The Goldilocks Dilemma
Before we get down to the nuts and bolts of the FCR “Lite” clinical trial results, I would like to set the stage and tell you why this is an important approach. We do not have all the answers, yet; but we may get them over time as more patients go through this protocol and the statistics become more robust. I know a lot of you out there are interested in this approach.
We are all familiar with the childhood story about choices that do not quite fit. Too much or too little is not good enough. It is worth making the effort to find just the right fit. That idea may be particularly true when it comes to treating CLL.
Mainstream oncologists treating solid cancers with short fuses have a justified mind-set: cancer is the enemy that needs to be rooted out, burned and poisoned until there is no trace of it left behind. Surgery, radiation and chemotherapy (respectively) are designed to maximize their ability to kill cancer cells. Of course, there is a price tag of collateral damage and toxicity to normal cells in this take-no-prisoners approach. This may be unavoidable and necessary in order to control an aggressive and dangerous enemy. Concepts such as maximum tolerated dose (enough to kill the cancer but not enough to kill the patient – most of the time!) and non-overlapping toxicity grew out of this mindset. For patients that face imminent death from their particular cancer, this approach makes sense. It is amazing how much toxicity patients are willing to accept when faced with the other alternative, imminent death.
CLL Marches to a Different Drum Beat
But this approach developed in the context of rampaging solid cancers may not be the right handle on things when it comes to CLL. Remember, many CLL patients blessed with good prognostic indicators may be able to coast along with little or no therapy for a long time. Many of the chemotherapy drugs used to treat cancers are mutagenic – they can cause further chromosomal damage. “Clonal Evolution” is a fact of life with CLL. Many patients start out with minimal chromosomal damage and then gradually accumulate more FISH defects over time. Clonal evolution is all the more likely in patients undergoing chemotherapy with drugs such as fludarabine, cyclophosphamide etc.
Here is one analogy of how things work in CLL land. Homeland security is aware that there is a general sense of dissatisfaction among a segment of the law enforcement officers, and this morale problem has spread through out the police precincts in the whole country. These are not your average bomb-throwing terrorists per se, but they are malcontents that do not do their jobs right, mouth off and spread discontent by means of their constant bitching and moaning. It is hard to pin-point and identify them exactly, since they look just like their innocent colleagues. Unfortunately, their poor attitude is infectious. Soon enough other officers stop doing their jobs and sit around complaining as well. While these malcontents and their side-kicks / new converts lounge around mouthing off, bank robbers and murderers roam the city with no one to challenge them. The longer we wait, the worse it gets. As if this is not enough, there is always the chance that one of the malcontents may stew in his crazy ideas long enough that he goes over the top, goes “postal” and morphs into a card-carrying member of bomb throwing terrorists. Pretty soon, this tough guy becomes the leader in his ‘hood, encouraging more and more of the hoodlums start imitating his take on things – and we now have a serious problem on our hands. Evolution is a fact of life, even malcontents evolve over time.
What to do? Nuking every police department in every city and thereby poisoning the whole country is hardly an appropriate solution. It might kill the offending cops, but it will surely kill off major part of the population as well, reduce the towns and countryside into a glassy radioactive rubble. Anyway, there is no guarantee that all of the bad guys will be killed by this process. They are too darn much like the average Joe Bloe walking down the street! This situation requires a more subtle approach. For starters, it is important to recognize this is not a 9/11 type of crisis that requires a knee-jerk response right off the bat. There is time to think things through and come up with the most effective and least damaging solution. It may take hard work, courage, resolve and persistence to select and implement the right plan but speed is not the overriding factor in most scenarios.
I think you can see the parallels. Most of the time, a diagnosis of CLL does not require immediate and urgently scheduled therapy with the biggest and baddest therapy guns at our disposal. “Watch & Wait” is entirely justified, to get a better fix on the lay of the land. Like our malingering cops in our analogy, CLL cells are spread all through the body — there is no place in your body that blood and lymph do not circulate and therefore there is no place that is entirely safe from CLL. Without a localized enemy, it does not pay to jump the gun and initiate all-out war, not unless you have no other choice.
On the other side of the equation, waiting indefinitely without a game plan is not a solution either, unless you are fortunate enough to have a very indolent, “smoldering” variety of CLL. As time passes, the tumor load grows and CLL cells gradually compromise other important cell lines. Even in patients with relatively slow-growing CLL, over time there may be a gradual drop in red blood cell, platelet and neutrophil counts. Over time other organs such as the liver and spleen may also get infiltrated, limiting their function and efficiency or causing them to behave in a destructive fashion.
There is one more very simple reason why it is not a good idea to wait until the last bitter moment — “B-symptoms”. I have no idea why they are called this, and why they are “B” rather than “A” symptoms. Whatever they are called, they are no fun and take a big chunk out of your quality of life. Overwhelming fatigue, drenching night sweats, frequent infections and unwanted weight loss are but some of the unwelcome symptoms in late stage CLL patients. In some if not all, lymph nodes and organs such as the spleen and liver grow big. Even if you don’t care whether or not you look like a chipmunk with the enlarged lymph nodes along your jaw-line, sometimes these nodes can be downright painful and they can press against vital arteries or nerves.
