Saturday, September 04, 2010

Update on FCR

There has been a great kerfuffle about FCR recently. I have to admit that I was very dubious about this drug combination when it first came out. It was extremely popular in America following its introduction by MD Anderson Cancer Canter (MDACC), and produced higher response rates than any previous regimen. However, MDACC doesn't do phase III randomized controlled trials so it wasn't clear whether FCR was the best thing since color television or whether there was special pleading going on.

Looking at the clinical trials it seemed to be the case that the entry criteria weren't particularly stringent, that patients were younger than normal and often of early stage. Moreover, because the patients were sometimes only seen once at MDACC, then the subsequent courses given by local physicians, the long term consequences of FCR were not particularly well documented.

I have long been wary of fludarabine. I was the one who first recognized the severe autoimmine hemolytic anemia it can trigger and our group was one of the first to recognize that rarely it can cause myelodysplastic syndrome. Indeed I wrote an article in Nature Clinical Oncology, a little while ago, which was entitled FCR: No Country for Old Men. This was in response to a summary paper from MDACC on their experience with FCR. I quote from my paper:

"A large, nonrandomized, phase II trial of FCR in patients with CLL was performed at the MD Anderson Cancer Center.6 In this trial, 300 patients were treated every 4 weeks for a planned total of 6 courses of FCR (rituximab 375–500 mg/m2 on day 1, fludarabine 25–30 mg/m2 daily, cyclophosphamide 250–300 mg/m2 daily on days 1 to 3 of each course and days 2 to 4 for the first course only). The patients were followed up for a median of 6 years, and the complete response rate was 72%—far higher than for previous treatments such as fludarabine plus cyclophosphamide
(35%)7 or fludarabine alone (29%). In CLL, a complete response according to the 1996 National Cancer Institute criteria9 allows for a bonemarrow lymphocytosis of 30%, which might represent considerable residual disease. Consequently, methods for the detection of minimal residual disease have been developed that use either flow
cytometry or polymerase chain reaction (PCR). Tam and colleagues used both techniques and found that 35% of patients were negative for residual disease."

"Although their PCR technique achieved the new international standard of detecting
one tumor cell in 10,000, other researchers have described and used flow cytometry
and PCR techniques that are 5–10 times more sensitive. Among patients with a partial response or better (n = 285) the median time to progression was 80 months, with a projected 60% progression-free survival at 6 years. Again, this result is
impressive but it must be seen in the context of the characteristics of the patients treated. Firstly, the patients in this study were relatively young; the median age was 57 years, and only 14% were aged 70 years or older, whereas in the general CLL population, 70 years is the median age of presentation. As a group, patients over the age of 70 years were significantly less likely to complete the optimum six cycles of therapy (46% versus 79%; P <0.001) and significantly less likely to achieve complete remission (P = 0.02). Secondly, most modern prognostic markers such as ZAP-70 expression, IGHV mutational status and fluorescence in situ hybridization were not studied in this trial. CD38 expression was assessed, but only 21% of patients had more than 30% of cells that expressed this marker. The corresponding
percentage of patients treated in our center is 64%."

"Lacking a contemporary comparator group, the main interest in this trial is the long-term safety profile of the FCR regimen. The actuarial risk of Richter syndrome was 2.5% at 6 years – no more than for historical series. Likewise, the actuarial risk of myelodysplastic syndrome was only 2.8% at 6 years. The well-established effect of fludarabine in depleting circulating T cells is certainly responsible for the 10% risk of serious or opportunistic infections during the first year of remission and 4% risk in the second year. Four of the five late deaths from infection, however, were caused by bacteria rather than fungi or viruses."

"The most unexpected toxicity was persistent cytopenia after completion of therapy, which continued for at least 3 months. This effect occurred in 19% of patients; however, following recovery of blood counts, recurrent late cytopenic episodes occurred in 28% of patients, predominantly in the first year of remission. The use of salvage therapy for patients with persistent cytopenias who relapse is particularly demanding, both for the patient and physician."

