Bone marrow: a most unique and vital piece of equipment
There is only one location in your body where new red blood cells (platelets and neutrophils etc.) are created. And that is your bone marrow. As CLL patients, we know only too well that lymphocytes (B-cells, T-cells) can multiply in lymph nodes. Not so red blood cells, platelets and neutrophils. Each of these crucial blood cell lines need to be created from scratch in the bone marrow, starting from healthy blood stem cells (also called hematopoietic stem cells).
In adults, bone marrow is usually found in the large bones of the skeletal system, namely hip and pelvic bones, ribs and the long bones in thighs. 100% of the bone marrow is active and able to produce new blood cells when we are born. As we age, more and more of the bone marrow becomes inactive, filled with fatty cells. The white blobs in the picture above are collections of fat cells. Think of it as moth-balled production capacity. As you can imagine, a growing child needs to produce a lot more blood cells on a continuous basis than someone who is in his “golden years”, where new blood cells need to be created only to make up for cells lost to general wear and tear.
Here is a quick rule of thumb: subtract your age from 100%. That gives the percentage of your bone marrow that is still active. In other words, a seventy year old man has only 30% of his bone marrow active and available for production of new blood cells. This is often referred to as “bone marrow cellularity” in lab reports. Sometimes, under duress, the body brings back hitherto mothballed production capacity and this is seen as “hypercellularity” (more cellular bone marrow and less fatty deposits) – always with reference to the age of the patient.
What makes the bone marrow so important? Active and functioning bone marrow is the only location of “pluripotent hematopoietic stem cells“. That is quite mouthful, but it is actually quite simple. “Pluripotent” means capable of doing many things. “Hematopoietic” refers to blood. So, pluripotent hematopoieitc stem cells are capable of making all the different types of cells that make up your blood supply.
These blood stem cells are capable of making new blood cells as well as renew their own numbers, thereby keeping a nice supply of blood stem cells for future use. Below is a chart of how these very important group of stem cells go about their business. As you can see, depending upon the needs of the body, they first differentiate into either lymphoid or myeloid stem cells. Lymphoid stem cells can only make B-cells, T-cells and NK cells. Myeloid stem cells can make red blood cells, platelets, neutrophils and many other vital cell lines.
Damaged blood stem cells
Blood stem cells can get damaged for a variety of reasons. It could be due to congenital or inherited problems, gene mutations that cause Fanconi’s anemia, for example. Some viruses can also cause stem cell damage, among them the ever popular Epstein-Barr virus and hepatitis B. Lack of proper nutrition (folate or vitamin B12 deficiency) can also damage blood stem cell health. Obviously of importance to us CLL folks, infiltration of the bone marrow by large numbers of CLL cells will also interfere with proper functioning of the stem cells that live there.
Last but not least, many of the chemotherapy agents used to treat CLL and other cancers are quite toxic to blood stem cells. High on the list of drugs that can cause hematopoietic stem cell damage are fludarabine and cyclophosphamide. I have no doubt that pentostatin (the other purine analog of fludarabine) and chlorambucil (another alkylating agent similar to cyclophosphamide) and bendamustine (the latest darling of the chemotherapy crowd) can also cause blood stem cell damage, to varying degrees.
Consequences of blood stem cell damage can be varied, depending upon the cause of the damage. If it is due to poor nutrition, once the cause is identified, proper use of supplements can correct the deficiency. If it is due to viral infection, treating the underlying infection can bring out renewed health of the stem cells. If it is due to CLL infiltration of the bone marrow, therapy targeted at reducing the CLL infiltration can bring out better working conditions for the blood stem cells living there, thereby improving their morale and production output. If the blood stem cells are lazy and not doing their job because the body is no longer producing the growth factors that are, in essence, marching orders for the production of specific types of blood cells, then using man-made growth factors such as Procrit, Aranesp (red blood cell growth factors) or Neupogen, Neulasta (neutrophil growth factors) will remedy the situation.
