Do FCR Response Statistics Translate Into Longer Life?
There is no question that addition of Rituxan to FC (fludarabine + cyclophosphamide) improves the response statistics. Study after study has shown this. There are better overall response rates, more CRs, more pcr negative remissions (really deep remissions where we cannot detect even a trace of CLL with our most sensitive detection methods) with FCR compared to FC. Mouse juice (Rituxan) seems to improve response rates every time it is added to straight chemotherapy.
But, and this is the most important question as far as patients are concerned, do our guys live longer because of addition of R to FC? Who cares about the tag researchers give to your particular remission, CR, PR, nPR – whatever. What matters to you and your family is if this means you will live longer and your quality of life is better. These question had not been answered satisfactorily – up to now.
German Study Group: FC versus FCR, frontline therapy
ASH 2009 abstracts are now available on line, and one of the most interesting abstracts is the one from the German study group. Excellent paper, very credible group, and most encouraging results – I was delighted to read it. The abstract is below. My two cents follow right after, in plain English.
Abstract number 535
First-Line Treatment with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Improves Overall Survival (OS) in Previously Untreated Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Results of a Randomized Phase III Trial On Behalf of An International Group of Investigators and the German CLL Study Group
Michael Hallek, MD1, Guenter Fingerle-Rowson, MD, PhD1*, Anna-Maria Fink, MD1*, Raymonde Busch2*, Jiri Mayer, MD3*, Manfred Hensel, MD4*, Georg Hopfinger, MD5*, Georg Hess, MD6*, Ulrich von Gruenhagen, MD7*, Manuela A. Bergmann, MD8, John Catalano, MD9, Pier Luigi Zinzano, MD10*, Federico Caligaris Cappio, MD11*, John F Seymour, MD, PhD12*, Alain Berrebi, MD13*, Ulrich Jaeger, MD14, Bruno Cazin, MD15*, Marek Trneny, MD16, Anne Westermann1*, Clemens-Martin Wendtner, MD1, Barbara F. Eichhorst, MD1, Peter Staib, MD17*, Sebastian Boettcher, MD18*, Matthias Ritgen, MD18*, Myriam Mendila, MD19*, Michael Kneba, MD, PhD18, Hartmut Doehner, MD20*, Stephan Stilgenbauer, MD20 and Kirsten Fischer, MD1*
Introduction: In 2008, first results of a multicenter, international randomized phase III trial (CLL8) were presented, showing superiority of FCR chemoimmunotherapy for response rates and progression-free survival (PFS) when compared to FC chemotherapy. We now report updated results with a longer median observation time of 37.7 months (mo).
Methods and Patients: 817 treatment-naïve patients (pts) with good physical fitness and CD20-positive CLL randomly (1:1) received treatment with 6 courses of either FCR or FC therapy. Both treatment arms were well balanced with regard to sex, age, stage, genomic aberrations and IGVH gene status. The median age was 61 years (range 30 to 81), 25.7% pts were female in both arms, 64.1% were Binet B, 31% Binet C and 4.9% Binet A. The median cumulative illness rating scale (CIRS) score was 1 (range 0-8). The overall incidences of trisomy 12 and abnormalities of 13q, 11q23, and 17p13 detected by FISH were 12%, 57%, 25%, and 8%, respectively.
A mean number of 5.2 treatment courses were delivered in the FCR arm vs 4.8 courses in the FC arm (p=0.006). Dose reductions by more than 10% in at least one treatment course were performed in 47% (FCR) and 27% (FC) of pts (p<0.001), respectively. 74% (FCR) and 67% (FC) of pts received 6 cycles (p=0.02). The total median cumulative dose applied per pt was 775 mg for F and 7712 mg for C, with no statistically significant difference among the two treatment arms. Pts in Binet stages A and B received more treatment cycles (5.31) than Binet C pts (4.52; p<0.001). Only 57.1% (FC) and 60.3% (FCR) Binet C pts received 6 cycles. Dose reductions by more than 10% were observed in 49% of FCR pts (vs 28% FC (p=0.001).
Results: As of June 2009, the median observation time was 37.7 (mo). 761 pts (FCR 388; FC 371) were evaluable for response, 790 pts (FCR 401; FC 389) for PFS and all for OS. FCR induced a higher overall response rate than FC (95.1 vs 88.4%) and more complete remissions (44.1 vs 21.8%; p<0.001). Median PFS was 32.8 mo for FC and 51.8 mo for FCR pts (p<0.001, Hazard Ratio (HR) 0.56, CI 95% 0.460-0.689). The largest benefit for FCR was observed in Binet stage A and B for CR, ORR and PFS (Binet A: p=0.08, HR 0.423 CI 95%, 0.157-1.135, Binet B: p<0.001 HR: 0.504 CI 95%, 0.390-0.651, Binet C: p=0.08, HR 0.732 CI 95%, 0.514-1.041). In Binet C, the median PFS was 14 mo for pts treated with up to 3 courses FC, but 44 mo for pts that received 4 courses or more (p<0.001). Median PFS for pts treated with up to 3 cycles FCR was 12.5 mo, while for pts with 4 cycles or more, median PFS has not been reached (p<0.001). Statistically significant differences were observed in OS between the two treatment arms. The OS rate at 37.7 mo was 84.1% in the FCR arm versus 79.0 % in the FC arm (p=0.01). In both arms, the median OS has not been reached. Only patients in Binet stages A and B showed a superior OS after FCR treatment (Binet A: HR 0.19, CI 95%, 0.023-1.613 p=0.09; Binet B: HR 0.45, CI 95%, 0.296-0.689, p<0.001; Binet C HR1.4, CI 95%, 0.843-2.620, p=0.168).
