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).
(www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=36113)

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.
(http://tinyurl.com/lgxy3q)


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."
(http://tinyurl.com/m9ropo)

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.
(www.geocities.com/m_mcghan/ourpage.html?20066)


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."
(www.jco.ascopubs.org/cgi/content/abstract/27/4/498)
(www.medicalnewstoday.com/articles/138141.php)

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.

Rumors in CLL Treatments

I had an interesting discussion with a CLL researcher who said that there have been some indications of a reconstitution of a patient's immune system after successful treatment.

This is big news. Of course, I don't know (and I don't think the researchers know) if this will hold up, or if the trend towards a revamped immune system will continue to total normalcy. However, as we've been often told, even in molecular remissions, the native immune system remains disrupted. This may not be the complete truth.

My feeling was from what he said was that this is in a minority of patients. But I think the true import of this development is that there may finally be some light at the end of the tunnel. I hope enough of a trend continues that a paper will be written that discusses these developments (if they remain developments) more completely. I look forward to the day!

Since infections kill most CLL patients, having a full-functioning immune system would be big news indeed.

Since this was an off-handed comment, I just don't know the particulars. However, I hope this does hold up. Certainly, this is another indication that research is extending lives. Is this an indication that, caught early enough, and treated properly with powerful, dangerous, but effective drugs, a cure might be possible?

Biggest Bang for the Donated Buck?

Check this out!

http://www.bcrfund.org/howtohelp.html

Yes, a generous donor has made a challenge grant to the Blood Cancer Research Fund (yes, for CLL). So for every dollar you donate, another dollar comes from this fund and goes right to work!

Apparently this has been going on for a year, but I just read about it a few weeks ago, and haven't had time to post on it.

Seriously, folks, now is the time!

Please, rare reader, think about making a donation to Dr. Kipps and the hard-working team in CLL. I have heard from many others that cutting edge research is coming from the mind of Dr. Kipps and other talented people, all of whom depend on funding to further understand CLL.

I know times are tight, but as the article says, just $10 per month for the next year would match this grant.

(I'm not neglecting other funds myself, and I am not saying don't contribute to CLL research groups. I think right now, by doubling our donations, this is a very effective way of making our contribution go as far as possible.)

Think about it.

Addendum to "When to Treat"

It did dawn on me that for those who are 11q or especially 17p deleted at diagnosis might not have a watch and wait period, but might be given treatment shortly thereafter. Therefore, there is no trend to watch before the first treatment, but there may be a trend to watch before second treatment (if it is necessary).

There are other indications for treatment as well. I must confess that I am basing my recommendation on my own experience and what I believe to be accurate. It is based also on the experiences of others and conversations I've had with people, those with a medical background and those who are just careful researchers, as well.

I confess I don't know if a reputable oncologist would initiate a watch and wait patient simply on the basis of reported increase in fatigue. Or with bothersome night sweats. Or on the basis of Rai/Binet stage alone.

I suppose I should really say that it is my opinion that if one is tracking one's absolute lymphocyte counts, and they make a radical change north (as mine did), it's a sign things are changing. People I respect have concurred with me. But, as I've said, this is not a complete picture. Perhaps it's only good for a subset of CLL patients. (But remember that night sweats and other 'B' symptoms aren't always related to CLL. Other diseases or even coming off drugs for pain can lead to this problem. Or, I understand, even menopause?)

When should I start treatment?

If this isn't the most important question the newly-diagnosed CLL patient needs to ask, it's in the top five. And it's for these reasons:

1. The first treatment is most likely to give the patient the longest and best response to treatment.

2. The CLL cells haven't been exposed to any treatment, and thus generally consist of nice, 'squishy', easy-to-kill CLL cells. None of your cells have been through 'chemo boot camp', thus aren't toughened up by 'combat'.

3. The patient generally is in as good of shape as he ever will be.

4. The choices for treatment are wide-open (all things considered). The oncologist can generally offer many different treatment modalities.

So, how can the patient decide when he needs treatment? Well, I suppose the simple answer is that he can't, at least by himself. He needs to do so with the assistance and the guidance of his oncologist.

At this point, let me make it clear that my perspective comes not from a medical background, but from that of a patient who has survived over 10 years with CLL, and, more importantly, have researched the topic in some depth.

There are two proven guides to when treatment might be necessary. One is the stage of your CLL (stage 0=1 is unlikely to need treatment, but it may). The second, and over-riding one to me, is the doubling time of the Absolute Lymphocyte Count (ALC). (The count is easy to derive: take the total white blood count, and multiply by the percentage of that count that are lymphocytes. In other words, if your WBC is 100, and your percentage that are lymphocytes are 90%, then the ABC is 90,000.)

You've probably seen a number of sites and posts which offer the ability to enter in data which will then produce a graph. Excel is spreadsheet which allows one to chart blood numbers, there are others as well.

Starting with the blood counts taken at diagnosis, I recommend creating a spreadsheet and entering at least two data sets: the absolute lymphocyte count and the day the blood was taken.