But what if the problem is none of the above, the reason for reduced or stopped production of new blood cells (platelets, red blood cells, neutrophils etc) is because too many blood stem cells have been killed, and there are too few around to do the job? People with drastically reduced numbers of blood stem cells cannot make enough red blood cells, platelets, neutrophils etc to make up for the daily losses of these cell lines due to wear and tear. Giving them growth factor injections is of no use, since there are not enough blood stem cells present to listen to the marching orders and crank up production. By the way, another good way of killing off stem cells is excessive radiation exposure to the bone marrow.
Cancer Biother Radiopharm. 2002 Aug;17(4):399-403.
Chemotherapy and bone marrow reserve: lessons learned from autologous stem cell transplantation.
Aksentijevich I, Flinn I.
The Johns Hopkins Oncology Center, 1650 Orleans St., Baltimore, MD 21231, USA.
Cytotoxic chemotherapy is often complicated by hematopoietic toxicity. The degree of aplasia and the rapidity of count recovery following chemotherapy are indicative of bone marrow reserve. Patients who generally have a normal bone marrow function will recover from chemotherapy-induced cytopenia relatively rapidly. In contrast, patients that have poor bone marrow reserve will have significantly prolonged period of aplasia. Predicting the hematopoietic toxicity of radioimmunotherapy is an important dosimetry consideration. Unfortunately, there are no good models for predicting toxicity from chemotherapy that could be applied to radioimmunotherapy. However, models used to predict the ability to harvest autologous stem cells for use after high dose chemotherapy may be useful in predicting bone marrow reserve and potential toxicity from radioimmunotherapy. These models indicate that the successful mobilization of stem cells into the peripheral blood is inversely proportional to exposure to stem cell toxic drugs. Establishing criteria that will help predict the amount of myelotoxicity sustained from radioimmunotherapy could lead to improved dosimetry and ultimately to better therapy for patients.
PMID: 12396704
Pancytopenia (reduced capacity for production of multiple cell lines) caused by irreversible loss of blood stem cells is a dangerous situation. Only two approaches remain for patients suffering from drastic loss of blood stem cell reserves. One is regular transfusions of all the necessary cell lines from blood donors. Red blood cell and platelet transfusions are quite common. Neutrophil transfusions are very rare.
This is not as simple as it sounds; becoming transfusion dependent on a long term basis is complicated business that can cause many other problems down the road (iron overload, risk of serious viral infections inherent in using any blood product etc). The other approach is a stem cell transplant, where the loss of the patient’s own stem cells is corrected by transplantation of blood stem cells donated by a matched donor. As we know only too well, even with modern improvements, fatality rates and long term complications of stem cell transplants are still too high for comfort.
Aging process
While we have a number of young members of CLL Topics, as a general rule CLL strikes an older segment of our population. There are some undeniable effects of increasing age that no amount of Botox and plastic surgery can reverse. One of the downsides of growing older is that the number and production capability of blood stem cells decreases. Age related anemia and age related deficits of immune function are only too well documented. This means the smaller numbers of hematopoietic stem cells remaining are all the more precious for our elderly patients.
Oncol Rep. 1998 Mar-Apr;5(2):397-400.
Effect of age on human peripheral blood stem cells.
Egusa Y, Fujiwara Y, Syahruddin E, Isobe T, Yamakido
Second Department of Internal Medicine, Hiroshima University School of Medicine, Kasumi 1-2-3, Minami-ku, Hiroshima 734, Japan.
We evaluated the correlation between the number of peripheral blood stem cells (PBSCs) and aging by monitoring those of CD34+ cells (PB-CD34+), colony-forming unit granulocyte macrophages (PB-CFU-GM) per 1 ml of peripheral blood in normal volunteers (n=50) including 20 males and 30 females (median age 67, range 20-90). The numbers of PB-CD34+, PB-CFU-GM were monitored by flow cytometry and methylcellulose-based colony assay, respectively. An inverse correlation between the number of PB-CD34+ with age (r=-0.33, p=0.020) was found. Furthermore, the number of PB-CFU-GM also showed an inverse correlation with age (r=-0.58, p=0.003). Based on these results, it is suggested that the number of PBSCs decrease with age.