As previously reported more hematologic adverse events, particularly neutropenia, were observed with FCR treatment, but this did not result in an increased infection rate. More deaths have occurred in the FC arm (86/396, 21.7%) than in the FCR arm (65/404, 16.1%). In the majority of cases, the underlying cause of death was progressive disease (FC 48/86, FCR 33/65), secondary malignancies (FC 13/86, FCR 5/65) or unrelated causes of death such as myocardial infarction (FC 15/86, FCR 17/65). Treatment related mortality occurred in 8 (2.0%) of pts in each arm. Of these, 7 FC-treated pts and 5 FCR-treated pts died from infections related to treatment. In 7 pts (3 FC vs. 4 FCR), treatment was discontinued before the third treatment course due to fatal toxicity.
Multivariate analysis was performed to evaluate factors predicting outcome. Age, sex, FCR-treatment, response, number of cycles (0-3), 17p-deletion, increased serum levels of thymidine kinase and ß2-microglobulin and unmutated IGVH genes were independent prognostic factors predicting OS or PFS.
Conclusion: Treatment with FCR chemoimmunotherapy is more effective than FC chemotherapy. The partial failure to demonstrate a benefit for FCR in Binet stage C patients may be related to an insufficient treatment intensity in these patients with higher tumor load. To our knowledge, this is the first time that a randomized trial is able to demonstrate that a specific first-line treatment for CLL results in an improved overall survival. The results corroborate the recommendation to use FCR as standard therapy in physically fit pts with CLL requiring therapy.
Trial Description
This trial did a head-to-head comparison of F+C versus F+C+R in a large cohort of previously untreated patients. 817 patients were recruited for the trial and randomly assigned to either the FC or the FCR arm. Patients in the two arms were well matched for sex, age, FISH and IgVH status. This is an important point. Without well matched and randomized double arm studies such as this one, it would be impossible to do a truly kosher apples-to-apples comparison and the results would be suspect.
All the patients received 6 cycles of therapy (roughly 6 months). Or that was the intent going in. As it actually turned out, on average the FCR crowd got 5.2 cycles of treatment and the FC guys called it a day after 4.8 cycles, on average. As you can imagine, some of the patients just could not handle all six cycles and that dropped the group averages from the optimum six cycles, in both FC and FCR arms. Some of the patients needed dose reductions in order to tolerate the treatments. It is encouraging that the FCR combo was not harder to tolerate than FC, if anything the number of patients who failed to finish all 6 cycles was smaller in the FCR arm.
Looking at the overall group, only 5% of the patients were in the early Binet Stage A; a further 31% were in the intermediate Binet Stage B and a whopping 64% were in the advanced Binet Stage C. There was the usual smattering of tough FISH abnormalities (25% 11q deletions and 8% 17p deletions). In other words, these were by no means “easy” patients cherry picked to improve response statistics. That has been a nagging worry at the back of my mind every time I read the stellar response statistics in earlier single arm FCR studies. Call me a cynic, but I am enough of a scientist to be convinced by credible results when I see them.
Results
As of June 2009, the patients in this trial had clocked a median observation time of 38 months. This is not very long, but long enough that interesting statistics have begun to emerge. No doubt this precious group of study volunteers will be followed for as long as possible and we will get full length papers based on this study in the years to come. Longer follow-up will further solidify the results. But let me hasten to repeat: the results published in this abstract are statistically significant and valid. They are not due to happenstance or wishful thinking. That is what makes the good news so very encouraging.
As you can see in the table above, FCR did better than FC on all counts. We have come to expect FCR will do better on response statistics, and it did: better overall response, more CRs and longer remission times; and all of these met the test of statistical significance.
I have highlighted the new information. Patients who got randomized into the FCR arm lived longer than those that got only FC. The overall survival rate at 37.7 months (the duration of the trial at the time of writing of this abstract) was 84.1% in the FCR arm versus 79.0 % in the FC. And the difference met rigorous test for statistical significance, meaning you can actually have some faith this result is not a fluke. The difference may not seem like much to you, just a 5%. But these are early days. It will be interesting to see if the difference becomes more and more pronounced over time. My bet is that it will. We will see more starkly the advantage of adding R to FC in terms that matter to us – longer life.
My cheat-sheet table also breaks out the causes of death, since this was interesting as well. As you would expect, CLL progression was less of an issue in FCR than in FR. But did the addition of R cause the FCR arm to have more immune suppression and therefore more infections or more secondary cancers? It seems not. While there was indeed a bit more neutropenia in the FCR arm, there were not more infections. And there were not more deaths due to secondary cancers. Both of these are very good things to see, since they suggest FCR is no more immunosuppressive than plain FC.
Careful reading of the abstract points out a couple more details: the advantage of FCR over FC was most obvious in the earlier stage patients, those that were in Binet Stage A and B. Patients who were further along, in Binet Stage C, did not see as much of a benefit. This has huge implications and I will talk about them in the Editorial section.
Careful sub-set analysis revealed what we have come to expect. Prognostic indicators do make a difference. Patients with good prognostics did better, whether they got FC or FCR. Some of the indicators that influenced overall survival and progression free survival were:
- Age (younger patients did better, in both arms. No surprise, younger patients are in better shape overall and have fewer co-morbidities. I would expect your actual physical health matters more than your chronological age – another reason to get into shape while you are in W&W! )
- Sex (women fared better)
- FCR-treatment (lucky ones got inducted into the FCR arm)
- 17p-deletion (lucky patients did not have this bad prognostic indicator),
- Increased serum levels of thymidine kinase (not good)
- Increase ß2-microglobulin (not good)
- Unmutated IGVH genes (not good
Editorial
First things first. Please join me in offering our heartfelt thanks and gratitude to the 817 brave volunteers who made this trial possible. They put their necks on the line so that we and future generations of CLL patients can benefit from these important findings.
