Taming the Killer
As we have seen in the first and second installment of this series, the single biggest hurdle in the way of improving mini-allo transplants is the dreaded graft-versus-host disease (GVHD). It is always a good idea to understand the nature of the enemy before we explore ways to defeat it.
Below is a quick tutorial on GVHD, followed by breakthrough clinical trial (phase II) results of a cellular approach to defeat GVHD. The results are very encouraging. Since the FDA has given this technology fast-track designation as well as Enhanced Access Process (EAP), and the Phase III trial results are expected in late 2009, I thought it is time for you to hear about this very encouraging new technology.
The New Broom Has to Start Sweeping Right Away
Mini-stem cell transplants depend on the donor’s immune system to take over the job that your own immune system has flunked. As the transplant scenario unfolds, preconditioning has reduced the number of CLL cells to a minimum and made sure there are no T-cells and other killer cells left over from your own immune system to bother the graft coming in to the rescue. Here is a thumbnail sketch of what should happen immediately after you get the graft from your carefully chosen donor:
- The donor’s stem cells gradually find their way to the recently vacated bone marrow, and once they are comfortably settled in their new home it is hoped they will begin making perfectly good platelets, red blood cells, neutrophils and other cell lines needed for your long and healthy life. This typically takes a little while, sometimes as long as a month, the engraftment period. During this time you may need transfusion support while the new stem cells gear up and get ready to work.
- During this period, the donor’s T-cells that were infused along with stem cells have several important duties to perform. First, with your own immune system just about wiped out by the pre-transplant conditioning, you are wide open to every bug out there, an easy target with no defenses. This is where the donor T-cells do the heavy lifting. If all goes well, they will do a good job of protecting you against infections. This is called the Graft-versus-Infections effect (GVI).
- Another vital function of the donor T-cells is to seek out and kill all the remaining CLL cells in your body. Remember, this is a mini-transplant we are talking about. Most patients have at least some traces of CLL left over after the pre-treatment process, and these malignant cells would love nothing better than a chance to grow back up to full fighting levels. Giving them a chance to do that would be the kiss of death, literally. The ability of the donor T-cells to hit the ground running is important, so that they can start hunting and killing the remaining CLL cells almost as soon as they are infused into the patient. This is the critical Graft-versus-Leukemia (GVL) effect. Patients with a strong GVL response are a lot less likely to relapse.
- This GVL effect is what gives the hope of a full cure and sets apart allogeneic (donor derived) transplants from autologous transplants (stem cells harvested from the patient himself). Another point to remember, large, well-entrenched armies of CLL cells will have a better chance of defeating the efforts of the new immune system to get rid of them. That is why it is important to reduce the ranks of the enemy as much as possible before the transplant.
- Would your identical twin make a perfectly matched donor for you? Not a good idea, an identical twin is a little too perfectly matched for comfort. Think of it as the consequences of nepotism and you will not be far off the mark. The new graft has to be sufficiently different from the old immune system in order to avoid making all the old mistakes. You don’t want the new immune system getting too cosy with the CLL cells, letting them thrive – the mistake made by your old immune system that allowed the CLL to take hold in the first place.
GVHD: The Pebble in Your Transplant Shoe
Basically, patients go into transplants right after pre-conditioning (usually with our ever popular fludarabine, as well as low dose radiation). Radiation and chemotherapy target rapidly dividing cells, since this is the common profile of cancer cells. However, another set of cells that divide rapidly as normal part of their functioning are skin cells and mucosal cells lining your mouth, stomach and gut and elsewhere. These cells are sloughed off daily as part of normal wear and tear, and must replenish their numbers to keep up with the losses. It is therefore no surprise that your skin and mucosal linings of the mouth, stomach, gut etc often take a beating during chemo and radiation therapy, leading to skin and gut inflammation.
