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Therapy Choices


Rituxan plus Low Dose Fludarabine

Date: February 12, 2003

by Chaya Venkat

A Protocol Waiting for a Trial

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I hope at least a few of you folks are following the complex web of logic that links CD20, Rituxan, Complement, and complement inhibitors CD55 and CD59. If you have been with me thus far, you might find the abstract below more than a little interesting. 

We are all aware that the combination of Rituxan with other chemotherapy drugs such as fludarabine increases the overall response rate quite a bit, gets a lot more complete responses (CR), and even gets not a few lucky PCR negative patients. The effect of combining Rituxan with fludarabine is not just additive, it is not just 1 + 1 = 2, in this case the effect is synergistic, you get 1 + 1 = 3 or more. 

The theory was that getting tagged by Rituxan makes the CLL cell much weaker, and more readily killed by the fludarabine. Based on the clinical data of high response rates, most studies focused on using full dose Rituxan, and full dose fludarabine, with cyclophosphamide thrown in sometimes for good luck. The logic was innocent sounding phrases like "maximum tolerable dose" and "non-overlapping toxicities". Easy for the docs to say, may be they should ask some of the patients who have been holding the short end of the stick in terms of living with these toxicities. 

If you recall, in one of my previous articles I described how Rituxan monotherapy works, how the Rituxan tags the CD20 positive B-cells, and the bulk of the killing is done by the efforts of the immune system, including the complement system (see Complement Dependent Response in Rituxan Therapy). I described why even after forming the required antigen-antibody pair (Rituxan-CD20 pair) on the CLL cell, thereby getting the complement system activated and having the CLL cell covered (opsonized) by C3 fragments, all this fuss and bother does not always result in cell kill. Markers such as CD55 and CD59 on CLL cells are thought to inhibit the action of the complement system. One of the reasons why CLL patients do not respond as well as several NHL cancer patients is because CLL cells often carry these markers CD55, CD59 (and others markers as well) that inhibit the proper functioning of the complement system. If these pesky inhibitory markers can be neutralized some how, so that complement can do its proper killing of Rituxan tagged B-cells, we can hope to see improvement in response rates for CLL patients as well. 

It turns out that one of the results of administering fludarabine is that it down regulates the expression of CD55, the major fly in the ointment. Light bulb goes off in my head. It sounds like the situation is not that the Rituxan is the minor player making the cells easy for the big guy fludarabine to kill. The minor role assist is by fludarabine, controlling the inhibitory marker CD55, so that complement can go ahead and kill the cells tagged by our hero Rituxan.
That raises an interesting possibility: RF certainly has a lot higher response rates than R alone in CLL. Until now, I had thought that the higher response rate with RF was due to the robust cell kill by fludarabine. What if all that is needed is to use just enough fludarabine to inhibit the CD55 and CD59, and thereby let the Rituxan and the body's own immune system to do the lion share of cell kill? Would very low dose fludarabine in combination with standard dose Rituxan be enough to get us better response rates than Rituxan alone, and yet stay away from the less-than-wonderful toxicity profile of full dose fludarabine? This is now especially easy to do clinically, since fludarabine is now orally bioavailable. Some thing to think about. 

For those who wrote and asked, my husband is doing very well on the Rituxan only frontline therapy. After just two Rituxan infusions, his WBC and absolute lymphocyte counts are below the levels where he was first diagnosed with CLL, barely borderline. I am hopeful he will have a "normal" CBC after the full course of 4 infusions, with no other hassle than the weekly 2 hour drive each way to Scottsdale, AZ, since that is where our local oncologist hangs out. That and boredom with the slow infusions. Needless to say, we are both very pleased, and very happy with the decision we made. And if it turns out ever that Rituxan is not enough to hold the CLL down to a friendly stalemate in my husband's case, I would seriously advise him to explore Rituxan plus low dose fludarabine to up the stakes some. 

There is the possibility of resistance to fludarabine resulting from an exposure to low dose fludarabine treatment. The Rituxan plus low dose fludarabine approach would be the right chess move in this game, if and only if, the remissions obtained by this approach are statistically as good as the remissions obtained by Rituxan plus conventional dose fludarabine. If the two approaches give about the same results, you are not taking additional risks or burning additional bridges, but gaining the advantage of lower toxicity for the same benefit. Same size bang for a smaller buck. 