Despite my reticence there is now clear evidence that FCR is a superior regimen in CLL. This comes from the German CLL8 trial, which still has not been published in a peer reviewed journal, but was presented at ASH in December 2009. This is how I reported what it found:

The German CLL8 trial was a large one, involving 817 patients with CLL that needed treating. They were randomized to either FC or FCR in standard doses. The group receiving FCR had a higher response rate (95.1 vs 88.4%) and more complete remissions (44.1 vs 21.8%; p<0.001) and a longer progression-free survival 51.8 months v 32.8 months (p<0.001). We've seen this sort of result before, but do the patients live any longer? Note that the follow up is relatively short (median just over 3 years). The Overall Survival rate was 84.1% in the FCR arm versus 79.0 % in the FC arm (p=0.01).

They were able to do a multivariate analysis to look for what factors predict poorer survival. Several factors acted as independent prognostic factors for both progression-free survival and overall survival, including age, sex, FCR-treatment v FC treatment, receiving fewer or more than 3 cycles of treatment, response, 17p-deletion, serum levels of thymidine kinase and ß2-microglobulin, and mutational status of the IGVH genes.

Adding rituximab seems to lead to more neutropenia, but this does not lead to more infections. I presume that the neutrophils are consumed by the CD20/anti-CD20 immune complexes. In fact there were more deaths in the FC arm (86/396, 21.7% versus 65/404, 16.1%). Most commonly death was cause by progressive disease (FC 48/86, FCR 33/65), but there were also more deaths from secondary malignancies in the FC arm (13/86 v 5/65). Of course, in this age group there were also deaths from unrelated causes. Treatment related mortality was just 2.0% in each arm.

One strange finding was that the benefit of FCR did not reach statistical significance for stage C patients (Rai stages III and IV). Why this was so is not clear, but it might be due to the relative immaturity of the study or it may be that these patients, with a higher tumor load, need more intensive treatment. Since platelets falling to below 100 or HB falling below 10 are indications for treatment, perhaps a higher threshold for starting treatment should be adopted.

To summarize: FCR is the only regimen that has been shown to lengthen life over what was previously believed to be the gold standard treatment. However, there are other acceptable treatments that have never been compared head-to-head with FCR. These include FR, FCR-lite, Bendamustine-rituximab and PCR. It is not known whether substituting ofatumumab for rituximab would be an improvement.

It is clear that FCR is too toxic for some patients, and in the UK the combination of chlorambucil and rituximab has recently been shown to be very well tolerated with a high response rate.


Anonymous said...

Do you have a reference for the UK chlorambucil and rituximab study you mentioned?

Anonymous said...

Dr. Hamblin,
Thank you for this overview. In the UK, you've mentioned Chlorambucil and Rituxan showing positive results. Are you using 70 mg/sq m per month, or some weeks on and some weeks off? Is Rituxan once per week or once per month? Lastly, is this a 6 month protocol, or until disease progression? Thanks for your comments.

Terry Hamblin said...

Yes. Hillmen et al BJH 2010; 149: Supplement 1 page 2. These are abstracts of the British Societ for Haematology earlier this year.

The overall response rate was 84% compared to 67% for chlorambucil alone in LRF CLL4. The median age was much higher than in comparable trials.

Terry Hamblin said...

Chlorambucil was given 10mg/sq m/day days 1-7 every 28 days for 6 cycles. Rituximab was the same as in FCR. 52% were stage C.

This is an interim analysis of the first 50 patients of a projected 100.

Anonymous said...

Thanks Terry, a really interesting article.

For someone in the UK would chlorambucil and rituximab be an easier treatment option to complete compared with FCR ? (i.e. more chance of being able to complete treatment with fewer side effects and collateral damage) Thank you.

Terry Hamblin said...

Yes. I have been recommending Chlor + R as an alternative, though outside a clinical trial it would be difficult to get the rituximab on the NHS, except as FCR.

Anonymous said...

FCR is associated with Richter's transformation and myelodysplastic syndrome. Both of these secondary cancers carry grim prognoses.

Dr. Kipps is 'moving away' from FCR. He offers a number of other options.

Dr. Furman has recently authored a paper in which he convincingly argues against striving for a 'deep' remission, since all patients fall out of that remission at some point, and then they are in a very bad place indeed.

FR or rituximab+revlimid or another type of treatment seems to be much, much better alternatives.