Now the new graft comes in, with its bright eyed and bushy tailed new immune system cells ready and anxious to go to work. All that eager enthusiasm of the new recruits means that when they spot the inflamed areas of the skin, gut etc, they assume the worst, they assume an ongoing infection is causing the inflammation. Donor T-cells and other immune system cells from the graft flood into the area, and the mayhem that ensues can be described as a case of friendly fire gone berserk. In a nutshell, GVHD happens because the new graft cannot yet tell the difference between friend and foe and starts attacking the host – hence the name graft versus host disease. GVHD over-kill makes the initial chemo induced inflammation far worse.
Our skin and lining of the mouth and gut are important barriers that protect our vulnerable insidest from the nasty bugs and pathogens out there in the world. Inflammation often causes breakdown in this important defence barrier, and the problem is made worse by GVHD. The net result is increased risk of dangerous infections. You can see why it is important to bring this spiraling out of control inflammation under control quickly. The standard approach to controlling GVHD is to use immune suppressants (steroids like prednisone, or other immune suppressive drugs such as cyclosporine, tacrolimus etc).
Immune Suppression: a Double-Edged Sword
What is wrong with using massive doses of immune suppressing drugs such as steroids to control GVHD? Well, while your new immune system is taking a little steroid induced nap, thereby weaned away from doing GVHD damage and lulled into complacency by heavy doses of immune suppressive drugs, it is not doing much of anything else either. Like not keeping an eye out for legitimate infections; like not going after the remaining traces of the CLL cells still lurking around; like not doing its job in all the ways an immune system is supposed to do.
You get the picture. Put the brakes on too hard to control GVHD, you can also say bye-bye to effective GVL, as well as effective protection from infections. Patients who develop severe and acute GVHD and therefore need aggressive immune suppression for long periods of time to control it, are at increased risk of life threatening infections, as well as relapse of the CLL because the new immune system does not go out and hunt down the last of the CLL cells, before the cancer has a chance to re-establish itself. That is why transplant experts like to see a just a little bit of GVHD after transplant, because it tells them the grafted T-cells are frisky and doing their job (killing CLL cells and keeping infections under control), but not so much GVHD that it becomes a problem by itself needing lots of steroids and immune suppressive drugs.
What are mesynchymal stem cells?
I bet most of you have never heard of mesenchymal stem cells (MSC). It is important that we learn a little bit about this important variety of stem cells so that we can better evaluate this latest technology for controlling GVHD. I promise I will be brief.
Stem cells come in many flavors. Hematopoietic stem cells (HSC), for example, are the stem cells we talk about when we discuss stem cell transplants. HSC do one thing only: they create brand new copies of all the cell lines in your blood – red blood cells, platelets, T cells and B cells, neutrophils etc. That is why some researchers call these procedures HSCT rather than just SCT, “H” standing for hematopoietic.
Mesenchymal stem cells (MSC) are another variety of stem cells. Like HSC they too prefer to hang out in the bone marrow, but once in a while they take a little trip and circulate in the blood and tissue before going back home to the bone marrow. Mesenchymal stem cells are attracted to any sign of inflammation in the body and rapidly migrate to the place where inflammation is happening. Once they get there, they put out cytokines (chemical signals) that soothe the ruffled feathers of the T-cells and other killer cells firing away at random and making a bad situation worse. This is inflammation control at a cellular level, at the precise spot where the inflammation is happening. By contrast, steroidal drugs and other immune suppressive drugs effect the whole body. Think of MSC mediated inflammation control as effective crowd control at the scene of a riot, rather than country wide clampdown that causes more problems than it solves. MSC immune suppression is more subtle and far more effective than any man made chemical immune suppressant since it has the advantage of being targeted to the spot that needs it.
In addition to tuning down the overly aggressive function of T-cells at the site of inflammation, MSC also perform another function. They put out chemical signals that encourage the local cell lining to regenerate, make new lining cells quickly in order to patch over the inflamed areas. This means the damaged areas heal more quickly and which in turn means the T-cells are no longer interested and drift away from the area. Steroids cannot accomplish this healing function.
There is one further aspect of mesenchymal stem cells that is pretty unique. Since they have to get into the thick of the melee in order to stop T-cells from making inflammation worse, they have evolved over time the ability to avoid getting attacked themselves by the T-cells. MSC do not exhibit any of the markers on their cell surfaces that attract the attention of T-cells or other killer cells. This makes MSC almost stealth cells, undetected and therefore not attacked by the immune system.
