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    FCR Lite: The Search for Efficacy with Lower Toxicity

    Date: January 12, 2024

    by Chaya Venkat

    The Goldilocks Dilemma

    We are all familiar with the childhood story about choices that do not quite fit. Too much or too little is not good, it is worth making the effort to find just the right fit.

    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 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. But this may be unavoidable and necessary in order to control an aggressive and dangerous enemy. Concepts such as maximum tolerated dose (not enough to kill the patient, most of the time) and non-overlapping toxicity (one drug makes you barf, while the other ones gives you a serious attack of the runs, Presto! no overlap!) grew out of this mindset. For patients that face imminent death from the cancer, this approach may well make sense.

    Then there is the other end of the spectrum. There is an entire industry that caters to patients’ wishful thinking that would cure cancer by minimal diet and lifestyle modification, magic potions, “coral” calcium and cottage cheese. I am the first one to agree that unhealthy lifestyle choices (smoking, obesity, 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 has little to complain about. You absolutely need to do all you can to improve your general health, 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. But merely leading a blameless life is not going to be enough to control most cancers. (I do acknowledge that 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, you can skip reading the rest of this article).

    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, nor too weak to do much good. CLL is not your average short-fuse cancer. In most cases it is not a ravening beast that must be killed 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 good news is that there are many new options open to us. The bad news is that there are so many new and bewildering options that we have trouble making sense of it all. How are we to make the right choices? Before you throw up your hands in frustration, it is important to know there are some common threads, some light that is making the CLL landscape just a little easier to figure out. Some researchers are beginning to think 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. More aggressive therapy may not always be the best choice.

    Rituxan Everywhere

    The advent of modern prognostic indicators (What Type of CLL Do You Have?; FISH-ing for Answers; Dawn of a New Era; Risk-adapted Strategies; Are We There Yet?) and monoclonal antibodies such as Rituxan have changed the picture dramatically. It is no coincidence that Rituxan features as a single agent or in combination with other drugs in most of our recent therapy options. Here are some of the Rituxan combinations we have discussed before on our website:

    I think you can see the pattern. Rituxan has a way of improving the response of just about every other drug that is used in the treatment of CLL. This drug targets the CD20 marker expressed by most B-cells, and as such it does a great job of increasing the CLL-specificity of any drug combo in which it is included. The other good thing about of Rituxan is the lack of serious adverse effects, barring in a small percentage of patients who may be allergic to it. The pity of it is that not too many CLL patients respond sufficiently to plain vanilla Rituxan therapy, not even when it is goosed up by low-toxicity adjuvants such as EGCG in our favorite “RHK protocol” (see The Difficult Case of the Round-headed Kid). Using our Goldilocks analogy, Rituxan as single agent may be too light, especially for patients who have been previously treated or who have less than wonderful prognostic indicators. The next step is then to decide which, if any, of the above smorgasbord of Rituxan combos is just right, packs enough punch but is not too heavy-handed.

    Two of the best known combinations above are RF (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 CRs (“complete responses”). 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 hematological cancers. Is there a way in which we can keep the high response rates, but reduce the adverse effects?

    We have discussed this concept before. Since Rituxan is the drug that is doing the targeting of the CD20 positive B-cells, with little by way of adverse effects, and the more conventional chemotherapy drugs fludarabine and cyclophosphamide play a secondary role of making the monoclonal more potent, might we not be able to keep the efficacy by increasing the role of Rituxan and reduce the adverse effects by reducing the amounts of chemo drugs used in combination with it? In other words, will we get the best of both worlds, the perfect Goldilocks choice by going to RF “Lite” or 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 to report, this is no longer a mere speculation on the part of yours truly. There is a brand new clinical trial that is up and running, recruiting patients as we speak, that is evaluating FCR “Lite”. If you are in the market for therapy options right now, and thinking about one of the more potent chemo-immunotherapy combinations, this is one trial that you should consider.