Reality Check
I have a real problem with doctors and institutions that have a shoot-first-and-ask-questions-later approach to treating CLL patients. Sometimes, less may be more in controlling CLL. Lengthening the alphabet string of drugs in ever more complicated combos is not a slam dunk good choice when it comes to treating CLL.
Then there is the other end of the spectrum. There is an entire industry out there that caters to patients’ wishful thinking – that it is possible to cure full fledged, clinically diagnosed CLL by diet and lifestyle modification, magic potions, “coral” calcium and cottage cheese.
Can one cure (I mean really CURE) aggressive CLL by leading a blameless life? Will buying and using magic potions marketed by snake oil peddlers do anything more than lighten your wallet and perhaps shut your window of opportunity for getting more realistic therapy if and when you need it? I will be right upfront with my take on this issue, the answer is “no” – especially if we are talking about an aggressive form of CLL. You of course have the right to disagree. But lets keep this discussion polite, OK?
A percent of CLL patients, those fortunate enough to have the extremely indolent “smoldering” variety of CLL may never need therapy. If you are one of these lucky folks, you get a free pass. If you are so inclined, you can even tell yourself that the magic potions you take (with little or no credible clinical trial information backing their efficacy) are the reason why your CLL is under control. As always, for the rest of you not so lucky in your prognostic markers, “Buyer Beware” is a good mantra to remember.
I am the first one to agree that unhealthy lifestyle choices (smoking, obesity, junk food, excessive UV exposure and a couch potato lifestyle spring to mind) contribute a great deal to the incidence of cancer. Anyone who continues to smoke even after getting a swift kick in the backside in the form of a cancer diagnosis loses a big chunk of credibility. Furthermore, you absolutely need to do all you can to improve your general health after your diagnosis of cancer, if for no other reason than to get ready for the fight ahead. Cancer therapy is a lot more taxing on your body if you have unrelated co-morbidities. People in good fighting trim fare a lot better and more likely to survive the adverse effects of cancer therapy. There is this little phrase called “treatment related mortality” that says it all: Yes, we cured the cancer, but unfortunately we killed the patient in the process.
This is then the crux of our problem — how to make sure the therapy we decide on is just right: not so heavy-handed as to cause a lot of collateral damage, but not too weak and therefore ineffective. CLL is not your average short-fuse cancer. In most cases it is not a ravening beast that must be killed immediately at any cost. In fact, for the majority of CLL patients, it is quite possible to shoot yourself in the foot by opting for the most potent (and most toxic) therapy out there. The smart thing to do is weigh your options, do your homework and play the cards you have been dealt as best as you can.
FCR “Lite”
We floated the concept of “Lite” chemoimmunotherapy combinations such as FCR-Lite on our website back in 2005. The good news is that it is no longer just a concept on a patient website. Some researchers are thinking outside the box and beginning to treat CLL as a unique cancer that does not fit the general stereotype, recognizing that it needs more finesse than the standard take-no-prisoners approach of oncologists used to treating solid cancer patients.
Two of the best known combinations above are FR (pioneered at Ohio State University) and FCR (championed by M. D. Anderson). Both of these combinations show impressive overall responses with a goodly number of “complete responses” (CRs). But neither therapy is without risk. Both have associated immune suppression, neutropenia, opportunistic infections such as pneumonia, shingles, higher risks of hospitalizations and a potential for secondary cancers such as basal cell carcinoma or squamous cell carcinoma or other hematological cancers. Is there a way in which we can keep the high response rates, but reduce the adverse effects?
In all chemoimmunotherapy combinations such as FCR and FR, Rituxan is the drug that is doing the targeting of the CD-20 positive B-cells, painting a bull’s eye on the cancer cells. Conventional chemotherapy drugs such as fludarabine and cyclophosphamide provide the killing power. Is it possible to keep the efficacy of FCR by increasing the role of Rituxan and at the same time reduce the adverse effects by reducing the amounts of chemo drugs used in combination?
In other words, will we get the best of both worlds, the perfect Goldilocks choice by going to FCR -Lite, where the emphasis is increased on the “R” part of the combination and we cut way back on the “F” or/and “C”? I am glad this is no longer a mere speculation anymore. Below is the abstract that spells out the results of the FCR Lite trial at University of Pittsburg Medical Center. If you are interested in this approach, you really should read the full length article as well as the accompanying and very thought provoking editorial. Send me a personal email and I will help you locate both of them.
J Clin Oncol. 2008 Dec 15.
Chemoimmunotherapy With Low-Dose Fludarabine and Cyclophosphamide and High Dose Rituximab in Previously Untreated Patients With Chronic Lymphocytic Leukemia.
Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L, Meisner D, Laman A, Sulecki M, Butchko A, Schaefer P, Lenzer D, Tarhini A.
Department of Medicine and Biostatistics, University of Pittsburgh School of Medicine, Graduate School of Public Health, and the University of Pittsburgh Cancer Institute and the University of Pittsburgh Medical Center Cancer Centers, Pittsburgh, PA.