What does this mean for us? Why, it means we can use mesenchymal stem cells from donors without having to make sure they are a match for us, since they are not attacked by our T-cells! Studies have shown that these cells are universally compatible. Similar to Blood Type O which can be transfused into all patients, these MSCs may be used without tissue type matching for specific patients. How neat is that!
To date, MSCs have been tested for many different inflammatory diseases in over 1,000 patients. As best as I can tell, no major safety concerns have been observed. What happens when the inflammation is resolved and the MSC have finished their job? Animal studies have shown the MSC return to the bone marrow, and go forth again only if new tissue damage due to inflammation is detected.
“Prochymal”
Osiris Pharmaceutical has developed a mesenchymal stem cell product that they named “Prochymal”. Prochymal is adult mesenchymal stem cells harvested from the blood of normal healthy adult volunteer donors and grown into huge armies in the lab. As we discussed above, MSC do not have to be matched to the individual patient and therefore Prochymal can be used by patients across the board.
Prochymal is being evaluated in Phase III clinical trials for three indications: steroid refractory acute GVHD, newly diagnosed acute GVHD, as well as Crohn’s disease (an inflammatory autoimmune disease where the GI tract is attacked by the patient’s own immune system). It is also being developed for the repair of heart tissue following a heart attack, the protection of pancreatic islet cells in patients with type-1 diabetes, and the repair of lung tissue in patients with chronic obstructive pulmonary disease (COPD). The common theme in all these diseases is out of control inflammation.
Both of the Phase III GVHD trials completed recruitment in record quick time and no longer accepting new patients. (But read below about the “Expanded Access Program” the FDA has approved for Prochymal, to allow gravely ill patients access to this drug). Results from these late stage trials are expected later in 2009. In the meanwhile, we do have results from the earlier Phase II trials and I review them below.
Phase II Trial Overview
The results of the Phase-II trial were presented at the 2006 ASH conference. You can also access the results at the company website.
This Phase II trial was a randomized, prospective, open label trial, conducted at 16 leading cancer centers in the US. The objective of the study was to evaluate the safety and efficacy of Prochymal at two drug dose levels (given to patients on day 1 and day 4).
Thirty one patients were enrolled in the trial, patients between the ages of 18 and 65 who had received an allo SCT transplant (mini or full blown myeloablative variety), and had been newly diagnosed with acute GVHD. Patients were also given the usual standard of care for GVHD with steroids and second line immune suppressive drugs as needed. (It would have been unethical to do otherwise. Untreated acute GVHD is a sure killer).
Patients entering this disease all had acute GVHD spanning grades II – IV, high risk patients with grave prognosis. It is important to note they had received the SCT for a variety of blood cancers including acute leukemias such as ALL, AML, multiple myeloma, aggressive lymphomas such as Hodgkin’s diesase etc. There were only 4 CLL patients in this group. But GVHD is an equal opportunity killer and the results of this trial are relevant to us.
Response to Prochymal
The table below outlines patient response to Prochymal at the two dose levels.
Pretty impressive results, you have to admit. For comparison, a 2002 study evaluated 443 patients with acute GVHD at the same grades II-IV, and found that only 35% of patients had a complete response to steroids by day 28. Here is a quote from one of the participating physicians:
“In this trial, approximately twice the number of patients achieved a complete response when given PROCHYMAL as we would expect with steroids alone,” Hans Klingemann, M.D., Ph.D., Director, Bone Marrow and Hematopoietic Cell Transplant Program, Tufts New England Medical Center. “But what is most important is that this improvement in response carried over into high survival rates.”
That is a powerful recommendation, the fact that the control of acute GVHD by prochymal resulted in improvement of patient survival. Parsing the results further, here are details reported as pretty pictures on the company website.
As you would expect, patients with Grade-II acute GVHD fared better than those with the much more serious Grade-III and Grade-IV variety.
