Acid and extracts of Turmeric.
The results being that when two 5 CM swellings of lymph nodes were detected I requested the Dextrose / FCR be administered and after three infusions they completely disappeared much to the oncologists amazement.
We do not know for certain if my adjunct therapies have effected the outcome in my case, however they are non toxic. The exception is that no antioxidants should be taken while undergoing any chemotherapy as they interfere with the action of chemo.
Kind regards,
R. Worldie
Chaya,
Thank you for the analysis and info about this trial. I assume using single agent Revlimid first line would not apply to patients like my husband (11q del)with a large node in the throat due to the potential for tumor flare…?
Best,
Leslie Eisenberg
Great article Chaya! Your explanations for us non-scientists are always so lucid. Specificity is going to be the name of the game going forward short of transplants. Revlimid is a welcome weapon in the arsenal.
Two question: Do cll cells typically express brighter CD-20 than normal cells?
If one has never been treated & has very high WBCs (200+) but NO other symptoms- does this mean Revlimid will likely be very difficult?
Finally there is an interesting small trial coming out of France for fNHL that may have some future hope for Cllers.
http://www.ncbi.nlm.nih.gov/pubmed/20044233
I often wonder if we knew exactly which combinations, doses, and the best timing of all the treatments currently in the arsenal if we could not achieve much longer remissions.
MS
Chaya,
Thanks for the ‘education’ on Chemoprevention and the theory of Revlimid’s role as an immune system activator. At one time I was considered a candidate for Revilimid maintenance therapy but was not qualified because of previous chemo—6 rounds of Bendamustine and still in remission 12 months after the last round.
(Lastly, I want to say that I greatly admire your ability to make complex things clear with such graceful prose—I’m a fellow chemist and this is a skill few of us share with you.)
Al Sullivan
ljeisenberg:
Better check with Dr. Chanan-Khan about your husband’s eligibility. I am not surprised by the large node under his chin, that is the classic hallmark of 11q deleted patients. Since this trial is specifically recruiting 11q and/or 17p deleted patients, large nodes will be the rule and not the exception in the patient cohort.
It is a sad commentary on the human condition that a person of your caring intelligence who has always approached the treatment of CLL with scientific caution and attention to the toxic nature of chemo, should be taken to task by the ignorant lucky ones!!
Having been unable to complete any more than the 2 cycles of RF concurrent TX due to a renal(kidney) failure event, I am suspended in a sort of Limbo in which I am enjoying a good recovery in the kidney dept. with near normal blood counts and enjoying excellent health absent of fatigue or infections of any kind but far from a Complete Remission (CR) as nodes are still quite visible though small.
This is after being initially treated with a WBC of 319k, bone marrow infiltration at 91% with huge and profuse nodes. Dr. Byrd has suggested I consider Revlimid (Lenalidomide)as a follow-up TX. Though I have not talked with him about my options to date, his reasoning “May” have to due with the cause of the renal failure being somewhat of a mystery because the Uric Acid levels appear not to be the cause of the kidney failure as in classic Tumor Lysis Syndrome (TLS) and could be due to a rare reaction to Fludarabine.
Your article supports my ongoing suspicion that I maintain active healthy B-cell sites due to remarkably high IgG counts and absence of infections that rival my pre diagnosis health of Sept.’06.
My dilemma is whether to pursue a monoclonal anti-body mono therapy with Rituximab or Ofatumumab or to go for a Revlimid TX. My concern is based on my gross node involvement and what I might expect in the way of internal tumor flare should I choose Revlimid?
The issue of Revlimid’s enhancing the immune response is encouraging but confusing as to why the addition of Rituxan would not also be beneficial as it is indicated as an immune restorative agent in several research papers. I know of at least two CLLers who have been on Rituxan mono-therapy for several years and have not suffered from abnormal infections. As with everything CLL we are all quite unique and are in desperate need of better ways to characterize that uniqueness.
Wayne
Chaya,
Thanks for a very interesting article. Do healthy B-cells eventually return after rituxan mono-therapy? If one has very indolent disease, no chemo, and required rituxan monotherapy two years ago do you suppose that the revlimid alone could increase Ig levels and once again knock the cll down? This article is exciting stuff!
Deb
Chaya,
The unproven potential of Revlimid to slow or even control disease progression in different stages of disease and in patients with different markers is a game changer.
