Decisions, decisions…
I am one of those people who gets flustered when the checkout clerk at the supermarket asks me whether I want paper or plastic bags. That is nothing compared to making literally life or death therapy choices in controlling CLL. What makes it particularly difficult and frustrating is the lack of clear cut information on which to base sensible decisions and valid one-on-one comparisons between drugs .
The results of clinical trials are only as dependable as the agendas of the trial designers. In a perfect world human volunteers would not be subjected to clinical trials that are designed to prove a preconceived concept dear to the heart of the researcher involved. That is not the way science is supposed to work and scientists are supposed to rise above such pettiness.
Even more suspicious are the “straw man” comparison trials done by drug companies trying to make their drug candidate look as good as possible and satisfy arcane FDA requirements as quickly as possible. Witness the recent flurry of clinical trials testing modern day marvel drugs against a less than adequate dosing of chlorambucil. Treanda and alemtuzumab (Campath) are two drugs that won recent FDA approvals based on such questionable comparisons.
But once in a while a clinical trial report comes along that goes the extra distance in giving us credible, actionable information. Here is one such trial. It is not sexy, it will not win the authors any great brownie points, but it will help some of you make difficult therapy decisions. And for that I sincerely thank the authors. The abstract is below. Write to me if you want help in locating the full text PDF of the article.
Blood. 2009 Jul 15.
First line therapy with fludarabine compared to chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia.
Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann MA, Ritgen M, Kranzhofer N, Rohrberg R, Soling U, Burkhard O, Westermann A, Goede V, Schweighofer CD, Fischer K, Fink AM, Wendtner CM, Brittinger G, Dohner H, Emmerich B, Hallek M.
Department I of Internal Medicine, Centre of Integrated Oncology Koln Bonn, University of Cologne, Cologne, Germany.
While CLL is a disease of elderly patients, subjects older than 65 years are heavily underrepresented in clinical trials. The German CLL study group (GCLLSG) initiated a multicentre phase III trial for CLL patients older than 65 years comparing first line therapy with fludarabine to chlorambucil. 193 patients with a median age of 70 years were randomized to receive fludarabine (25 mg/m(2) for 5 days intravenously, every 28 days, for 6 courses) or chlorambucil (0.4 mg/kg body weight with increase to 0.8 mg/kg, every 15 days, for 12 months). Fludarabine resulted in a significantly higher overall and complete remission rate (72% versus 51%; P = .003; 7% versus 0%; P = .011). Time to treatment failure was significantly shorter in the chlorambucil arm (11 versus 18 months; P = .004), but no difference in progression-free survival time was observed (19 months with fludarabine, 18 months with chlorambucil; P =.7). Moreover, fludarabine did not increase the overall survival time(46 in the fludarabine versus 64 months in the chlorambucil arm) (P = .15). Taken together, the results suggest that in elderly CLL patients the first-line therapy with fludarabine alone does not result in a major clinical benefit when compared to chlorambucil. This trial is registered with www.isrctn.org under identifier ISRCTN 36294212.
PMID: 19605849
Background
These two drugs have been the mainstay of treating CLL, before the advent of monoclonal antibodies such as Rituxan, Campath etc.
Chlorambucil (trade name “Leukeran”) is the oldest drug in our armory.It is an alkylating agent (another well known alkylating agent is cyclophosphamide, the “C” in FCR). Chlorambucil is an orally administered small brown pill, available as 2mg tablets. All the physician has to do is write the prescription and the pharmacy fills it – no fuss, no muss. It is a very cheap drug since the patents on it have run out a long time ago. It is also generally accepted that chlorambucil is a lot less immunosuppressive than fludarabine.
Fludarabine (trade name “Fludara”) is a purine analog (similar to its sister drugs pentostatin and cladrabine) and in its heyday just a few short years ago it has been considered the “gold standard” frontline therapy for CLL. Until recently the only way fludarabine could be administered is as an intravenous infusion – a trip to the back room of your oncologist’s practice and a short stint in the fake leather reclining chair.However, unlike Rituxan infusions, getting fludarabine infusion is a relatively quick and low drama affair. More recently an oral form of fludarabine has been available in Europe and the USA.