The most common sites of acute GVHD are skin and GI tract, followed by inflammation of the liver. Typically, skin based GVHD is the easiest to handle since it can be treated with topical steroid creams and such. Liver GVHD can quickly turn lethal. Prochymal seems to have remarkable efficacy in all three sites of GVHD.
As we reported above, Prochymal was given as two infusions one each on day 1 and day 4. As you can see, the impact of Prochymal gradually increased over time, as you would expect from a cellular process.
How about safety? Prior work in European centers with MSC has shown very little toxicity. (Please write to me if you wish to read the excellent European article as well. This review has become long enough that I decided not to include it). The same benign profile was reflected in earlier pediatric GVHD clinical trial conducted using Prochymal. Here is the safety profile in the Phase-II adult acute GVHD trial we are discussing here:
Expanded Access Program for Prochymal
Originally back in May of 2008, FDA had approved expanded access to Prochymal for the treatment of pediatric GVHD patients. It was the right thing to do. Kids with steroid refractory acute GVHD are very sick patients and majority of them never make it. A clinical trial with Prochymal showed remarkable success in saving many (not all) of these kids.
Following on the heels of the Phase-II trial results reviewed above, on January 2009 the FDA broadened its expanded access program (EAP) for Prochymal. The drug is now available to adults with life-threatening GVHD.
Under the new EAP, patients anywhere from two months to 70 years of age who have been diagnosed with GVHD that is unresponsive to steroid therapy are eligible to receive Prochymal. In other words, it is possible to get access to Prochymal ahead of its final FDA approval as a commercially available drug, if you fit the criteria listed above. If you think you can benefit from it and you cannot afford to wait, best thing to do is talk to your transplant team about it. Heck, I would talk to my transplant team about Prochymal even before the transplant. In your shoes I would like to have Prochymal in my back pocket, just in case. Here is another quote from our helpful Dr. Klingemann of Tufts.
“As a transplant physician who has used Prochymal, I have seen first hand the power of this promising therapy to reverse otherwise non-responsive GvHD. This is a disease that is so devastating that survival is often measured in days. This action by FDA is significant because it now enables us to provide all of our critically ill GvHD patients with faster and more reliable access to Prochymal”
I think this quote from Dr. Klingemann says it all. Since this post has become longer than I thought it was going to be, I will cease and desist from adding verbose editorial comments. I think the data are impressive enough. I look forward to your comments and a good discussion.
24 comments on "Stem Cell Transplants – Are They Worth It? (Part III)"
I am at stage zero with 32.0 wbc and no lymph node involvement three years after diagnosis. My Medicare/Kaiser doctor isn’t excited about these early studies as they are not on his menu board for treatment. I just hope they become options if and when I need treatment.
An excellent explanation of a new and exciting addition to the arsenal of potential treatments for CLL patients.
I am still a stage zero, since my 2007 diagnosis of CLL, with WBC at a near normal 8.4 at my last check up. I am hoping that my numbers and situation remain this way for many years to come, I am now 62.
Looking ahead to this new research, and the encouraging results, should give new hope to all CLL patients who may someday fit the criteria for this drug.
Once again Chaya you have done us all a great service with your down to earth explanations of these complicated processes.
Thank you and God bless you.
Hope.
Thank you again Chaya, life saving information
for sure. Mike
I write as a recently retired English family doctor who was diagnosed with CLL about 5 years ago and, fortunately, have so far had few problems.I just felt I had to say that I found the above article a triumphant example of making a complicated subject understandable and wish to congratulate Chaya on this and indeed all her postings. I followed with great sadness the saga of your husbands transplant and subsequent problems and tragic death and the whole CLL community owes a great debt of gratitude that you have continued to educate and support us. Thank you from us all.
Very instructive and educational article. You really have a knack for getting complex concepts across efficiently.
Marshall
Great info! I hope the doctors pick up on it.Hey Fredm- can I trade bone marrow with you? I’m up to 14(ha,ha, just kidding):)
As stated by others; excellent, clear and succinct! I would have felt a lot more comfortable if the professionals I have encountered had had just a fraction of your straight clear language.