One of these days someone is going to publish clinical trial results of this approach, I am sure of it. The conventional wisdom of the past was — hit the cancer with everything you've got, maximum tolerable toxicity, maximum doses that kill the cancer just ahead of killing the patient. Even now, questions are being raised if the cyclophosphamide, the "C" in the "RFC" therapy is needed, or is "RF" sufficient to do the job. Full blown BMTs are giving way to less drastic mini-BMTs. I guess the question I am asking is can R + mini- F do the same job as R + full-dose-F, with a lot less toxicity.  

Obviously, there will always be a group of patients for whom it is important to proceed with aggressive therapy. The too little, too late, strategy can be a poor choice too. It always boils down to interpreting the statistics to make intelligent, specific therapy choices for the individual patient. 


Br J Haematol 2001 Sep;114(4):800-9

Synergism between fludarabine and rituximab revealed in a follicular lymphoma cell line resistant to the cytotoxic activity of either drug alone. 

Di Gaetano N, Xiao Y, Erba E, Bassan R, Rambaldi A, Golay J, Introna M.

Laboratory of Molecular Immunohaematology and Department of Oncology, Istituto Ricerche Farmacologiche Mario Negri, via Eritrea 62, 20157 Milan, Italy. 

We have shown previously that the anti-CD20 chimaeric monoclonal antibody rituximab exerts its effects on neoplastic B-lymphoma cell lines in part via complement-dependent cytotoxicity. In addition, membrane expression levels of complement inhibitory proteins CD55 and CD59 play a role in determining susceptibility to lysis. We have identified one t(14;18)-positive human B-cell non Hodgkin's lymphoma cell line (Karpas 422) that is resistant to rituximab and complement and used it for subsequent studies on the possible interaction between this novel therapeutic agent and established antineoplastic drugs. We have exposed Karpas to several chemotherapeutic agents (doxorubicin, idarubicin, cisplatin, taxol) for different time periods and subsequently exposed the cells to rituximab and human complement. The combination of these drugs with rituximab induced an additive cytotoxic effect. In contrast, exposure to fludarabine (1 microg/ml for 48-72 h) showed a synergistic effect, with cell lysis increasing from 10% to 20% using fludarabine or rituximab and complement alone to about 70% with both cytotoxic agents. Analysis of the mechanism for this synergistic effect showed that fludarabine downmodulates the membrane expression of CD55 (from 96% to 55% positive cells) without significantly altering CD20 levels. Northern analysis demonstrated that fludarabine induced a general downmodulation of steady state mRNA levels with no change in transcription rate detected in run-off assays. The study of the effect of fludarabine and rituximab in six freshly isolated B-cell chronic lymphocytic leukaemia (B-CLL) samples showed that, in most cases, fludarabine has an additive cytotoxic activity with rituximab and complement. This report gives a rational support for clinical studies with combinations of drugs, including monoclonal antibodies and fludarabine.  

PMID: 11564066

I do not know of any formal clinical trials underway that combine Rituxan with low dose fludarabine for CLL patients.  But that is not surprising since it is only in the last couple of years that Rituxan has become a serious therapeutic option for CLL patients (Thank you, Dr. Hainsworth!! Your message is getting through, slowly but surely.). The early studies of Rituxan in heavily pretreated CLL patients that showed low response rates have been unfortunate red herrings that slowed down the evaluation of this important drug for CLL patients. The landscape is changing now, in the years to come I have little doubt that Rituxan therapy, either by itself of in combination with other drugs, will become a very important therapy modality for CLL patients. 

Rituxan therapy seems to work best when the following conditions are met:

  1. Patients with good expression of CD20, both in percentage and intensity terms.
  2. Previously untreated patients.
  3. Earlier stage patients with lower tumor burden.
  4. Patients with relatively intact immune systems.
  5. Possibly patients who do not express inhibitory markers such as CD55, CD59.
  6. Possibly patients with the "good" chromosomal aberrations, but up-regulation of bcl-2 does not seem to be a problem.
  7. Possibly patients who have sufficient levels of complement.
  8. Other criteria we have not yet discovered.