Fludarabine earned its “gold standard” status because it packed a mush bigger wallop; a lot more people got “complete remission” (CR) from fludarabine frontline therapy, compared to good old chlorambucil. The overall response rate (percentage of patients who got any kind of a response) was also much higher with fludarabine. This much we knew already from prior clinical trials and historical information.
But it is important to remember a CR does not mean a cure. The CLL will return, sooner or later, even for people who got a CR. I think you will agree with me, from the patients’ perspective the million dollar questions are these:
- How long did the remissions last, when did it become necessary to start therapy again?
- Are there good choices for treating people who have relapsed after fludarabine induced remissions?
- Overall, did patients live longer overall, if they used fludarabine instead of chlorambucil as their front-line therapy?
- How did the quality of life compare after treatment?
Chlorambucil and fludarabine are still the two major drugs available for treatment in much of the world. This rigorous and well conducted trail from the prestigious German CLL Group gives us much needed information on which to base a choice between these two drugs.
Trial design
The researchers correctly point out that many of the clinical trials done in recent years use patient cohorts who are younger than 65 and this may not be representative of the general CLL population which tends to be older. This trial recruited patients who were between the ages of 65-80 years, whose disease met the standard guidelines for initiating therapy.
The trail used 193 “elderly” previously untreated CLL patients age 65 or older (hey, watch out who you call elderly! Dontcha know 65 is the new 55?) They were randomized into two groups to get either fludarabine or chlorambucil. Fludarabine was given intravenously for 5 consecutive days. This was repeated every 28 days for a total of 6 courses. Chlorambucil was started at 0.4mg/kg of body weight and gradually increased to 0.8mg/kg every day for fifteen days on and fifteen days off, for a total of 12 months. Neither group got any routine antibiotic or anti-viral medications, nor did they get growth factors such as Neupogen or Procrit etc. In other words, both arms are your standard issue no nonsense chemotherapy regimen minus all the fancy bells and whistles.
Patient Profile
Below is a table that summarizes the description of the patient cohort.Details are important when making these comparisons and I am happy to report the two groups seem very well balanced, making it a true apples-to-apples comparison.
Toxicity
CTC grade 3 and 4 myelotoxicity was significantly more frequent in the fludarabine arm than in the chlorambucil arm. But surprisingly, severe infections or infections in general (32% in the chlorambucil arm versus 26% in the fludarabine arm) was not all that different. Three of these severe infections in the fludarabine arm were lethal pneumonias, compared to one lethal infection (septic shock) in the chlorambucil arm.
Conventional wisdom is that fludarabine is contraindicated for patients at risk of autoimmune disease. But in this study the rate of severe AIHA was not statistically different between both arms.
Eight patients developed a secondary cancer and 6 patients developed the dreaded Richter’s transformation during fludarabine therapy. In the chlorambucil arm there were 5 secondary cancers and 2 Richter’s transformations.
All in all, I must confess I am a little surprised there was not more difference between the two drugs in terms of their toxicity. It seems the reputation for being “kinder and gentler” is a little exaggerated in favor of chlorambucil.
Quality of life is not merely measured by these dry blood test statistics. This is one of the few studies that bothered to ask patients how they felt. A detailed quality of life survey was administered to patients before start of therapy and 6, 12 and 24 months later. There was significant improvement in general health and fatigue immediately after treatment but this good news went away (dramatically so) at the 24 month mark as more than half the patients had relapsed by then.
Bang for the buck
Now we come to the meat of the paper, description of how the two groups responded to therapy. Few surprises here, fludarabine showed its mettle in getting far more overall responses and complete responses than chlorambucil across all risk groups.
Patients with 17p53 deletions fared poorly on both drugs. None of the 5 such patients in the chlorambucil arm got any kind of response, let alone CRs. There was a lone patient on the fludarabine arm (out of 5 such patients) that got a response but it was not a CR.
How did the remissions play out over time?
They say a picture is worth a thousand words and the picture below shows how the patients fared long term.
These kinds of graphs are depressing reading but it is important that you learn how to understand them.On the horizontal (x-axis) are months. The vertical (y-axis) has the fraction of patients still in remission. The graph shows there is very little difference between the two drugs! Eighteen months out, roughly half the patients have relapsed.