As a victim of FCR, I'd urge most everyone to avoid the regime. Perhaps it's of some use as a last resort before a transplant.

Terry Hamblin said...


What you say may be true, but it still remains to be the fact that no regimen has been shown to cause patients to live as long as FCR does. It may be that patients having FCR will die of MDS or Richters, though there is no evidence that they do so more commonly than with other treatments, but the evidence is that they still live longer.

Anonymous said...

How is the quality of a persons like measured for any treatment ?
Although FCR may prolong a persons life does it prolong or lessen their suffering overall ?

Terry Hamblin said...

There is some early information on this point. At last year's ASH Barbara Eichorst reported the following: "A comparison of the two treatment arms at interim or final staging after 3 and 6 months respectively showed no significant difference between both arms with regards to the global health status, functional scales and symptom scales. Dyspnoea was scored significantly higher during FC treatment in comparison to FCR (23 versus 18; P = 0.023). At 12, 24 and 36 months of FU no significant difference between FC and FCR in all functional scales, symptom scales, single item and global health status was found. Both treatment arms showed slight improvement (defined as difference of 5-10 points) of global health status at 12 months FU in comparison to baseline (FC: 62 at baseline vs 68 at FU 12; FCR: 62 vs 70).

Most quality of life studies have shown improved quality of life for patients in remission compared to patients not in remission.

The problem with all these studies is that what is fine for the majority may be disastrous for the unlucky minority. If you are one of those who develops MDS or Richter's syndrome, you cannot know whether it is due to teh fact that you had CLL or whether it was because you wee treated with FCR. The question then is do the benefits for the majority outweigh the harm to the minority. With any treatment there are always winners and losers. The aim is to have far more winners than losers. Or to be able to predict ahead of time who teh losers will be (like those with del 17p for example).

Burke said...

I keep reading that FCR is not good for older people, but I had 70% marrow involvement, a massive spleen, pancytopenias and underwent FCR at age 65. I got a MRD neg response according to four (or six) color Flow despite having only 4 cycles and slightly reduced F. Plus, I had another B Cell disorder, probably SMZL, that disappeared after the 3rd cycle according to a BMBX.

My treatment ended over 3 years ago, and I've had no problems except diarrhea for a couple of weeks not long after I finished treatment. My doc is thrilled.

I'm hoping that my remission lasts long enough for another treatment to come along that will work better as salvage than FCR. Would you be willing to hazard a guess as to what that treatment could most likely be?

Terry Hamblin said...

All these comments about the utility of FCR and its toxicity are generalisations No-one can predict how an individual will react, but it is possible to get a feeling from the overall figures. That feeling will sometimes be wrong.

The next salvage treatment? Lots of candidates, but I guess that treatment will be tailor-made according to what genetic lesions are present.

Anonymous said...

I'd like to comment on your statement that "no treatment has shown has been shown to cause patients to live as long as FCR does."

A couple of things: FCR has been around a relatively long time. Rituximab was approved in 1997, and it was used in CLL early in its history.

That means that comparing FCR to another regime that hasn't been around as long is impossible. Let's say they discover a cure for CLL tomorrow, and it goes into clinical trials in two years. Even after five or six years after that, because the treatment wasn't around as long as FCR, you'd still be able to say that this mythical cure "hasn't been shown to cause patients to live as long as FCR does."

The other thing to think about is by using a series of more benign treatments, you may well exceed FCR. Dr. Kipps in my opinion does this. He started me off with high-dose methylprednisolone plus rituximab, helped get me into the ISF-35 trial, then the mistake with FCR, and finally flavopiridol.

I firmly believe that if I had avoided FCR like the plague that it is, I'd still be stuck with CLL, but I'd now be ready for re-treatment with flavopiridol (maybe as a maintenance drug) or perhaps CAL-101 or ABT-263). Eventually, I suppose I'd run out of options, but I'd still be healthier for a stem cell transplant.

As far as the stats you look at, I learned from you a long time ago, you treat the patient, not the numbers. I know that's in a different sense, but I think there is validity when trying to fit statistics of the many to the treatment plan of the one.

Terry Hamblin said...