PMID: 9468566
Translating the abstract above into plain English, older people have fewer blood stem cells (CD34 positive cells) and their blood stem cells show less capacity for making new blood cells as well as regenerating themselves.
By now you should have figured out that older CLL patients needing therapy for controlling their CLL are often between a rock and a hard place. Aggressive chemotherapy regimens such as FCR and BR (bendamustine + Rituxan) may be nice to get deep and long lasting remissions. But on the cost side of the equation, you and your physicians should also pay attention to your bone marrow’s status. After all, it will do you precious little good if the CLL is knocked back into a deep remission, but in the process of getting there you have done a seriously bad number on your precious bone marrow stem cells. Blood transfusions can be kept up only for so long, and age restrictions may shut out stem cell transplant possibility. This is the reason why new guidelines suggest full strength FCR therapy, all six cycles of it, are contra-indicated for elderly patients.
I have no doubt that down the road the same recommendation will also be made regarding B+R therapy. Frankly, I am becoming increasingly worried about the new-found fascination with bendamustine. It is a potent new addition to our collection of bullets, I agree on that. But it is by no means a kinder and gentler form of chemotherapy. Younger patients may do fine with it. But older patients, especially those with other age-related health problems, may be smart to discuss the potential stem cell toxicity of aggressive chemotherapy in their specific situation. As always, it is a case of weighing the costs versus rewards.
Effective CLL control without excessive stem cell damage
When there is something of importance that the editors of “Blood” wish to highlight, they ask an expert (who is not one of the authors) to write an editorial discussing the article in question. Here is the link to the editorial piece, titled “Toward chemotherapy-free treatment of CLL“. An abstract of the article itself is given below. As always, send me a personal email if you want help locating the full length article for your own reading pleasure.
Blood. 2011 Sep 29;118(13):3489-98. Epub 2011 Jul 1.
Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia.
Badoux XC, Keating MJ, Wen S, Lee BN, Sivina M, Reuben J, Wierda WG, O’Brien SM, Faderl S, Kornblau SM, Burger JA, Ferrajoli A.
University of Texas M. D. Anderson Cancer Center, Houston, TX
The best initial therapy for elderly patients with chronic lymphocytic leukemia (CLL) has not yet been defined. We investigated the activity of lenalidomide as initial therapy for elderly patients with CLL. Sixty patients with CLL 65 years of age and older received treatment with lenalidomide orally 5 mg daily for 56 days, then titrated up to 25 mg/d as tolerated. Treatment was continued until disease progression. At a median follow-up of 29 months, 53 patients (88%) are alive and 32 patients (53%) remain on therapy. Estimated 2-year progression-free survival is 60%. The overall response rate to lenalidomide therapy is 65%, including 10% complete response, 5% complete response with residual cytopenia, 7% nodular partial response, and 43% partial response. Neutropenia is the most common grade 3 or 4 treatment-related toxicity observed in 34% of treatment cycles. Major infections or neutropenic fever occurred in 13% of patients. Compared with baseline levels, we noted an increase in serum immunoglobulin levels across all classes, and a reduction in CCL3 and CCL4 plasma levels was noted in responding patients. Lenalidomide therapy was well tolerated and induced durable remissions in this population of elderly, symptomatic patients with CLL. This study was registered at www.clinicaltrials.gov as #NCT00535873.
PMID: 21725050
Now for the highlights
- This clinical trial addresses the needs of an often ignored (and yet very large!) group of CLL patients – namely, those 65 years or older.
- Unlike M. D. Anderson’s usual penchant for aggressive dosing regimens, this clinical trial starts with a carefully modulated dosing schedule. Patients started off with 5mg/day of lenalidomide (“Revlimid”), and after a month and a half, the dose was gradually increased to a higher limit of 25mg/day – the actual dosing limit being determined by how individual patients tolerated the drug. This is a sensible way of initiating Revlimid therapy. Start with a low dose to minimize tumor flare type of adverse effects, and after a significant length of time, when the tumor load is hopefully reduced greatly and the patient has become used to the drug, gradually escalate the dose to a level that is customized to each individual patient.