Now there is an option, albeit unproven, to consider for young CLLers who are not in “Bucket A” and who will need treatment or who have already had treatment.
As Susan O’Brien pointed out, those who need Rx for CLL usually die of CLL. The only way out for the younger patient was a transplant.
If Revlimid, alone or in combo with a monoclonal therapy can slow the disease progression with minimal risks and side effects, one needs to carefully weight that option of buying time in the hope that a magic bullet is found or that transplants continue to improve. The jump to transplant is a big one and GVHD is no picnic.
That is exactly where I am at, as I consider a second transplant or buying time with Revlimid, likely combined with Ritiximab. My ITP makes me wary as Revlimid is associated with low platelets, but my biggest concern is that it just doesn’t not work.
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 then CR w BMB MRD neg. – lost graft w growing nodes at 6 months 2.8% BM involvement and ITP again at 13 months, controlled w IVIG now at 28 months
Wayne, Deb:
There are some things we know for sure:
1. Rituxan (and ofatumumab) target all cells expressing CD20 marker.
2. All mature B-cells express CD20. That means CLL cells and healthy B-cells are both targeted by Rituxan.
3. Therefore, anti-CD20 monoclonal drugs such as Rituxan will kill healthy B-cells too, not just cancerous CLL B-cells.
4. Healthy B-cells go on to become plasma cells, the only cells capabale of making immunoglobulins (Ig).
5. Lower than normal levels of immunoglobulins – IgG variety (“hypogammaglobulinemia)increases risk of infections. Patients with low IgG may need IVIG (intravenous immunoglobulin) therapy.
Will healthy B-cells grow back some time after completion of Rituxan therapy? They might, but so will the CLL cells. Will the healthy B-cells be able to compete effectively against the CLL B-cells as both groups try to grow back once the Rituxan is out of the body? We do not know for sure. But my sense is that the competition for grow back will not favor the healthy B-cells.
In keepingt with this analysis, here is a recent article that says repeat use of Rituxan precipitates deep hypogammaglobulinemia. Once again we learn there is no free lunch. Even Rituxan use has downside risks if repeated too often – in this case precipitating hypogammaglobulinemia.
Br J Haematol. 2009 Jun;146(1):120-2. Epub 2009 May 9.
Repeated courses of rituximab for autoimmune cytopenias may precipitate profound hypogammaglobulinaemia requiring replacement intravenous immunoglobulin.
Cooper N, Davies EG, Thrasher AJ.
PMID: 19438506
Chaya,
A year ago when I was about to start therapy Dr. Zent at Mayo told me PCR with lenalidomide is protocol therapy at Mayo Clinic. I opted for FCR with my local guy, maybe I’m mixing my apples and oranges, but I’m wondering if you are aware this protocol at Mayo, and how it stacks up against what Ohio State is doing.
Scottk8123:
Yes, you are mixing apples and oranges.
The clinical trial reviewed here (at Roswell Park, not Ohio State) is for chemo naive and relatively early stage but high risk patients, using single agent Revlimid to see if they can slow down the rate of progression of high risk CLL.
The Mayo study is a far cry from that, they are looking at Revlimid as possible consolidation therapy after patients complete PCR therapy. Multiple agents, later stage patients, post chemoimmunotherapy.
Chaya,
Thanks for your hard work and dedication to further educate those of us who suffer from this disease!!I personally appreciate this recent article that you have shared with us,it effects me as well as many others!!!Please keep up the hard work!! Regards,Gary
Everyone:
I thought I would share with you a personal email I got today. Below is a direct quote of the entire email message. I have not included the sender’s email address to protect his privacy:
====================================
Chaya,
what can I say, shame, shame, shame. You build your reputation on and on, and then you flush it down the toilet in a moment with something like this. What kind of deal did you make with Celgene to coral 25 subjects among your trusting readers for another made-to-order study by their kept man, and your pro-bono friend, Chan? Gee, I got to go take a shower.
Arnold
PS: hope, for your sake, that your readers will see through this naked attempt at subject selling, and you fail to deliver.
==================================
I made no kind of a deal with Celgene or with Dr. Chanan-Khan (I assume that is who “Arnold” is referring to when he talks about my friend “Chan”).
While I think this is a good clinical trial and therefore reviewed it positively on this site, I strongly advice each and everyone of you to do your own due diligence, make sure you read and understand all the details of this clinical trial before you sign up for it; if you sign up for it.
