The Goldilocks Dilemma

UPMCBefore we get down to the nuts and bolts of the FCR “Lite” clinical trial results, I would like to set the stage and tell you why this is an important approach. We do not have all the answers, yet;  but we may get them over time as more patients go through this protocol and the statistics become more robust. I know a lot of you out there are interested in this approach.

We are all familiar with the childhood story about choices that do not quite fit. Too much or too little is not good enough. It is worth making the effort to find just the right fit. That idea may be particularly true when it comes to treating CLL.

Mainstream oncologists treating solid cancers with short fuses have a justified mind-set: cancer is the enemy that needs to be rooted out, burned and poisoned until there is no trace of it left behind. Surgery, radiation and chemotherapy (respectively) are designed to maximize their ability to kill cancer cells. Of course, there is a price tag of collateral damage and toxicity to normal cells in this take-no-prisoners approach.  This may be unavoidable and necessary in order to control an aggressive and dangerous enemy. Concepts such as maximum tolerated dose (enough to kill the cancer but not enough to kill the patient – most of the time!) and non-overlapping toxicity grew out of this mindset.  For patients that face imminent death from their particular cancer, this approach makes sense. It is amazing how much toxicity patients are willing to accept when faced with the other alternative, imminent death.

CLL Marches to a Different Drum Beat

But this approach developed in the context of rampaging solid cancers may not be the right handle on things when it comes to CLL.  Remember, many CLL patients blessed with good prognostic indicators may be able to coast along with little or no therapy for a long time. Many of the chemotherapy drugs used to treat cancers are mutagenic – they can cause further chromosomal damage. “Clonal Evolution” is a fact of life with CLL.  Many patients start out with minimal chromosomal damage and then gradually accumulate more FISH defects over time. Clonal evolution is all the more likely in patients undergoing chemotherapy with drugs such as fludarabine, cyclophosphamide etc.

Here is one analogy of how things work in CLL land. Homeland security is aware that there is a general sense of dissatisfaction among a segment of the law enforcement officers, and this morale problem has spread through out the police precincts in the whole country. These are not your average bomb-throwing terrorists per se, but they are malcontents that do not do their jobs right, mouth off and spread discontent by means of  their constant bitching and moaning. It is hard to pin-point and identify them exactly, since they look just like their innocent colleagues. Unfortunately, their poor attitude is infectious.  Soon enough other officers stop doing their jobs and sit around complaining as well. While these malcontents and their side-kicks / new converts lounge around mouthing off, bank robbers and murderers roam the city with no one to challenge them. The longer we wait, the worse it gets. As if this is not enough, there is always the chance that one of the malcontents may stew in his crazy ideas long enough that he goes over the top, goes “postal” and morphs into a card-carrying member of bomb throwing terrorists. Pretty soon, this tough guy becomes the leader in his ‘hood, encouraging more and more of the hoodlums start imitating his take on things – and we now have a serious problem on our hands. Evolution is a fact of life, even malcontents evolve over time.

What to do? Nuking every police department in every city and thereby poisoning the whole country is hardly an appropriate solution. It might kill the offending cops, but it will surely kill off major part of the population as well, reduce the towns and countryside into a glassy radioactive rubble. Anyway, there is no guarantee that all of the bad guys will be killed by this process. They are too darn much like the average Joe Bloe walking down the street! This situation requires a more subtle approach. For starters, it is important to recognize this is not a 9/11 type of crisis that requires a knee-jerk response right off the bat. There is time to think things through and come up with the most effective and least damaging solution. It may take hard work, courage, resolve and persistence to select and implement the right plan but speed is not the overriding factor in most scenarios.

I think you can see the parallels. Most of the time, a diagnosis of CLL does not require immediate and urgently scheduled therapy with the biggest and baddest therapy guns at our disposal. “Watch & Wait” is entirely justified, to get a better fix on the lay of the land. Like our malingering cops in our analogy, CLL cells are spread all through the body — there is no place in your body that blood and lymph do not circulate and therefore there is no place that is entirely safe from CLL. Without a localized enemy, it does not pay to jump the gun and initiate all-out war, not unless you have no other choice.

