Expanding Role of Rituxan
The number of chemo combinations that use Rituxan (or its newer analog ofatumumab) is exploding at an ever greater rate – FCR, PCR, R+HDMP, FR, R+Revlimid, FCR Lite, RCVP, RCHOP. These are only the more well known combinations.
(For the newly diagnosed and acronym challenged members of our community, here is a cheat sheet: F = fludarabine; P = pentostatin; C = cyclophosphamide; HDMP = high dose methylprednisolone; RCVP = Rituxan, cyclophosphamide, vincristine and prednisone; RCHOP = Rituxan, cyclophosphamide, doxorubicin, vincristine and prednisone)
These are all very potent chemo combinations and addition of Rituxan has increased response rates for most of them. The idea is to develop protocols that work for ever higher percentage of patients and give very long, trouble free remissions. The ideal would be a remission that lasts for the rest of the natural life of the patient – what we would call a full CURE.
But we are not there yet. With the exception of allogeneic stem cell transplants, none of the available therapies can claim to CURE this cancer. Remissions invariably fail, sooner or later. Given that fact, it is only commonsense that we would like to see remissions last as long as possible, as trouble free as possible, for as many patients as possible.
What is Rituxan Maintenance Therapy?
Early work with single agent Rituxan made it clear that this monoclonal antibody is not very good at doing the heavy lifting. In patients with high tumor load Rituxan was not able to do a good job of killing all those zillions of CLL cells by itself and patients got short lived remissions that soon relapsed.
But how about patients who have just finished therapy with a more potent combination such as FCR and are therefore cleared of most (but not all) of their CLL burden? Can regularly scheduled infusions of Rituxan do a maintenance job of keeping things under control? Can Rituxn kill off the stragglers and newly minted CLL cells as they show their ugly faces, roll back the disease and thereby prolong the remission?
More and more patients and their physicians are exploring Rituxan maintenance therapy after completion of various chemo protocols, as a means of prolonging remissions. Some examples are FCR-Lite followed by long term infusions of Rituxan over one or more years; R+HDMP (high dose methylprednisolone) protocol followed by Rituxan maintenance.
Is Rituxan maintenance therapy the proverbial free lunch? It is generally accepted that Rituxan has (relatively) low toxicity compared to other more conventional chemotherapy drugs. Does this approach allow patients to prolong failing remissions without too much additional toxicity? What is the catch?
Downside of Rituxan Maintenance Therapy
You are right, there is a catch. And it is one that is kind of obvious, once you think about it. Here is the abstract in ASCO 2009 that talks about it in scientific terms, followed by my own cartoon version of the science.
Hypogammaglobulinemia in pts receiving rituximab immunotherapy and the impact of rituximab maintenance.
Citation: J Clin Oncol 28:7s, 2010 (suppl; abstr 8088)
Abstract No: 8088
Author(s): C. Casulo, J. Maragulia, A. D. Zelenetz, Lymphoma Service, Department of Medicine; Memorial Sloan-Kettering Cancer Center, New York, NY
Background: Several randomized studies demonstrated that rituximab maintenance (RM) prolongs PFS but not OS following induction with rituximab immunotherapy (I) alone or chemoimmunotherapy (CI) in patients (pts) with indolent lymphoma. The long-term impact of rituximab (R) on immune reconstitution has not been well studied; however R has been associated with hypogammaglobulinemia (hypogam) with recurrent infections.This retrospective study sought to evaluate the relationship between R, hypogam, and treatment with intravenous immune globulin (IVIG). Methods: We identified 215 pts treated with R for lymphoma between 12/1998 and 4/2009 and also had quantitative serum immunoglobulin levels (sIg) evaluated prior to and after treatment with R. Data on the use of IVIG was collected. Frequencies were compared using Pearson χ2. Results: Histologies included: DLBCL, N=68; FL, N=42; CLL/SLL, N=38; MZL, N=26; MCL, N=22; other subtypes, N=19. Pts received a median of 6 doses of R (range:2-50). Prior to treatment with R, 85% (183/215) of pts had normal sIg levels and 15% (32/215) had low levels. Histologies among 32 pts with baseline hypogam were well distributed: DLBCL, N=10; CLL/SLL, N=5; FL, N=5; MZL, N=4; MCL, N=2; other, N=6. Of 183 pts with normal sIg levels prior to R, 26.7% (49) received RM while 73.2% (134) received R as I or CI alone. Hypogam was documented in 39% (71/183) of pts with baseline normal sIg levels following R.RM was associated with a higher risk of developing hypogam, 55% (27/49) compared to 33% (44/134) receiving I or CI alone, p=0.006. IVIG was administered to 13% (23/183) of pts with normal baseline sIg. Among patients who received RM, 20% (10/49) received IVIG compared to 10% (13/134) among patients treated with I or CI alone, p=0.05. IVIG for treatment of symptomatic hypogam was administered to 10% (18/183) of pts with normal sIg prior to R therapy. Conclusions: R was associated with developing hypogam in 39% of pts with normal baseline sIg. Pts receiving RM had a significantly higher risk of developing hypogam and requiring IVIG. The risk of symptomatic hypogam should be considered in the use of R maintenance.
Life of B-Cells
Immature B-cells leave home (bone marrow) with a single minded determination to find their purpose for living, to find a specific enemy to fight. Once they find a worthy enemy (usually a snippet from a bacteria or some other pathogen), they get fixated on that one particular enemy for the rest of their lives.
The majority of mature B-cells (those that have found their particular nemesis and gotten fixated on it) become plasma cells. Plasma cells do one thing and only one thing. They produce antibodies that can tag the enemy, the particular enemy that their B-cell mother identified. Pathogens that get tagged by antibodies are easy targets for killing by T-cells and NK-cells. Each plasma cell can produce several thousand copies of their particular antibody per second. As a result of this heroic effort, plasma cells live only a few days before they become exhausted and die.
Since each antibody produced by a plasma cell binds to a specific antigen (for example, a snippet of protein that is on the surface of the small pox virus), how many different kinds of antibodies do we need so that our bodies can fight the hordes of invading pathogens? Scientists have calculated we need about 100 million different antibodies to do the job adequately.
In a nut-shell, immature B-cells become mature B-cells, which then become plasma cells. Plasma cells make antibodies (immunoglobulins) that are essential for fighting infections of various sorts. People who do not have a wide repertoire of all the various kinds of immunoglobulins are at risk of more frequent infections and less able to shake the infection once it sets in.
Rituxan Kills B-Cells, All Mature B-Cells
Now we get to the heart of the problem. Rituxan targets CD20, the marker that is present on the surface of all mature B-cells. It is important to understand this: Rituxan targets all mature B-cells, not just the nasty B-cells that turned cancerous and became CLL cells. Long term treatment with Rituxan – especially maintenance regimens that schedule regular infusions for one or more years – runs the risk of killing off all the mature B-cells. Sure, it may keep the CLL hordes under control and thereby prolong remission. But one of the unwanted side effects is that the process kills of perfectly healthy mature B-cells as well.
You get my drift. No mature B-cells means no new plasma cells can be made, which in turn means no more production of immunoglobulins. Patients undergoing long term and regularly scheduled Rituxan maintenance regimens run the risk of tanking immunoglobulin levels, increasing their risk of infections.
What do do?
For starters, do not throw the baby out with the bathwater. Rituxan is a very powerful and extremely valuable addition to our arsenal against CLL. Anyone who has CLL and refuses to use Rituxan (or ofatumumab, if they are hypersensitive to Rituxan) when it becomes necessary are missing out on one a very good drug.
The jury is still out on whether Rituxan maintenance can truly prolong remissions and if this in turn means patients will live longer. In the meantime, patients who are on Rituxan maintenance can ask their physicians to order periodic blood tests to keep an eye on their immunoglobulin levels. The one to watch out for is IgG (immunoglobulin gamma) variety. If your IgG levels fall below the norms, it is time to consider IVIG therapy (intravenous immunoglobulin therapy). This is particularly true if you are getting a lot more infections than normal.