Several things in response. The only valid comparisons are randomized controlled trials. All other trials are unsound because they are biased by other changes in treatment over time, by the inadvertant selection of better or worse cases, by inappropriate dosing, by inter-center variation, by inadequate case selection or monitoring, by manufacturer wishful thinking and many other factors. So far only one treatment has been shown to make patients live longer than any other treatment andthat is FCR over FC given first line.

That does not mean that High dose steroids + rituximab as first line is not a better approach, just that there are no data to support it.

Before the German CLL8 data were out, I thought as you did, that it was alwways better to satrt on something less toxic and build up to more toxic drugs.

You said, ""Even after five or six years after that, because the treatment wasn't around as long as FCR, you'd still be able to say that this mythical cure "hasn't been shown to cause patients to live as long as FCR does.""

This is not true, because the survival curves would diverge, even if the follow up were short.

Flavopiridol is still chemotherapy, and my experience with it is that it can be quite toxic. Getting the schedule right has proved very difficult.

Obviously not every regimen is going to suit everybody, and MDS and Richters are both slightly commoner in patients who have had F or FC, though I have seen both in patients who had had no treatment at all.

CAL101 and ABT-263 are both promising agents but the data are too immature to pass judgement on.

I agree that treating the individual patient is ideal, but guidance comes from experience and data. My daughter has just started practising as a haematologist/oncologist. She rings me up almost every night with a litany of impossible cases. I am able to offer some advice. She knows the literature but she hasn't had the 35 years of preactical experience that I have. Nuances are all.

Anonymous said...

Dr. Hamblin:

Thank you for the article. I have CLL with low WBC(2.0). My new onc. said I have to chemo and recommended FR vs FCR. I have been seen 3 differents onc. for last year and half and all three said I should be treated with FCR. My onc. concern about toxicity of FCR because of low WBC. She recommended that because of risk of infection , she does first cycle with FR and remaining of the cycles with FCR.
Afetr reading some article, it is look like that the F is more toxic than the R.
Would you let me know your though about her recomendation and how could I prevent infection or can I use any medication to increase WBC before the chemo?

Your advise will be appreciated.


Terry Hamblin said...

For FCR some of the F is substituted by C compared to FR. This should make it less lymphotoxic and slightly more marrow toxic. There have been no head-to-head comparisons so nobody knows the truth. Cyclophosphamide has its own side effects, but we have no way of kowing whether it adds or subtracts from general toxicity. R alone has some activity, but more when combined with chemotherapy. FCRlite reduces the chemo dose but increases the R dose. I don't think it is so effective.

Why do you have a low WBC? Is it lymphocytes - all in nodes, spleen, marrow? Is it neutropenia? if so why? The remedy depends on the cause.

Sandra said...

Dear Terry
I am new to all this. My husband aged 46 was diagnosed a year ago with CLL. After a fairly stable eight months his white blood counting is increasing quite fast and the possibility is he will start treatment during the second half of this year. We are at the Marsden. We have been told FCR is the gold standard treatment and I have read the German phase lll study. We have been told he is young enough to cope with the six months of treatment and they want to try and achieve MRD and a long remission. I asked what happens afterwards and they were vague.
We have heard nothing of MRD and Richters being more common with FCR treatment and no one has mentioned the possibility of having FR instead. I had a second opinion at Barts and again FCR was the recommended treatment.
My husband has 11q deletion but I understood from the German results that 11q responds well to FCR. Can you advise?

Terry Hamblin said...

Despite an increased risk of MDS in patients having F and C together, and of Richters in anybody having fludarabine, FCR gives the best chance of a long survival, especially in those with del 11q. So I agree with Dr Dearden and Prof Gribben if that is who you saw. FCR is definitely indicated. As to what happens after relapse, things are moving too fast to know. In a year of two we should have the enzyme inhibitors but some patients will be candidates for transplant and possible cure. There are other drugs like acadesine in the pipeline that might also be beneficial.

Sandra said...

Thanks. We saw Estella Matutes and Samir Agrawal at Barts. I've talked to people having FCR who say the treatment is not as bad as they thought and they continued working throughout. Fingers crossed that's our experience. Thanks for your advice