- This dosing approach showed a gradual improvement over time. Perhaps for the first time, we have a therapeutic approach that works better for older patients than good old chlorambucil!
- Neutropenia continues to be the number one hematological toxicity. Surprisingly, the number of patients experiencing severe infections was lower than expected – this may have to do with the unique mechanism of Revlimid’s action. Unlike other standard issue chemotherapy drugs, Revlimid is thought to work by increasing the activity of the patient’s own immune system. for this reason, it is called an “imid” or immuno-modulatory drug. There is reasonable hope that immunomodulatory drugs do far less damage to hematopoietic stem cells.
- Much work remains to be done to determine how exactly Revlimid works in CLL. But this much seems clear: Revlimid causes increased activity of T-cells. Equally important, unlike other chemotherapy drugs, treatment with Revlimid actually increased immunoglobulin levels in patients!
- Revlimid is thought to interfere with BCR (B-cell receptor) signalling, something that is a very active pathway in unmutated IgVH type CLL patients. So, and wait for the good news, unmutated IgVH patients may in fact be better candidates of Revlimid therapy than patients with the (good ) mutated version of IgVH!
Other details – such as patient characteristics, overall survival, adverse effects etc – were described in an earlier article I wrote on the same subject, titled “Revlimid for Elderly Patients” and I refer you to it for these details.
Editorial
So, you may fairly ask, why this second review of the same clinical trial? Very simple. Reading through my analysis in the earlier article I felt I had not just justice to the importance of preserving bone marrow stem cells and their ability to function properly. Recently I have heard from more than a couple of our members who now face irreversible bone marrow damage, resulting in across the board pancytopenia and are now transfusion dependent. Three of the group are also ineligible for mini-allo transplants because of their age. End of the road. The common theme among all these folks: somewhat elderly patients and more than a couple of layers of aggressive chemotherapy regimens.
Older patients have fewer of these precious progenitors of blood cells and preserving them is of great importance. If the remaining level of bone marrow reserves are depleted, you may find yourself in a situation where there are few options left. Please take seriously the guidance given in recent research suggesting therapy options such as full strength FCR are contra-indicated for older patients. If your physician suggests B+R instead of FCR, and you happen to be an older patient, it is definitely worth asking your physician about potential damage to bone marrow stem cell reserves.
CLL and its treatment is not yet an exact science. And there are enough individual differences that almost any rule I may come up with may not be appropriate in a particular case. All I am suggesting is making the best possible choices, in a sober and informed manner. It is foolish to bring out the biggest and baddest guns, when you may not be able to withstand therapy related toxicity. Equally foolish would be to forswear all chemotherapy drugs because they are toxic. Sure, they are toxic. And you would be a crazy person to use any of them, except that you also happen to have this incurable cancer called CLL. As always, think carefully about the risks and rewards, talk it out with your doctors and then make the decision based on what feels right for you.
And once you have made your decision, please do yourself a favor and don’t look back, second guessing and worrying yourself to a fare-thee-well.
26 comments on "SOS: Save Our Stem Cells"
Chaya,
A wonderfully well written article.
One question: How does treatment with Ofatumumab or other mabs fit into your picture
Lavie
Good question Lavie. Monoclonal antibodies such as Rituxan and ofatumumab (Arzerra) are different from standard chemotherapy drugs, in that they are not considered harmful to blood stem cells. Unfortunately, neither of these biologic drugs packs enough of a punch to give deep or long lasting remissions as single agents. Only when combined with standard chemo drugs (as in FCR, FR, OFC etc) do the regimens give high response rates.
You know, the more I hear and read, the less inviting any form of treatment appears; it appears that one is better off just taking ones chance as long as one can manage without anything. The benefit versus cost seems heavily stacked against most, if not all treatments. I get the feeling that once you “require” treatment, the game is over. Sorry to be so pessimistic, but I find all hope and optimisme has long gone.