This trial points out some of the human heartache that is unavoidable in the process of conducting double arm randomized trials such as this. How would you like to be the spouse of one of the patients that got randomized to receive FC, and your guy died soon after? Would he have lived if he had been lucky enough to get into the FCR arm instead? Toss of a coin or toss of a few bits in a computer code that randomized him into the FC arm might have made all the difference between life and death. Bitter pill to swallow, and that makes their sacrifice all the more poignant.
But it is precisely because the study used such an ‘inhuman’ and unbiased method for putting patients into the two groups that the results are so very credible. Randomized and double arm clinical trials such as this one are truly the gold standard of clinical research. Because of this trial, we now know that any patient in future treated with FC rather than FCR is not being given the best possible therapy. FCR is now the gold standard, no questions about it. There are always exceptions to the rule. One exception is older patients who may not be able to tolerate FCR. For them chloramabucil may be a better choice, as pointed out in Dr. Gribben’s Best Practices article that we reviewed last week.
Patients who were in earlier Binet stages A and B got more bang for buck with FCR, patients who were further along in their disease progression did not see as much of an advantage because of the addition of Rituxan to FC. Does this mean patients will be better off pulling the trigger and opting for initiating FCR therapy, sooner rather than later? Are they risking shooting themselves in the foot by waiting until the last bitter moment before initiating therapy? Remember, conventional wisdom to date is that Watch & Wait is the best thing to do until onset of B-symptoms and falling platelet counts and red blood cell counts require start of therapy. Should these guidelines be modified, suggesting patients are better off starting therapy sooner?
The results of this trial seem to suggest it is better not to wait too long, not to drag out W&W just a bit longer. That is a finding that can have a huge impact on how we treat CLL patients. But I wonder if there is a twist in this particular finding, if there is a bit more to it than just that.
Let us do a thought experiment. Let us invent two identical CLL patients (there are no such identical pairs, but hey this is a thought experiment, right?). Patient A goes through W&W for only 2 years and while he is still in Binet Stage A, decides to opt for FCR therapy. Patient B is a bit more dogged about resisting therapy for as long as he can, he waits it out for 5 years – by which time he is in Binet Stage C – before starting FCR. Patient A gets a good remission, his overall survival is a solid 10 years after completion of FCR. Patient B is not so lucky, he lives for “only” 7 years after completing FCR. Who came out ahead?
The answer is neither patient lived longer than the other. Patient A had 2 years of W&W + 10 years after FCR, a total of 12 years after CLL diagnosis. Patient B had 5 years of W&W + 7 years after FCR, he too had a total of 12 years post CLL diagnosis.
I have obviously jury rigged the numbers in this thought experiment to illustrate my point. It may be that there is real advantage to initiating FCR sooner, but this trial does not confirm that. The other issue to consider is quality of life. Did Patient B do himself a disservice struggling along with increasing CLL load, increasing B-symptoms and poor quality of life in the last couple of years of his dogged W&W? Would he have had better overall quality of life, averaged over his 12 years, if he had gone into therapy sooner? Conversely, did Patient A sail through his FCR therapay and did he get a really clean and hassle free remission that gave him good quality of life for the next 10 years? Or was his immune system so shot by the FCR that he remained neutropenic and prone to infections for a big chunk of his 10 year remission?
These are important questions and I doubt any clinical trial will give us slam dunk answers that are right for all patients. It is never easy to decide to wait or not to wait. Each of us is unique in our own way and each of us has unique therapy needs. The smart thing to do is get yourself top notch medical advice, then sit down with your family and trusted advisors and make your decisions, the ones that are right for you and your family. And remember this: once you have made your decision, know it is the right one – for you. Don’t look back, don’t second guess yourself, don’t torture yourself with what –ifs. No one is more qualified to make decisions for you than you are. Don’t let anyone bully you into thinking otherwise. It is your life, your body, you and your family have most skin in this game. Just remember that, OK?
49 comments on "Do patients live longer with FCR?"
“The smart thing to do is get yourself top notch medical advice, then sit down with your family and trusted advisors and make your decisions, the ones that are right for you and your family. And remember this: once you have made your decision, know it is the right one – for you. Don’t look back, don’t second guess yourself, don’t torture yourself with what –ifs. No one is more qualified to make decisions for you than you are.”
What could I add to this profound summary of the proper course?
Thanks always.
Dave Mikol
Thanks Chaya,
For getting this to us even before ASH. It is certainly one of the most significant studies in quite a while, and future years with this cohort will be increasingly important.
Since the split among many doctors is between FR and FCR, do you know if, and when, any studies may begin to show survival differences between those two?
(You looked gorgeous in the Niagara conference video – I had no idea!)
Helene
I couldn’t agree with Dave more.
Speaking of important research questions to be answered… there is a study that Dr. John Byrd is heading up that is available throughout the US and Canada (actually the NCIC just opened this up).
This trial looks to see if treatment for high risk CLLers (those with unmutated IgVh status) is benefitial early on and comparing that to CLLers who wait until they become symptomatic.
This is for CLLers who have not yet been treated for their CLL.
Knowing the answer to this question could dramatically change the when and how treatment is most effective for high risk patients.
More information is available at
http://www.cancer.gov/clinicaltrials/CALGB-10501
cllmom
Thanks for posting important studies Chaya.
