Saturday, April 04, 2009

Rituxan + fresh frozen plasma

"Here I come to save the day!" -- Mighty Mouse

Modern-day alchemists have been trying to turn rituximab into Mighty Mouse for years now. The partially murine-derived monoclonal antibody, best k
nown by its trade name Rituxan, can be used alone or in combination with chemotherapy to treat chronic lymphocytic leukemia. It doesn’t work too well as a single agent, but that hasn’t stopped some of us from using it that way because it is considerably less toxic than the alternatives.

When Rituxan attaches itself to B lymphocytes, including literally billions of CLL clones, it creates antibody-antigen complexes; it is the immune system’s response that determines to a great degree the effectiveness of the cell kill. That response involves activation of complement (more below) as well as the onslaught of our immunity army macrophages, neutrophils, natural killer cells, and the like. Finding ways to boost the attack, through means that are also comparatively benign, has a been a focus of research.

At MD Anderson, they added Leukine to Rituxan in a study of elderly patients. Leukine is a Granulocyte-Macrophage Colony Stimulating Factor, which means it encourages the growth of granulocytes (neutrophils, eosinophils, and basophils) and monocytes, which mature into macrophages. This booster was somewhat effective, according to the researchers, and had the added benefit of upregulating CD20 expression. CD20 is what the Rituxan gloms onto on the surface of the B cells — the more CD20 you have, the better. (CLL cells don’t have that much CD20 when compared to those of, say, non-Hodgkins Lymphoma, on which single-agent Rituxan is much more effective and for which it was first approved by the FDA.)

Neupogen, which stimulates the growth of granulocytes but not macrophages, was advanced as a booster some time ago by CLL Topics
. Despite a few mouse studies and the like, the idea never made it to clinical trial in humans, which means the evidence we have is anecdotal. I tried it in 2004 and 2005 and it didn’t do much for me, either in terms of lowering my lymphocyte count or, more importantly, reducing stubborn lymph nodes. It did allow me to experience the unusual sensation of rodents running around in my bones, which was actually the sensation of cells reproducing madly, not unlike that crazed Octomom we’ve been hearing about of late.

Similarly, I tried adding Beta-glucan to Rituxan in October 2006; there is an open clinical trial on this based on some evidence that it might encourage activation of the complement system. In my experience, this was, again, more theoretical than real.

The bottom line
on all these boosters is that they are pretty mild, and therefore unlikely to do much for anyone except those who have mild CLL. Those like me, with progressing disease, need a little more mighty with our mouse.

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A promising area of booster research focuses on complement. Complement, a system of proteins circulating in blood plasma, forms our innate immunity. It is what gives some of us CLLers a fighting chance against infection long after our immunoglobulins have declined to frighteningly low levels.

Through a comp
lex series of events, these proteins can be brought into action, focusing the body’s attack on the offending Rituxan-CLL complexes; macrophages play a close, interactive role with complement and even create some of the proteins found in complement. Derived from the Greek for “big eaters,” macrophages are powerful tools, capable of gobbling up huge numbers of CLL cells or, if misdirected, as in autoimmune hemolytic anemia, red blood cells. (If there were a way to get macrophages to destroy CLL cells with the same efficiency that they go after red cells in AIHA, my CLL would be cured in a few weeks.)

It is this process known as Complement Dependent Cellular Cytotoxicity that accounts for much of the cell kill when Rituxan is used, so finding ways to tweak it has been a focus for researchers.

One thing they have fo
und is that complement tends to be depleted rather quickly after Rituxan is infused. Typically, there is a cell-killing frenzy in the first 24-48 hours, which declines as time goes on. Successive Rituxan infusions are accompanied by less dramatic results as complement gets used up and has little chance to recover.

This has been my pattern. For example, when I was on Dr. John Byrd's thrice-weekly Rituxan regimen in October 2006, I reported the following in this blog:

The plan was to do Rituxan three days a week for two weeks, 375 mg/m2 each time. To this I added 2000 mg of Beta-glucan daily, the same product being used in a clinical trial of CLL patients at the University of Louisville, Kentucky. My CBC was done before each infusion, so I had the opportunity to see what was happening more frequently than in the past.