On the other side of the equation, waiting indefinitely without a game plan is not a solution either, unless you are fortunate enough to have a very indolent, “smoldering” variety of CLL. As time passes, the tumor load grows and CLL cells gradually compromise other important cell lines. Even in patients with relatively slow-growing CLL, over time there may be a gradual drop in red blood cell, platelet and neutrophil counts. Over time other organs such as the liver and spleen may also get infiltrated, limiting their function and efficiency or causing them to behave in a destructive fashion.

There is one more very simple reason why it is not a good idea to wait until the last bitter moment — “B-symptoms”. I have no idea why they are called this, and why they are “B” rather than “A” symptoms. Whatever they are called, they are no fun and take a big chunk out of your quality of life. Overwhelming fatigue, drenching night sweats, frequent infections and unwanted weight loss are but some of the unwelcome symptoms in late stage CLL patients. In some if not all, lymph nodes and organs such as the spleen and liver grow big. Even if you don’t care whether or not you look like a chipmunk with the enlarged lymph nodes along your jaw-line, sometimes these nodes can be downright painful and they can press against vital arteries or nerves.

Reality Check

I have a real problem with doctors and institutions that have a shoot-first-and-ask-questions-later approach to treating CLL patients. Sometimes, less may be more in controlling CLL. Lengthening the alphabet string of drugs in ever more complicated  combos is not a slam dunk good choice when it comes to treating CLL.

Then there is the other end of the spectrum. There is an entire industry out there that caters to patients’ wishful thinking – that it is possible to cure full fledged, clinically diagnosed CLL by diet and lifestyle modification, magic potions, “coral” calcium and cottage cheese.

Can one cure (I mean really CURE) aggressive CLL by leading a blameless life?  Will buying and using magic potions marketed by snake oil peddlers do anything more than lighten your wallet and perhaps shut your window of opportunity for getting more realistic therapy if and when you need it? I will be right upfront with my take on this issue, the answer is “no” – especially if we are talking about an aggressive form of CLL. You of course have the right to disagree.  But lets keep this discussion polite, OK?

A percent of CLL patients, those fortunate enough to have the extremely indolent “smoldering” variety of CLL may never need therapy. If you are one of these lucky folks, you get a free pass. If you are so inclined, you can even tell yourself that the magic potions you take (with little or no credible clinical trial information backing their efficacy) are the reason why your CLL is under control. As always, for the rest of you not so lucky in your prognostic markers,  “Buyer Beware” is a good mantra to remember.

I am the first one to agree that unhealthy lifestyle choices (smoking, obesity, junk food, excessive UV exposure and a couch potato lifestyle spring to mind) contribute a great deal to the incidence of cancer. Anyone who continues to smoke even after getting a swift kick in the backside in the form of a cancer diagnosis loses a big chunk of credibility. Furthermore, you absolutely need to do all you can to improve your general health after your diagnosis of cancer, if for no other reason than to get ready for the fight ahead. Cancer therapy is a lot more taxing on your body if you have unrelated co-morbidities. People in good fighting trim fare a lot better and more likely to survive the adverse effects of cancer therapy. There is this little phrase called “treatment related mortality” that says it all: Yes, we cured the cancer, but unfortunately we killed the patient in the process.

This is then the crux of our problem — how to make sure the therapy we decide on is just right: not so heavy-handed as to cause a lot of collateral damage, but not too weak and therefore ineffective. CLL is not your average short-fuse cancer. In most cases it is not a ravening beast that must be killed immediately at any cost. In fact, for the majority of CLL patients, it is quite possible to shoot yourself in the foot by opting for the most potent (and most toxic) therapy out there. The smart thing to do is weigh your options, do your homework and play the cards you have been dealt as best as you can.

FCR “Lite”

We floated the concept of “Lite” chemoimmunotherapy combinations such as FCR-Lite on our website back in 2005. The good news is that it is no longer just a concept on a patient website. Some researchers are thinking outside the box and beginning to treat CLL as a unique cancer that does not fit the general stereotype, recognizing that it needs more finesse than the standard take-no-prisoners approach of oncologists used to treating solid cancer patients.

Two of the best known combinations above are FR (pioneered at Ohio State University) and FCR (championed by M. D. Anderson). Both of these combinations show impressive overall responses with a goodly number of “complete responses” (CRs). But neither therapy is without risk. Both have associated immune suppression, neutropenia, opportunistic infections such as pneumonia, shingles, higher risks of hospitalizations and a potential for secondary cancers such as basal cell carcinoma or squamous cell carcinoma or other hematological cancers. Is there a way in which we can keep the high response rates, but reduce the adverse effects?