Elmer:
The tentative leads are that FCR is more potent than FR, that it leads to better overall response rates and longer remissions. We do not yet have concrete head-to-head double arm randomized trials such as this one between FR and FCR. We do not know if addtion of cyclophosphamide to FR increases overall survival (life).
However, Dr. John Byrd (who pioneered the FR concept at Ohio State) has recently written that in cases where the patient has poor FISH prognostics (11q and / or p53 deletion), addition of C to FR is probably a good thing. I would tend to agree. These tough luck guys need all the help they can get, and addtion of C to FR increases the oomph. It also increases the adverse effects, but that cannot be helped.
Thanks for the kind words about how good I looked at the Niagara conference. When was the last time you had your eyes checked Helene?
Thanks again Chaya! It certainly worked for me. The fact that now for the first time patients can
hope for a life-prolonging treatment. This was something I could not understand when I set out on treatment 4 years ago. “Its won’t make me live longer, just better” I said a I took the first dose. However being completely free of symptoms now would have been out of the question if i had not decided to do this. It was my decision, they started me off on Leukeran,but I insisted on FCR. Luckily it was available here in Iceland at that time. And free! (That is not why we are having money troubles though!)
Hello Chaya. For me this is both fascinating and encouraging just when my attitude needed a boost. Thank you so much for your careful interpretation and clarity.
Have this week completed second chemo of FCR + “M” phase II trial in UK.
I would echo your admiration for those who are placed in the less “glamorous” control groups – I know how hugely disappointed I would have felt with this choice.
Separate point / selfish question please?
I had much heavier side effects than first round.
Can exercise, diet regime, hypnotherapy or other preparation help prepare or strengthen the body / mind prior to the chemo sessions? Any anecdotes, experiences or interpreted research would be most gratefully received.
Best wishes to all readers and to you Chaya – your warmth and generosity of spirit come through very strongly reading this site.
John1606:
I can vouch for regular exercise, balanced and nutritious diet and getting mentally prepared to handle the stress of chemotherapy. My husband PC practiced all these and more (7-8 hours of sleep, staying well hydrated, careful avoidance of skin cancer and infections, staying the heck away from fad diets and crazy cancer “cures”, pragmatic evaluation of each lab report – looking for trends and not getting bent out of shape with each number).
He had very aggressive CLL that needed therapy intervention almost from the word go. Nevertheless, he lived for 8 wonderful years with the CLL. Those eight years were full of life and laughter. He had terrific quality of life right up to the end. No infections, no hospitalizations and no regrets. He could not control the hand he was dealt, but I am convinced he played the hand he did get with grace and intelligence.
Things catch my attention:
Only 8.2% of the deaths following FCR are due to progressive disease. 4.2% are due to unrelated causes. And TRM is 2.0%. So, if you survive the period during and immediately following the treatment, I would think that you are past the real threat of TRM. That leaves your chances of dying due to progressive disease and secondary cancers at only 9.4% for the remaining part of the 37.7 months following treatment.
According to the MD Anderson folks, 72% of cll patients using FCR as frontline treatment are getting CRs lasting a median of 7 years.
http://abstracts.hematologylibrary.org/cgi/content/abstract/112/11/2090?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=FCR&searchid=1&FIRSTINDEX=0&volume=112&issue=11&resourcetype=HWCIT&eaf
Dr. Hamblin has written on his blog that the CR’s referred to in this abstract are CRs under the old ’96 guidelines, and there have been several recent reports stating that MRD neg CR’s are lasting longer. I aaked Dr. Hamblin on his blog how long he thought the MRD neg remissions should last, and he responded with “who knows?”
I had a very heavy tumor burden (70% marrow involvement and a huge spleen), and I achieved what appears to be a MRD neg CR with only 4 cycles of FCR and slightly reduced fludarabine (because of my age). My treatment was finished in May of 2007, and I have had no problems except itchy skin. Dr. Hamblin wrote that the longer people live without relapsing, the longer the expected total time should be (as with older people who are expected to live beyond the average life span because they survived the many years they have lived).
So, I’m sitting here reasonably hoping to have a 10 yr remission and reasonably hoping there will be better salvage treatments available by the time I relapse.
Just surviving and surfing the technology wave like most cll patients, but doing pretty well from what I can tell, thanks to FCR.
John, I would second all the things PC did to help himself stay well. After reading on CLL Topics that PC ran miles, I’ve taken up jogging every day. Only 20 minutes, on grass, very slowly but it makes me feel wonderful, full of energy and the effect lasts all day. I’ve also been drinking more water which has helped with recurring water-work infections. I found travel sickness wrist bands helped a lot with the nausea from the chemo. After my first chemo last year I’ve now become intolerant to alcohol and feel a lot more energy from cutting it out completely – I still enjoy myself socially but now I dont fall asleep. It feels so good to be in this complete remission state, every day is a bonus, full of potential. I’m glad the consultant at Barts Hospital persuaded me to start FCR sooner rather than later. Are there any survival figures yet for people who have had bone marrow transplants?
Chaya-Reading your posts about CLL has been so helpful to me-Ijust found this website after losing my Dad to Cll this October-My Mom also has Cll-what are the odds and now we are trying to learn all we can about this disease-Has this disease ever manifested itself in a married couple around the same time in any of the studies-Should the rest of the family be tested-We will continue to follow the posts as we try to understand this illness-Thank You for helping us understand –
Chaya,
Thanks for the review. (Its funny, but since I’ve had CLL, the ASH conference has become kind of a seasonal marker for me, something to look forward to each year, jut after Thanksgiving and before the hubbub of the December holidays.)