PURPOSE: Chemoimmunotherapy combining fludarabine, cyclophosphamide, and rituximab (FCR) is an active regimen for untreated patients with chronic lymphocytic leukemia (CLL) with 70% complete responses (CRs) and 95% overall responses (ORs). However, grade 3/4 neutropenia was reported in 52% of cycles of treatment. The purpose of this trial was to maintain the high responses but reduce the toxicity of FCR by decreasing the fludarabine and cyclophosphamide (FCR-Lite). PATIENTS AND METHODS: We conducted a single arm study of FCR-Lite which includes maintenance rituximab in 50 untreated CLL patients. Patients were evaluated for response using both the 1996 National Cancer Institute Working Group (NCIWG) guidelines and the 2008 guidelines. Two thirds of patients were treated by community physicians. RESULTS: The median age was 58 years (range, 36 to 85 years); 20 patients had Rai stage 1, 22 had Rai stage 2, and eight had Rai stage 3 and 4. The OR and CR rates were 100% and 79%, respectively, using the 1996 NCIWG guidelines and 100% and 77% using the 2008 guidelines. Median duration of complete response was 22.3 months (range, 5.2 to 42.5 months) and none of the complete responders have relapsed. Grade 3/4 neutropenia was noted in 13% of the cycles of therapy. CONCLUSION: FCR-Lite is highly effective in previously untreated CLL patients. Grade 3/4 neutropenia was dramatically reduced compared to standard FCR and our data demonstrated FCR-Lite can be safely administered in the community setting.
PMID: 19075274
Comparing FCR and FCR Lite Drug Dosages
This clinical trial was a single arm trial and the same is true of many of the full strength FCR trials pioneered at M. D. Anderson. What that means is that we do not have a perfectly matched head-to-head comparison between the two approaches. The best we can do is see how the data matches up, but with the caveat that there is wriggle room on account of the two patient groups may not be strictly similar and there is room for researcher bias in results interpretation. The table below outlines the two protocols in terms of the drug dosages and how they were scheduled.
The units used for the drug doses in each case are “milligrams per meter square”, or “mg/m2”. This is done in order to take into account for the variable body size of individual patients. To get the dosage right for you, you need to multiply the dosages in milligrams by your BSA (Body Surface Area, measured in square meters. The BSA Calculation link will show you how to do that, given your weight and height.
As you can see, FCR “Classic” used quite a bit more fludarabine and cyclophosphamide whereas FCR “Lite” used a lot more Rituxan over a much longer time period. I understand in subsequent tweakings of the FCR Lite concept the researches further reduced the dependence on fludarabine and cyclophosphamide.
FCR Lite Results
As most of us know by now, FCR combination pioneered at M. D. Anderson has demonstrated impressive overall response statistics (95%) as well as high percentage of CRs (72%). Those that had squeaky clean remissions (no trace of CLL detectable by four color flow cytometry or MRD negative) at the end of treatment stayed in remission much longer compared to those that had detectable disease (85 months verusus 49 months).
How did these statistics compare with FCR Lite results? Did this “kinder and gentler” approach have sufficient oomph? Below is a quickie comparison of the response statistics.
Bear in mind this is not a strict apples to apples comparison since we are looking at data from two single arm trials. Also, while the FCR response rates are based on a very large size cohort monitored over a very long time, the FCR-Lite statistics are based on a much smaller group of patients and the results have yet to meet the test of long term monitoring.
With these caveats in mind, it seems to me there is no significant difference in the overall response rate. Generally speaking, FCR-Lite seems to be plenty strong in getting people into “complete remission”. How many of these CR patients were also lucky enough to have no trace minimum residual disease (MRD) when examined by four color flow cytometry or pcr technology? That information is not available. How long did the FCR-Lite remissions last? This paper reports early results and we cannot hang our hats on remission duration or overall survival data – not just yet. But this much seems to be true: as expected, FCR-Lite does indeed seem to have lower toxicity. Reducing the amount of fludarabine and cyclophosphamide did indeed reduce the percentage of patients who had high grade neutropenia or thrombocytopenia.
Was FCR-Lite strong enough medicine to work across different risk buckets? The paper does break out the results by FISH status, one of the important prognostic indicators.
Once again, as expected, the really tough cases with 11q and 17p deletions (as reported by FISH test) had a harder time getting full fledged “CR” status.
Questions Remain
So, do we now know all we wanted to know about FCR-Lite? Not by a long shot. Here are some questions that linger in my mind, I am sure you will be able to add to the list.
- Are remissions obtained by using FCR-Lite as durable as those obtained using full strength FCR? In other words, does a “CR” obtained after using FCR-Lite of the same quality and durability as a “CR” obtained after FCR-Classic? Something tells me that mere “CR” status is not enough to answer this question. We need more details, such as MRD (minimum residual disease) status, by four color flow cytometry or pcr (polymerse chain reaction) technology.
- There seems to be reasonable grounds for accepting that FCR-Lite is less toxic, smaller percentage of patients had high grade neutropenia or thrombocytopenia. Does this “kinder and gentler” approach mean patients will live longer even if they come out of remission? Can we hope that for FCR-Lite patients there will be reduced incidence of opportunistic infections and secondary cancers down the road?