    FCR “Lite”: the Clinical Trial

    Below is the contact information for this important clinical trial, currently recruiting patients at University of Pittsburgh Medical Center. This trial is not yet listed on but we understand that the information has been submitted. The following link to the clinical trial information on the University's website, 03-136,  will provide inclusion criteria and the like. We have several members participating in this clinical trial and have succeeded in getting hold of the more detailed patient information document given to prospective participants. It is attached below as well, in PDF form. I fail to see why these documents are not routinely made available to the general patient community. I am delighted to be able to share this information with you, but as a journalist, I am of course not going to disclose my sources. As our patient community grows, I am finding it easier to get hold of information that I can then share with the rest of you. Remember, we are all in this together, we benefit when we share our resources.

    Clinical Trial Details

    Listing in



    University of Pittsburgh Cancer Institute

    Clinical Trial Identifier


    Institution's Trial Listing

    UPMC listing for this trial

    Therapy Agents

    modified dose fludarabine, cyclophosphamide, rituximab -
    reduced FC, increased R

    Trial Description

    Phase II clinical trial for previously untreated patients

    Study size

    15 - 50 patients  


    Offered at UPMC only

    Cancer Center Web Link

    University of Pittsburgh Medical Center 

    Principal Investigator

    Kenneth Foon, MD

    Contact Phone Number

    (412) 648-6466

    Additional Contact

    Patricia Schaefer 
    (412) 623-4881



    Patient Information Sheet in PDF form.

    Looking over the details of this clinical trial as disclosed in the PDF document above, several things become obvious right away. Like the FCR trial at M. D. Anderson, there are six cycles of one month each. But this trial goes beyond the 6 months, with an additional 24 months of Rituxan only in a  maintenance phase. The patients may continue to be monitored for a year or two after that. This trial is using a lot more Rituxan, and somewhat less fludarabine and cyclophosphamide when compared to the classic FCR trial pioneered at M. D. Anderson. (Drug Dosages in Popular Standard Therapies). Here is how the comparison stacks up:

    FCR "Classic" vs FCR "Lite"

    Protocol Feature

    FRC Classic

    FRC Lite

    Therapy Duration

    6 months

    2 years

    Number of Cycles

    6 cycles

    6 cycles (months)
    + 24 months maintenance
    with Rituxan only

    Rituxan Dose: Induction Phase

    2,875 mg/m2 5,875 mg/m2

    Rituxan Dose: Maintenance Phase

     None 4,000 mg/m2

                Rituxan Dose: Overall

    2,875 mg/m2

    9,875 mg/m2

    Fludarabine Dose, Overall

    450 mg/m2 360 mg/m2

    Cyclophosphamide Dose, Overall

    4,500 mg/m2

    2,700 mg/m2

    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 above by your BSA (Body Surface Area, measured in square meters. The BSA Calculation Links in our Reference page will show you how to do that, given your weight and height). I think you will agree my name tag of FCR “Lite” is justified for this new trial. It uses a boatload more of Rituxan and somewhat less of fludarabine and cyclophosphamide. I must admit though, my preference would have been to see even smaller amounts of fludarabine and cyclophosphamide in this trial. The direction is right, but I wish the researchers went a bit further out in reducing the toxicity of the combination by cutting back further on the chemo components. (By the way, rumor has it that later versions of the FCR trial at M. D. Anderson have also decreased the amount of F and C, but I cannot confirm that since I have not seen the details of these later versions. If some of you have participated in these later versions of the Anderson trial, I invite you to send in the details).

    There are several other details in the patient information document of this trial that are worth noting. For example, there is a serious attempt at preemptive medication to nip infections in the bud. In addition to the usual pre-infusion medications (allopurinol to protect your kidneys, Benadryl, Tylenol, dexamethasone to minimize infusion-related side effects), the design includes prophylactic measures. This is one of the few trials where I have seen such consistent efforts at using antibiotics (a combination of trimethoprim and sulfamethoxazole, used to treat a wide variety of bacterial infections), an anti-viral (acyclovir, brand name Zovirax, used to treat Herpes Zoster infections - shingles) and a growth factor (filgrastim, brand names Neupogen / Neulasta to prevent neutropenia) in order to prevent opportunistic infections.

