Thursday, August 13, 2009

Is FCR Losing its Golden Luster?

It's not been too long ago that I, among many others, dubbed FCR (fludarabine, cyclophosphamide, and rituximab) as the 'gold standard' in treating CLL. The basis for that claim was the fading significance of chlorambucil (Leukeran) in treating CLL, at least in the United States. (It remains a popular drug in the UK and elsewhere.) Also, monotherapy with fludarabine has been linked to autoimmune hemolytic anemia (AIHA) a serious complication of CLL that is characterized by the development of antibodies to a patient's own red blood cells. Combination therapies such as FCR, which add other drugs to fludarabine, appear to be free of the risk of initiating and promoting AIHA.

The complete remission rates of FCR, reported primarily out of MD Anderson, are extremely impressive, and far exceed that of chlorambucil. For example, at the 2007 ASCO meeting (American Society of Clinical Oncologists, a major cancer group), MD Anderson reported on the long-term results of 300 patients who were treated with FCR at the institution. The group reported that 72% of patients enjoyed a Complete Remission, 11% obtained a nodular PR (PRn) & 12% ended up with a Partial Remission. Saving the calculation, that is a phenomenal over-all response rate of 95%. In spite of the immune suppression associated with the drug combination, infections were manageable with prophylactic antiviral, antifungal, and antibiotic drugs.

However, the long-term survival pattern showed no plateau, meaning that the rate of death did not level off at any point, meaning that most if not all patients would eventually fail FCR. Quoting the study: "Median Times to Progression (TTP) were 80 months for CR (n=216), 80 months for PRn (n=32) & 27 months for PR (n=36), with 77%, 65% and 28% projected to be progression-free at five years; projected 5 yr survival were 90%, 81% and 37% respectively."

These data are superior to single agent fludarabine, and fludarabine in combination with cyclophosphamide (FC) or mitoxantrone (FM).

The down side? Well, it is not a cure, nor does it appear to have that potential. There are some very long-term survivors, out 10 years or more. But based on projections, it is possible, if not likely, that most everyone will eventually relapse. And even in the case of those who have deep, long-term molecular remissions (data not available in the 2007 ASCO abstract, but has been reported to be about 32% in complete responders, meaning the over-all MR rate is about 24%) it is expected that they, too, will fall out of remission down the line.

So, what will replace FCR as the 'gold standard'? It must be noted that this is a moving target. For decades, chlorambucil was termed the gold standard, even though complete remission rates were only about 5-10%. Then single agent fludarabine took that exalted spot.

I think that the best initial treatment for CLL might very well be high-dose methylprednisolone plus rituximab (HDMP+R). I had a discussion with a couple of nurses at UC San Diego, where Dr. Kipps has a great deal of experience with the drug combination, and they said they just don't use FCR too much any more. Instead, they do a lot of HDMP+R. I have to admit that off-handed comments by several oncology nurses isn't definitive proof, but it is very interesting that, at least in one institution, FCR has seemingly fallen out of favor.

So what does HDMP+R have going for it? For one thing, it doesn't damage the bone marrow like fludarabine does. Fludarabine has a deserved reputation for enhancing the fatal rates of infection for up to two years. This is due primarily as a consequence of prolonged neutropenia. Grade 3/4 neutropenia were encountered in FCR. That makes the patient much more likely to have a serious illness, or even death.

First developed as a salvage regime for those patients with refractory CLL (and still used for this application), patients were given five cycles of the drug combination. It was not for the faint of heart. Numerous infections occurred and deaths were reported. The regime was tailored for a less-impacted crowd; as an initial treatment for CLL patients. The duration of the regime was shortened to three cycles.

A report in 'Leukemia' 2008 reported that in patients who were refractory to fludarabine and had adverse genetics, fully 93% of patients responded to the combination, and 36% had a complete remission. This compares favorably to the FCR regime. The paper states that median survival "has not been reached after a median follow up of 40 months."

There are also anecdotal reports that some patients who have completed HDMP+R have begun to normalize their immune system, as reported in a previous blog post here. That is simply astounding to me; I am unaware of this happy development in anything less than a stem cell transplant.

It also should be noted that adding a Campath 'chaser' to those who responded to the drugs, and did not develop bulky lymph nodes, may have enhanced responses.

Another development in CLL needs to be reported as well: 'FCR-lite'. This regime seems quite promising, with good results in spite of the reduction of the dose of fludarabine and cyclophosphamide, and an increase in the dose of rituximab. Reports are that the side effects are lessened compared with FCR, and the responses seem to be (at least initially) almost on par.

The paper states: "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."

It must be noted this trial was in untreated patients, most of whom had early stage CLL (only 16% had stage 3 or 4 CLL). (I'm not sure why a stage 1 CLL patient was even treated, but 40% were here.) That might be considered 'stacking the deck', and making comparisons with FCR and HDMP+R difficult if not impossible.

The bottom line: It may be premature to dethrone FCR as the gold standard, but recent advances in research suggest that we might need to rethink exactly who's on top in caring for CLL patients.


David Arenson said...

There are some differences between leading CLL doctors when it comes to defining the "Gold Standard," which is a phrase that really ought to be retired. The doctors at MDA believe in FCR; those at UCSD tend to want to avoid giving more mutragenic, toxic drugs when possible (not to say they haven't recommended FR or FCR in some cases, and not to say MDA always recommends FCR). When I saw Dr. John Byrd at OSU, he said different centers have different "styles" of when to treat and with what. (OSU often goes with FR, without the C). Then there is FCR Lite, as you pointed out. I believe CLL Topics ran a piece showing it had pretty much the same success rate as FCR. . . . R-HDMP, by the way, does not provide the length or depth of remission as FCR or FCR Lite . . . What it all comes down to on some level is patient preference, your comfort zone. This, of course, often has something to do with how aggressive one's disease is. And let's not forget that centers often have their own areas of research/(vested)interest when it comes to recommending a treatment. You get a Big Mac at McDonald's, you get R-HDMP at UCSD and FCR at MDA.

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Peggy said...

I'm new here, very interesting research. I am newly diagnosed CLL. stage one
Thanks for doing this work or all of us that don't know where to start!

Jay said...

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