Mette
Something I don’t understand.
If ordinary chemo can cause extensive and permanent marrow destruction, as I understand it can, what are they doing with transplants that makes it possible for the graft to be successful? Atren’t they wiping the marrow out completely, especially with full myleosuppressive conditioning?
I’m in remission from FCR now, and my red blood indices hang just below or a little over the lower end of normal limits. If they wiped everything out for a transplant, what does the graft do? Does it grow completely new marrow or what?
Chaya,
Thank you for this invaluable and honest translation of such critically needed information. We realize that nothing is 100% full proof, but you are giving us greater hope and inspiration that adds to the quality of our lives. And, these stats are so much stronger in our favor! Thanks for al you do, Chaya.
JJ
Burke:
The high dose chemo and radiation of myeloablative conditioning is supposed to wipe out the immune system you were born with, since it has become diseased. This makes room in the bone marrow for the new immune system, the graft donated by your generous donor to replace the old one. That is why it is called a stem cell transplant. In the old days it used to be called a bone marrow transplant. Same thing.
Once again Chaya has exceeded all expectations in bringing this forum cutting-edge advances that likely will shape the future management of CLL. Thank you again for sifting through the mountains of oncology information and presenting us with timely, well-organized data that is critical to all of us with CLL. Despite over 30 years of advancement in HSCT/bone marrow, there has been little to cheer about or much reason for hope regarding advances in the areas GVHD management or immune reconstitution following transplant. This truly is welcome news.
I wish Jon and au1981 the best of luck and good fortune on their upcoming journey. I also wish continued success for Spike, Chonette, and Clum in their continuing journey. Likewise, best wishes to all of you who are entering or have already started this unusual process in hope for a cure or at least more time to smell the roses.
I am also in the Spring 2009 class of CLL transplant patients (day 136 post-transplant). Like au1981, I had a problem with bulky nodal disease that did not respond well to my initial treatment (6 cycles of CFAR). Six months following my initial treatment, I had three rounds of OFAR. I was nearly ready for transplant but still had at least one node > 5cm. Another round of OFAR was out of the question due to the profound effect the 3rd cycle had on my platelets, white count, and red blood cells (most patients with fludarabine refractory disease only tolerate 2 or 3 cycles of OFAR). Once my counts recovered, we decided to give one or two cycles of Bendamustine (100 mg/kg) a try. After one cycle my largest node was down to 3.5 cm. We hoped to slip in a second round of Bendamustine before the transplant, but my white count started to disappear the weekend before the second cycle was scheduled. Instead, I packed my bags and was off to the transplant center.
In retrospect, it might have been better to start with the 70-mg/kg dose of Bendamustine if I really wanted to get a second cycle of Bendamustine. However, we did achieve the pre-transplant goal of nodal disease less than 5 cm. I still had hope that my conditioning regimen would compliment the work of the previous chemotherapy. My conditioning regimen was a combination of Zevalin, fludarabine, and total body irradiation.
The use of Zevalin in the conditioning regimen required me to show up six weeks before the transplant date rather that the usual three weeks. The extra time was necessary to receive a test dose of the drug as well as allow time for the majority of the radioactive particles attached to this drug to decay (it takes almost two weeks to get to the point where greater that 97% of the particles have decayed). This waiting period is required to prevent significant radioactive risk to the incoming graft.
I was the last of 42 patients in the Zevalin clinical protocol. Hopefully the published results of the study will be available in the near future. This protocol seemed to make sense for my presentation of CLL (bulky nodal disease). Zevalin works well for patients with lymphoma so maybe it would also be useful in CLL patients with bulky nodal disease. When used as a chemotherapy agent, its use is limited to patients with less than 25% marrow involvement to limit marrow toxicity. Another concern when using Zevalin is the approximate 5% rate of myelodysplastic syndrome (MDS) following its use. Since the ultimate goal of the transplant is to eliminate all the old marrow and blood cells, marrow toxicity would not be an issue. Also, by significantly limiting the new graft’s exposure to the drug, the risk of MDS should also be much less.
