Sunday, October 10, 2010

If pigs could fly, we'd all choose the perfect treatment

There was an interesting exchange in the comments section of Dr. Terry Hamblin’s recent blog post The ultimate FCR advice

The post concerns a pivotal study of 817 patients by the German CLL Study Group. The investigators conclude that there is a survival advantage for most patients who use FCR as frontline therapy and that FCR can change the natural course of chronic lymphocytic leukemia.

The respected study shows that FCR is more effective than FC, meaning that the addition of rituximab is essential to getting the best results. 

The exception to the “FCR is golden” rule is those patients with dysfunctional TP53 pathways, including those with the 17p deletion. FCR needs a functional cell-kill pathway to work, and giving FCR to these high-risk patients is so counterproductive that, Dr. Hamblin indicates, it crosses the line into criminal incompetence.

Of particular interest to my 11q-deleted self is that the our group responded well to FCR. Says Dr. Hamblin: “It is important to recognize that the del 11q patients now fall into this intermediate group. CLL8 has removed indecision as to whether they should be intermediate or high risk. If they are getting FCR they are at intermediate risk.”

All of these are big bullet points in the world of CLL.

After reading Dr. Hamblin’s analysis of the study, one reader was still not convinced that FCR is a good way to go and left this comment:

“Unlike Dr. Hamblin, I don't think FCR should be used as a first-line therapy. Why? Because when the patient relapses (and he will relapse), he will be in a precarious situation indeed. Fludarabine-refractory disease means that the patient has a poor prognosis.

 “My opinion is that there are many treatments now available that are more benign than FCR. These include HDMP+Rituximab, Revlimid+R, flavopiridol, EGCG and others. Clinical trials using such agents as CAL-101, ABT-263, Perixifor+R and others could be considered as well.

“When you use FCR, you shoot the whole wad. Why not try something less toxic to start?”

(I don’t want to get sidetracked here, but except for Rituxan, steroids, and perhaps Revlimid, most of the treatments mentioned above are not feasible for most patients, few of whom have access to clinical trials. EGCG is not a reasonable alternative as it doesn’t appear to do much except in the most indolent of cases.)

Here’s Dr. Hamblin’s reply:

“None of the treatments you mention has ever been compared to FCR so you are asking people to buy a pig in a poke.

“It is true that we don't yet know where to go after FCR, but that is the time for all your experimental treatments.

“I'd rather buy my pig in a poke after I'd been eating roast turkey for 10 years.”

The first thing that ran through my mind is this: It wasn’t that long ago that FCR was the pig in the poke.

* * *

I was diagnosed in 2003, seven years and one month ago. At the time, all I knew is that I was CD38 negative, a good prognostic sign. None of today’s other important prognostic tests -– IgVH mutational status, ZAP-70, FISH -– were available to me. Our CLL researchers were still examining those pigs.

MD Anderson was just starting to report good news about FCR, albeit based on retrospective studies that came in for some criticism. People were intrigued by the results but a little wary of MDA’s pig farming techniques. The German Study confirms that MDA was basically right, even if some of the I’s weren’t dotted and some of the T’s weren’t crossed.

The idea of risk-adapted therapy in CLL was just gaining a foothold. It may be hard for today’s new patients to believe, but most doctors used to make treatment decisions in the dark. They assumed all CLL cases were basically the same,  and pretty much treated everyone with the same thing (chlorambucil, and later fludarabine).  
Clinical symptoms were used to decide when treatment should begin, which is the one thing that has not changed, nor should it. A recent editorial in haematologica includes this comment:

“In spite of this clinically relevant risk hierarchy, the decision to treat is currently not based on the risk profile but on symptomatic disease.  This is important and further supported by the observation that in some subgroups of patients, such as those with 17p deletion (and mutated IGHV), the disease may have an indolent course.”

In other words, we know a lot more thanks to prognostic tests, but the most reliable bottom line resides with symptoms such as swollen nodes, dropping hemoglobin, dropping platelets, frequent infections, and lymphocyte doubling time. Assumptions -- such as “all 11q patients are high risk” or “all 17p patients are screwed” –- may not always be correct. With CLL, the learning curve goes on well into the horizon. The more we know, the more we realize we don’t know.

* * *

So, back in the Dark Ages, I was faced with a decision: FCR or single-agent Rituxan?