OK, so much for long lasting remissions. How about overall survival? Did fludarabine do much better on that front? Did patients live longer because they happened to be randomized to the fludarabine arm of the trial?
As you can see, for the first 24 months are so there is almost no difference between the curves for fludarabine (lower curve) and chlorambucil (higher curve). The curves diverge a bit in the middle period but by 72 months they are both roughly the same, with slightly less than 45% of the patients surviving. Please bear in mind these are significantly older patients with more comorbidities than one would expect in a younger group. Your mileage may vary.
Putting it all together..
Here are some quotes from the authors themselves:
- This trial is the largest randomized study in an elderly CLL patient cohort.
- The median age of 70 years is approximately five years older than in most previous clinical trials and represents a different patient population in CLL.
- Without a question the fludarabine arm got much higher overall response rate and higher percentage of complete responses (CRs).
- But the better overall response rate and complete remission rate with fludarabine did not translate into a longer progression-free survival.
- This result is likely to have some impact on the general practice of CLL therapy.
No kidding! The modern “gold standard” is not all that much better than the old standby when it comes to long term survival or lasting remissions. But good old chlorambucil is not all that much gentler and kinder either. Take your pick.
As I said in my opening paragraphs, this is not a sexy study or one that will generate a lot of chatter in the research community. But it is solid work like this that is important to us chickens as we make life and death therapy decisions. All of us face very individual choices depending on medical, financial and family situations. One choice does not fit all, and the only right decision for you is the one that you make, that feels right to you and your family. All I can do is provide credible information on which you can hope to make sensible decisions.
But I think it is good to know that if you are not exactly a spring chicken and have more than your share of other health problems, you need not feel underprivileged if you have to “make-do” with taking a few little brown pills of chlorambucil to control your CLL, rather than getting the new-fangled fludarabine. Not a bad thing to know as you make tough choices.
29 comments on "Chlorambucil vs Fludarabine: Which is Better?"
Thanks Chaya. While I’m still only 53, that was a simple enough explanation that even a non-scientist like me can grasp the issue! My doc is trying to get me to start Chlorambucil just because my WBC is 133K. All my other numbers are fairly good. I’m holding off so I can remain a “chemo virgin” as long as possible. Having this study in my hip pocket will definitely help me make smart decisions in the future. As always, thanks for the great info!!
as someone who was forced through a back-door (breast screning) into the CLL camp, I think I have understood correctly, that as long as it is feasable, (ie. one is not ill, other than through having been made to have lots of tests, and has had ones mental state and relations with all and sundry altered, having to conceal thinfs etc. because all forms of cancer are stigmatised) not consenting to any treatment is the best option. I have also had the “well tolerated” and can be hit again and again thrown at me. Must admit I did and do not believe that kind of statement. My standpoint seems, unfortunately to be very well grounded.
Thanks for the useful site and information. I do not know if people are being patronised and sidelined as “sufferers” as much in your country, as over here in the UK.
Mette
Just come from my regular consultation after 5 years of W.W .Have been advised today that it may be time to start treatment-my platelet count has fallen to 116.To-date my specalist has advocated FCR when the time comes.Today he was much less positive and mentioned my age(73)as an issue,and the immune system problems resulting from FLUD.. I now suspect he may have read the research paper.
I am in excellent health-visit the gym regularly ,and have no lymph problems.I will have my platelet count checked again in 6 weeks and a further fall will lead to treatment unless I refuse.Iwould be gratefull for any comments from fellow CLLERS. BOB
The study which you reviewed was well conceived, well conducted and important for demonstrating the relative efficacy of chlorambucil vs. fludarabine monotherapy in this group of patients.
Knowing how medicine is practiced in the US, however, I am uncertain that it’s likely to influence medical decision making all that much in this country.
Considerations for treating any medical problem include:
Does the patient need therapy at all?
What is the risk/benefit ratio of a particular therapy?
How much grief will come to the patient (and to his physicians) if/when the downside comes home to roost?
What therapies are “hot” and which ones are “not”?