I've worked with a spreadsheet from scratch, but you don't have to do that. You can download a spreadsheet ready to enter your blood numbers from CLL Topics: www.clltopics.org/YourCharts.htm .

Once you have developed a worksheet, you can add to it with each blood test. Let's assume you have fairly stable absolute lymphocyte count (other data such as the total white blood count won't work). This is typical in early CLL. Plot each value, and pay attention to the trend. To make the trend more clear, create a chart using time as the x-axis and the ALC as the y-axis.

One tried and true indication that treatment might be in order is when the absolute lymphocyte count (ALC) shows a pattern that will result in the number doubling in less than one year. (Check with your oncologist to see if this is how he views treatment decisions.)

Once you start plotting data, thing those of you are going to need treatment will see an obvious jump in ALC. The trend must hold for some period of time, or over several tests.

It is at this point that something has changed in your CLL. Perhaps you have picked up a change that causes your CLL to start proliferating at a higher rate. Perhaps for some reason your CLL cells are not dying at the same rate they were previously.

In any case, I personally think this may mark the best time to hit your CLL.

The other indicator that treatment might be considered is your stage. If you are diagnosed with a stage IV CLL, you probably have noticeable illness in terms of a low platelet and/or hemaglobin number. I'd still chart out your ALC and share with the doc to see if the disease is making a move.

Barriers to Clinical Trials-the CT scan

I'm not going to write a book as I did on my last post!

Suffice it to say, some of the barriers to entry of clinical trials are listed on the last post.

I want discuss one real barrier to clinical trial entry that is easily remedied. That is the demand that participants undergo multiple CT scans to track progress (if any) in the trial.

Why is there a barrier? CT scans involve high levels of radiation, and they have definitely been linked to subsequent cancers.

The risk is low, the authorities say. But any increase in cancer risk sort of defeats the search for a cure for CLL, doesn't it? It certainly makes no sense when there is an excellent alternative: MRIs.

Clinical trials are done to look for results. The ultimate hope is a cure, because the drug in tests would be a huge success! Most likely, a more modest goal is envisioned: better results than current drugs.

Determining whether a drug is better than the standard treatment is surprisingly difficult. Drug companies can't wait around for 20 years to see if patients continue to do well (i.e. survive). Instead, they look for 'end points'. These generally include signs of tumor shrinkage or elimination. That is the reason drug companies want to check your nodes. The way most doctors are used to doing this is ordering a CT scan.

Yet we've seen the danger to the patient is real. Given a choice between a trial using an MRI and one demanding multiple CT scans, most people who are aware of the dangers of CT scans will pick the safer one, in other words, the one allowing the use of MRIs.

Why do drug companies deliberately rig their trials so people are less likely to sign up? It's a mystery, with perhaps a partial solution. Several of the drug companies I've talked to are aware of the concerns on the part of patients, and know that an MRI can track lymph node size just as well (or better) than CT scans.

Well, who then is the moving force behind this unfortunate situation? The drug companies blame the CLL researchers themselves! It is the research community that apparently doesn't care about patient safety to the point that they will allow safe alternatives to dangerous radiation exposure to patients.

I've discussed this with a few researchers in light of these claims. Rumor has it that there is a group of CLL researchers who are (pardon the expression) really anal about scans. The Germans.

I suppose we who are not German can recall the reputation the Germans have for meticulous record-keeping and administration. It apparently extends to CLL clinical trials.

Who ever is to blame, it's time the patient community help end the danger. Some of us need clinical trials if we are going to stay alive. We are sacrificing our bodies to advance science. It is incumbent upon researchers to watch out for our health. We are helping them (and the drug companies) when we sign up for a trial. They need to help us avoid doing more damage to our bodies than the investigational drug might cause.

Should you enroll in a clinical trial?

Clinical trials are big business in the United States; indeed, around the world. One group estimates there are 40,000 clinical trials on-going at the present time in the US. Virtually any drug that seeks FDA approval must go through the clinical trial process. This includes already-approved drugs that seek approval for another use; an example of this is our old friend Rituxan, the first monoclonal antibody approved in the US. It is used frequently for CLL, but it was never approved for such a use; instead, it was approved in 1997 for non-Hodgkin's lymphoma. It is undergoing tests now for approval for use in CLL; that's important because any health care 'reform' will limit drug use. It may even make it illegal for Rituxan, or any other drug, to be used off-label.

Any clinical trial needs two things: a new drug or device, and bodies to test them. Cancer, as one can imagine, is chock-full of new drug applications, and clinical trials. Go to the excellent site for the government's clearinghouse for clinical trials (clinicaltrials.gov), and you'll find about (about because it changes every day or so) 23,000 trials in the US and overseas that involve some aspect of cancer.

Some trials seem almost silly. There are, for example, a number of trials examining the value of music to soothe the savage cancer patient's breast. There are some that seek to find the value that art has in calming dying cancer patients.

Mostly, however, clinical trials seek to ascertain the dangers and values of drugs in fighting advanced cancer. (There are some trials, of course, looking at treating patients early in the disease; CLL is a particular hotbed of such studies, since previous research has not uncovered a value in starting treatment early, as opposed as to when it is most definitely needed.