- Does FCR-Lite mean less collateral damage and therefore better quality of life for patients undergoing this protocol? It is also worth noting the FCR-Lite protocol used rigorous guidelines for prophylactic protection of patients: antibiotics, anti-virals were used, along with standard pre-infusion drugs such as Allopurinol, Benadryl, Tagamet and Tylenol.
- When patients relapse, will FCR-Lite patients be less refractory than those who relapse after FCR-Classic? Does the reduced dosage of chemotherapy drugs translate into patients who are not as tough to “salvage” with other therapy regimens? As we have seen in prior articles, life after FCR relapse is pretty tough. Is it any better after FCR-Lite relapse?
- While Rituxan enjoys the reputation for lower toxicity – at least when compared to conventional chemo drugs such as fludarabine and cyclophosphamide – it is by no means a free lunch. Patients in FCR-Lite are exposed to long term maintenance use of Rituxan. Are they more likely to develop hypersensitivity to the mouse juice? Would it better to shift to FCA-Lite where the “R” of Rituxan is swapped with “A” of arzerra (aka Humax-CD20 and ofatumumab) since this new monoclonal is a fully humanized antibody?
- Last but not least, what is the dollar impact of FCR-Lite? Rituxan is many times more expensive than old fashioned chemo drugs such as fludarabine and cyclophosphamide.
A Brighter Future Ahead
I am an optimist. I really think there is a brighter future out there for CLL patients. I do not mean way out in the distant future, I mean in the near term and soon enough to make a difference to many of you reading this article; definitely in the lifetime of your kids or grandkids, should they be unlucky enough to inherit this familial cancer from you. That is why I think it is so important for us to understand the stakes, play this game to win. The short term tactics you decide on should not leave you out in the cold, when better choices become available for longer term survival strategy. And I urge each and every patient out there to consider the possibility of volunteering for clinical trials. We must thank those that went before us, and pay our way forward by doing our share of heavy lifting. In the final analysis, the only way we are going to get a cure for this awful disease rests in our hands.
39 comments on "FCR “Lite”"
Chaya –
well reviewed, as always. Makes you almost want to start chemo early – NOT! My questions to add to yours include: Do you know whether these researchers [or any others taking up this cudgel and template] have in place plans to: 1) follow to see if FCR lite changes/doesn’t change the probability/rate of clonal evolution? 2) Follow to see not only the duration of the CRs in total, but to see if the “staggered” of remissions achieved, even in CR’s follow the well-known 13 > normal > 12 > 11 > 17 pattern? 2) Make the change as you say to “FCA-Lite”, and just to make you work even harder – pre- or concomitant or post- treatment with Lenalidomide?
Thanks for your continuing efforts on our behalf
Hotdog59
Chaya,
So glad you are addressing this treatment. I’ve googled around for some detail on the administration and it appears that rituxan is given every other week during the first six months and then every three months during maintenance. Am I correct about the initial rituxan and the rituxan maintenance? Seems like a lot of time in the chemo chair. Hope folks who were part of the study will comment on their experience. Also would be interested to know if anyone on Medicare has been able to try this, outside of the trial.
Thanks again for all you do for us !!
Lynn
Chaya,
Again you have shown the proper attitude for CLL and how patients should consider new research. The point about medicare coverage is not trivial. You are also correct that Rituxan is not cheap and escalating it may sound great in theory but its bite out of the pocketbook might be an unwanted factor, when there are other choices. Perhaps competition may finally drive this price down. It is about time for the truly humanized efforts to start paying off.
I was just curious about your statement that FR started at Ohio State. Am I missing a study or are you speaking of them putting it into common use. This NY paper is the one that I see as 1st.
Leuk Lymphoma. 2003 Mar;44(3):477-81.
Combined fludarabine and rituximab for low grade lymphoma and chronic lymphocytic leukemia.
Savage DG, Cohen NS, Hesdorffer CS, Heitjan D, Oster MW, Garrett TJ, Bar M, del Prete S, March R, Lonberg M, Talbot S, Mears JG, Flamm M, Taub RN, Nichols G.
New York Presbyterian Hospital. Columbia Campus, New York, NY 10032, USA. dgs5@columbia.edu
As both fludarabine and rituximab are active against indolent lymphoproliferative disorders, we have studied the combination of fludarabine and rituximab in patients with low-grade lymphoma and chronic lymphocytic leukemia (CLL) in phase I/II fashion. Of 33 patients enrolled, 21(63.6%) had low-grade lymphoma and 12 (36.4%) had CLL. They received fludarabine 30 mg/m2 on days 1-4 and rituximab 125, 250 or 375 mg/m2 on day 5 at intervals of 28 days to a maximum of 8 cycles. Three patients were removed from the study because of rituximab-associated anaphylaxis and four because of prolonged hematopoietic toxicity. Toxicity and responsiveness did not differ at the different dose levels of rituximab. For 29 evaluable patients, responses were seen in 82.8% and complete responses in 34.5%. Of 7 responding patients not referred for stem cell transplantation, 6 remain in complete remission at a median follow-up of 16 months (range 4-30 months). Of 13 previously untreated patients, all responded and 46.2% had a complete response. Of 16 previously treated patients, 68.5% responded and 25% had a complete response. The combination of fludarabine and rituximab has major activity and acceptable toxicity in patients with low-grade lymphoma and CLL.