The treatment opened with a bang. My absolute lymphocyte count of 153,600 dropped to 48,200 within 48 hours. My chipmunky neck began to slim down. Another 48 hours put my count at 26,600. And that’s about where it stopped. By the middle of the secon
d week I was reaching my Rituxan plateau, both in terms of nodes and counts. . . . My doctor suggested, and I concurred, that there was little point in doing the sixth infusion.

Aside from depletion, complement deficiencies have been identified in some CLL patients, especially those with more advanced disease. It is also thought that these deficiencies may be the cause of autoimmune problems.

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So what if we give the patient more, possibly healthier complement from an external source?

That leads us to the latest booster in the news, fresh frozen plasma (FFP), used in a small study of Stage 4 patients by doctors in Israel and Greece. The results were published last year under the title Adding fresh frozen plasma to rituximab for the treatment of pa
tients with refractory advanced CLL. (The study appeared in QJM: An International Journal of Medicine, a peer-reviewed publication of the Oxford University Press.) The idea was to take FFP, filled with all those complement proteins, and give it to patients along with Rituxan.

Five patients with “severe, treatment-resistant CLL,” including three who had failed Rituxan, were given two units of FFP, followed by the standard dosage of 375mg/m2 of R
ituxan. Treatment was repeated every one to two weeks for two to five cycles. The authors reported that “a rapid and dramatic clinical and laboratory response was achieved in all patients. Lymphocyte counts dropped markedly followed by shrinkage of lymph nodes and spleen and improvement of the anaemia and thrombocytopenia. This could be maintained over 8 months (median) with additional cycles if necessary. Treatment was well tolerated in all cases.”

The full paper provides some useful detail; I have a hard copy, purchased by my hem/onc, who finds the R-FFP idea intriguing.

All patients showed an improvement in hemoglob
in and platelets. Rituxan usually improves these figures on its own, so it is hard to say how helpful the FFP was in this regard. But since we are dealing with a group of treatment-resistant salvage patients, my guess is that the progress is meaningful. Here are the before-and-after results for each patient: Hemoglobin — 9.0/11.1; 9.7/13.0; 6.4/11.0; 9.7/14.2; 10.2/14.7. Platelets — 40,000/92,000; 75,000/128,000; 13,000/58,000; 70,000/83,000; 117,000/140,000.

Of particular interest to bulky-disease-me are results on lymph nodes. Certain nodes were measured in each p
atient, with these before/after results: 7cm/2cm; 1.5 cm/normal; 6 cm/3 cm; 2 cm/normal; 2.5 cm/normal. Of course, CT scans would have provided a much more accurate measurement, especially since Rituxan like most treatments tends to be less effective on deep abdominal nodes, which cannot be palpated (measured by hand). While I would not expect R-FFP to perform miracles in node reduction, it does seem to be more effective than Rituxan alone.

The patients were followed for a median of eight months (range 4-24) and were described as having “durable
” responses, “already well over a year in two of the patients.”

The authors discuss how FFP may work by correcting “qualitative and quantitative abnormalities of the complement system reported in patients with advanced disease. Even normal complement may be rapidly depleted as a consequence of RTX therapy. Thus, supplying complement and enhancing compleme
nt-dependent cell lysis by the FFP/RTX combination may be the crucial factor. However, this is not the only mechanism possible. FFP would have provided immunoglobulins which are frequently very low in most patients with CLL and could affect the kinetics of RTX metabolism. These postulates require further study.”

The authors understand that the results of their study need to be “confirmed in larger series of patients and in controlled settings.”


But they conclude, “Our initial observations in the treatment of five patients with advanced, treatment-resistant CLL suggest that the concurrent administration of plasma with RTX may afford a remarkable clinical response that can be maintained. The clinical and hematological improvement was observed within days and occurred even in three of the patients who had failed standard RTX treatment. The administration of plasma may have corrected complement abnormalities associated either with the CLL or with RTX action and appears to be safe. Further controlled studies are required, but even now, the possibility that RTX action may be enhanced by this simple, cost effective method should be noted.”

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Before we do our R-FFP h
appy dance, it is worth remembering that nothing we put in our bodies to treat cancer is risk-free. FFP has some potential side effects worth noting.