IVIG
IVIG therapy involves giving the patient immunoglobulins (IgG variety only) collected painstakingly from the pooled blood of generous blood donors. The process is complicated, carefully controlled and a lot of blood is needed to get sufficient immunoglobulins for just one patient infusion. As a result, IVIG therapy is expensive and the product is often in short supply. Neither your insurance company nor your doctor would be thrilled about prescribing regular IVIG for you. Nevertheless, it is important for you to know CLL is one of few diseases for which the FDA has approved IVIG therapy.
There is an inherent risk in any blood product therapy. The risks are greatly decreased where blood is carefully screened and modern protocols are followed to isolate immunglobulins. You can learn a lot more about IVIG infusions by reading an earlier article I wrote on the subject. As always, it is a question of balancing risks against rewards. Yes, there is a small and non-zero risk of IVIG therapy (contaminated blood, allergic reactions etc). But if you are getting serious infections that require hospitalization, in your shoes I would worry about that a lot more than I would worry about the risk of IVIG therapy.
Seriously folks. Many of the things we have to do as CLL patients are not fun and carry some level of risk. That goes for any kind of therapy, including Rituxan maintenance therapy or IVIG infusions. The trick is not to get so worried about a smaller risk (risk of therapy) and in the process fall prey to a much larger risk – risk of dying sooner than necessary from this incurable cancer. How is that for a blunt and stark lesson. One of these days I would love to report on a truly free-lunch option that has no downsides at all.
26 comments on "Downside of Rituxan Maintenance Therapy"
You must be reading my mind, Chaya! Recently, I’ve been thinking of discussing the possibility of some sort of maintenance therapy with my doctor since I don’t think my “remission” is going to last forever, and I would guess that the longer I go, the shorter the time to the next out-break of CLl and the sooner we should be discussing the possibility of another treatment.
When designing control systems, we always tried to start adjusting the corrections before the output showed a change, in order to keep the conditions stable. Guess that makes me think the same may apply to the human machine…small inputs now may all that may be needed to keep the results stable.
I digress…anyway, we have been keeping track of my IgG, but, even though it’s lower than “normal”, it’s been oscillating around 400-550. Up about 200 since my treatments. During my treatments, it got down to 230, but that was early and never got lower. Although we discussed the possibility several times, we never found the need for an IVIG infusion. I haven’t been getting any infections, and it’s not getting any lower, so Jane feels that I don’t yet need any help.
What mystifies me is that it is staying so low after all this time (over two years). I would think that the Rituxan (and maybe the Campath chaser…does that have the same effect?) would be “wearing off” by now.
Because of the lack of side effects during my treatments, and the excellent results since, I would have no objections to trying out some kind of maintenance therapy when and if needed. Would the Campath be a possibility for maintenance as well? And would starting either one earlier and at lower doses have the same effect?
Chaya.
Thanks again
The unanswered questions include will R maintenance add days to our life or even life to our days? Will we live longer or better (more quality time)?
Next does low immunoglobulin levels from R translate into more infections? We all know, treat the patient, not the lab report.
The jury is still out on these questions and will be for years. The studies should help
It’s a guess now, and one that is not risk free as you point out.
On a personal note, my CLL is measurable in my blood for the first time since my transplant 2 years ago, my nodes are growing with a cluster > 6 cm in the mesentery, and my ITP has escaped control with just IVig. I am R and cyclosporin again, heading towards a second transplant.
Brian
bkoffman.blogspot.com
just wish to say thank you for your no-nonsense apptoach to some very difficult subjects,clear and direct as always! It is good there are people like you; you keep someone like me sane
Mette
Fascinating! Your article explains a couple of things that I have experienced. In just a week or so I will be having my last Rituxan maintenance round. My oncologist has been watching my CD4 levels closely this past year or so. It was puzzling that my immunity was not bouncing back like he thought it would. Fortunately I have only had to have one IVIG infusion. I have an appointment with him later this week and will mention the abstract to him.