Chaya, once again, thank you! I have to admit, being a Trisomy 12 and an FCR-Lite treated person, I was very excited to see 100% CR for those with the Trisomy 12. However, I did come tumbling down off my cloud as you raised the question about how long the CR would last. In my case, I have achieved CR and next month my oncologist is requesting another FISH. Both my doctor and I are thinking we will see favorable results.
Lynn, my Rituxan maintenance is not every three months. During chemo I did receive Rituxan about every other week. FCR-Lite’s chemo cycle is slightly longer than FCR. Since the R is stronger in the Lite, it is split between the first week of the cycle and then is given again two weeks later without the FC. However, the maintenance cycle I am on is once a week for four weeks every six months. For example, every Monday for four weeks in December and every Monday for four weeks in June. The maintenance portion lasts two years. I will get my last maintenance round in June.
Thus far I have not experienced too many problems with FCR-Lite. The only fly in the ointment seems to be my immunity level. All my counts are coming back in the normal ranges with the exception of immunity. My oncologist fears that since it has been a year and a half since I finished the chemo portion of my treatment, I may never get my full immunity back. He is keeping a close eye on it.
Again, thank you Chaya! While my treatment was not a part of a clinical trial, I feel like I am in the front line and hope that whatever the outcome will eventually be, it will serve to help further our understanding of this monster.
Elaine
Chaya
An excellent article. A lot to think about for all of us on the waiting list and not yet treated…wondering what to do/choose when the time comes.
Your reference to researchers now thinking outside the box, and, perhaps not waiting for a 9/11 type chemo attack…makes your article even more relevant.
For years and years it’s been watch-and-wait…sip green tea until it’s time for the big bazookas.
The research teams seem to be spot on…high fives for each one of them.
However, if it wasn’t for you..we would never have known about it.
Sooo…that means..High Fives for you too..Chaya.
Many thanks for the article.
WillB
Chaya
Thanks for the article. I particularly liked the BSA calculation link. Not having had therapy, these approximation formulas were new to me.
Jim
Thanks again Chaya for this.
I have never been categorised so i can´t say what group I belong to.
I had FCR four years ago. I wad supposed to have six rounds, bur after four I was so ill that I decided to leave the fludarabine out so I had altogether 4 rounds of FCR followed by two of CR.
All I can say is after a very bad time with falling blood counts I ended with splenectomy I am still in full C.R. and there are no signs of anything going wrong yet.
Michael
Thank you, Chaya.
Chaya,
Thanks once again. I thought you might be interested to know – I am in bucket C – 48 years old. I received FCR over 8 months. Got CR, however my counts never recovered. Just had a bone marrow biopsy and discovered I now have MDS (no CLL cells present). Talk about the cure being worse than the cancer. So I now have a secondary cancer. Once again, the only “cure” for MDS is a transplant, which is already in my future, however MDS caused by chemo is harder to treat than MDS that develops naturally. I will be seeing all my geniuses in Boston this week and can only hope they have a good plan for me. I will keep in touch. I don’t know if my doctors would have tried FCR lite with me given my genetic deletions but it still would have been nice to have the info anyway for consideration. I have somehow managed to remain infection free for the last 6 months even though my wbc is 0.3 and ANC .11 – everyone is amazed. Thanks for the hard work you do on our behalf. I don’t know what I would do without you.
Marci
I guess I am wondering if the VA will offer any of the treatments you talked about. I go in for my second CT scan the end of this month(march). I will ask about them then. As for the last one in Jan. the CLL was NOT in my bones or lymph’s “yet”.. guess I am in the watch and see stage right now. I am 52. I really enjoy reading your articles and hope that my Dr. has some answers.
Thank you for the updates on possible cures..
Tim
Really liked your article and a lot of the comments here ….. I have a VERY advanced form of CLL because of late detection ….. It had already gone through my blood and 90% of my bone marrow when I was finally diagnosed …… I started on FR the first week in February and the results have been VERY promising so far …. My Platelyd count has increased dramatically and all other counts in my blood have become very good also … All this and the side effects have been minimal …. I still have my hair …. I am am not sick daily …. I do have the fatigue and night sweats still and can not get around anyone sick without catching it myself ….. But after being given only 7 or 8 months to live in January, the results have been promising. I will keep updating my progress on FR as I continue each cycle …..
Gary
I know chlorambucil is outdated but I am still wondering whether high dose constant frontline therapy would give me enough kill of CLL cells with less toxicity and most important at my age a better quality of life? I am 78 years, WBC of 212K, low platelets (85K) enlarged spleen and fatigue but no night sweats or lymph node enlargement. My WBC count first passed 10K in 1994 so I have been on watch and wait for almost 14 years. My oncologist has been wanting me to start bendamustine which seems pretty toxic according to your articles. I also am having numerous squamous cell carcinomas and had a heart attack lasr year. I am trying to do a good job evaluating my options but it is not at all clear to me yet quite what therapy to agree to. At my age quality of life in my remaining years is of first order importance. Any ideas?