Although my nodal disease did not completely disappear on CT scans at 28 days and 84 days post-transplant, the nodes have continued to shrink. Continued evidence of nodal disease was expected on these scans since it was too early in the course in the transplant to see significant GVL activity. The coming scans at 6 and 12 months post-transplant will be better indicators of GVL activity.
I am on my final week of the cyclosporine taper and have not needed steroid therapy up to this point. My experience with GHVD has been limited to oral involvement that started on day 81 post-transplant. Although I do experience some dry mouth symptoms, the symptoms have been manageable with routine oral care. My skin has started to itch in the past week but so far there is no sign of redness or rash.
I am 50 yrs old male and have remained in good shape up to this point. My sister was my donor (10 point match). My course to date has been very mild. I required no transfusions. The protocol was designed as a total outpatient protocol and I was fortunate enough to avoid hospitalization. The first 7-10 days of the transplant was the only time I had trouble with nausea and dietary limitations. I developed a mild but concerning superficial Hickman catheter infection during the third week that responded well to IV antibiotics that were self-administered at my apartment with a mini-infusion pump. Like most people on cyclosporine, my renal function became impaired. Fortunately it returned to normal once they started to wean my cyclosporine dose. I did not have any trouble with fatigue and was able to exercise daily. Now that I have been home for 6 weeks, I am back to my pre-transplant aerobic and strength training routine.
I find it interesting that I share similarities with Spike and Clum in that we are all males that had sisters as 10-point match donors yet all have had somewhat different experiences with the transplant and GHVD. I think it is strong evidence that there are still yet to be identified minor match points that play into both GHVD and GVL expression. Hopefully one day the site for GVL expression will be identified and new ways to control GVHD will be discovered.
One final note, I received the last of the EOB’s/bills for the transplant today. My insurance company was actually easier to deal with during the transplant process than it was for my cycles of chemotherapy. I found it interesting when I compared the cost of my chemotherapy for 2007 and 2008 with the cost of the transplant in 2009. In each of the three years the insurance company has paid out about $190,000.00 per year. Transplant is expensive, but chemotherapy can be even more expensive. At least in my case it seems that insurance companies would actually save money by approving transplant rather than continuing to pay the cost of chemotherapy year after year.
Steven
Alan
At the age 55 I have been diagnosed with CLL with 11q deletion. My current WBC is 180, I have numerous enlarged lympho nodes and my spleen is 26 cm. I am sweating a lot and loosing weight. My doctor still does not recommend chemo treatment till hemoglobin or platlet count will go down (they are still normal). I have been advised by other oncologists to start chemo about a year ago but I did not. Frankly speaking I am confused. If someone has similar experience or confusion please share it.
Chaya, you are doing an outstanding job to educate us. Thank you so much. God bless you.
Chaya,
As always, you bring clarty to a complex process. Thanks, from an admiring CLLer (in chemical remission), fan and fellow chemist.
Note to Alan (galina): I’m 15 years older than you and my WBC went above 500k before I had Chlorambucil followed by Bendamustine. My CBC is still normal 6 months after completing BEN treatment. Hang in there with your Dr.
Al
Chaya,
Thank you for transforming complex research, into a form that CLL patients (without medical training)can understand. My husband (who has CLL) worked in industrial construction, and would not be able to understand any of this research without your clear,concise discussions.
The feedback from others is also informative and appreciated.
CLL presents itself with many faces,and medical decision making is unique and difficult for each individual that has this disease. The education available at this web site is critical when attempting to make those decisions. This is the material CLL patients need, to be pro-active and educated in managing medical care.
Your beloved husband and this web site directed us to a second opinion,which saved us from making the wrong decision about treatment.
My husband was told he needed treatment with Fludarabine and he had not been thoroughly evaluated. We had to ask for the FISH etc and found out he is 13q, ZAP 70 neg, CD 38 neg, mutated with normal HGB, normal RBC, WBC of 70,000 and platelets that fluctuate between 150,000 and 120,000. The MD who gave us the 2nd opinion said no treatment was necessary. That was 2 1/2 years ago. My husbands lab values basically have not changed and he feels great (no symptoms i.e. fatigue, night sweats, no palpable lymph nodes, etc.) We feel currently that no treatment remains the correct decision. My husband feels he will be better equipped to make a decision about treatment, when it is needed(he is 66Y/O), because of the knowledge he has gained at CLL Topics.