Look after yourself and be healthy! And thanks for your super “translations”.
Mette:
I empathize with how you are feeling, but I most definitely do not agree with your conclusion.
No, it is NOT better to just take ones chances and do nothing once therapy is required. And YES, there are plenty of reasons to be optimistic. More so now than before.
To make this somewhat personal, my husband PC had highly aggressive (Bucket C) version of CLL. He needed therapy right from the get-go. But several different therapy regimens kept him quite healthy, very active and alive for 7 wonderful years. But for a bit of bad luck, I like to think even his last throw of the dice (mini-allo stem cell transplant) would have worked and we would be celebrating his 63rd birthday in a few months. I will not trade those seven years for all the riches in the world and I am eternally grateful to the doctors (Thanks Terry!) and researchers that made it possible for him to live those precious years. If he had decided against therapy, I doubt if he would have lasted even a couple of years. And his quality of life would have sucked even for that reduced time period.
I understand the frustration and how hard it is to take responsibility for making tough decisions. But in the vast majority of cases, modern cancer treatments (yes, even bad old chemotherapy drugs!) improve both the length and quality of life.
When I write cautionary articles such as this, I always worry about people over-reacting to the cautions and throwing the baby out with the bathwater. Once again, I plead for balance, careful understanding of the pros and cons.
Thanks Chaya – I’m with you on this. For years I lived in Hampshire UK, and although I was seeing the medics regularly my CLL was not diagnosed. As a result it progressed some considerable distance and I was perpetually weary and run down.
Then I moved to Cornwall, 200 miles west, and my new doctor decided on a batch of fairly simple medical tests to get to know me, INCLUDING A CELL COUNT. He called me and said, “Lawrence, we’ve got a problem”. I thought, “AT LAST I know what’s wrong with me”.
I’ve since had chlorambucil, single agent Fludarabin, and finally the magic FCR, and altho it has taken me a year to get over it, I’ve now got about 90% of my life back. And I’m very grateful. And if anyone took me back to that diagnosis and said, “knowing all the facts, would you have that chemo again?” my answer would be, “YOU BETCHA!
Thanks again for an excellent summary Chaya, and for distilling stuff which is important but which would otherwise be inaccessible to your average patient.
Hi
I am 63, CLL patient for 14 years, started fludarabine and cyclophosphamide,1st time, in October lasy year for 6 months. My white cells count was 140 before starting and 2 after finshing. Still same count. Not sure for how long in remission but hoping for 6 to 10 years. Keeping my fingers crossed.
I read a lot of CLL topics, and thank you Chaya for keeping us up to date. Know very well that part of our medications is to keep optimistic and hopeful.
Hanna
Mette:
I have to agree with Lawrence and Chaya. During my life before CLL, I was always extremely healthy…never really experiencing anything worse than a cold.
After the CLL diagnosis, during my “watch and wait” period, I developed a couple of major diseases. First was a kidney disease that was attributed to the CLL, and a year later AIHA. This was followed by good ol’ “chipmunk cheeks”, which is when they decided to treat me for the CLL. It seemed like I was always being treated for some disease.
In the five years since the treatment, I have felt as good as I remember I did before the CLL popped up around 1999. Have had no medical problems (other than carpal tunnel from typing all the replies in this and my other forums!)
Since my treatments, I have been as active and feeling as good as I recall I did before all this started. And am again considerably more active and relatively healthier than many of my contemporaries here.
I can only attribute this to the chemo (PCR with Campath chaser) and can imagine that I probably wouldn’t even be here if it wasn’t for the treatments. I’m doing things that I haven’t done since I was a young pup (I’m 70 now)…just restored a 1952 truck, will probably be flying the airplane I’m building by next summer!
I realize this is only anecdotal, but the treatments certainly looked like they worked for me. And I’m glad they did!