In all chemoimmunotherapy combinations such as FCR and FR, Rituxan is the drug that is doing the targeting of the CD-20 positive B-cells, painting a bull’s eye on the cancer cells. Conventional chemotherapy drugs such as fludarabine and cyclophosphamide provide the killing power. Is it possible to keep the efficacy of FCR by increasing the role of Rituxan and at the same time reduce the adverse effects by reducing the amounts of chemo drugs used in combination?

In other words, will we get the best of both worlds, the perfect Goldilocks choice by going to FCR -Lite, where the emphasis is increased on the “R” part of the combination and we cut way back on the “F” or/and “C”? I am glad this is no longer a mere speculation anymore. Below is the abstract that spells out the results of the FCR Lite trial at University of Pittsburg Medical Center. If you are interested in this approach, you really should read the full length article as well as the accompanying and very thought provoking editorial. Send me a personal email and I will help you locate both of them.

J Clin Oncol. 2008 Dec 15.

Chemoimmunotherapy With Low-Dose Fludarabine and Cyclophosphamide and High Dose Rituximab in Previously Untreated Patients With Chronic Lymphocytic Leukemia.

Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L, Meisner D, Laman A, Sulecki M, Butchko A, Schaefer P, Lenzer D, Tarhini A.

Department of Medicine and Biostatistics, University of Pittsburgh School of Medicine, Graduate School of Public Health, and the University of Pittsburgh Cancer Institute and the University of Pittsburgh Medical Center Cancer Centers, Pittsburgh, PA.

PURPOSE: Chemoimmunotherapy combining fludarabine, cyclophosphamide, and rituximab (FCR) is an active regimen for untreated patients with chronic lymphocytic leukemia (CLL) with 70% complete responses (CRs) and 95% overall responses (ORs). However, grade 3/4 neutropenia was reported in 52% of cycles of treatment. The purpose of this trial was to maintain the high responses but reduce the toxicity of FCR by decreasing the fludarabine and cyclophosphamide (FCR-Lite). PATIENTS AND METHODS: We conducted a single arm study of FCR-Lite which includes maintenance rituximab in 50 untreated CLL patients. Patients were evaluated for response using both the 1996 National Cancer Institute Working Group (NCIWG) guidelines and the 2008 guidelines. Two thirds of patients were treated by community physicians. RESULTS: The median age was 58 years (range, 36 to 85 years); 20 patients had Rai stage 1, 22 had Rai stage 2, and eight had Rai stage 3 and 4. 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. CONCLUSION: FCR-Lite is highly effective in previously untreated CLL patients. Grade 3/4 neutropenia was dramatically reduced compared to standard FCR and our data demonstrated FCR-Lite can be safely administered in the community setting.

PMID: 19075274

Comparing FCR and FCR Lite Drug Dosages

This clinical trial was a single arm trial and the same is true of many of the full strength FCR trials pioneered at M. D. Anderson. What that means is that we do not have a perfectly matched head-to-head comparison between the two approaches. The best we can do is see how the data matches up, but with the caveat that there is wriggle room on account of the two patient groups may not be strictly similar and there is room for researcher bias in results interpretation. The table below outlines the two protocols in terms of the drug dosages and how they were scheduled.

FCR Lite vs FCR dosages

The units used for the drug doses in each case are “milligrams per meter square”, or “mg/m2”. This is done in order to take into account for the variable body size of individual patients. To get the dosage right for you, you need to multiply the dosages in milligrams by your BSA (Body Surface Area, measured in square meters. The BSA Calculation link will show you how to do that, given your weight and height.

As you can see, FCR “Classic” used quite a bit more fludarabine and cyclophosphamide whereas FCR “Lite” used a lot more Rituxan over a much longer time period. I understand in subsequent tweakings of the FCR Lite concept the researches further reduced the dependence on fludarabine and cyclophosphamide.

FCR Lite Results

As most of us know by now, FCR combination pioneered at M. D. Anderson has demonstrated impressive overall response statistics (95%) as well as high percentage of CRs (72%). Those that had squeaky clean remissions (no trace of CLL detectable by four color flow cytometry or MRD negative) at the end of treatment stayed in remission much longer compared to those that had detectable disease (85 months verusus 49 months).