My disease looked more like an indolent thing that had finally started getting out of control than it did a goose-stepping disaster. After I was diagnosed, I recalled my last CBC –- from 1996 -– and began to suspect that I had CLL back then. The results showed my lymphocyte count to be a little high, which was chalked up by my doctor at the time to me having an infection, even though I didn’t feel sick.

In 2004, when I got my first FISH result, it gave some credence to the relatively-indolent theory. My result was “normal,” meaning whatever chromosomal damage I had was not on the test. I was not 17p-deleted, nor 11-q deleted.

But because of clinical synptoms –- swollen spleen and nodes and a high lymphocyte count –- the doctors I was seeing seemed to agree that I needed some sort of treatment. Two years later, CLL expert Dr. John Byrd told me I probably could have waited awhile longer, and in retrospect I think he was right. (This is why I suggest all new patients see a CLL expert doctor or two before deciding when and how to treat.)  But at the time I was living in the universe of knowledge that I was living in. 

Do I chose the pig in the poke? Or the other pig in the poke?

FCR struck me as overkill given what I knew about my disease. It was also fraught with questions about side effects and after effects. These weren’t so evident in the early days, and we have learned a lot since: FCR can severely weaken the already weakened immune system, giving rise to a host of problems. Viral reactivation can lead to Richter’s Transformation. Potentially fatal pulmonary problems can develop. Myelosuppression can be severe. Autoimmune hemolytic anemia (AIHA) can result. And so on. FCR has a bit of a Russian Roulette aspect, assuming your gun has about 30 chambers.

The other pig was single-agent Rituxan, also new and virtually untested as a treatment concept. The remission wouldn’t be as good or as long, but the side effects and risks were much more benign. Since it was a soft-glove treatment, it seemed reasonable to start it sooner rather than later, when the disease would be even more out of control.

So that’s the way I went. I responded pretty well for a couple of years, during which I also learned that my disease was worse than I had thought: I tested positive for 11q, I was IgVH unmutated, I was ZAP-70 positive.

* * *

Dr. Byrd also told me that CLL is a long journey, and that the nature of that journey is profoundly influenced by your first treatment.

If I could go back to 2003, armed with the results of the prognostic tests that I have had since, as well as the results of the German Study and other clinical trials conducted since,  would I have chosen FCR?

Probably. Given the full scope of my prognostic markers, the argument in favor certainly would have been stronger. And the weakness that single-agent Rituxan has demonstrated in most patients over the long haul would have made that option less attractive.

Knowing that FCR would be my first treatment, and having had the sense to see Dr. Byrd at the outset, I might have been able to wait another year, perhaps even two, before undertaking it. Judging by the way I first responded to single-agent Rituxan, I probably would have gotten a CR, and the remission probably would have lasted a good three to five years but no longer. We know that unmutated folk like myself relapse faster. That card was dealt when the CLL was born.

Would my FCR experience have been uneventful, giving me years of “worry-free” living? Or would I have not dodged all the bullets that come with firing that big gun?

I have enjoyed relatively good quality of life along the path that I did choose, with the exception of coming down with AIHA in 2007. Might FCR have spared me that? Or might it have caused it to happen, as it recently did to a fellow patient I know?

Might the 11q have been avoided? Or might 17p have resulted from FCR’s selection of CLL clones with dysfunctional TP53 pathways?

Assuming all had gone well, I’d likely be in relapse now, on my second treatment, perhaps even a third. Ironically, I might be on Revlimid to keep the disease in check, which is exactly where I am.

Either path would have led me to the same place, namely the likelihood of needing a stem cell transplant to survive in the long term.

Either path is likely to have prolonged my life. The German Study cannot answer long-term survival questions: How many FCR patients will be alive after, say, 10 years, compared to others? A study in the 1990s showed that single-agent fludarabine led to longer remissions than chlorambucil, but as time went on, it became clear that fludarabine did not provide longer overall survival. Rituxan will probably make a difference in the statistics. But will it have to be part of a chemoimmunotherapy regimen (FCR) to make that difference, or will using it as a single agent also have an impact? 

I said before that I'd probably choose FCR if I could go back in time. It would be the logical thing to do given my prognostics and the options available in 2003. (Would I have tried  Revlimid first had it been a choice? Hmmm.) But there is no guarantee that, had I chosen FCR, I would be in any better shape than I am today.