I always wondered how this treatment would turn out after living in Pittsburgh & knowing the trial was here. I did go through a trial of PCR & got 5 1/2 years remission. I agree with changing to Azerra would make sense plus really watching the remission follow-up time-frame.
Thank you so much for your wonderful insight & comparison.
Anne
Lynn – my husband was a trial participant and yes, your understanding of the maintenance regimen is correct, at least as it is administered at the Hillman. He achieved CR but obviously it’s too early to say how long that will last (he had his last maintenance dose of R last week).
One thing I will say is that during the last 2 1/2 years we’ve been doing this the antivirals and antibiotics seem to have done their job – he hasn’t caught a single bug.
Jennifer
Looks like FCR-lite just might be the next “gold standard”. I will say, though, that the median follow up of 27 months is way too short to really know. Tom was in the 300 person trial of FCR and relapsed at around 30 months after reaching an nPR with minimal residual disease detected by flow cytometry.
The remission he did get was a fantastic QOL for 30 months. Relapse comes on quickly and we are still trying to do better than just stable disease. We would do FCR all over again if we could go back in time. As I have stated before, Tom had a harder time, albeit different type of side effects, on Revlimid than FCR.
jlou
Chaya,
Thank you for a very informative article.
Stay well,
Monique
Chaya,
I hope folks pay particular attention to your emphasis on the W&W and when to get treatment. Too much emphasis on waiting before treatment is placed on peripheral blood tumor load (WBC or ALC) without consideration for lymphnode involvement. I never experienced “B” symptoms or tumor doubling time criteria before I had treatment. I was still being advised by an NIH CLL expert that I had the “Option” to W&W longer when I threw in the towel and opted for treatment. The sheer bulk of nodes, not painful, began impacting my ability to sleep. The main risk factor in waiting too long may be not the high tumor in the blood but in the nodes because it adds to the risk of TLS (Tumor Lysis Syndrome) and other complications depending on ones health.
I am continually struck by the reports of people like myself and Marci who experience high ffunctioning immune systems in spite of high tumor burden and treatment, this in contrast to those who have very poor immune function with minimal CLL presence. Much is yet to be learned about how immune system functioning may help subtype patients for optimal treatment.
One aspect of this article which is unclear to me is a comparison of the toxicity between FR and FCR-Lite. Dr. Kanti Rai advised me to get FCR and admitted that I would get more infections than if I went with FR. My response to FR was almost too good in the killing dept and led to an aborted shortening of tx at 2 cycles due to kidney failure as yet not fully explained. In a comparison of lessoning the F in FCR-Lite but substituting C is there any way to tell how much more effective or toxic the one would be over the other since both FR and FCR-Lite seek to decrease toxicity? It would seem that comparisons could be made by mining the data.
WWW
If Timmyj is reading this I would urge him to question the VA oncologists to justify the use of CT scanning. I am a veteran and my experience with the VA was that the oncologist was very pushy about having me get a CT scan. I refused based on the inability of the onc to give me a valid reason for her have a scan given the risk of the radiation and contrast that could negatively impact my kidneys. Dr. Byrd of OSU and a CLL expert never suggested that he needed a CT scan even when I had extensive internal lymphadenopathy. Please read Chaya’s earlier article on Imaging and scanning and know that there is a major recognition by most doctors and institutions that this practice needs to be used much more judiciously than in the past.
Chaya,
Thank you for this very interesting update.
I am still trudging along with R/B. I have two more two/day treatments.
Take care and Blessings,
Rita
I don’t believe I had light but I did have FR instead of FCR over a 6 month time period. Prior to the first cycle I received lower dosages of R 3x to get the ALC down some before starting the FR regimen.
It will be 2 years in May and I get my CT Scan April to see what’s what. My last blood draw showed a level of ALC a bit high (13).
Right now I am 13q and I’ll have to ask my doctor how much time I have before I start getting the 11, 12 and 17 markers as well. Sad news but it is good to be aware of that progression.
My thanks to Chaya for providing such pertinent and current info.
Chaya,
As ever, thanks for being aropund; it keeps me semi-sane, apart from which the atricles are so well written and easy to understand.
The articles and their interpretation of “what’s out there” or up and coming, also gives hope.
Thanks again,
Mette
Marci – What does MDS stand for? I don’t seem to be able to find that abbreviation anywhere. Thanks! Celosiana
LynnS:
You are right about the Rituxan administration schedule for FCR Lite. During the first 6 months Rituxan is given at 500mg/m2 every alternate week. During the 24 month maintenance phase it is given once every 3 months. The details are all spelled out in the full length article that I cited.