    This is good news. Patients who are generous enough to volunteer their bodies in clinical trials need and deserve our best efforts to protect them against adverse effects. This approach sure beats another clinical trial design we reviewed recently where a drug with proven cardiac toxicity (Mitoxantrone) is administered without taking the precaution of prior MUGA heart scan as part of the inclusion criteria, a precaution that is in fact required by FDA regulation. I have to admit, that one still rankles with me. Patient safety in clinical trials should not take a back seat for the sake of expediency.

    FCR “Lite”: Expectations and Questions

    I give the FCR Lite investigators credit for thinking out of the box, reducing the dose of the chemotherapy agents needed to increase the potency of Rituxan, and maximizing on the dosage of the monoclonal. I also think they deserve thanks for a detailed clinical trial design that makes every effort to protect patients against potential adverse effects. So far so good. But the million dollar question that needs to be answered is whether this approach is the Goldilocks optimum best choice, whether it will have enough oomph coupled with lower toxicity. What will be the overall response? How will it compare with the response rates obtained with FCR “Classic”? Will there be as many CRs, and as many “pcr negative responses”? Only time will tell.

    But response statistics immediately after end of therapy are only the early questions that need to be answered. The more important answers will come later, as the patients are monitored over the longer term. What is the progression free survival? What is the overall survival? Does this therapy provide a good option for patients with poor prognostic indicators, such as those with unmutated IgVH or 11q and 17p deletions, or are they likely to get a whole lot less bang for the buck? Will there be significantly lower neutropenia, infections and the like? As we discussed in a very recent review of a paper from OSU discussing the RF trial results (RF Risks and Benefits), what should matter most to patients is the length and quality of the remissions, as well as overall survival. I am willing to bet you don’t give a fig what your remission is called, what fancy scientific label is used to describe it, just so long as the remission lasts a good long time, you enjoy good health while it lasts and when / if you relapse you will not have burned too many bridges in the process of using this particular therapy.

    There are other questions as well. In the interview below, I discuss some of these with Dr. Foon, the principal investigator for this clinical trial.

    The principal investigator for this clinical trial, Dr. Kenneth Foon, agreed to do an electronic interview with us. Our questions and his replies are reproduced below. Right there, we can give this clinical trial one more thumbs up, for making the extra effort to communicate with patient groups such as ours. We deserve to be informed and empowered partners in clinical trials, not so many lab rats signing on the dotted line, too terrified to learn the details.

    Last but not least, if you do decide to participate in this trial, do keep us in the loop. We look forward to publishing first person accounts of other patients participating in this trial, in our “Patients’ Corner” section of the website. While such accounts are obviously anecdotal information specific to individual patients, they nevertheless provide an interesting backdrop for more formal papers written in professional journals. As always, we will be scrupulous in doing all we can to maintain patient confidentiality.

    The standard game plan used for aggressive cancers may not be our best option, not when we are dealing with a more indolent cancer such as CLL. For those of us with relatively good prognostic indicators, the price tag of no-holds-barred warfare against the disease may be too high. Why take on the significant toxicity of heavy duty therapy when a much lower toxicity approach will let you manage the disease? It is not as if anyone has proven that any of the elaborate chemoimmunotherapy mixes are truly curative. For now, the only approach that has been proven to cure even a certain percent of CLL patients is an allogeneic stem cell transplant. Drug combos such as RF (Rituxan + fludarabine) or FRC (same as RF, with the addition of cyclophosphamide) have been shown to get very high overall response rates, as well as a goodly portion of “complete responses” and even “pcr negative” responses. But as we have seen in the last article we published on this website (RF Risks and Benefits), a complete response does not mean a cure. In fact, the value of a complete response seems to be defined by your prognostic indicators to begin with.