Thank you, can never express how grateful we are.
MB & JP
Steven:
Thank you for your detailed and informative comment.
I was particularly interested in the use of Zevalin as part of the preconditioning. As you correctly pointed out, Zevalin is a CD-20 monoclonal that carries a radioactive isotope with it, as does its sister compound Bexxar. (For those of you who are interested, we reviewed radioimmunotherapy using drugs such as Bexxar and Zevalin on our website http://www.clltopics.org and you can find the articles by searching for the key phrase radioimmunotherapy).
A recent article from M. D. Anderson points out that even in patients with minimal bone marrow involvement, Zevalin (and by analogy Bexxar) carries risk of too much toxicity to the precious stem cells. That is a hugely important issue if (and I repeat, IF) these drugs are to be used for conventional therapy. But the logic is exactly the other way around when these drugs are used as preconditioning ahead of a stem cell transplant – as you point out. Host stem cells getting damaged and killed is of little consequence in a transplant setting. The bums are going to be thrown out and replace by brand new stem cells from the donor in any case.
It sounds like zevalin added to successful preconditioning in your case. Do you have any idea when we are likely to see formal results of the clinical trial you were in?
Thanks again for your informative comment.
fredm: Just out of curiousity, what basis did your doctor base your CLL diagnosis on?
Chaya,
Once again, thank you for your untiring efforts on behalf of all of us who find your site so much more understandable & informative than the usual sources of information that are available( which are few & far between.) I am a 59 yr old female diagnosed w adult T cell CLL 8 years ago. I had a splenectomy 4 years ago & my platelets have remained at about 37,000 since that time. I wonder if Prochymal therapy would be an option for people with T Cell disorders? I’m still a bit unsure about the differences between B cell & T cell disease & there seems to be so little known about therapy for T cell, just for the future I wonder if this promising therapy would also work for patients w T cell disease. Once again, Chaya, thanks for all you do.
Lorraine
Another excellent article, Chaya, THANK YOU! And the news about prochymal is very encouraging, particularly for patients who have both CLL and Diabetes and because of the latter, need to avoid steroids…
Encouraging – thanks again!
Lawrence
Lawrence:
You might be interested in knowing Prochymal is in early stage trials for Type-I diabetes! One stone to kill two birds?
Lorraine:
T-cell CLL is much more rare than B-cell CLL. Much of what we write about on this site has to do with B-cell CLL. However, the information about Prochymal is relevant to all blood cancer patients undergoing stem cell transplants. In fact, majority of patients in the Phase -II clinical trial we reviewed were not CLL patients.
Chaya,
This is good news for alleviating at least some fear for those needing the HSCT option and your explanation is clear and great as usual.
Referring to Bexxar and Zevalin which carry radio isotopes into the bone marrow, I am still wondering what is known about the damage done by the radioactivity? Would it not be of great importance even in HSCTs to consider the potential danger to the internal environment of the bone cavity that contains an important layer of cells (stromal) for the nurturing of healthy blood cell line development? Radioactivity is indiscriminant in its killing of cells and would seem to me to pose an unacceptable or unknown risk.
As impressive a response rate that you have provided for Prochymal there are still failures and I wonder how close researchers are in speculating on reasons for these failures.
The environment of the bone marrow from physical size to the recently discovered role of excess adipocyte (fat cells, by transplant researcher George Daley gives hope that GVHD and drug response to CLL therapy will reduce the side effects and fear from Treatments and HSCTs.
To those struggling with increasing and high tumor burden. We are all different and guidelines are just that “guidelines” and not a bible of dogma to adhere to in spite of suffering. I am about to start cycle 2 of RF after fighting off TX calls by many Drs. I had no “B” symptoms when I threw in the towel. I just could not sleep well do to the nodes and the shortness of breath not to mention leg cramping which made my Quality of Life not so good. Trust your Dr. but listen to your body. At the time of my TX I had one CLL expert saying I had an option to still Wait & Watch while another Expert had clearly felt I had waited too long.