Since it is a blood product, FFP carries a small risk of viral transmission similar to that of red blood cell and platelet transfusions. While red blood cells are sometimes irradiated to kill viruses, this is not done to FFP. Donor-retested FFP is probably the safest form available; this involves holding the plasma in quarantine for a minimum of 112 days until
the donor can be retested to check for viruses that may not have shown up during initial screening. This is a cumbersome process, which makes donor-retested FFP difficult to come by.

An easier “fix” is for FFP to be given through a filter that should catch any errant white blood cells that may be carrying an infection such as CMV. (The plasma is supposed to be free of white cells, but a few may s
neak in.)

Upon infusion, allergic reactions occur in a small number of patients, usually consisting of urticaria (hives), a
rash that can be mild to severe.

Antibodies in donor plasma can also wreak havoc. According to the UCSD Laboratory Services Guide, “Antibodies in the plasma may react with the recipient's red cells, causing a positive direct antiglobulin [Coombs] test.” In other words, it could open the door to AIHA. I should point out, though, that one patient in the Israeli study had AIHA, that his HGB rose from 9.7 to 14.2, and that he was described as “asymptomatic” after treatment.

Wikipedia reports that “the potential for alloimmunization is present, as demonstrated by the infrequent formation of Rh antibodies.”

One rare, unintende
d side effect is the possible development of Human Anti-Mouse Antibodies in other words, the FFP might create an allergy to Rituxan! This can happen over time anyway, as this link explains, and it doesn't necessarily mean Rituxan can't be used again. Dr. Terry Hamblin once wrote, "HAMA responses can inactivate the effect of the rituximab, but not always. Sometimes giving more antibody overcomes the response."

Another problem, UCSD adds, is that “In rare instances, noncardiogenic pulmonary edema (transfusion-related acute lung injury) may develop due to antibodies in donor plasma that react with recipient leukocytes.”

I discussed some of these issues with my doctor, who noted that FFP is a commonly-used product that seldom results in a worst-case scenario. Two units, she added, is a relatively small amount. Patients need to be watched for
blood clots, which can be warded off by taking enteric-coated aspirin. (Indeed, FFP has been given in cases of ITP since it helps with clotting.) Fluid retention is also a concern, and can be relieved by diuretics such as Lasix. Those issues, and possibly a mild rash, are more likely to present themselves than exotic antibody problems.

I am left to conclude that FFP is relatively low-risk as these things go, probably on the order of Rituxan itself. Rituxan, of course, is not benign for everyone; it can cause anaphalactic shock during infusion, and later on can cause severe skin problems, lead to viral reactivation, and so on. This doesn’t happen to most people, but it does happen. Similarly, FFP appears to be easily tolerated by most, and a real problem for a fe
w.

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I am going to try it. I need to do something to kee
p my disease in check, and I have long been fascinated by the possibilities of this combination. I enter the protocol with my eyes wide open, knowing that it is experimental and that it may not work. If it were a run-of-the-mill Rituxan booster, I wouldn't even consider it; the potential of FFP to deliver a much more powerful punch has convinced me to go ahead.


My best-case scenario is a response similar to the patients in the study, especially in terms of lymph nodes.
If the protocol can make a reasonable dent in my lymphadenopathy, it will have done so at minimal cost in comparison to the alternatives. Giving R-FFP a try is unlikely to burn any bridges, and I will know in fairly short order whether it works on me.

The most likely worst-case scenario is that FFP, like the other Rituxan boosters I have used, simply won’t do much. Outside the Israeli study, I know of one patient in the USA who tried R-FFP, every two weeks for three cycles. He reported to the ACOR CLL List that he found it “arduous and ineffective.”

In which case, should my results mirror his, it may
well be time for me to go a more traditional route perhaps high-dose steroids accompanied by Rituxan and Campath, or else Revlimid.


It is worth stepping back here for a little perspective as supplied by Dr. Hamblin. "Monoclonal antibodies," he once wrote, "are not the magic bullets that people hoped they would be." Cancer cells have defenses against attack, and the way Rituxan works is not completely understood, which is why so many booster ideas are better on paper than in real life. Perhaps there is no way to create a
Mighty Mouse that is truly strong enough to save the day.

Nonetheless, FFP is the most promising idea to date. The theory behind it is sensible. The study results, limited though they may be, are encouraging. And you never know what your body might respond to. My doctor and I figure it is worth a shot.
Based on my history, I expect to tolerate the protocol well. I have used Rituxan extensively, with no problems, and the one time I had a blood product (IVIg), it went smoothly.