So, if you are a patient who meets most of these criteria, you would be well advised to consider Rituxan only therapy, and not wait until the last bitter moment of w&w. My husband met the first 4 of these criteria, no information on item 5, or 6, and he most likely met item 7. For us, once the logic was in front of us, the choice was clear: get into Rituxan frontline mono-therapy and sooner is better than later. 

The question is obvious, what about the folks that are not quite optimum candidates for Rituxan only therapy? If you have dim CD20 expression, and you have had hints that your immune system is not up to the job (frequent infections, low neutrophil counts, anemia and/or low platelets indicative of a bone marrow that is not able to produce all the important cell lines), large lymph nodes and other organ involvement (spleen and/or liver), you can still try Rituxan, and hope for the best. Me, I like to line up the odds a little more in my favor, I don't like playing with a deck stacked against me.

What are the choices if R alone is not likely to do the job?

  1. RF
  2. RFC
  3. RPC, P for Pentostatin
  4. R plus various steroidal drugs such as prednisone
  5. R plus Campath
  6. Various and sundry vaccines, other monoclonals and gene therapies
  7. Others I have forgotten to mention in this list.

Personally, I would like to avoid steroidal drugs like the very plague. There may be situations where they are necessary, such as ITP; in that case, I would like to see them kept to low dose, tapered off gradually soon as possible. But, frankly, there are good indications that Rituxan is effective in treating ITP and AIHA, so in future Prednisone type of drugs for this application may come to be replaced by the significantly less toxic monoclonals. Prior to the advance of the purine analogs such as fludarabine and Pentostatin, we are talking about more than a decade ago, alkylating agents such as Chlorambucil (Leukeran) were used as strictly palliative drugs (made you feel better for a while and got rid of the symptoms, for a while), with no illusion of curative intent. Very large and well defined clinical studies have shown that there is no survival advantage of initiating Chlorambucil therapy, it did not prolong life, the toxicity is cumulative and irreversible. It is still the drug of choice for poorer countries, and its oral bioavailability made it an easy and convenient drug to administer, especially to older patients. Not any more. Oral fludarabine is a much better choice, if ease and convenience of administration is the criteria. Fludarabine is clearly more effective and gives longer remissions than Chlorambucil, which is why it became the gold standard for CLL, prior to the debut of Rituxan. 

I am undecided about Campath. It would not be my first choice, right out of the gate. It is way too immunosuppressive and potentially dangerous because of the risk of opportunistic infections. Some of the T-cell lines killed by Campath do not recover even after several years. In my naive youth, year and a half ago, I paid good money and bought Dr. Kanti Rai's book on Campath, and thought it was the greatest thing since sliced bread. I am not so bullish about this monoclonal now. But there is no doubt Campath is a powerful monoclonal, and I believe it has a role to play, perhaps as low dose, subcutaneously administered drug to handle minimum residual disease, or as a backup in refractory cases for patients who have fewer choices. 

Vaccines, gene therapy: great ideas whose time has not yet come. Let me be the one to set the cat loose among the pigeons, the Phase-II gene therapy trial at UCSD has been a great disappointment to me. No doubt the scholarly papers written in a year or two will show how much we have learned from it, and I agree that science **has** been furthered and that **is** important, but any of you guys out there who are keeping yourselves pure for the cure, hoping you will be inducted into the next phase of this particular approach, and you will thereby be **cured** of CLL, I suggest you check out the stories on Gene Therapy. Your children or grandchildren may some day be cured as a result of some version of Gene Therapy, and they would owe a debt of gratitude to the patient volunteers of the world, but it won't happen in time to be of much use to you, not if you have been on this train for a year or two and getting anxious.

That leaves Rituxan and combinations thereof. If you are likely to be just shy of getting a good response with Rituxan alone, but you are looking to get maximum benefit from this relatively non toxic drug, it seems counterproductive to me to combine it with full doses of fludarabine and/or cyclophosphamide. For starters, both F and C are immune suppressive. Wait a minute, is that not supposed to be a no-no, if you are looking for Rituxan to do all it can do? I am not disputing the need for the more aggressive approaches such as RF and RFC, clearly there are patients for whom a full strength RF or RFC is exactly what the doctor ordered. I am trying to speak of the in- between crowd, those who can perhaps make it with a slightly less aggressive approach.