Once again, thank you Chaya for a job well done!
Harley:
Campath maintenence therapy is a whole another kettle of fish. Unlike Rituxan maintenance and possible risk of tanking IgG levels, Campath guarantees T-cell loss. In prior articles we discussed this risk. Folks treated with Campath have substantially reduced T-cell counts for as many as 9 or more months. Since T-cells are the frontline troops necessary to fight viral infections, Campath therapy carries the risk of viral reactivations as well as new viral infections.
Viral infections scare me a lot more than bacterial infections. Modern medicine has given us a number of powerful and broad-spectrum anti-biotics capable of fighting a host of bacterial infections. In sharp contrast, we have only a handful of anti-viral medicines, and none of them are broad-spectrum. In other words, each anti-viral drug fights only one or a very narrow range select group of viral infections. There are no really good drugs for the vast majority of viral infections – including the common flu.
Bottom line, in my layperson opinion, Campath maintenance therapy is too risky and may not be worth the reward.
Given that I have absolutely no understanding of the function of my very elevated IgG diagnosed with my SLL disease, may I ask if I could be a qualified blood donor to support others requiring IVIG therapy?
Dear Chaya:
Thank you for keeping us aware on our options; doctors don’t usually bring up the downside—and when you ask them about such matters, they play it down—ready to move onto the next patient in the waiting room. Knowledge is power.
Bless you.
Eden
QB:
No, I do not think you would be a safe blood donor. I strongly advice you against donating blood or any blood products.
Your very elevated IgG may be pointing to a different problem all together. One of the symptoms of myelodisplasia is elevated immunoglobulin levels. You should ask your doctor to look into it – if indeed the IgG levels are very elevated.
Once again thank you for your article. I have low IGG levels and have IVIG infusions monthly for the last 3 years since diagnosed with CLL. Even with my treatments I still have numerous infections. All respitory, sinus, bronchitis. Asthma diagnosed before CLL diagnosis. Im a breast cancel, uterine cancer survivor. Have been through Chemo for the breast cancer. Your articles and the feedback on this site is wonderful.
God Bless You
Barbara
Thank you as always, Chaya, for this very relevant article. I had RF in 2007 and about 3 maintenance treatments of Rituxan in 2007/8. I have had great blood counts, but now we think I have an auto-immune disease (rheumatoid arthritis? connective tissue disorder?). I finally got an appt with the rheumatologist for next week. Meanwhile, I’m in lots of pain. Anyway, do you think this type of problem could be related to too much Rituxan? thank you! Aditi
Chaya,
Thank you for a very timely and important article. I am recently finished with my rituxan/bendamustine chemo and happy to be finished.
Happy to be functioning without all the drugs, hormones, etc. Truthfully, it was a rough 6 months but no visible nodes at this time. My counts are responding well. CT scans and labs due in July.
Take care and Many Blessings,
Rita
Aditi:
Sorry to hear about your troubles.
However, if it is indeed rheumatoid arthritis, I doubt it is caused by Rituxan. In fact, Rituxan is being looked at as a possible therapy for RA.
RA is an autoimmune disease. There seems to be a higher risk of autoimmune disease associated with CLL. The more common ones are AIHA and ITP (reduced red blood cells and platelets, respectively), but I have heard of several CLL patients with RA – too small subset to make it into the professional papers I suspect.
Chaya:
Once again – thank you for another very interesting and informative article. I have a question and one comment, as follows:
First, my question: to your knowledge, is there any information available, or studies, if similar side effects occur with the use of ofatumumab – similar to the “side effects” of rituxan?
Second, my comment: as I have previously commented, your outline/article describes my treatment (fcr-lite), my “maintenance dose” of rituxan, and my adverse reaction to rituxan, etc. to a tee!