This last question is of great importance in the scheme of medical decision making. Most physicians are very busy caring for people and they depend upon the “buzz” from “thought leaders” in their particular field as well as regular input from so-called “pharmaceutical reps” who remind physicians constantly why their particular products are the ones to use.
Single agent therapy with chlorambucil isn’t very sexy and single agent therapy with fludarabine isn’t likely to make a comeback in the US because the risks of toxicity (including AIHA) and the lack of dramatically good outcomes when compared to combination therapies (such as FCR) outweigh all potential benefits. Neither is likely to be advanced by either “thought leaders” or pharmaceutical companies.
My sense is that the “thought leaders” in the US will continue to advocate more sexy therapies such as combinations of alkylating agents, purine analogs and monoclonal antibodies (we can really mix up the alphabet here) as well as other newer drugs targeting intracellular machinery to encourage apoptosis or those targeting the microenvironment and immune system such as the Imids (Revlimid).
I am surprised to hear that a relatively young man without symptoms was advised to use chlorambucil to “control” his elevated lymphocyte count…this is more typically recommended to the elderly in the US now. On the other side of the coin, I recently came across a 72 year old with over 20 years of (thus far untreated) CLL who was advised to enter an experimental treatment protocol for their initial therapy…what’s that all about?
Have a good day,
Rick
My strategy is to look at clinical trials first and use the “normal and accepted” method of treatment as a back-up if an when I need treatment. So far, I am chemo-free, play tennis two to three times a week, and am in good physical shape. I will resist treatment in the hopes that there is something better coming along. I note that former Senator Fred Thompson mentioned that he had Rituxan treatment for CLL and was in complete remission. I think it would be useful to get info on late stage 2 and early stage 3 clinical trials along with some ideas on how to select the best trial for each individual situation.
Rick:
You make some good points, as always.
If it were up to me, “sexy” therapies first have to prove their worth before they take upon themselves the grand title of “gold standard”. FCR has proven its value in inducing long term remissions in a large percentage of the patients, especially if they are chemo naive going in and have half-way decent prognositcs.
But woe to the unlucky patient who does not get a deep remission or a long lasting one after FCR. As we reviewed in a recent artilce “Life after FCR”, there are not very good choices for treating FCR “relapsees”. Barring the brave ones who chose a stem cell transpalnt, none of the salvage options available for treatment after FCR relapse gave acceptable quality or quantity of life.
It seems to boil down to this: you can sneak up on your CLL by low impact and low “cost” therapies, getting short remissions that need to be repeated frequently. The remissions are additive and the toxicity is cumulative. The other approach is to go for the big guns right away, hope to get a long and deep remission right up front, but then be prepared to face a relapse down the road that will be tough to control. You pay the piper now, or you pay the piper later. Take your pick. No free rides here.
The only game changer in this whole complicated maze of therapy options is a mini-allo stem cell transplant. A brand new immune system from a healthy and well matched donor is the only get-out-of-jail free card we have right now. The survival statistics keep inching up ever so slowly and that is good. But I would be the first one to admit it is a very difficult decision to make and implement.
How does rituxan compare with these?
Singer99
No one has done a clinical trial directly comparing Rituxan versus fludarabine (or chlorambucil) in a head-to-head study. All we have are some single arm trials where Rituxan (single agent) was tried in chemo naive patients, but without a second comparison arm.
Some early work at M. D. Anderson using single agent Rituxan as front line therapy gave disappointing results. Both the overall response rate and the percentage of CRs was low and most patients relapsed between 6 months to a year, needing re-treatment. Nevertheless, some patients have used this approach of repeated Rituxan therapy (4 weekly infusions, usual dose 375mg/M2)after each relapse. I know of one patient who has been doing this successfully since 2001.
However, in most cases, the single agent Rituxan remissions start getting progressively shorter each time therapy is repeated. There is little doubt that resistance builds up over time and does so faster in some patients than in others. Some patients also develop hypersensitivity to the drug over time, as did my husband PC. Toxicity is manageable but it is no free lunch. There have been a few troubling reports of JC virus reactivation in Rituxan treated patients (reports that we have reviewed on this site).