Harley
thanks for this article,Chaya. It really explains how the stem cells in our bone marrow work and what can happen to them with various chemo regimans. I am assuming that one of the new kinase inhibitors (
Cal 101 Etc) will not damage our stem cells but my understanding is that they block the signaling pathways the bad Cll cells use to cont. to reproduce or they cause apoptosis. Do I have this right? If this is the case do they look to be as affective as the FCR, PCR or bendamustine combos? I was encouraged by them thinking they will not damage our bone marrow but still wonder if they will work as well or give us as deep a remission etc.
Chris R
Lupner9:
Your understanding is correct, it is thought that the new kinase inhibitors (CAL-101 and PCI32765) are not likely to damage blood stem cells.
The caveat is that it is still very early days and the learning curve is very steep ahead of us. There is a lot we do not know about this new breed of drugs. For example, I have been hearing a couple of anecdotal stories that CAL-101 can cause significant lung toxicity – drug induced inflammation leading to serious case of pneumonia. At this stage, it is anecdotal information. Drug company has been mum on the subject, so also the researchers involved. How this will play out when larger studies are done remains to be seen. You can bet your bottom dollar I will be keeping a close eye on this in the months ahead.
Great article, Chaya! As I am just into that age group, but I read about so many people that have no other options left to them due to the previous aggressive treatment that they have had. It is sad for them, but a learning experience, and one that I plan to take to heart. Better to continue to hit singles when I need treatment next than a home run, that gives me no options for the next go round. The last one caused major lung issues, so I cannot afford that. I plan to leave the two new trials alone until more is known.
Anne
Wonderfully written article. I have always been skeptical of FCR being over hyped. It obviously has its place for many patients. If there has been a steady move towards diagnosing patients earlier and treating CLL complications, it could make OS look better than it really is with FCR. CLL and blood counts and nodes work on people’s minds and treatments like FCR do produce great lab numbers; however, the longer-term negatives are too often ignored while patients are often convinced that they have “bought” years of survival. It’s been a multi-billion dollar windfall for drug companies. It is time to move on from these harsh treatments. Revlimid, PCI-32765, and Cal 101 have been in trials 3 years now (sometimes complimented with mab therapies) and we need make faster decisions on their availability and advisability to the CLL population- especially older ones. It is too bad all the vaccine and other immunotherapies seem to lack funding now after poor results at their first efforts.
I’m an 88 year old CLL survivor for over 22 years without treatment and am one of the participants in the NIH longitudinal study. Based on the team’s recommendation I have begun IVIG infusions, have had 3 now, but do not see very significant results. How are your findings likely to impact my situation now that I’m beginning to question whether the cost (over $500 per infusion every 2 months) is justifiable?
Del:
IVIG therapy (intravenous immunoglobulin therapy) is not meant to treat CLL per-se. It is an approach to boost immunoglobulin (Ig) levels in patients. Low Ig levels are a frequent side effect of CLL, and the consequence of this is that CLL patients are at risk of frequent infections. It is hoped that boosting Ig levels by giving patients intravenous immunoglobulins (gathered from blood collected from blood donors) improves immune function of CLL patients and thereby prevent some of the infections. But IVIG therapy is not intended to treat CLL itself.
Chaya,
As always, a very excellent analysis and synthesis to help us laymen understand this complicated material. Your articles and information have been a godsend to me and my husband for over 12 years. He is 67 yr. now (diagnosed at 55 yr.)and in remarkably good health in spite of having had quite a number of treatments to keep the CLL under control, including Rituxan(multiple times in varying combinations with other agents)and FCR (2 yr. ago). The most recent tests at the Mayo Clinic show progressive disease with increased infiltration of the bone marrow (no gene deletions but unmutated). The recommendation was for him to participate in UCSD’s ongoing clinical trial involving the use of high dose methylprednisolone in combination with ofotumamab. Any thoughts about that?
Kathryn
It has come to my attention, that teeth-in particular the pulp-, are a new source of pluripotential stem cells. I will check on the facts for this.