    Hillman Atrium

    The Atrium at UPMC Hillman Cancer Center


    Interview with Principal Investigator, Kenneth A. Foon, MD

    Editor's Note: There is a web page on Dr. Foon, where you will find some background on him. You can get an idea of Dr. Foon's earlier work on CLL by reading this PubMed generated list of papers with him as an author.

    Chaya: Thank you for agreeing to this interview.

    Does myelosuppression due to fludarabine and cyclophosphamide track dosage levels, and for that reason do you expect to see less immune suppression and lower risk of opportunistic infections in patients following this protocol, as opposed to the prior MDA protocol? Also, can you point us to any references (prior published articles) that link dosage levels of fludarabine and/or cyclophosphamide with degree of immune suppression? I was not able to find any specific articles in my surfing of PubMed.

    Dr. Foon: By significantly reducing the total dose of fludarabine and cyclophosphamide we expect major reduction in neutropenia (low white blood counts), neutropenic fever as well as opportunistic infections compared to the MDACC. All our patients also receive prophylactic antibiotics to prevent opportunistic infections.

    There are no publications I'm aware of that demonstrate lower doses of fludarabine and cyclophosphamide translate into lower toxicity, and I expect our study will be the first to demonstrate this. It's intuitive if you reduce the chemotherapy drugs you have overall less toxicity including the major toxicities of infection and neutropenia!

    Chaya: What made you decide to include cyclophosphamide in your trial, as opposed to just Rituxan with lower dose fludarabine? Do you agree that there is increased risk of secondary myeloid cancers by combining purine analogs with alkylating agents? Did you feel that addition of cyclophosphamide was necessary in order to increase efficacy and response statistics?

    Dr. Foon: I would agree that alkylating agents will increase the risk of secondary AML. However, using the very small dose of cyclophosphamide in our study and with the upside potential of the synergy of fludarabine and cyclophosphamide, I see this as a minor issue. While I agree there has not yet been a front line comparison of FCR vs FR, the MDACC data with 70% complete responses and 95% overall responses is the most impressive to date and it would be many years before one could determine in a randomized trial of FCR vs FR whether it would demonstrate a difference in acute leukemia incidence.

    We have just submitted our abstract to ASCO today on our first 20 patients and while I can't share this with you the results appear to support my initial hypothesis regarding toxicity and efficacy. Obviously long term toxicity (e.g., AML) will take many years to determine.

    Chaya: This clinical trial uses a lot more Rituxan (combining the induction and maintenance phases) than is typically used. Do you see this posing a potential problem in terms of costs, insurance coverage and acceptability in countries with cost-controlled socialized healthcare?

    Dr Foon:Rituxan is already being widely used as maintenance and my dose is considerably lower than the currently used dose. The higher dose we use during induction, if it demonstrates less neutropenia and sepsis as is expected, will save the insurance companies and public many dollars by preventing the need for hospitalizations, antibiotics, growth factors, etc.

    Chaya: I realize your protocol has prophylaxis against Herpes Simplex viral infections. However, there are several other viral infections such a CMV, Hepatitis, HPV that are quite common in CLL patients, and frequently reactivated during the course of immune suppressive therapies. CMV reactivation in particular has been a real problem during Campath therapy. EBV reactivation has been cited as one of the potential reasons for increased risk of secondary lymphomas (including the dangerous Richter’s transformation) in patients with deep immune suppression. We would like to have your comments on this issue, as well as your plans for monitoring patients for these opportunistic viral infections / reactivations.