My guess is that for patients with “mild” cases of CLL, FCR will prove more of a game changer than it will for us “intermediate risk” folk. It makes sense that the more you beat down something that doesn’t grow very fast, the longer it will take to come back.

Will a study conclude in, say 2018, that FCR increases survival of 11q-deleted, unmutated patients by three years, or three months, or not at all? (For that matter, will 11q deletion be an antiquated measure, having given way to some new, more specific way to understand what is driving an individual’s CLL?)

My point is that, as my experience demonstrates, CLL choices are ever-shifting. Nothing is frozen in time. And treatment results can vary greatly by individual because, on some level, CLL cases are as unique as fingerprints.

We are at the beginning of the era of risk-assessment, not the end of it. For all our knowledge -– and the light shed by the German Study should not be discounted -- we are still playing a guessing game. Given everything we don’t know, everything is still, to one degree or another, a pig in a poke.

So judge your pigs as best you can and hope that the one you choose doesn’t turn out to be a turkey.


Anonymous said...

This is an excellent summary of the dilemma of how to (or not to) approach the treatment of any medical problem in which the problem, the treatment and the outcomes are not clear-cut from the get go.

Many people wandering cyberspace in search of answers about what to do regarding their CLL do not grasp the reality that even the experts really don't know what the right approach is in most (if not all) instances.

The experts certainly want to do the best thing for everyone that they deal with as do most doctors, but there are too many uncertainties and "X-factors' which can send any decision path awry.

People need to understand that any therapeutic choice (including the choice to do nothing) should be based on an evaluation of the upsides and downsides, because everyone is operating in a Casino Royale and there are no certain choices or certain outcomes.

My suggestion for everyone is to evaluate all decision points reasonably, be 'nimble" on your feet and always to remember that "they can kill you, even when they mean to help you".

A CLL traveller with 11q- who deferred FCR based on best information in 2008 and needed it in 2010 only to nearly die from severe AIHA and PRCA who still doesn't (and by my philospophy, shouldn't) have a concrete plan going forward.

ms said...


Who are the top CLL guys? I don't think those names are clear to the patient community.


David Arenson said...


If you look at CLL Forum or ACOR, you will see posts about some of the top names and centers. In the USA these include UC San Diego (Kipps, Castro); MD Anderson (Keating, O'Brien, Weirda); Ohio State (Byrd), Mayo Rochester, MN (Kay, Call, Zent, Shanafelt) and Dr. Kanti Rai at Long Island Jewish Hospital. These come to my mind as the top of the list, though I've no doubt forgotten some. Among this group, some are more conservative about treatment than others. Dr. Terry Hamblin is retired in the UK and makes himself available on patient forums and through his blog.

Brian Koffman said...

As always, very thoughtful Your question about whether early FCR would have changed things will never be answered. What interests me more is will one of the new therapies in trial or used off label such as CAL 101, Revlimid, ABT263, TRU-016, or any of a score of other molecules will create an alternative to a transplant as a path to a long life? If the answer is no, we will know soon, if yes, it is many years away. So if you are going for the long haul, you are deciding between a nasty but potential effective transplant versus a sleeker cooler, but unproven "designer" drug. That is the choice many of us face. Be well

Shari said...

This is a great synopsis of the challenges in making the best treatment decisions with CLL. It's hard to explain this to anyone who has no understanding of the disease. It behaves so very differently in every patient and responses are varied as well.

Hindsight is 20/20 and you know going into anything that you may regret the choice you've made or see clearly (in hindsight) what would have been the better option. But we never know on the front end.

After trying Rituxan as single agent in 2008 and getting very little results, my husband decided to go ahead to FCR (plus experimental Lumiliximab) in 2009. We have an excellent specialist, Dr. Ian Flinn, in Nashville. He believed John would get a good response to FCR; maybe several years of remission. I feared he would be one of those patients who didn't get the long remission. But I didn't expect what happened.

My husband failed FCR. (He is 13q, Zap 70- and CD38-, but unmutated). His blood has never been the problem. His problem has been very large lymph nodes. There was good reason to expect positive results from FCR. But he got nothing. And we started talking about transplant because failing FCR is not good news.