But many patients are getting slightly different versions of FCR Lite with their local oncologists who are modifying the treatment schedule as it seems appropriate to them. Basic premise is still the same, to increase the “R” component and decrease the F+C part of the equation. Especially in the case of older patients or those with poor health going in, FCR Lite may be a good option – that is what I am hearing from my oncologist contacts.
timmyj:
VA tends to drag its heels a bit. With them as in all aspects of life, you get what you negotiate for. It took several years for the VA to acknowledge that veterans who had been exposed to agent orange have a higher risk of developing CLL – we and other patient advocacy groups had to fight hard to get VA benefits for our members who could document Agent Orange exposure. You can read more about this by going to http://www.clltopics.org and searching for the key phrase Agent Orange.
Rituxan in combination with F+C has just been approved by the FDA for treating CLL patients. FCR LIte is nothing more than a specific protocol using these three drugs. I cannot see how the VA can turn you down. Fight for your rights!
Wayne:
There are lots of unanswered questions, lots of clinical trials that will never be done. My guess is that the momentum behind FCR (and variations on the theme such as FCR LIte) is so strong that FR will only be used in special situations and for special patients with co-morbidities or drug sensitivities.
Celosiana:
MDS stands for myelodisplastic syndrome, which can be early stage cancer of the myeloid cell line.
Chaya:
Thanks so very much for researching and publishing this update regarding FCR-Lite. (As some of “us” had requested). I was patient number 28 in the FCR-Lite protocol study at the UPMC Hillman Cancer Center in Pittsburgh (I beleive that “Forest Bump” – you published articles about him – was also a patient of this protocol”!). I was initially diagnosed with Stage 4 CLL (using the Rai staging system) and at the age of 56 and started on the protocol in February, 2006. I had no prior indication of any cancer or leukemia and I was pretty sick at the time of my initial diagnosis.
Due to allergic reactions with Rituxan, including neutropenia, I was hospitalized several times. Also, the “F and C” component of the protocol effected my immune system (igg, iga, and igm levels).
The good news is:
1. I achieved “CR” (complete response) within the initial six month protocol. In fact, I achieved “CR” after 4 treatment cycles. At that time, my oncologist thought it would be best if I continued on the protocol for all 6 cycles (6 months) – “to obtain a deeper level of response”.
2. 3 ½ year later, I am still in complete remission!
The “not so good news” was:
1. It was determined that I was having an allergic reaction to Rituxan (which according to the protocol was to occur on a quarterly basis for 2 years following the end of the intensive/initial 6 month treatment). My Rituxan treatments were discontinued and I have not been hospitalized with neutropenia since!
2. Evidently, the “F and” component of the protocol, even though it was deemed to be “Lite”, was still very strong/toxic and impacted m bone marrows ability to produce: Igg, Iga and IGM and thus my immune system is suppressed.
3. I receive IVIG treatments every 4 to 6 weeks, which as you know temporarily boosts my Igg levels, but does nothing for my Iga and Igm levels. Thus, I am prone to respiratory and upper respiratory infections.
4. I also have an allergic reaction to the IVIG treatments, so I take steroids – starting with the treatment and lasting on a taper dose for 7 days.
All in all for me the “FCR-Lite” protocol was effective, as I was lucky to achieved a lasting “CR” (3 ½ years and counting!). I consider the side effects of the Rituxan and my needing to receive ongoing IVIG treatments to be minimal, as compared to being in Remission/CR.
Questions: What has happened to the FCR-Lite protocol? Will this protocol be further studied? Are there any further updates available on the long term status of the patients?
Many Thanks!
FCR-Lite Protocol Patient # 28 – Pittsburgh, PA
I just want to add my thanks to Chaya. Without you making sense of all this I would be lost. You not only give us good information to think about but also equip us with questions for our doctors. You are appreciated!!
I believe a modified version of FCR Lite protocol clinical trial (even smaller amounts of F and C) is still open and recruiting patients. Dr. Ken Foon (the principal investigator) has moved to the Nevada Cancer Center and the study has moved there. We gave the contact information for Dr. Foon in an earlier article on Updates:
http://updates.clltopics.org/964-a-very-promising-vaccine-trial-for-cll
Thank you, Chaya, for all the great information you provide. Thank you, also, for encouraging participation in clinical trials. My husband was part of the MD Anderson FCR trial and had a great remission for 4 years. Afterwards, he was on Treanda for 5 cycles – but without good results. Again, he was positioned to be part of another clinical trial at MD Anderson last November but wasn’t able to participate due to what appears to be an auto immune problem requiring transfusions of red blood and platelets several times a month. Our insurance will not cover what appears to be the next step – a stem cell transplant – but, he should be able to proceed in that direction once Medicare (and a supplental plan) kicks in this June. Never thought we’d be desperately looking forward to his 65th birthday!
Thank you, again, for helping us wade thru all the information!
Susie .. Been there, done that. My dx was at age 64. What an expensive year (thank you Blue Cross) !! I was ecstatic when I turned 65 and got that magic card. I believe my premiums are an order of magnitude less now.
I wonder if anyone on for-profit insurance (i.e. pre-medicare) has been able to persuade their insurance company to pay for the rituxan maintenance. Comments from anyone who has gone through the treatment with insurance paying?
Best of luck to you, Susie, and your husband.
Lynn
Another brilliant article – and timely for so many of us. Thanks, Chaya.
–Aaron
Thanks again Chaya – this is very useful in a “be prepared” sense for me.