Rituxan seems to have more of an impact when used in combination with standard chemotherapy agents – such as FR, FCR, R + high dose steroids, R + Revlimid etc.
ROBERTO – It surprises me your physician is suggesting that treatment may be necessary simply because your platelet count is at 116. While that number may be a bit low compared to “normal”, it is by no means alarming. If you have the opportunity, I would seriously consider consulting with a CLL specialist (or two) before making any decisions. If your only real symptom is a 116 platelet count, I seriously doubt that most experts would recommend treatment.
Thank you Chaya for this very informative report on the pros and cons of these 2 drugs. At this moment I am still watch and wait. I have low platelets @ 85 last CBC but my oncologist doesn’t feel I warrant any treatment yet.I do have my CBC done each month to keep an eye on the numbers. So far I am pretty healthy, keep active with swimming,biking, kayaking,walking. Trying to eat properly as well, and staying away from large crowds.My brother in law is in the VA hospital now with treatment of FCR. Started Monday. He will be doing this after the initial start every 3 weeks. He did have FCR 2 years ago because of an elevated WBC. His count this time was 110,000. He also has lymphoma in the nodes around the neck. SO we are praying this will put him into remission for a long while and that he stays clear of stressful situations. He is 62 now. I am passing this info along to my sister so she can be more informed as well.
Thank you for keeping us up to date.
Anita
Thank you for a really interesting article.
I like to think of the long-term treatment for my CLL as a strategy game, and both chlorambucil and fludarabine have played their parts, with no side-effects from either.
My CLL was diagnosed in 2003, when I was 56, the main symptoms being tiredness, bruising, swollen lymph glands and spleen, and severe night sweats. I had 6 rounds of chlorambucil tablets which got the symptoms under control. It hardly seemed like modern medicine to be taking a drug with a close relationship to the mustard gas of the First World War, but it bought time, and that’s important.
The remission lasted almost two years. When symptoms returned I received 6 rounds of FCR at about monthly intervals. My routine was to attend the hospital for a Rituxan transfusion and go home with five-day courses of cyclophosphamide and fludarabine tablets. Under the British National Health Service no one gets paid extra for giving transfusions so fludarabine has been used in tablet form for many years.
Fortunately, I got a complete remission, and 3-monthly MRDs have so far been negative. I am maintained on 6-weekly transfusions of gamma globulin in my ‘Life after FCR’ stage.
I note Chaya’s comments above about becoming a ‘FCR relapsee’ and I don’t look forward to it. But last week my wife and I had a particularly nice bottle of wine with dinner to celebrate the sixth anniversary of the day I was told that my life expectancy was under two years.
PS. I hope you are enjoying your holiday, Chaya, and not having to spend too much time on the website.
Thank you for a very informative article. I was diagnosed at age 40 with CLL and did the watch/wait routine for almost 10 years. I was then enrolled in a clinical trial around 2004 where I received fludarabine and cytoxin and was to be given campath after 6 cycles. However, I received a CR with the F/Cytox so never did the campath. I made 4+ years before the CLL returned; however, when it did return, I had moved from the slow moving variety to the aggressive 17p- deletion and CATsshowed I also developed a variety of lesions in multiple organs (kidneys, thyroid, etc.) which so far have been benign. I had been asking my doctor if fludarabine was known to be more likely to cause transformation to worse varieties of CLL and had been told “no”. This study seems to indicate otherwise. I am now being offered a mini allow transplant with C-FAR as the prep. I am going to ask a lot more questions as I had not been comfortable with the prospect of doing fludara again even before I read this article.
I would also like to warn readers not to make the mistake I did of not insisting my doctor immediately run a chromosome study upon the return of my CLL. My doctor assumed I had the same 13- clone as before. which is slow moving, so no alarm was raised. Chaya article on the “3 buckets” of CLL types and her warning to periodically check your status is right on the mark.
Pam
Roberto
My plats went down steadily for 3 years until they hit 110. I have few other symptoms except a WBC over 200. My local MD was contemplating treatment because of the low plats. Amazingly they have just stayed around 100 for the last 3 years. I have never had and clotting problems. Barring other symptoms, I think I will stay with W&W until they hit 80. Definitely get a second opinion from a CLL specialist. CLL is an unpredictable disease.