I don’t mind the hard work, but I most definitely do not want to take responsibility for your medical decisions. This site provides information from a layperson perspective. I am neither qualified nor do I want the responsibility of providing medical advice. Will this clinical trial pan out? I do not know. If I or anyone else could guarantee the results of this study there would not be much point in doing the clinical trial. The whole point of clinical trials is to find answers to questions.
One of the problems associated with throwing open the Updates site to all visitors is that we get all kinds of visitors. There is something to be said for keeping the access limited to our registered members. That is why we decided to keep at least the comments section closed to members only – to make sure you don’t have to deal with this kind of stuff. Our open access is an experiment. If it causes more hassle than it is worth we might very well go back to members only format.
In the meantime, I have a favor to ask of you, our registered members. Ever since we went to the open access format I notice many of you are becoming a little lazy and reading the articles without logging on. But that means you don’t get to participate in the discussions. I miss your voices. Please make the effort. This site depends on our grassroots support for its survival. It would be a shame if the discussions part of this site withers away because our registered members don’t make the effort to participate, support this effort as you see fit.
Your silence and lack of participation also makes me feel sort of lonely pounding away on my laptop.
Chaya,
As a newly diagnosed 50 year old CLL pt, your site was the first one I came to and have turned to time and time again as I stumbled through the CLL minefield. From here I learned the questions that I needed to ask my doc and insist that he listen and understand as well. Read your article about getting a second opinion and the second doctor insisted on a the FISH test. Just found out today 13q deletion with him questioning zap70+ results. Your insight and ability to make sense of it all for the lay person has made my intial stumbles easy and have served as a reference not available anyplace else. Keep up the good work and continue to provide us newbies the answers we desperatley seek.
Bill
Chaya,
Thanks as always for opening doors for new possibilities and thanks for your great gift of clarity. While this treatment is being directed toward high risk patients, what of those of us who are chemo naive with seemingly good prognosticators yet ALC’s around 150k and thus not of the indolent smoldering variety? Or, would the high ALC mean this treatment with its tumor flare is not appropriate? (Not “early stage”?) I’m at the place where treatment will probably be suggested soon because of my high ALC and some spleen enlargement. However, I feel great, don’t really have many B symptoms and so am wary of taking on the toxic chemo experience right now, with the fatigue that it might bring, the possibility of mutation, reduced immunity etc. Do you see a potential role for this sort of chemo prevention for patients other than high risk?
Chaya,
I don’t always agree with your assessment (in truth, I rarely disagree), but I NEVER doubt your integrity.
Stay strong
Brian
To use a UK expression, I was totally ‘gobsmacked’ (gob is slang for mouth) by the rude personal attacks on your integrity in the information you provide for this Forum.
I have been using your wisdom for 5 years to help ME make my own decisions about treatment, although in the UK our options are more limited.
Having advanced CLL makes the need for information crucial for patients – please continue your work!!
Jaq
LynnS:
As I pointed out in this and several other articles on Revlimid, the drug is not an easy one to take. “Tumor flare” is observed in majority of patients. Tumor lysis syndrome, while less common is nevertheless something to watch for. Patients should be on allopurinol if at all possible. Many patients develop red itchy rash over big parts of their body. My husband PC did. The thing that worked for him was heavy doses of Benadryl every four hours, round the clock, for a couple of days.
Since this is a first of its kind chemoprevention trial with Revlimid, the researchers prudently restricted recruitment to high risk patients. Why subject low risk patients to the unknowns? As with everything, it is a case of weighing possible rewards against known and unknown risks.
If any of you are looking at Revlimid therapy outside of clinical trials, I strongly advice you to make sure your local oncologist is on board with your choice and that he/she is fully familiar with the details of Revlimid administration.
If Arnold has the guts to post such a thing, I think his name should be posted too. I am a Cller with lots of problems ahead and need every bit of info that i can digest. I was dx at 43 and will surely die from this shitty disease, and i post my name each time.
Love Ya Chaya!!
Raymond Parker
Raymond: it seems that Arnold lacks the physiology – both orthopaedic and organ-related –, required to log on and post publicly, as he sent Chaya a private email. Otherwise, his guts would have been exposed to responses from we CLLers, and his back bone would have been shattered with pointed fingers motioning “tisk-tisk-tisk — what lack of professionalism and manners–not to mention distructive behaviour.”