FCR continues to be the most highly thought of frontline treatment for CLL. Just over a year ago, I completed my first round of treatment with PCR. The Mayo specialist who oversees my treatment suggested PCR over FCR. Do you know of any good studies that compare PCR to FCR? Is there evidence to demonstrate that FCR is the better choice or is it a matter of marketing muscle that makes F the dominant treatment? If I remember correctly, the Mayo team felt Pentostatin was less immunosuppressive than fludarabine. In any event, one year out, I feel great. My bone marrow involvement decreased from >90% to 0.1%.
Thanks for the info.
Steve
Tucson
Hi Chaya,
Wonderful summary of the ASH abstract. Wondering if one can extrapolate any thoughts about use of pentostatin, cyclophosphamide and rituxin instead of FCR from this. I think I know your answer, but just checking!
All the best,
Leslie
Why does Mayo stick with PCR and not FCR, almost all the research data I see seems to be along the FCR line, my wife has CLL and is W&W status and good prognostic data. We are pleased with Dr.Zent but wonder why when the time comes for treatment that they chose PCR. Thanks for any thoughts. Everett
Chaya:
I always find your updates to be very interesting and informative. Thank you for continuing with this publication – which I know is a “labor of love” for you.
When I was initially diagnosed in February, 2006 with Stage 4 CLL (I was very ill at that time!) , I was “enrolled” in a small little know clinical trail called “FCR-Lite”. The hypothesis behind this protocol was to go “Lite” with the “FC” (which can be very toxic), but “full steam ahead” with the Rituxan component. My first six months on the protocol included the “FCR” component. Additionally, as my IGG, IGA and IGM levels became severely suppressed during treatment (and they still are!), I also started receiving routine IVIG treatments (and I still do).
At that time, with the protocol, I was to receive “routine/ongoing” Rituxan treatments on a quarterly basis for at least 2 additional years (and possibly longer) following the end of the FC component.. Unfortunately, I developed severe “allergic reactions” to the Rituxan treatments (I became neutropenic, had flu like symptoms including high fevers, etc.) and I was hospitalized several times. As a result of my reactions to the Rituxan and some of my other complications, my “new” oncologist consulted with “The Dr. Rai” (the Rai staging system) about my individual situation. As a result, my use of Rituxan was discontinued and I have not been either neutropenic or hospitalized since!
It is now, November, 2009 and I continue to be in CR (complete remission). Some of my blood counts are periodically “up and down” (i.e. platelets) and I receive routine IVIG infusions for my suppressed immune system, generally every 4 to 6 weeks. I also experienced severe allergic reactions to the IVIG treatments – so prior to and after each treatment I take: benedryl, Tylenol and steroids on a taper dosage.
My questions to you are as follows:
1. Are you aware of any studies and/or differences between the FRC and the FCR-Lite protocols?
2. Do you know what (if any) is the “current wisdom” of the continued use of Rituxan (for at least 2 years) following the end of the FCR treatment phase?
3. Are there any studies re: suppressed immune systems, reoccurrence of the CLL?
4. Are there any studies re: long term effects form routine IVIG treatments?
Thank you,
I was diagnosed with CLL in March 2006. I have mixed/complex cytology and am IvGH unmutated. I started 6 months of treatment on FR in a study comparing 1)FR, 2) FCR and 3) FR + a followup drug. After treatment all of my lymph nodes had been reduced to essentially normal size and the CLL cells in bone marrow were less than 10% of the total (the latter not as good as I had hoped). At the present, 14 months out of treatment all of my counts are good, including total white counts.
I will have followup CT and bone marrow analysis in March which will tell a lot. Already, I am told that that some FR patients who had difficult cytology, etc. have been placed on the followup drug. The hope for FR is that it might be effective with less risk. I feel better now than any time since 2006. Dr. Byrd is very positive but making no guarntees about the expected time until more treatment. RS
Chaya,
Thanks for the great analysis. This is good news for the CLL community and something to weigh if tx. time is near. I am most excited about the CAL-101 trials going on and the reports of pts. who have written on lists that they are seein results in this trial. Dr. Furman believes this drug could be a valuable weapon in the arsenal perhaps combined with a mAB like Rituxin or the new one Azerra. It would be so great to have a less toxic tx. that is specific to our CLL cells and not decimating our good white and red cells. I am all ears waiting to hear more on the clinical trial results for CAL-101.
Chris, Adks NY
CLL:
Sounds like you have a very aggressive version of CLL. I am sorry.
I am very familiar with “FCR Lite”. In fact, that name was coined by us and we pushed hard to get that trial done. You can look up more about it by searching our flagship website http://www.clltopics.org with the key word “FCR Lite”. A detailed article was published in JCO 2008 regarding FCR Lite. Please send me an email (offline) and I will help you locate the full text article. The authors do compare FCR Lite and standard issue (historical) FCR results, but this is not the same as a double arm study.
A small percentage of patients do develop hypersensitivity to Rituxan, especially after repeated use. My husband PC was one of them. Hopefully the new anti-CD20 monoclonal ofatumumab (Humax-CD20, recently FDA approved) will be useful to this segment of people since it is fully human monoclonal with none of the murine (mouse) protein that is thought to create allergy problems with Rituxan.
Suppressed immune system is very much part of the game with CLL, and potent chemotherapy combinations leave the patient even more compromised and vulnerable to infections. This is a simple fact of life after CLL diagnosis. IVIG infusions are thought to help decrease the frequency of infections, but there is the balancing risk of allergic reactions in very sensitive patients.
I do not believe anyone has done long term studies of IVIG use.
Hope these answers are useful to you.
chaya:
thanks for addressing my questions! you are amazing!