Hi Chaya,
Your article should remind all how important it will be to push for individualized evaluation to better match patients with an increasing number of therapy options. We now have an array of promising tools i.e. DNA scanning methods and computer analysis programs. The European Multidisciplinary Cancer Congress has held the first conference that I am aware of to address the steps necessary to initiate this needed approach, where is the US?
Currently we have treatments but little knowledge as to how well the tumor will respond and less as to the collateral damage that any given treatment is likely to cause. The recent LRF Conference saw Dr. Cheson touting BR and while I am sure it may work wonders for some patients the results are not to be known until after therapy is begun or completed. I was sitting near a guy who had a near fatal reaction to BR as I nearly had with RF.
In reading your remarks regarding % of alive bone marrow, I am wondering how much variation there is from patient to patient. I also remembered reading about the production of perforin used in cell lysis that drops off after age 70. Given the standardized amounts of drug given to patients based on weight and height I would now question whether bone size might be a critical factor for some patients as an independent factor for optimal dosing.
I am an appreciative Lab Rat doing well on PCI-32765 using the drug as a monotherapy at the lower dose of 420mg (# caps per day) I have heard of one serious Viral activation and one patient who is not responding out of 20 patient first hand accounts of great responses with very minor side effects so far. The long range side effects may well be from the frequency of CT-scanning:)
WWW
Chaya,
A very honest and worthwhile article. I have had both R/F and B/R. I thought B/R was less toxic. I’m not really sure.
With R/F I had a few infections and a wild time with Shingles but as I say, B/R was not a walk in the park. I am now in remission for 18 months from B/R and feeling good and still very active.
Rita
Chaya,
Interesting that researchers are now having second thoughts about FCR treatment for Cll patients over 70 because of stem cell decline in the bone marrow as we age. Think it would be a mistake if all patients over 70 were only given Revlimid or some similar immune enhancing drug.
I was 74 when I was offered the FCR treatment, and although the treatment reduced my red blood cell and platelet count below normal, I think it was a good tradeoff. I am now almost 77, have lots of energy, and have an active life. Although some patients might not want to undergo this harsh treatment, I hope this option will remain open to those over 70, because if there is not a cure, let the patients have a longer period of remission through FCR. I know this is what my wife would want.
After many years of dealing with CLL/SLL it has become clearer to me that the greatest perversity of this ultimate perversion to one’s B cell function is that the best results of the most toxic therapies (let us use FCR as the example of this) occur in those with the least aggressive disease who in many cases may never have really needed the treatment which is subsequently hailed as having helped them so much!
I cannot convince myself that lenalidomide is much better overall, given it’s multifaceted toxicities and little evidence that it really prolongs survival. The data revealing marginal increases in immunoglobulin levels is unimpressive…what really matters is how well the patients do, ie, are there diminished instances of serious infections and if so, how many people suffer other side effects/complications (such as thromboembolic disease) in the process.
At present the agents which interrupt cell signalling seem to hold the most immediate promise, but they are designed to stop the growth of the lymphoma more so than to kill it. Perhaps this is the best approach for now, at least until other pathways that simultaneously lead to cell death (?the MEK pathway) can be exploited in concert with them.
Interestingly I have personally had difficulty getting enrolled into one of these protocols because they are filled.
A grassroots effort to whip up enthusiasm for more studies (perhaps extended studies away from only a few mwdical centers) would go further toward finding better therapeutic pathways for our disease than marching like sheep for therapies with demonstrated toxicity and limited longterm efficacy for those with more aggressive disease.
When I hear about people remaining in remission for prolonged periods following one course of FCR I am beginning to believe that these particular individuals may have done just as well in the interim without FCR. MY own course with FCR was frought with toxicity and the benefit derived was relatively short lived. I don’t think that lenalidomide would be worthwhile for me and I seem to be between & betwixt in enrolling into the rather limited trials for PCI 32762 and CAL101, so I find myself in a sort of no man’s land. contemplating therapies with varied toxicities which hold, at best, the promise of a limited duration of response.