Chaya– thanks for this fascinating article. Not my need at the moment, but all the info you post make me think! And that, my health and my oncologist favor greatly.
Keep up the good work,
Cristina
Chaya,
There is no doubt that you are one of the most honorable and well intentioned person in CLL and I do not condone the person’s over the top attack but let me try to read between the lines.
1. It was obvious that from day 1, revlimid was a miracle drug in multiple myeloma. It has had its chance in CLL for years at many large, well respected cancer centers with a few anecdotal type improvements.
2. Placebo cures at least 10% of cases and recently 30% rates have been common in diseases considered much more “serious” and “life threatening” than CLL.
3. Given the global warming scientists data faking exposure, people must be more vigilant than ever when trusting only 1 or 2 labs, no matter the lab’s reputation. The Lapalombella paper is the only one in pub med when searching revlimid and CD154. I have seen data faking and fudging at every level of my science career, its real, damn real and that is the shame, not you presenting potentially ground breaking research. I don’t give my name because most scientists think we should look the other way and eliminate the truth tellers.
Indeed the same lab concluded that the 25 mg/d dose of revlimid was associated with unacceptable toxicity:
Higher doses of lenalidomide are associated with unacceptable toxicity including life-threatening tumor flare in patients with chronic lymphocytic leukemia. Byrd JC. J Clin Oncol. 2008 May 20;26(15):2519-25. Epub 2008 Apr 21.
Below is the abstract for Revlimid’s best chance for success in CLL to date. The 38% overall response rate can be compared to another Byrd lab paper, (J Clin Oncol. 2009 Dec 10;27(35):6012-8. Epub 2009 Oct 13.
Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease) treating a similar high risk group with flavopiridol, (although this is a much more toxic agent). The claim that is does “higher than demonstrated with other agents in comparable patient populations” does not mean it is the best. Scientists intentionally use wording to let people read in meaninf that “stretches” what the data really supports.
The bottom line is that revlimid may have a niche in CLL treatment, and modulating the immune system is a fantastic idea, but I would not suggest to a relative they sign up since the clinical data is schetchy and the in vitro work has not been replicated.
Leuk Lymphoma. 2010 Jan;51(1):85-8.
Efficacy of lenalidomide in patients with chronic lymphocytic leukemia with high-risk cytogenetics.
Sher T, Miller KC, Lawrence D, Whitworth A, Hernandez-Ilizaliturri F, Czuczman MS, Miller A, Lawrence W, Bilgrami SA, Sood R, Wood MT, Block AW, Lee K, Chanan-Khan AA.
Department of Medicine, Roswell Park Cancer Institute, NY 14263, USA.
Patients with chronic lymphocytic lymphoma (CLL) with high-risk cytogenetics [del(11q)(q22.3) or del(17p)(p13.1)] have limited therapeutic options and their prognosis remains poor. This analysis was conducted to determine the clinical activity of lenalidomide in patients with high-risk disease. Relapsed/refractory patients with CLL enrolled in a phase II clinical trial who had del(11q)(q22.3) or del(17p)(p13.1) were included in this analysis. Patients received single agent lenalidomide for 21 days of the 4 week treatment cycle. The overall response rate among patients with high-risk cytogenetics was 38%, with 19% of patients achieving a complete response. Median progression-free survival was 12.1 months, which is higher than demonstrated with other agents in comparable patient populations. In addition, the estimated 2-year survival probability was 58%, demonstrating that the responses achieved with lenalidomide are durable, even in patients with CLL with high-risk disease with poor risk cytogenetics.
Here are the numbers for the flavo trial, 53% vs 38 for revlimid
Thirty-four patients (53%) achieved response, including 30 partial responses (PRs; 47%), three nodular PRs (5%), and one complete response (1.6%). A majority of high-risk patients responded; 12 (57%) of 21 patients with del(17p13.1) and 14 (50%) of 28 patients with del(11q22.3) responded irrespective of lymph node size. Median progression-free survival among responders was 10 to 12 months across all cytogenetic risk groups
J Clin Oncol. 2009 Dec 10;27(35):6012-8. Epub 2009 Oct 13.
Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease.