I was diagnosed with Cll in Jan 06. We opted for the w/w method so we put off treatment until Feb of this year. I had 6 courses of FCR. I was really sick prior to treatment, enlarged spleen & lymphs, severe warm blooded anemia. The first few treatments were really tough because I was so ill. But after the second treatment my health turned around. I am a housekeeper by trade and I was able to maintain my clients after that, with the exception of the week I was in treatment through out the rest of the four months. I ate well, drank lots of water, used probiotics ( a must to help my body offset the effects of being on anti-biotics for so long). I was also given 12 injections of Neuprogen after each treatment. We used procit for 2 months but I did not need it after that. These injections kept my immune system from totally crashing. My last treatment was done mid July and today I can almost forget I have Cll. My immune system is recovering nicely and I have all my old energy back. I never gave up, never backed down. I was determined to not allow the disease or treatment take away my life. This info gives me great hope as my doctor is reluctant to set a time frame on my recovery. This is a great site, very informitive & supportive. My heart felt thanks to you Chaya
Thanks for another lucid report on a very important study. I appreciate your comment that physical condition is probably more important than chronological age. I had FCR at age 70 and seven years later I am still in remission. I had low platelets, an enlarged spleen, and very frequent infections, but it wasn’t a question of having to start treatment–I wanted to do it before things got worse or I picked some other health problems.
I do salute those patients who entered this trial knowing that they might not get the FCR treatment, a risk I didn’t have to take with the Phase 2 trial I was in.
Although some of my numbers are low (IGG’s) my immune system seems to be functioning pretty well.
There seems to be a lot of positive news for CLLers these days–and we need it!
Thanks for the informative info makes me feel better. I was treated with FCR back in 2002 in an early stage trial and thankfully have been symptom free through my last check up in Dec 2008 I am on a 2 year check up schedule at MD Anderson.
I have had several skin cancers during this period. The latest was Merkel Cell Carsonoma that I finished chemo for in August. It is my understanding MDA has current trials looking at immune system improvement and the effects of the poly something virus.
Thanks again, Chaya;
I was diagnosed with CLL 5 months ago and am (accordig to my “doc” at stage zero) presently WAW. Your ability to “un-obfuscate” the jargon is extremely helpful. Being a boat captain and being away from home for weeks ata a time, a sedinentary life style was the rule rather than the exception. Reading your postings have enlightened me and changed my “oh, well, what happens, happens” attitude. I realize that there ARE alternatives that I can do and not just sit and wait for a “miracle drug” to suddenly pop up and “blammo!, I’m well again”.
Keep up the wonderful work. You are truly an inspiration!!!
Chaya,
This is good news. A small but significant step forward.
When I was first diagnosed, I was diagnosed with an incurable cancer and soon discovered that nothing could be done to add a day to my life.
Now CLL can be cured, at least sometimes with a HSCT and this study tells us that time can be added to life with FCR. I hope this is just the beginning of the lid being lifted off this disease.
Nelson Mandela said: Many things seem impossible until they are done.
Control and a cure seem more possible.
Be well
Brian
Chaya,
Thank you for your very good and lucid articles; also for the main site. It has been one or maybe the only clear and unsentimental source of information about this malignancy. As Brian said, you get served an incurable cancer which does not seem to behave much differently in the long term with or without treatment; at last there seems to be something more than prayer which works in the long term.
I have “spoken” to your friend in GB and he seems likewise very frank. I can only say thank you, I am sure you also save some people’s sanity.
I felt so dishartened and so hopeless both because of lack of proper information and potential toxicity of all treatmments, that I have been wondering if it is worth even considering any. (am not ill at all, or at least not from the CLL) Maybe it might be worth reconsidering.
Love your sign-off; be well.
You surely are some aldy!
Thanks again; think your site should be compusory first line for information.
Mette
God Bless You Chaya!
Steve
southern California
Chaya –
Fantastic News, Fantastic Article, Fantastic Chaya-Review! For those who develop allergy to Rituxan – Do you know of any studies looking at substituting Azerra for Rituxan, either as “AFC” first time out of the box, or substituting it upon sensitivity to the Rituxan? How about using it in those patients who were suggested to use Campath post FCR, instead of the Campath (-for marrow suppressive reasons, long term infection, etc)?
Keep up the great work!
Michael
Hotdog59:
“AFC” – substituting Azerra (aka ofatumumab and Humax-CD20)in place of Rituxan in FCR)- in chemo naive patients is an ongoing clinical trial. And the pivotal trial that won Azerra FDA approval was as single agent in patients who were fludarabine refractory and inelgible for Campath due to bulky nodes. So, in a sense, both of the studies you talked about are ongoing studies. Great minds think alike.
Chaya,
Thank you for the updates. For people with cll, your site is first line information.
Stay well,
Monique
Wished I would have known PC, and had his strength.
Wow. Another great discussion. Thank you Chaya.
b.lee
I was recently introduced to your website and already have learned more from it than from many the other sites combined. Now I understand why my oncologist suggested FR instead of FCR. I got 4 rounds of the FR before becoming so neutopenic that I had to terminate further chemo…. that was in 2006 and I still remain in remission. I now think the FCR would have been too strong for me and that is why it was not used……am interested in the results of trials comparing PR / FR results versus Azerra (or any combination thereof) for when the CLL returns.
Thank you for all your thorough research and for keeping us in the CLL community up to date on new findings.You explain things in a sensible, pragmatic way and encourage feedback from those of us going through treatments, thus creating a real sense of community among your readers. Stay well and THANK YOU THANK YOU. THANK YOU
Paul
Chaya
Thank you for your wonderful work. I was diagnosed with CLL in July, 2005 as stage II. I was w&w until fall 2006 and had treatment with chlorumbacil and it worked for about one year. Then, large tumor load and falling red blood and platelet counts occured. My oncologist started me on FCR for 4 months of treatment. My wbc, neutrafils, and lymphocytes have now been good and stable for a year and a half. It is encouraging to read of folks with years of some degree of remission after FCR treatment.