I wondered how we could know that he would have a successful transplant after completely failing FCR. Fortunately, having failed FCR so quickly qualified my husband for a phase 1 clinical trial with CAL-101. He was one of the last CLL patients accepted into that study with CAL-101 single agent and at the lowest dose (50 mg.). It was closed to new patients within days of his acceptance. And it has worked like a miracle drug for him (so far). The nodes have shrunk and his blood is perfect. He began treamtment May 27 and responded immediately (within days).

So looking back, we would have avoided FCR if we could have known he would not get even a partial remission. But failing FCR got him the lowest dose of CAL-101 single agent, which he will be able to receive for as long as it's working for him (no matter what happens overall with the trial). So there is definitely a silver lining in our case. But without my strong faith in God and His sovereignty in our lives, I could only look at these decisions as a roll of the dice.

Anonymous said...

Hey, dude, you have avoided FCR and the risk of Richter's and MDS. Why kvetch about it? I wish I had avoided that fate.

There are SO MANY choices for CLL now, why risk it? WHY????

In that regard, I envy you.

BTW I penned that response to Hamblin, which you probably guessed.

David Arenson said...

There are some thoughtful, interesting responses here that show just how tricky all this decision making can be.

BTW, I'm not kvetching. I'm simply playing a game of "what if," which I think most of us play from time to time, as a way to illustrate the difficult choices we face. Imagine trying to play a game where the rules are constantly changing and you'll be "playing CLL."

Whether I would have been better off with FCR, I'll never know, but I don't regret my choices.

In the coming weeks I'll have more to say about Revlimid. This "sleeker, cooler" designer drug just might prove to be an alternative to transplant for some of us.

I am also intrigued by CAL-101 and have heard great things about its node-reduction capabilities. It's several years from FDA approval (if all goes well) but could prove to be an important tool in the arsenal.

When playing the game, it helps to look at what may be on the horizon to help you. CLL is all about playing for time.

It's also important to know when your clinical symptoms tell you to act decisively. This can be extremely tricky in some cases. I have been fortunate in that my clinical symptoms have been better than my prognostics, allowing me to take a slower approach to treatment. Not that I haven't been advised by experts, both medical and layperson, to have done more faster, but I haven't seen the survival advantage in it.

Yes, you take a chance by reacting to the disease as opposed to being proactive, but you take a chance when being proactive, too. A lot of those transplants fail. "Killer chemo combos" like FCR may fail, too, and even when they lead to a remission they may fail to provide a meaningful survival advantage. As I recall, the FCR arm of the German Study shows a paltry 3% survival advantage over the FC arm after something like 3 years. That's not much of a bandwagon to jump on given the risks involved.

~chris said...

>>As I recall, the FCR arm of the German Study shows a paltry 3% survival advantage over the FC arm

Actually it is 4% David, but that is meaningless! Lets see what the data says at 5 years. Bet the FC arm is better than the FCR arm.

The important figures to notice in this study is the difference in side effects, particularly Grade 3 and 4, between the two.


Adverse Effects Overall Grade 3-4 76% 63%
Side Effect: Grade 3-4 neutropenia 34% 21%
Side Effect: Grade 3-4 leucocytopenia 24% 12%

(by the way Grade 5 side effect is death)

I suspect the FC group in remission is out enjoying life, getting into car accidents and falling off cliffs and that is why there is a difference of 4% in OS.

The FCR group on the other hand are in bed nursing shingles outbreaks, pneumonia, thrombocytopenia, etc etc etc. These folks are to ill to fully participate in life on on a regular basis.

It is about quality of life... not just quantity of life...

Anonymous said...

I am so Lost. I am 29 yrs old & I was diagnosed with SLL in April 2010. The doctors at Duke University say they believe I have CLL but my doctors here have not done a bone marrow test to be positive.

I already did a single round of R between May & June and it barely helped. I am starting FCR today & I am terrified. I have read your blog before but this one has me very very lost. I do not understand a lot of the letter/number combinations.Can you maybe explain those a little to me please?

Thank You for sharing your story & taking time out of your day to share it.

~Tara (in NC)

David Arenson said...


There are three sites where you can easily get up to speed with the help of other patients. One is CLL Forum, one is the ACOR CLL List, and one is CLL Topics (now CLL Topics Updates).

Best of luck,