Lin TS, Ruppert AS, Johnson AJ, Fischer B, Heerema NA, Andritsos LA, Blum KA, Flynn JM, Jones JA, Hu W, Moran ME, Mitchell SM, Smith LL, Wagner AJ, Raymond CA, Schaaf LJ, Phelps MA, Villalona-Calero MA, Grever MR, Byrd JC.
Division of Hematology and Oncology, The Ohio State University, Columbus, OH 43210, USA.
PURPOSE: Patients with chronic lymphocytic leukemia (CLL) with high-risk genomic features achieve poor outcomes with traditional therapies. A phase I study of a pharmacokinetically derived schedule of flavopiridol suggested promising activity in CLL, irrespective of high-risk features. Given the relevance of these findings to treating genetically high-risk CLL, a prospective confirmatory study was initiated. PATIENTS AND METHODS: Patients with relapsed CLL were treated with single-agent flavopiridol, with subsequent addition of dexamethasone to suppress cytokine release syndrome (CRS). High-risk genomic features were prospectively assessed for response to therapy. RESULTS: Sixty-four patients were enrolled. Median age was 60 years, median number of prior therapies was four, and all patients had received prior purine analog therapy. If patients tolerated treatment during week 1, dose escalation occurred during week 2. Dose escalation did not occur in four patients, as a result of severe tumor lysis syndrome; three of these patients required hemodialysis. Thirty-four patients (53%) achieved response, including 30 partial responses (PRs; 47%), three nodular PRs (5%), and one complete response (1.6%). A majority of high-risk patients responded; 12 (57%) of 21 patients with del(17p13.1) and 14 (50%) of 28 patients with del(11q22.3) responded irrespective of lymph node size. Median progression-free survival among responders was 10 to 12 months across all cytogenetic risk groups. Reducing the number of weekly treatments per cycle from four to three and adding prophylactic dexamethasone, which abrogated interleukin-6 release and CRS (P < or = .01), resulted in improved tolerability and treatment delivery. CONCLUSION: Flavopiridol achieves significant clinical activity in patients with relapsed CLL, including those with high-risk genomic features and bulky lymphadenopathy. Subsequent clinical trials should use the amended treatment schedule developed herein and prophylactic corticosteroids.
I’ve been fighting the CLL dragon since 2005, first with FCR and several brief courses of rituxan alone, until John Byrd discovered my 17P deletion in summer 2009. Campath seemed the only choice, so I began my TX first with PCR to reduce the nodes and spleen (plus lots of prophylactic drugs including the antiviral Acyclovir), and Campath in November. I managed to get through 7 full doses (out of an expected 36) before CMV put me in the hospital in the middle of December. So my Campath TX came to an end (at least giving me greatly reduced lymphocytes)
Now my doctor in New Mexico and I are searching for what to try next. He put Revlimid on the table and we’ve begun to search for clinical trials and articles. It would appear from the Byrd article, however, that my past use of Rituxan would make Revlimid ineffective. Is that how you interpret the findings in the article, Chaya. Would combining Revlimid with frequent infusions of IVIg help at all?
Right now it looks like I will give Campath another try, but not before a few months of immune system recovery.
Betty:
Having had earlier exposure to Rituxan does not rule out use of Revlimid. That is not the take home message from this article.
What this study does say is that one aspect of immune recovery, namely recovery of immunoglobulin levels, may not happen to the same degree if the patient has had Rituxan therapy just prior to Revlimid therapy.
Most CLL patients who have been around the block a couple of years and been through one or more rounds of therapy are pretty resigned to having low immunoglobulin levels. Many get routine intravenous immunoglobulin therapy (IVIG) to make up for it. That it is even remotely possible to stage a recovery of Ig levels by Revlimid therapy in patients with intact populations of health B-cells is a welcome NEW concept.
If you can get regular IVIG, the problem of prior exposure to Rituxan is moot in any case.
Chaya,
Thank you for a great article! As someone probably somewhere between buckets A and B (no FISH abnormalities and my numbers are progressing moderately but inexorably), I look forward to hearing of the results of this research down the road – and if it is ever considered for patients with better prognostics. It makes great sense that Bucket C patients, besides needing the most help of course, would also show results most clearly. Bravo that they should get the first trials. But it also seems like those with slightly better prognostics, who may also have a decent load of T and NK cells with immunoglobulins still linging to the range of effectiveness, would be great candidates for Revlimid if it works.