Be well – Live Well
WWW
WWW:
Most preconditioning protocols include low dose whole body radiation – even in mini-allo versions. The radiation dosage due to Bexxar or Zevalin is far smaller than the radiation patients will absorb in the preconditioning in any case.
Radiation causes damage to stem cells – that is the major risk factor of radiation. In the case of a SCT this is of no consequence since that is precisely what is needed, kill off the previous host stem cells to make room for the new graft stem cells from the donor. No doubt radiation will cause some damage to other systems as well. It is once again a question of weighing the odds, the need to replace the diseased immune system with a healhty one (to control the CLL), versus the systamic toxicity of the radiation and the many other drugs used in the process of the SCT.
Prochymal is by no means the magic bullet that will take care of every single patient with acute GVHD, every time. We are not there yet with any GVHD treatments – yet. It is a case of making incremental improvements and having more therapy options. Why does Prochymal work in some patients but not in all? That is a complex question and one that I cannot answer here.
Chaya,
I have read your last three articles on stem cell transplantation with great interest and must praise you for the clarity you bring to this complex subject.
I live in Scotland and I was diagnosed at the age of 46 with stage 4 CLL. I was at that time still playing a little rugby and doing a lot of mountaineering. I was still able to do some modest hill walking whilst waiting for my first chemo doses. I received CF treatement at that stage and recovered sufficiently to return to mountaineering and rugby.
About 2 years ago the CLL started coming back. Not in any way that I’d notice but enough to be detected by blood counts, bone marrow samples and CT scans. This time I rceieved CFR and I must say feel a lot better than I did after my first treatment. This time I worked between doses, cycled to work (about 7.5 miles) and remained active.
I know the CLL will come back and have been discussing with my consultants what we do next. We are looking at a mini allo. I have 3 siblings all of whom match me! If there is a deity, then he seems to be on my side.
From the outset I opted for minimal intervention. The idea being to keep me in the game for as long as possible. My reasoning being that even without major break throughs doctors will simply get better at doing what they currently do. Since diagnosis the development of mini allos and now the discovery of powerful means of managing GVHD all give me cause for optimism. Once again thanks for bringing great clarity to the complexities of our disease.
So many things that CLLers need to look out for, should know, has NOT come from my doctors. It usually just the W&W. I ask about my CLL but they oddly prescribe, CT scans, or many other tests, which come back negative.
I inquired about the radiation, and am told that it’s such a low dose or that it is less than I’d get from the sun in a normal day.
Then for 8+ months they forgot to tell me my igG was low, then a couple weeks after last CBC a nurse calls to tell me he ordered an infusion now, but forgot to tell me. Really? Is this normal?
Another area of complete confusion is the different normal range averages for blood work. The igG varying 200 between the two charts. Is this also normal? Isn’t there a set range to judge from so a patient knows what is a true normal range, and what is low or high.
Thank you Chaya for all the valuable information. I was able to get a second pneumo-vaccine several weeks ago because of your valuable information.
I am 59, Dx 2003. Current, WBC in last 3 months has been 180s then dropped down to 140s in 3 weeks, then back to 160s a month later. My igG is low, and platelets are low. Cough, head ache, sweats, am slight of build, but seem to be maintaining, and appetite ok, but not ravenous. I am in W&W. I’m told they would “never” do a transplant on me, but no explanation why not and how could they make such a decision unless it is lack of finances. Only treatment so far has been one IVIG 2 months ago.
Please, is there a link to explanation of CDs trisomy, etc FISH, BMB details and what the meaning are and what areas mean what? I have had a FISH and BMB, but not a ZAP 70. Was told not necessary. What it is and why or why not necessary? I am active, eat well, live low stress life, have friends and pets, volunteer in my community and feel have a good quality of life for the most part (other than low income and minimal health care coverage). A women with CLL told me I should not have pets. Any comments on this?
Thank you.
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