Search clinicaltrials.gov for CLL trials and (as of this moment) 1209 trials show up. The site seems to list trials that only mention CLL in passing; there are far fewer trials that have CLL as the main focus of study. There are probably fewer than 200 that are of serious interest to the CLL patient.

So, should you enroll in a clinical trial? That is a tough question, but, over-all, I'd recommend you seriously consider it. Why? Because every effective drug for CLL has gone through the clinical trial process, and you'd have first (or second, or third) crack at it. When you have run out of options, that is not a small factor.

(There is also the altruistic nature of trials as well. By joining, you will help future CLL patients have access to proven drugs. But studies have shown that most participant hope to have some benefit as well).

Let's say you've decided to at least look at clinical trials. Are they all created equally? No, of course not. Unless Bach or Picasso really rocks you, you might just say no to music and art clinical trials. You are not going to get cured by such a trial. But what should you look at?

I'll give you my thoughts on the subject, but remember that I'm 'only' a CLL patient, one who has (thank the Lord) outlived his projected lifespan by a number of years, and who is hanging in there as I write.

First of all, you have to decide what drug to look at. This takes research, even if it is just talking to your oncologist. I relied on a CLL expert to guide me in my choice of clinical trials, up to a point. I must admit that, while I am an expert on my own body and how I feel, the CLL expert has seen hundreds of cases, and is more of an expert on how my disease will, in general, progress.

I thought long and hard about my first trial I undertook in 2006. I researched everything the CLL doc told me were my options (and the field is pretty wide open when you are untreated). Yes, I was drowning in green tea back then, but I was still progressing, so my doc and I agreed that I needed something stronger to knock the CLL back.

I also looked at the trials his institution offered. I asked about each of them. I then searched on the top five or six that seemed as though they might be good for me. I printed out study after study, and, using a highlighter, I marked the response rate, the side effects, the burden of treatment (would I have to stay in the hospital) and so on. I then went to clinicaltrials.gov and looked at everything that seemed familiar, and a few that didn't. I had been tracking and thinking about clinical trials since I had been diagnosed some eight years before, so I wasn't unfamiliar to the terrain.

Next, I needed to make a decision about what phase trial to look into. A refresher: a phase one trial is a dosing safety trial, meaning they ramp up the drug until unacceptable toxicities are found. A phase two trial is an efficacy trial, that is, does the drug show any activity in the disease. The phase three trial compares the new drug with the standard treatment. (Placebos are never used now in lieu of treatment; it is considered unethical to withhold at a minimum the 'gold standard' treatment, though that hasn't always been the case, in the old, bad days.)

The problem with phase one trials is poetically described in another way to look at these trials: First-in-Man trials. (Many drugs have been used elsewhere, but the name tells a lot.) The phase one trial is given over a range. The first patient usually gets a dose that is far too small to do anything at all. The subsequent patients are given higher and higher doses, until bad things start popping up. Pre-clinical trials give a hint of activity in humans, since they use human cells in culture, as well as the ubiquitous mouse and rat studies.

I have undergone a phase one trial, but I try to avoid them for the reasons outlined above. If you press the trial coordinator, he or she will generally tell you what the other patients in the phase one trial have experienced. But that isn't a foolproof guide. In my phase one trial, the trial coordinator told me to expect flu-like symptoms. (This is such a common description of side effects, it's a little like telling a diner that mongoose or arctic wombat 'tastes like chicken'.) To say I had 'flu-like symptoms' was something like saying the Titanic had a little problem with an iceberg.

I puked my guts out! It was horrible. Yes, I experienced projectile vomit! It was even green, something like the Exorcist (I had a huge helping of spinach quiche the night before.) I've never had such a terrible flu, or if I had, I've blocked it from my memory to protect me from insanity. (Because of my, and others, experience, they now give anti-emetics, or drugs to quell nausea. Thanks, guys, what took you so long?

I prefer the phase two trial. Generally, in a phase two trial you are guaranteed to get the drug (not so in the phase three trial, which is, after all, a comparison trial). The maximum tolerated dose has been established. Anti-nausea drugs have been prescribed. Dosing schedules may been worked out, more or less. Results have been published on the experiences of the first trial (yes, my experience is now part of the record...). You have a better idea of the risks and benefits of the trial.

The phase three trial, as I mentioned above, has the huge disadvantage of not giving the investigational drug to all comers. This is very important in a serious and fatal cancer such as CLL. Why, you could get the standard treatment without going through the qualification process, all of the scanning, all of the prep work, and so on. Some trials do try to 'sweeten the pot' by offering the new drug to 2/3 of participants, instead of a 50/50 split. This is much better for the patient, but this isn't a common practice, for some reason. The best option of all is to give the drug to everyone, and compare their results with historical controls. Hardly any researcher likes this option, which is too bad for the patient community.

My next post will deal with the very real barriers to patient's signing up for trials. It seems to me that not enough researchers are concerned with how we feel about the clinical trial process.