By the way, as a journalist, I’m well aware that no good deed of informing others goes unpunished. But your meticulous research, your rock-solid integrity, and your crystal clear ommunication are as much an inspiration as your generosity of spirit. Thank you so much, Chaya.
Having been in school forever to attain my degrees, I told myself that when I FINALLY get to the day where I pay off all my school debt (we’re talking huge six-figure debt here), only then can I make donations to good causes.
A couple of weeks ago, I broke my rule for the very first time. I donated to this site to show my ABSOLUTE support of it. To all you naysayers. Stick that in your pipe.
As to a comment I saw on a posting from last month. (I know I should have written then, but it still applies.) I was surprised to see that some of you receiving immunoglobulin therapy, also are treated with steroids in order to reduce the incidence of allergic reaction. This doesn’t make sense to me UNLESS nothing else can control the allergic reaction. The reason that it doesn’t make sense to me….and maybe I’m way off here…..the steroids will minimize/suppress the maximal benefits of the immunoglobulins? We don’t want to do that….we want ALL the benefits of the immunoglobulins. Just my 2 cents.
Can someone help me find the Leuk Lymphoma 2010 Jan. article referred to in Azzy’s comment?
Is there a journal called Leukemia Lymphoma?
Thanks in advance!
Azzy:
Thank you for your thoughtful comments. We need more patients like you participating in this discussion. Please allow me to make a few points to further expand on the issues you raised.
I fully agree with you that Revlimid the “miracle drug” that worked so well in multiple myeloma was less of a hit in CLL. Please read our less than favorable review of Revlimid a couple of years ago “Revlimid to the Rescue?” (especially my editorial at the end of the article) and two critical Topics Alerts titled “Pushing Revlimid” and “Revlimid – a Breakthrough?”
http://clltopics.org/Chemo/Revlimid.htm
http://clltopics.org/Alert/direct_display_alert.php?reqnum=176
http://clltopics.org/Alert/direct_display_alert.php?reqnum=96
Like you I was appalled by the level of marketing being done. I still am. But, there are few drugs that work in high risk CLL patients with 17p (and perhaps late stage 11q) deletions. Among the ones we know that might be useful are: flavopiridol, lenalidomide (aka Revlimid) and Campath. We have reviewed all of these drugs extensively in http://www.cllltopis.org as well as this website. Each has a role to play but none of them are without risks.
For example, flavopiridol is still available only as part of a clinical trial at OSU. John Byrd, the main driver behind flavopiridol is a good friend and a member of our informal advisory board. He would be the first one to tell you that using flavopiridol is tricky business. There is significant risk of tumor lysis syndrome if flavopiridol is not properly used and the patient monitored appropriately. I doubt Dr. Byrd would recommend use of flavopiridol in a chemo naïve patient.
The article that has caused an up-tick in my interest regarding the possible chemoprevention applications of Revlimid (for use in high risk but chemo naïve patients) comes from Ohio State University. Dr. Byrd is the lead author. I discussed this paper with him and asked him the level of importance he gave to it. He was quite excited about it. While I wrote about the Revlimid chemoprevention trial at Roswell park (in high risk but chemo naïve patients), I think it is OK for me to let the cat out of the bag a little, even OSU is planning to start their own chemoprevention trial using Revlimid (along with an as yet unannounced vaccine of some sort).
So, the one single lab that has pioneered the art and science of using flavopiridol in CLL patients is also the one that is now spearheading the use of Revlimid as a possible chemoprevention agent in high risk CLL patients. I am willing to bet you any number of dollars to donuts that it will be a long long time before we will see use of flavopiridol as a continuous chemoprevention agent in early stage and chemo naïve patients.
Comparing response rates between flavopiridol and Revlimid in two different studies and two different and not matched patient cohorts is like comparing apples and oranges. Sorry, I do not buy this comparison.
Are either of these drugs easy and fun? Of course not. Have our researchers made errors in dosages and methods of administration of these drugs in the early trials? Yes, in both cases. Flavopiridol ran into some serious problems because it binds to proteins in human serum, something that was not recognized while doing lab work. A couple of patients died due to tumor lysis syndrome, several were hospitalized. Byrd etal are excellent researchers because they learned from the earlier mistakes, we now have safer and more effective protocols for dosage and delivery.