After my 6 month fcr-lite treatment was completed and I achieved complete remission (cr), I started to receive ongoing rituxan treatments every 3 months and this was to continue for 2 years. During my 6 month initial treatment phase on fcr-lite, as well as after I received each ongoing maintenance rituxan treatments, I became neutropenic and needed to be hospitalized. To make a long story short – my oncologist conferred with Dr. Rai (via a phone conversation) and together they thought that the best course of action would be for me to discontinue my rituxan maintenance treatments. Also, several months into the initial fcr-lite treatment, since my igg, iga and igm levels were all extremely low, in addition to the fcr-lite treatments, I started to receive ongoing ivig treatments (to try to boost my igg levels). Fyi, for those who are not totally familiar with IVIG, the IVIG treatments do nothing to boost the iga and igm levels.
The “bottom line” is that thankfully, I continue to be in remission, some of my “levels” fluctuate (platelets, etc) and my igg, iga and igm levels continue to be suppressed. As such, I receive ongoing ivig treatments (approximately every 4 to 6 weeks – depending upon my levels). Overall, I have remained relatively healthy!
Alan
Pittsburgh, PA
Alan:
No data exists on the possible adverse effects of ofatumumab maintenance therapy.
However, since ofatumumab also targets CD20, the same mechanism of action is in play and long term continued use of ofatumumab will no doubt be shown to deplete healthy B-cells and therefore impact immunoglobulin levels.
You are very right when you point out IVIG therapy is intended to increase IgG levels only, not IgA or IgM.
Thank you again Chaya, Do you know if there has been any follow-up to the Rituxan plus Fresh Frozen Plasma study and if this combination would be benefical in this context?
Elaine
Santa Cruz
Chaya, thanks for the informative article on CLL maintenance with Rituzan. You have given me something to discuss with my oncologist. Finished FCR in Dec 2009 resulting in complete remission and will now ask about R maintenance, immunoglobulin and treatment during my next appointment.
Chaya,
Another good article. I have long wondered why the oral form of IVIG has not caught on when it it needed in a prophylactic type situation.
A bit off this specific topic, but someone mentioned a lack of understanding. The Russians have an old saying, you can never know enough about your enemy! There is a long standing immunology myth you bought up that I can debunk for your insiders. You repeated a statement said by many esteemed immunologusts for many years, we need 100s of millions of different antibody types, and by definition, 100s of millions of B cells to make these things. Jerne won a nobel for this so called lock and key theory. Of course it could never be proven, it takes DNA sequencing to tell the difference in antibody structure and 100s of millions of dna sequence reactions would take a person many lifetimes.
Here is the dogma for 21 BILLION possibilities: http://bcs.whfreeman.com/thelifewire/content/chp18/1802005.html
I remember thinking in high school this was absurd, but it took long into my science career to find the truth. A person with a physics degree showed me a book by a biochemist. These objective people found out that almost all these possibilities cannot possibly exist in nature due to the charges of the amino residues. Think putting 2 magnets together from the wrong end. They stated only about 1500 real possibilities exist. Immunologists love to make a big deal about recombination for a tighter fit, but the fact is most antibodies are made by B-1 cells, (the kind we think CLL cells used to be) and they never mutate their heavy chain. They get by the way God made them. Normal B cells work like a set of sockets, swapping out the business end till an exact fit is achieved, but the B-1 cell makes antibodies like an old crescent wrench, there is a little flexibility, but no changing in a new top. Even wiki says B-1 cells make polyspecific antibodies, but old myths die hard.
They work because they stick and then stick together, as you said. Once they have coated something, other cells lap it up like candy.
elainebe:
Nothing further on the Rituxan + fresh frozen plasma concept. It was just that one research group, very limited data on an extremely small group of patietns – sounded interesting back then but couple of years later and no progress on the concept – I don’t think it is going anywhere fast.
Dear Chaya,
Thank you so much for your timely article. My husband is finishing treatment with PCR soon and may be considering Rituxin or Revlimid maintenance.