    Dr. Foon: There has not been any major concerns with hepatitis (except if a patient is hepatitis positive prior to therapy — and these patients should be excluded), CMV and EBV with FR or FCR and therefore we have not included prophylaxis or stringent testing as is done with Campath. However, at the first sign of symptoms these patients would be tested

    Chaya: The patient information document suggests many additional tests will be done as part of research, and the results of these additional tests will not be shared with individual patients. First, we would like to ask that if you do prognostic screening (such as IgVH gene mutation status, FISH cytogenetics, CD38, ZAP-70, B2M), and we certainly hope that you plan to do these tests, that you please consider sharing this information with the individual patients who request it. This information is of great value to patients in their understanding of their therapy choices down the road, and it is often hard to get these tests done. Please consider this a serious request from the patient community, something that you can do to say “thank you” to the patients who participate in your clinical trial. We have succeeded In striking similar bargains with other researchers, I truly think it is a win-win situation.

    Second, while you may not be able to discuss all the research results with individual patients, we would like you to describe for us in this forum the reason for and interesting features of the research that you will be doing.  Participating in clinical trials is partly motivated by an altruistic wish to see increased understanding of this disease, and to progress the cause of science.  Our patients are often concerned about familial CLL, and participating in clinical trials is seen as a way of improving the odds for their kids and grandkids.  It will help improve recruitment and clinical trial participation if researchers address this aspect of clinical trials, make it clear to the patient community that the trials go far beyond mere response statistics reported in professional journals.

    Dr. Foon: I absolutely share all information with my patients (even if they don't request it unless they specifically ask me not to discuss these data). I always discuss the larger issues of familial disease, the purpose of trials and their importance with all of my patients

    Chaya: T-cell depletion as a result of therapy, and failure of reconstitution of full T-cell repertoire for a good length of time has become a hot button issue in fludarabine containing regimens.  Specifically, as a result of reduced T-cell surveillance,  there is increased risk of secondary cancers such as skin cancer.  Furthermore, skin cancer is a lot more dangerous in CLL patients.  Moh’s surgery, etc., are not as effective in immune compromised individuals. In spite of Best Practices reported from institutions such as the Mayo Clinic on this subject, we are chagrined that most local oncologists do not pay attention to this risk factor, and do not counsel their patients appropriately. We would like to hear your thoughts on this subject, and also the steps you plan to take to make patients and their local healthcare providers more aware of risk of T-cell depletion in this fludarabine containing therapy.

    Dr. Foon: T cell depletion as well as the higher risk of skin and other cancers are discussed with all patients. We follow our patients very closely on this study and address any issues that arise-hopefully early enough so we can deal with very early skin cancers which we commonly see in CLL patients whether they've received fludarabine or haven't even been treated.

    Chaya: All too often clinical trials go on for years without formal reporting of the results in peer reviewed journals. Press releases and short and sweet abstracts published at conferences such as ASH do not substitute for full length articles. We believe strongly that prompt and public reporting of clinical trial data is an ethical obligation of researchers conducting clinical trials. The FCR clinical trial at MDA is a case in point. It started recruiting patients many years ago, as early as 1999 I believe, and several hundred patients were recruited. Yet the first full paper to issue on the subject was as late as 2024. Even with the large patient cohort recruited, there is insufficient attempt to parse the data in terms of prognostic indicators. In sharp contrast, the RF trial at Ohio State University has set the standard for prompt reporting, frequent updates and detailed analysis of the data. We would like your assurance and commitment to prompt publication, including detailed assessment of how different prognostic groups fared in this clinical trial.

    Dr. Foon: I plan to publish in peer reviewed journals as soon as the data on the 50 patients is mature. Remember, MDACC was waiting for 100's of patients before publishing.

    Chaya: We are very pleased to see long term follow-up is part of your trial design.  Please assure us that you will be looking for overall survival and progression free survival as part of your game plan in monitoring patients, and these important statistics will be published as they become available.

    Dr. Foon: The protocol of course is designed to follow patients until recurrence and death and these data will be published in a timely fashion — please refer to my publication record and I think you will see I publish very quickly. This is the only way to get the information out to my peers and the public.




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