Chaya, Thank you for this interestng and affirming article. I consistently read that treatment doesn’t equate to longer life, but I haven’t been able to buy that, because if that were true, my husband would already be gone.
He was diagnosed with very agressive, very advanced cll in December 2003. He had pneumonia and was hospitalized at the time of diagnosis. He took 6 cycles of FCR which was extremely hard for him because of his already weakened state because of the severe pneumonia in one lung; the other lung was full of infiltrates. But, the good news is, the FCR was successful, and held him for 18 months. He also has taken IVIG (with anti-nausea meds and steroids) every 4 weeks since the diagnosis, which has been a great asset for him.
After the FCR failed (or wore off, or whatever one would call it) he took 6 treatments of PCR at 80% which got him in good enough shape for a splenectomy in January 2007. He spleen was enormous (approximately 10x normal size, and he had an open splenectomy, not laproscopy) with a very experienced surgeon.
He is still in w & w, and feeling good. He was diagnosed with diabetes earlier this year, and the steroids that were included with his IVIG were discontinued. Everything seems to be working good in spite of that. I, unfortunately, had the swine flu and he didn’t catch it!!
He is at the end of the predicted cycle of being ‘held’ 2-3 years from the PCR and splenectomy, and his numbers are only creeping so we are hoping for a longer period before treatment is necessary again.
The bottom line is, he started off with a probable maximum life span of 18 months 6 years ago, and is still going strong. Even with advanced disease, don’t give up hope.
Dear Chaya,
I can’t thank you enough for your CLL Topics updates. I read them eagerly looking for information to help me, and others, as we try to decide what is the best treatment or not path.
Because of my age, 77, I am cautious about FCR which is the next treatment suggested for me. I wonder whether a milder treatment would be preferable. (I have had CLL for 17 years and have been treated four times. The first was CVP from which I had a twelve year remission, this was followed by 6 CVP plus R from which I had a partial remission. I then participated in two phase 1 clinical trials, both of which were terminated after two rounds. The first was AT 101 and the second was clofarabine, from which I required two blood transfusions and one platelet transfusion and eventually was hospitalized with a non-specific infection, probably some kind of pneumonia. After 8 months, Ihave pretty much recovered from this, but am facing treatment again in 3, 6 or 9 months. I wonder whether any fludarabine type med is appropriate for me.
Your last article on “Are patients living longer with FCR?” was most interesting for me, but am I too old. My own inclination is to watch and plan, as that seems to do the least damage at least for the present.
Loved seeing you on the Face Book! Thanks, thanks!
Murre
Chaya
I think your comment that PC could not control the hand he was dealt but he lived with grace and intelligence says it all. That is exactly how I feel. I can not control this hand I have either but I just have to deal with it and make the most out of it. Being an informed patient is so important. That is what you provide to all us of in the cyber world. Becoming informed about the best places to go for treatment, the best approach is important. I also thought your discussion at Niagra was very well done and I think hearing you speak and watching you was awesome.
To All,
My CLL was diagnosed at Mayo in Jan 2008 and we went into the ‘watch and wait’. By April 2009 I had an enlarged spleen and liver with the WBC doubling from last blood test and all the other negatives indicators. Went on the FCR treatment immediately with the standard 6 month regime. At #4 I was in NR(near remission) and after #6 in September in CR. Went thru the 6 sessions with no severe effects, however, stayed on my regular walk workouts of two miles at least 3 days a week and if strong enough 5 days a week. Had to give up weight workout, as just had no strength to lift.
So now in CR, working to get back to as what ever that ‘normal state’ is and live for the next 25 years. Will let you know if I make it.
I wrote about comparison of PCR versus FCR in an earlier article.
The way I see it, there is not much difference between fludarabine and pentostatin. Both are “purine analogs”, both use similar pathways in killing CLL cells. Some experts believe that pentostatin is “kinder and gentler” while other experts believe it also packs less oomph. This much I can say from my anecdotal database. Fludarabine is easier to tolerate than pentostatin, since pentostatin is a lot more likely to trigger nausea.
Fludarabine was ‘invented’ at M. D. Anderson. Pentostatin was likewise invented at Mayo. There is some amount of invented-here involved in MDA’s preference for FCR and Mayo’s preference for PCR. Scientists are human too.
It boils down to this, I think. PCR and FCR may be equally good. But we know a lot more about FCR than we know about PCR. Many more clinical trials and many more patients who have gone through FCR and much longer track record. Until and unless someone shows me unequivocally that PCR is superior to FCR (and no one has done that to date in my opinion) my bet would be on the combination that has been studied more thoroughly. Roads less traveled are not all that smart when it comes to chemotherapy choices.
Dear Chaya,
You asked a very interesting question:
“Does this mean patients will be better off pulling the trigger and opting for initiating FCR therapy, sooner rather than later?” and made it transparent with a simple example.
With regard to your conclusion: “It may be that there is real advantage to initiating FCR sooner, but this trial does not confirm that.” I would like to amend an additional aspect:
The treatment with FCR or each component of it can cause various severe adverse reactions, which we should include in our decision if a sooner therapy is more favorable than a later one.
Maxi
Thanks Chaya for your continuing support and help when it comes to knowing what’s available and how it can help CLL patients. My husband, after help and advice from you and his physicians,did FCR from Sept. of 08 to March of 09 and achieved a CR. He did have some tendon difficulties as a result of steriods during treatment but is now doing well. We hope for a long remission and think positively each and every day. We also remember that every day is a gift.