There has been some amount of work done on a low dose approach for chemotherapy, sometimes called "metronomic" dosing. It seems that while toxicity is clearly dose dependent, and lower doses mean lower toxicity, the sensitization of the body's own defense systems may mean smaller doses of chemotherapy may pack a bigger punch that one would expect. Here is a case where less may be more. Low dose administration of fludarabine is also less likely to make your refractory to the drug down the road, compared to full dose. Think about it, if one uses full dose fludarabine, and kills each and every cell that is sensitive to this drug, the very cells that survive and multiply are going to be the ones that can resist fludarabine. The simple fact of killing sensitive cells breeds for the resistant cells, where chemotherapy is concerned. This has been shown in case after case with a variety of chemotherapy drugs. Some people seem to develop resistance to Rituxan as well, and we do not yet know exactly why this happens. Perhaps after the first series of Rituxan therapy, these patients have developed a clonal population which has much higher levels of the complement inhibitory markers such as CD55 and CD59 we discussed above. In a few cases, there is reason to suspect that CD20 expression has been significantly down regulated - the marker that Rituxan looks for is not there any more, or expressed as but a faint shadow of its former glory. Equally interesting, while some patients do develop resistance to Rituxan, some patients go the other way, responding much better to Rituxan the second time around. It is as if their bodies have become sensitized to the monoclonal and kick into high gear when they see it again the second time around. There is a lot we have yet to learn, and a lot we can improve upon, in the way this important monoclonal works for B-cell cancers.

If indeed fludarabine helps to down regulate the inhibitory proteins such as CD55 and CD59 that prevent cell kill by Rituxan based therapy, the million dollar question is how much fludarabine does one need to get this effect going? Is a smaller dose of fludarabine enough to serve as the enabling drug that makes Rituxan more effective, without getting in the way by suppressing the very immune system that we are counting on to kill the cells tagged by the Rituxan? 
Yes, I too wish there are good solid clinical trials and their results, to compare and contrast full strength RF with RF Lite. May be there will be some in the future. But for those of you who are having a hard time deciding between R alone versus full strength RF, here is a possible middle ground, RF Lite, that you may wish to discuss with your oncologists. A possible "protocol" would be the standard once a week for 4 weeks infusion of standard dose of 375 mg/m2 Rituxan, plus low dose oral fludarabine for the duration of the Rituxan therapy. How low is low? That depends on you, the level of your disease, and your oncologist's interpretation of what constitutes a low dose. There is little disagreement on what is full strength fludarabine is, that is pretty well established by now in many studies. 

This is a time of changing paradigms. Prior to immunotherapy with monoclonals like Rituxan, W&W was the right choice, wait till the last minute, then hit the CLL with big guns. Who cares if your immune system got progressively weaker as you waited, you are not counting on it to do much anyway once therapy started. Ten years or so from now, I predict we would have shifted entirely to the new paradigm, CLL will be treated as soon as it is diagnosed, with targeted and perhaps custom designed monoclonals and/or vaccines, that help your own immune system get rid of the cancer, no fuss, no muss, no risk. Right now we are in the uncomfortable in-between period, when it may not be smart to wait too long, and yet the monoclonals are not all the way there in desired efficacy, at least for a significant percentage of the patients. "RF Lite" may the Goldilocks choice for some of us. 

Many oncologists would consider what I am proposing to be nothing short of heresy. Patients do not define the parameters of their own therapy and come up with their own clinical protocols. I should be burned at the stake. But once the intellectual pique is set aside, what exactly is so wrong with what I am suggesting? If the choice is a toss-up between Rituxan alone on the one hand and Rituxan plus full strength fludarabine on the other, what is so wrong with splitting the difference? Going for Rituxan plus low dose fludarabine might buy you the oomph you need, while controlling the risk of toxicity. 

If any of you actually discuss this option with your doctors, do remember the rest of us out here, we would very much like to know how it plays out. Remember my friends, we are all our brothers' keepers where this fight is concerned, there is a blood bond between us that transcends individual differences.




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