Same thing happened with Revlimid as well. The higher doses that were well tolerated in multiple myeloma were too high for CLL, something researcher learned the hard way – at our expense of course. Unfortunately this is standard practice for new drug development. Campath was a much more toxic drug until we learned about the need for prophylactic use of antivirals and antibiotics to protect against viral reactivation and infections.
I do quite a bit of behind the scenes due diligence before I write one of my articles. For example, besides touching base with Dr. Byrd of OSU, I also had extensive email exchanges and phone calls with Memgen, the company that has pioneered the use of autologous CD154 tagged B-cells as a vaccine approach (UCSD, M. D. Anderson). On Revlimid itself I touched base with the folks at Roswell Park as well as the NCI.
Last but not least, none of us have a perfect crystal ball. The best anyone can see is murky truths. This much is true. Both Revlimid and flavopiridol are powerful drugs. Neither is perfect, neither is an easy drug to take, both have massive list of adverse effects, both need to be used only in the context of a clinical trial or a physician competent in their use. Both are welcome additions to our very alarmingly short list of drugs that work in high risk CLL. None of us would touch either of these drugs with a ten foot pole – except if we happen to have high risk CLL.
I think you and I agree on most of these “truths”. When the dust settles where exactly these two drugs fit into CLL pharmacology remains to be seen. I have been around the block enough not to have stars in my eyes anymore. Will Revlimid work well as a chemoprevention drug? I do not know. All I have done is bring to your attention information regarding (1) a very credible and interesting paper in Blood from OSU (2) information about a clinical trial at Roswell Park that is working along these lines. What patients do with the information is up to them.
As for recommending Revlimid to a family member: Ironic you should say that. My husband PC flunked FC+ofatumumab (FCR equivalent). His 11q deleted and bulky disease got next to nothing from this potent combination. We were hoping it would, set him up with a good remission ahead of this transplant. At the guidance of Dr. Neil Kay of Mayo Clinic, Dr. Adrian Wiestner of NIH and yes, Dr. Chanan Khan of Roswell park, PC went through three cycles of Revlimid salvage therapy. He got a good remission and was able to continue on to his double cord transplant. I was not a fan of Revlimid, as you can tell from the prior articles we published on http://www.clltopics.org . But I was impressed how well it worked in PC’s case when more well understood chemoimmunotherapy combination did not. Being a good scientist is all about changing one’s mind when the facts say otherwise.
Hi Chaya,
Thanks for the reply. I am a scientist, not a patient. I have two comments, 1. The trials are not identical, but wouldn’t you expect chemo-naive patients to do better than chemo resistant? Many things show good initial repsonse in chemo-naive patients, while very few work in the chemo resistant. We know it provided some response, as in your husband, but 38% response rate is not that much higher than placebo in some trials. If you are in the 38% that is a very good thing. If a genetic screen or in vitro test can indentify this 38%, they would have a winner, but until then, it seems there are much better choices for most people. Some people may think, lets try this less toxic thing and then go for the heavy stuff, but some drug resistance mechanisms apply to all chemo. I am sure you understand, this is the driving principle to wait and watch. I have not seen enough facts to change my mind about this drug but it looks like there will be plenty more people given revlimid, so maybe it will become more clear.
Azzy:
And you would be perfectly correct to evaluate the information I try to provide in any manner that seems correct to you. That is not just your right it is also your responsibility.
Chaya:
Thanks for all you have done and this wonderful site. I understand you have taken a break (much deserved per Dr. Byrd). I do hope you come back some day. Yours are the only articles this non-physician seem to be able to understand.
I was recently diagnosed with cll. My local oncologists did a FISH test and stopped. I have normal karotypy so he recommended W&W. I wanted to get established at a comprehensive cancer center so I went to OSU and Dr. Byrd. He completed the blood tests. Unfortunately I have unmutated igvh and high cd38 which put me at higher risk (bucket c) [BTW, thank you so much for that bucket article. I always take it with me to the docs]. He has recommended I start on the new trial you mentioned above – revlimid with a pneumonia vaccine. Your articles about issues with revlimid “tumor flareups” give me some pause but the more I read, it sounds like my best option. It is also helpful to see the positive comments here about Dr. Byrd – not just from you but from others in this and other articles. The information I was given so far (admittedly very brief) is that 70% are having positive response with several at normal wbc counts. I’m just in the process of asking questions before I sign up but suspect I will.
If anyone on here is participating in this OSU Clinical Trial, I’d love to hear your experience.
Thanks again Chaya
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