A final note: All this Rituxan-boosterism may be rendered a moot point within the next year as HuMax-CD20 presumably gains approval from the FDA under the trade name Arzerra. HuMax, a fully humanized monoclonal no mouse! works much better with the complement system than Rituxan does. If I could wait for it, I would. But my CLL moves faster than the government.

10 comments:

Richard said...

Good luck David! Your cost/benefit analysis makes sense to me. I'll be very interested to hear how your treatment goes.

Anonymous said...

David
You've made the right decision in my opinion. Please keep us all informed of how you go with the treatment. I have a good feeling about this for you. Thanks once again for all your information - you really are helping others and I am so grateful for your blogs.
kindest regards
Jeda, Australia.

Anonymous said...

If memory serves me correctly, the real downside is that the responses were of limited duration. I've read the same papers and my initial enthusiasm was tempered by the fact that most patients relapsed rather quickly. It's not a new idea, and has been tried at least several times over the past decade or so.

David Arenson said...

First, thanks for the good wishes.

As to duration, treatments based on single-agent Rituxan tend to be of limited duration by their very nature -- six months to a year being a pretty good remission. This comes with the territory.

To quote from the blog and therefore from the paper: "The patients were followed for a median of eight months (range 4-24) and were described as having 'durable' responses, 'already well over a year in two of the patients.' " That's not a bad track record.

The idea isn't brand new, and an abstract was published in 2003 by some of the same Israeli authors who described the results in the case of just one patient. I am aware of no other patient studies, however. The general concept has also been investigated by Ron Taylor et al in Virginia, who has written a fair amount about Rituxan and complement.

So while the idea has been kicking around for a good five years, little has been done in patients. The latest paper has helped kick-start some interest, especially among local hem-oncs who find a published study useful as a guide.

Justin said...

David, I have been following your blog for a few months now and I wish you a successful outcome with your latest approach. You mentioned in your Blog "My absolute lymphocyte count of 153,600 dropped to 48,200 within 48hours". I am confused by these numbers. How does it relate a lymphocyte count with x 10 to the power 9 per litre after the number?

Very best wishes, Justin H

Helene said...

David,
I found your blog first when my husband was diagnosed, then cll topics and the forum. Your experiences were my portal...now I follow your experiences and choices with such great interest, since you are a knowledgeable and proactive patient, and unfortunately, have faced different manifestations of this disease. I read the R + FFP study last summer and have wondered why it hasn't been more picked up. I think it is a logical choice and I hope it will really do the trick for you. I hate to call you my "canary in the coal mine", but seeing others pave the way....it's sort of like that!

Helene

David Arenson said...

Helene,

I'll be your canary, hopefully singing through the process, which may begin this week with any luck. I'll report to the blog as it goes along.

Justin,

According to Prof. Susan Leclair:

In the US, the reference range for total white blood cell counts is between 4,000 - 11,000 or 4. - 11. x10 raised to the 9th power per litre or 4. - 11. x 10 raised to the 3rd power per microliter..

Here are a couple of hopefully helpful links:

http://cll.acor.org/pp-blood-tests.htm

http://cll.acor.org/cllfaq/answers/14.html

bob larkin said...

Wow David, I was totally unaware of this. I like your decision. Thanks for your typically cogent rendition of the subject matter. I'm somewhat envious, as I enter my second week of R/Campath (650mg Ritux each Monday/30mg SubQ Camp on Mon, Tues, Wed). I'm doing this after a 14 month remission from SubQ Campath in '07. I think I might liked to have tried the R/FFP dance first. I'll be following you and wishing you well.

Anonymous said...

There may have only been two papers published on this idea, but I've heard about/read about this idea more than that. On the other hand, I correspond with some CLL experts on occasion over the years. I suppose that's where I've encountered the idea previously.

The fact that a handful of folks have durable responses is of cold comfort when one realizes that most don't.

Buying time isn't a bad idea of course, but since there is little on the short horizon, that's probably all we are doing. But, better than nothing.

Anonymous said...

David,

Just well wished here in case you have begun. I'll be checking the blog and cllforum for updates on your progress!

Maybe you are a journal article waiting to happen, who knows?

Helene