Do you plan to write on Revlimid maintenance as well?
All the best,
Leslie E
ljeisenberg:
Revlimid at low doses as a maintenance program over long periods of time has been proposed. We will know more about how well it works and the downside risks when the chemoprevention trial gets done. I wrote about this approach in a previous article titled “chemoprevention for high risk CLL”.
chaya and fellow cll patients:
according to my oncologist: rituxan, while it can be very useful, can have quite a few downsides – as your article clearly indicates. My oncologoist has indicated to me that he has personally witnessed quite a few adverse/pancytopenia effects with patients who are receiving rituxan. He has also seen/experienced a previously “not reported” adverse effect in the literature – a patient with a severe case of vaculitis.
so, as the article points out – there is a “catch”. my advise to all of my fellow cll patients: if currently on (or considering) a rituxan treatment plan, there needs to be caution and ongoing close monitoring by you and your oncologist.
Alan
There are very few drugs with absolutely no side effects.
While Rituxan does have an adverse effect profile that you should be aware of, and we have done our share of bringing the possible complications to your attention, I must nevertheless point out that this is one heck of a valuable drug for CLL patients. For the vast majority of CLL patients Rituxan’s potential rewards far outstrip its possible adverse effects.
Is Rituxan a good choice for you? That depends on your individual situation, your particular drug response profile and CLL risk category. I can provide the general statistics and drug information. You have to do the heavy lifting to find out how applicable the general guidelines are to your specific situation, consult with your doctors and then make the best possible and informed decision you can make.
Two commonsense rules to remember: compare the risks and rewards before you jump into any therapy; don’t throw the baby out with the bathwater – unfortunately, putting up with some amount of adverse effects is baked into the CLL cake.
Chaya, as you know my husband has been on Rituxan maintenance for about seven years now. With very little down side all of these years, we are glad this is the path we chose with his fairly aggressive disease. Still, would the RF or even the FRC that was suggested by Dr. P in 2003 and 2004 have done a better job over these years? Who knows. You are so right about the potential downside of Rituxan in many people though, and we need to realize that every treatment has a downside. Thanks for keeping us aware, I know I went many years thinking that R might be a free lunch and absolutely nothing is. I hope to hear more about the CAL-101 soon, that sounds interesting (especially with nodes) but I guess it is years away from general availability.
Chaya,
Thank you for an informative article.
Stay well,
Monique
Thanks for yet another great article. In 2008 I did not even blink when my onc suggested FCR (although I cringed and moaned!), and was thankful for Ritux to potentialize the actions of C and F. I had 3 months of treatment. 3 months later, when the doc strated talking about Ritux maintenance, I read everything I could (thanks Chaya, lots came from CLLTopics), consulted with other docs, and finally decided not to go the maintenance route.
This month it is a full 2 years later, and I am in absolutely great shape. All my blood indicators are healthy and in the normal range; very few nodes and very small. I am happy with my decision.
However, the onc-hema doc still insists that Ritux maintenance prolongs remission, and he still wishes I had opted for it.
Have now finished 4 treatments with PCO at Duke. Two separate doctors have looked at the results and both reacted “Wow”. Here is what happened with the CLL cells. First treatment dropped the CLL from 277 to 5.2. It actually declined to 4.6 by the third treatment. Initially, the crashing of the CLL cells knocked down the red blood as well. That is now back up and the platelets are 110 vice 92 at the start of treatment. The worst part of this treatment so far has been the neulasta shot – tired and queasy for a few days. I am on a six treatment every three week routine. Frankly, the doctors can’t find anything in the blood or anything in the lymph system so from the third treatment on we are flying on faith the the PCO is producing a deeper cleansing with each treatment. At this point, without a bone marrow biopsy —- who knows???
Nobody has really mentioned the idea of maintenance yet. Personally, I am tending toward not doing maintenace as there are so many new things coming down the pike that appear to improve on what is in being that I would not want to put myself through continuous PCO if the cost benefit favors the next generations of better living through chemistry.
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