You sent out a newsletter last year that warned of single agent treatment. Is that theory still valid?
duffyz:
Yes, the present guidance is to avoid single agent fludarabine treatment, especially in people who are prone to autoimmune disease. For some reason that is not yet clear to me, combination of fludarabine with monoclonals such as Rituxan seems to reduce this risk factor.
However, in this game it is a good idea to never say never. For many patients single agent fludarabine or chlorambucil are the only choices either because of financial considerations or what their country healthcare allows. Some of the price tags associated with next generation drugs such as monoclonal leave me speechless.
But let’s not get started down that murky path.
I don’t even know where to begin. I just turned 43 and was diagnosed less than 5 months ago with CLL stage 4. My flow test was at 98% when I went in and is less than 1% right now. I try to keep up with a lot of information on CLL. I can’t seem to locate much information on people who have it and are my age. I just don’t know what to ask. I am terrified about getting a bone marrow transplant. I don’t know if I want to do it. Probably because I never really felt bad…sounds odd. But I really just thought I had the flu. The chemo does not bother me. I even gained 25 pounds and never lost my hair. Anybody have any suggestions?
Steven
Chaya,
Thank you for being you. Your late husband is smiling up in Heaven! You have been an inspiration to all of us who are facing the chalenges of CLL. I have been diagnosed in year 2000 around my 60th birthday. 5 years later,I was treated with Fludarabin with Rituxan. My remission lasted about 2 years. Then I had maintenance treatment with single agents of Campath for 4 weeks and then 2 months later 4 weeks with Rituxan. We did this for 2 years. As of now,1 year later, I am in remission, however, my rbc is about 3.5, my wbc is 3.0 to 4.5, my platelets fluctuates between 83 to 110. I feel very lucky that I am still able to play tennis and lead a normal life. Many times I feel tired and lethargic, so I take afternoon naps. The only other complication that I have is diarreah. About a year ago I had a colonoscopy and they found CLL in my colon. Has anybody else have this problem? I would appreciate hearing from you.
Ronald
Chaya,
Thank you for your very honest and very appropriate(for me) update. Up till now I hadn’t really come to terms with my decision to have rituxan and chlorambucil. I do have more stamina and will know for sure when I get my blood work drawn in one week.
Blessings,
rita
Chaya,
so good of you to bring this study to our attention. While single agent treatments are forced options on many we can use this study as a model for other studies containing multiple drug combos.
The good problem we may soon be facing is the widening choice options of immunomodulators and micro RNA based therapies. Comprehensive testing to highlight the targets unique to subtypes of Blood Cancers expressing a high degree of heterogeneity should be a primo effort of patient advocacy. The time for throwing large groups of randomly selected patients into types of trials using the latest developed therapeutic will have to give way to specific disease characteristic trials if we are to succeed in managing CLL in a less toxic manner. Cheaper high resolution scanning particularly targeted for epigenetic abberations will be the key to better patient outcomes.
I am writing this in the 2nd day of my lesser of evils option (RF) in hopes of gaining enough time to see the benefit from targeting what ever is driving my CLL in spite of good markers.
Too many people are unaware of the drug protocol usage such as RF concurrent vs RF sequential that can possibly give one an edge regarding quality of remission. Many general oncologists either are unaware or play it safe by offering only the sequential administration of RF or FCR.
Generally if you have high tumor burden you will need to go to NIH or a CLL expert such as Dr. Byrd at OSU or Kanti Rai of Long Island Jewish Hospital to get the concurrent drug administration. In pediatric ALL an astounding difference was made by altering drug usage alone between 1971 and 2002, this without adding new drugs.
WWW
I was diagnosed 5 years ago at 47 and until January of this year was in W&W. My blood work has alsways been fairly normal but my lymphnodes were increasing in size in my neck making it hard to swallow and sleep at times. My energy level was way done and I was experiencing night sweats. My spleen was also enlarged which caused some discomfort as well. I elected, along with my heamotologist, to start a round of Chlorambucil, 8 mg per day for 14 days on, 14 days off for 6 months.