HSCT in this disease really seems to be a substitution of one disease for a whole host of others. While survival may be prolonged in a reasonable %age of people, the price is often rather high and very few, if any come out free of “disease” on the other end of the journey.
If we could get my disease to stop grwowing, I would be content not to try to “kill it”.
Can’t we band together to channel research to avenues which hold more ultimate promise?
I agree with the need to set up world wide trials for CAL101 and PCI 32762. These new Kinase Inhibitor drugs seem much more hopeful paths to follow. Chemo has given me a wonderfully healthy two year remission, but the six months of taking it and the year of recovering post chemo nearly did for me. Role on the new KIDs on the block!
IA,
I am in the PCI phase I/II trial. Nothing but good results in 14 months.
Fed approval may not be soon for CLL. I hear informally that I may get
the drug even after my trial ends. Hate to think of not having it.
I’m hoping that PCI will get an accelerated FDA approval as did BEXXAR and many AIDS drugs. This allows patients’ access while the FDA approval process grinds along. I’m in the NIH Natural History Study and have asked how can PCI ever get approved, given it is not a “cure” or is not comparable to the current standard of care. I’ve been assured that they are looking at that. NIH is also studying the drug in their back room labs and is hoping to have a trial soon. Given they work closely with the FDA, I think all these are good signs.
Randle, I’m sure they will continue to give you the drug. Where is your trial located?
All the best
Lynn
Lynn,
I am at OSU. PCI has worked for me after I responded minimally to chemotherapy and flunked lenalinomide. How it fits as a possible front line item is an open question. For myself, I would be all in. For chemotherapy refractory cases I think it should be available now. jmo.
I hope Mette has been convinced by these testimonials and citings. If not, I wonder why not? It has been addressed in the past that a major issue for any student is the quality of the teacher. I hope Mette’s doc is a good one, and if not get another. Beyond all this is the question of the depression which we with CLL or any other incurable disease face if we are not able or willing to take care of our brains along with our spleens.
Interesting article and discussion.
Update on my husband, Terry, age 63: He had 4 cycles of FCR Lite from Jan to May 2010. He is still in deep remission. However, one month post treatment he showed neutropenia with Absolute Neut 0.2. It reversed without treatment within 10 days. Months later he had one bout with pneumonia that did not require hospitalization. In late September this year he again showed neutropenia, Absolute Neut 0.4. It is reversing, but not as quickly. Numbers showed Abs Neut 1.3 two weeks ago. He goes in on 10/31 for labs and an appointment with his oncologist.
His oncologist had him eliminate gogi berries the first time. He’d asked an NP practitioner if he had heard of the berries causing marrow failure. He said yes, but it was rare. This second time his oncologist told him to eliminate all food supplements. His Neutrophil count began to increase after that. Whether the supplements are meaningful or not I don’t know. I’m just glad he is recovering! Terry said he felt better after he quit all supplements. During the lowest counts of neutropenias he had labs 2 to 3 times each week and monitored his temp AM and PM. They appear quickly, with no symptoms.
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I am 72 yr male. For my persistent temperature up to 102.5 deg F which was not responding to drugs and based upon various tests, it was concluded that it could be due to CLL for which I was under Wait & Watch for last 9 yrs by oncologists. I was given Bendamustine and Rituximab IV. There were no serious side effects but it took a fortnight for the temp to come to normal and WBC count dropped to 1100 from 200k(before the Chemo). The injections for boosting the growth of WBC were given and before the start of 2nd Chemo the WBC was normal (Hb 10.4, WBC 4100 and Platelets 235k). But the 2nd Chemo had to be disrupted after full dose of Rituximab and 1st dose of Bendamustine as I developed fever102 deg F next day, prior to injecting 2nd dose. After an additional stay of 5 days in the hospital the oncologist team concluded that it was due the side effect of Bendamustine. They want to discontinue with it and are deliberating upon some other drug combination to restart the Chemo treatment.
I seek comments/ advice to participate during deliberations for deciding the alternative Chemo drug by the oncologists.
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