(Currently happily in remission 20 months after a course of normal FCR – but facing the possibility of more treatment SOME time….)
Lawrence, UK
I am in round 5 of FCR “classic” this week. I meet with my onc prior to the chemo each time for a general checkup, review bloodwork, etc, and yesterday he says that he saw the FCR Lite study, the results looked as good as the FCR “classic”, and would I like to switch of to the FCR lite doses for my last to rounds of chemo.
I hadn’t seen the study, but I told him no….that I wanted to keep going at the full dosage for my last 2 rounds. He made no mention of rituxan maintenance either, so I don’t know if that would have been brought up if I had said yes.
That just seems kind of odd to me for him to bring up changing things up when I’m already two thirds done.
–Wish
Chaya,
I’m new to this site, but in short time I have learned lots. Thank you for all your research, dedication and caring for all who have CLL. Late last year Dx w/CLL @ 51. I was given stage IV d/t Neutropenia with 90% bone marrow involvement. I’ve completed 1st cycle of Rituxan x 4 weeks with 1 week of Treanda, only to discover this site. I’ve tried but have not found articles that support my Oncologist treatment recommendations. . Have you come across any articles that highlight using Rituxan and Treanda as first line? The article my oncologist handed me was for refractory patients and patients who had CLL come back. It seems all the articles I have read do not have this combination as first line. Now that my counts are up the oncologist has started me this week with (2) back to back of chemo and next week I start the weekly Rituxan for 4 weeks. Any direction would be helpful.
Mahalo, Cate
I am about to enter a clinical trial using PCA. This is a brand new initiative out of Duke in North Carolina. Since I have never been treated before, I visited Ohio State (Byrd) and Duke before deciding to start the trial. Byrd was concerned about the C in FCR and suggest FR. From what I was told, the ages between 65 to 70 are sort of a break point where the C causes considerable risk of serious and deadly consequences. The P is apparently easier on the blood and bone marrow while the F digs better into the nodes. Essentially, my take is that FCR lite would be a better choice as you age.
To LynnS:
I was a in a clinical trial and the Rituxan was paid for! so, i did not need to worry about that!. however, before i was on medicare, the insurance company that i was with denied the coverage my IVIG treatments (which i required every 4 to 6 weeks). I appealed and eventually won! My suggestion to you re: Rituxan – either get on a clinical trial that includes Rituxan, or appeal and fight with you insurance company! Also, get your oncologist (and as others) to call and/or write a letter to your insurance company. WE NEED HEALTHCARE REFORM – NOW!
52CLL:
Rituxan + Treanda is a plausable combination as frontline therapy for CLL. I have no doubt the manufacturer of Treanda would like to see this combination gain popularity amongst physicians, for obvious reasons.
Remember, Treanda is thought to act a little bit like purine analogs (such as fludarabine) and a little bit like alkylating agents (such as cyclophosphamide). So, the case can be made that R + Treanda is like R + FC or FCR.
However, R + Treanda does not have the time tested results. Recently the FDA has granted approval for use of FCR as frontline therapy. Not so R + Treanda. Well designed and well conducted clinical trials are needed before R + Treanda becomes the equivalent (one hopes) of FCR. We are not there yet.
I am at a loss as to why your oncologist would recommend untested R + Treanda over well understood FCR – unless there are details about your case that makes R + Treanda a better choice. This is a conversation that patients should have with their doctors BEFORE start of therapy – the logic for the recommendation, why it is a better choice than other better understood options. I am not sure it is helpful to rock the boat right now, considering you have already started on the R + Treanda protocol. Just my two cents.
Chaya, Thanks!
That’s great info and something to consider and watch.
Any updates on FCR-lite?
Lynn
No updates on FCR Lite.
Dr. Kenneth Foon who was the researcher and the major drive behind this clinical trial has left academia and gone over to the “dark side” ;-) Last I heard he works for some major drug company. I doubt we will be seeing too many new articles on FCR Lite.
Hello Chaya, and thanks for all of your updates, Been doing alot of reading, very informative articles. I have just finished 6 months of FCR-Lite on Feb 7th 2012, And to recieve the maintenance rituxan in august, once a week for 4 weeks, and then in another 6 months, was just curious, about all the dangers with the rituxan,Should i continue to follow this regiman?? Or see what kinda remission i get from the first 6 months of treatment, I know My DR. wants to go ahead with the protocol and he has worked with DR.Foon, I’m just thinking would it be more effective to wait and see if i relapse or keep treating and worry about longterm side effects down the road, I have labs scheduled for the 20th of march 2012, and have asked DR. about MRD testing, and he says he can run the test but very expensive,Like i care what it cost, I just want to know whats going on inside. well thanks for all you do and maybe you can shed some info my way. And by the way the side effects i do have are minimal just very Fatigued and running low temps, thats about my biggest complaints, just chilling all the time. Thanks Bernie
Gee Bernie .. seems strange not to have the MRD test based on expense when I’m sure Rituxan is very expensive and if you have no MRD then you don’t need any more Rituxan or am I wrong on that?
All the best to you,
Lynn
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