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 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.