(fortunately I had the time to think about what I wanted to do in terms of treatment). The results were amazing. My energy is up, my nodes have disappeared in my neck and my spleen is no longer enlarged. I feel like myself again. Hope it lasts for a while!
M.A.
I was diagnosed 14 years ago at the age of 46. Resisted conventional treatment for over 10 years then my immune system collapsed with shingles, I was also in a wheelchair with gout and a chest infection, swollen lymphs and enlarged spleen. I opted for chlorambucil as the least toxic treatment – I wasn’t in a condition to take anything stronger. Total remission time including treatment was about 18 months. Last year I took a course of FC (Fludarabine/Cyclophosphamide) currently considered the new ‘gold standard’. Over the period of both treatments I had innumerable infections – pneumonia, cystitis, eye infections, ear infections, sinusitus and haemoglobin counts dropping to 4 , all of which would probably kill someone 10 or 15 years older, and is in fact statistically the most common killer of CLL patients. So much as it pains me to admit it, I am alive due to chemo, blood transfusions and antibiotics !!
I am currently enjoying a remission and have started travelling again this year, I am told by my oncologist
(a top expert and very nice chap by the way) that FC works very well with my particular trisomy 12q deletion. However I’m under no illusions about my mortality (another 5 or 10 years, give or take?)
As a postscript -10 years ago I declined a stem cell transplant which might have given me “an extra 3 years” according to the young doctor who offered it to me. I wonder where I would be now, had I taken it?
The point being – things move on. Enjoy your ‘ Wait and watch’ with complimentary therapies as long as you safely can, you just don’t know what developments are coming which could overturn current options.
AND – keep reading CLL topics !! Love Alan
2 comments/questions…
First,
Ronald…did your doctors treat your gastrointestinal symptoms and did they differentiate between CLL infiltration and so-called “lymphocytic colitis’ which is one of the more common causes of diarrhea suggestive of Irritable Bowel Syndrome?
Lymphocytic colitis (also referred to as microscopic colitis) can be successfully treated with a variety of interventions and isn’t related to any malignant change in lymphocytes insofar as I know. At times it can be difficult to control, but trial and error with medication usually is fruitful. An alternative reason for diarrhea following therapy may simply be a side effect of the prophylactic drugs on which a patient remains.
Second,
Wayne…are you referring to a different protocol for administration of F, C and/or R than that which is most commonly used (as opposed to the truly sequential use of these drugs as has been studied in several trials in which first F was given alone for several cycles, followed by C for several cycles and finally followed by R in the hopes of acheiving good results with less toxicity)?
In most FC, FR and FCR protocols in use these drugs are given more or less together in s short time frame each cycle, though some physicians hold off a bit on the R until the WBCs are diminished a bit during the first cycle. To reiterate, are you referring to yet another protocol of administration?
have a good day,
Rick
Ronald – My CLL was discovered during the examination of my Sigmoid Colon that was removed because it was perforated and nearly obstructed by twisting from diverticulitis.
Rick – You’re observations always set me off on productive Internet searches that help me to understand my particular version of CLL. It seems as though 5% to 17% of us can have B-CLL infiltration of the GI tract that can happen either early or late. I think that may be an upper bound because it represents postmortem studies.
Jim
A question for Chaya and Rick:
I find the results of this study extremely interesting…. sort of damned if you do, damned if don’t result. Do you know of any study comparing these two treatments to the survival rates if one chooses to do no treatment at all? And no one seems to comment on the quality of life experienced as a result of the treatment. I am still in W/W mode.
Thanks much,
Betty
Dear Betty,
There are rarely any easy answers in our lives, so we find that the “damned if you do, damned if you don’t” scenario plays out over and over. I am not aware that any studies have been done pitting any particular therapy for CLL against no therapy at all in a “prospective” fashion and doubt that any will ever be done going forward.
Most trials use so called “historic controls” which refers to the history of individuals with no therapy from some time in the past. Because our lifestyles are constantly changing as is our ability to treat the complications of disease and it’s therapy (as well as other diseases that may befall individuals which are not directly related to the disease in question) there is an inherent unreliability in using historic controls for comparison.
The survival rate for CLL has tended to increase over time as newer therapies and better supportive care have emerged. By the same token there is some effect of earlier diagnosis on the statistics which are accumulated.