Thank you always,
Beth Havey
Hi Chaya
I would like to know more if possible about the IVIG…..my daughter in law was diagnosed with CLL in 2006, she is now 23 years old and has just been advised by her Hemathologist (Dr Peter Mulligan)that he is going to book her for 3 monthly sessions of IVIG due to her recurring chest and lung infections and her having to be constantly on antibiotics.
At this stage Dr Mulligan still likes her to be on the WW stage…..her white cell count is currently 117 but this higher count could also be due to the infection as normally the count is between 75 and 85….he did mention to her FCR when the need for treatment occurs…..and as at this stage the treatment is not covered by the PBS (here in Australia) we are hoping she won’t need to start treatment for another year or more….
I am a great believer of complementary alternative medicine and though I am aware that it will not “magically cure the CLL” I would like to explore the option of her having this as an extra complementary help on top of the “Western Medicine/treatment” do you think this to be worth exploring?…..would it interfere with her current IVIG (she is to start this treatment on the 1st December) any help, guidance you can provide will be very much appreciated.
Thank you in advance for all your help and also thank you for the great site which explains the medical “jargon” in plain english and in an understanding way for us “mere human”
Warm regards
Aurora Cartwright
Aurorama:
I am afraid I do not share your enthusiasm for “alternative medicine”. Whether it would interfere with IVIG or not depends on what alternative medicine she is on. Just because it is not “Western medicine” or because it is “herbal and natural” does not mean alternative medicine is guaranteed to be safe. Many herbs can be quite toxic when ingested in large quantities or in combination with each other. I advise caution, but it is obviously not my decision to make.
Aurorama:
Frequently you read recommendations for mistletoe therapies as complentary cancer-medicine. But especially for CLL mistletoe could be hazardous because of its immune system stimulation effects which would be fatal for CLL. At least in Germany hematologists say to CLL-patients: Hands off from mistletoe!
Aurora – we are also in Australia. My husband has been having FCR as an inpatient – he is just about to commence his third round(rather than travelling over an hour each day to and from the hospital) and as an inpatient it is covered by our private health cover. Why not look at those options if and when your daughter-in-law requires FCR.
Dear Chayka,
I am so grateful to finding this great site that allows us to understand the treatments available for CLL. My mother is 55 and was diagnosed with CLL. She lives in Europe and of course the drs told her she would get the FCR treatment. They are being very positive about my mom’s whole situation since she has a good health and at an early stage.She will start treatment in February and I have decided to go to Europe to be with her for few months during the chemo(6 month period). I will keep you updated and describe her overall results once she will start the FCR. The drs told her not to try hollistic cures because like you said it my interfere with her low immune system and not help her at all.
Thank you so much for your hard work and dedication!
Stephanie
Chaya,
My wife is about to go into her first treatments for her CLL. Her oncolgist is recommending RF, not FCR. Is FCR always a better choice, or are there advantages and disadvantages in adding the cyclophosphamide? Is it true that FCR may yield better results, but have higher toxicity than RF? Does the latest view by the experts recommend one strongly over the other?
Thanks so much for this wonderful site.
Bob
kb
chaya
Have had four rounds of FCR starting april 2009, it’s now End of summer, have have 10 blood transfusions, did bone marrow, cancer is still 50% in marrow, started treanda, had one treatment. what can I expect?
thanks
karen
Chaya,
Thank you so much for all you do! I was diagnosed in May of ’05. The disease remained very stable for over 4 years, but in the last 8 months my abs. lymphocytes have doubled to 78. All my reds are well within normal range; platelets at 144; neutrophils 4.3. I have no symptoms….no fatigue, node involvement, etc. Exercise and a healthy diet have been a priority. I am also Zap 70+ and unmutated. The clinic I go to is now on their 3rd CLL doctor, and the latest is right out of school. When your quality of life is not being impacted by the CLL, I’m finding it difficult to consider that treatment is imminent. I do plan on making an appointment with Dr. Kipps. With unmutated status, is it even prudent to think of anything less immune suppressive than FCR?
Chaya,
I have been reading your articles for the past eight years. I was diagnosed in 2001 and am still in W & W, so at age 70, I feel fortunate to have made it thus far w/o any treatment. In this article, as in others, you comment that “actual physical health matters more than your chronological age – another reason to get into shape while you are in W&W!” Would you amplify “get into shape?” I’m only slightly overweight (holiday enjoyments)and don’t smoke, walk my dog, have excellent blood pressure, take no meds, but I don’t do any strengthening exercises. Should I?
Bill139:
“Getting into shape” is a moving target. You are like me, you dont smoke, walk your dog and have good blood pressure. But perhaps you can step it up a little? You do not have to run marathons or become a body builder. But perhaps you can do a bit more aerobic exercise that improves your cardiac health? Please remember to check with your doctor before you start a new exercise program!
In addition to exercise it is also important to take care of other things such as good nutrition (plenty of fresh veggies and fruits, cold water fish such as tuna with lots of omega-3 oils, bare minimum junk food and no fad diets please!) good level of hydration (water is good at flushing out your kidneys) low stress, healthy patterns of sufficient resful sleep, taking care of routine stuff like prostate exams, watching out for sun damage.
All of these are things we know are good for us, whether or not we have CLL. Most of “getting into shape” is commonsense. Neither you nor I are looking to regain our lost youth, the aim here is to be active and healthy to the best of our abilities. Obviously the level of fitness that one can achieve depends on individual factors. Once again, the important thing is to use commonsense in setting your own targets.
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