How did these statistics compare with FCR Lite results? Did this “kinder and gentler” approach have sufficient oomph? Below is a quickie comparison of the response statistics.

FCR Lite vs FCR results

Bear in mind this is not a strict apples to apples comparison since we are looking at data from two single arm trials. Also, while the FCR response rates are based on a very large size cohort monitored over a very long time, the FCR-Lite statistics are based on a much smaller group of patients and the results have yet to meet the test of long term monitoring.

With these caveats in mind, it seems to me there is no significant difference in the overall response rate. Generally speaking, FCR-Lite seems to be plenty strong in getting people into “complete remission”. How many of these CR patients were also lucky enough to have no trace minimum residual disease (MRD) when examined by four color flow cytometry or pcr technology? That information is not available. How long did the FCR-Lite remissions last? This paper reports early results and we cannot hang our hats on remission duration or overall survival data – not just yet. But this much seems to be true: as expected, FCR-Lite does indeed seem to have lower toxicity. Reducing the amount of fludarabine and cyclophosphamide did indeed reduce the percentage of patients who had high grade neutropenia or thrombocytopenia.

Was FCR-Lite strong enough medicine to work across different risk buckets? The paper does break out the results by FISH status, one of the important prognostic indicators.

FCR Lite response by FISH status

Once again, as expected, the really tough cases with 11q and 17p deletions (as reported by FISH test) had a harder time getting full fledged “CR” status.

Questions Remain

So, do we now know all we wanted to know about FCR-Lite? Not by a long shot. Here are some questions that linger in my mind, I am sure you will be able to add to the list.

  • Are remissions obtained by using FCR-Lite as durable as those obtained using full strength FCR? In other words, does a “CR” obtained after using FCR-Lite of the same quality and durability as a “CR” obtained after FCR-Classic? Something tells me that mere “CR” status is not enough to answer this question. We need more details, such as MRD (minimum residual disease) status, by four color flow cytometry or pcr (polymerse chain reaction) technology.
  • There seems to be reasonable grounds for accepting that FCR-Lite is less toxic, smaller percentage of patients had high grade neutropenia or thrombocytopenia. Does this “kinder and gentler” approach mean patients will live longer even if they come out of remission? Can we hope that for FCR-Lite patients there will be reduced incidence of opportunistic infections and secondary cancers down the road
  • Does FCR-Lite mean less collateral damage and therefore better quality of life for patients undergoing this protocol? It is also worth noting the FCR-Lite protocol used rigorous guidelines for prophylactic protection of patients: antibiotics, anti-virals were used, along with standard pre-infusion drugs such as Allopurinol, Benadryl, Tagamet and Tylenol.
  • When patients relapse, will FCR-Lite patients be less refractory than those who relapse after FCR-Classic? Does the reduced dosage of chemotherapy drugs translate into patients who are not as tough to “salvage” with other therapy regimens? As we have seen in prior articles, life after FCR relapse is pretty tough. Is it any better after FCR-Lite relapse?
  • While Rituxan enjoys the reputation for lower toxicity – at least when compared to conventional chemo drugs such as fludarabine and cyclophosphamide – it is by no means a free lunch. Patients in FCR-Lite are exposed to long term maintenance use of Rituxan. Are they more likely to develop hypersensitivity to the mouse juice? Would it better to shift to FCA-Lite where the “R” of Rituxan is swapped with “A” of arzerra (aka Humax-CD20 and ofatumumab) since this new monoclonal is a fully humanized antibody?
  • Last but not least, what is the dollar impact of FCR-Lite? Rituxan is many times more expensive than old fashioned chemo drugs such as fludarabine and cyclophosphamide.

A Brighter Future Ahead

I am an optimist. I really think there is a brighter future out there for CLL patients. I do not mean way out in the distant future, I mean in the near term and soon enough to make a difference to many of you reading this article; definitely in the lifetime of your kids or grandkids, should they be unlucky enough to inherit this familial cancer from you. That is why I think it is so important for us to understand the stakes, play this game to win. The short term tactics you decide on should not leave you out in the cold, when better choices become available for longer term survival strategy. And I urge each and every patient out there to consider the possibility of volunteering for clinical trials. We must thank those that went before us, and pay our way forward by doing our share of heavy lifting. In the final analysis, the only way we are going to get a cure for this awful disease rests in our hands.