The best thing for anyone to remember is that statistics, while helpful in guiding our decisions, are of no import to the individual. By that I mean that when 1% of a given population has a bad outcome, it is bad for those who fall into that 1%, no matter how well the other 99% may do.
I believe that medical care decisions should be individualized based on the best information available, integrated with an individual’s own prior track record, goals, beliefs and family/social situation. By taking all of these disparate factors into account a physician and a patient’s family may counsel an individual to assist them in making the best possible decision for them. No decision need be “final” and flexibility should always be employed to permit a change in direction as one’s life situation changes.
By that I mean…just because I may decline a treatment at one point in time, I should be able to consider it again in the future, even though the likelihood of success may change over time.
An individual with a life threatening problem may dismiss a dangerous treatment such as HSCT, but may wish to reconsider it if they manage to overcome the first problem. The corollary also applies. If someone planning to undergo a HSCT suffers severe trauma in an accident, they may need to reconsider their plans and go forward with amended plans.
Patients and their physicians all need to be nimble on their feet and flexible in their considerations of treating any medical problem. Those who insist on following only a narrow path often find their progress impeded by unanticipated obstructions.
Quality of life is always something that should be considered before, during and after any therapeutic intervention. That is what medical care is all about…improving the quality of life.
I hope that this helps,
Rick
Actually, this is one study that bothered to do a quality of life survey at the time of starting therapy, then again at 6, 12 and 24 months post therapy. I made sure to mention that in my review. If you want to read the details of the QOL survey you need to read the full text of the journal article. Write to me personally and I can help you locate the article.
Second point: The whole Watch & Wait paradigm arose out of a much older study that compared use of chlorambucil early in the disease versus W&W and treating when symptoms required treatment. No advantage was seen in early interevention using chlorambucil.
Putting these pieces together, the conclusions seem to be that (1) there is not much to be gained by treating earlier than necessary with chlorambucil (2) since single agent fludarabine does not seem to be any better than single agent chlormabucil, the conclusion stated in (1) above is relevant to fludarabine as well.
Moral of the story is that frustrating as it is W&W is still the way to go. Treat CLL when symptoms and clinical situation requires treatment. I think most experts now agree that treatment decision should not be based on WBC numbers alone but on B-symtoms and other clinical parameters. The other important point (which we kind of knew already) is that single agent fludarabine is not (repeat NOT) any kind of gold standard as front line therapy.
I will end with a point that I have made often and that I think is extremely important. “Watch & Wait” is too passive a phrase for what patients need to do. I much prefer the term “Watch & Get Ready”. Patients are better off if they use the time they have available to come up the learning curve, get into better shape physically, emotionally etc.
CLL diagnosis is a storm warning that needs to be taken seriously. No need to board up the house right away, but it is a good idea to get hold of the plywood and screws, figure out how to evacuate if necessary, make sure you have a cache of water, food, flashlight and so on. Watch the weather reports and Get Ready.
I am about to start treatment for the first time, my oncologist is suggesting Rituxan, but I am also diabetic (type II) and have not been able to find data about CLL treatment of diabetic patients. Is anyone aware of any studies on this subject?
Elek
I do not believe diabetes is a contra-indication for use of Rituxan. High dose or prolonged use of sterioids (prednisone, dexamethasone etc) may be an issue, but not Rituxan.
Hi, Chaya —
Thanks so much for the analysis. I’m in agreement with Rick, tho, in not thinking it is not going to have much impact on treatment, at least in the US. The issue raised by my husband’s oncologist (at a major CLL research center) was, “yes, but no one does stand alone Fludarabine or Chlorambucil any more.” So my question is, is there a way of mapping these results into a prediction of how FR or FCR would compare to, say, Chlorambucil or Chlorambucil + Rituxan or anything else. It would be too bad, it seems to me, if a well-done and thorough study like this is ignored because it isn’t “the latest” treatment…
There also seems to be a very strong feeling on the part of the major CLL researchers (tho not on the part of their patients), that going for a long remission is a better strategy than what I think of as “managing” the disease with less effective but less toxic treatments. Are we missing something here?
Fran
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