More on Rituxan Maintenance

I had planned on writing about something else today, but Mylegacy left a comment with questions last night on my last post. I put the comment off to the side and got back to writing, but the Cancer Nerd got the best of me and I started doing some research, and I found the whole thing fascinating, so I'm just going to answer it here.

At least, I'm going to try to answer it. This is a good time to remind everyone that I am not an oncologist or a cancer researcher or a biologist. I'm just a patient who reads a lot.

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Here is Mylegacy's comment:

What follows is/are a/several convoluted question(s). I do not know enough to say what follows as a statement of fact. IF I've missed the boat - PLEASE give me the smack down I'll deserve!

I understand that most of us who die with our "incurable" guest will do so from "infection." Most likely pneumonia or other respiratory illnesses. We will not succumb to FL, as such, but to the failure of our - by the time we're near dying - badly damaged white B cells being unable to guide the T cells to the pneumonia in great enough numbers, and in a short enough time frame, for our immune system to save us. Is what I have just written there correct(ish)?

IF SO: Then that is why I'm opposed to R maintenance. R is an indiscriminate killer of white B cells (is it not?). Cancer, or no cancer, R kills them. The ONLY reason it is safe(ish) is because it DOES NOT kill white B STEM cells. These "Baby B cell factories" continue to produce new B cells in our bone marrow.

However - over time IF you use R maintenance - who are reducing B cells and you end up with mostly new(ish) immature B cells. Our immune systems suffer - those of us who will die, will do so from the infections our mostly "baby/immature" B cells can not destroy. Our adult, mature, effective B cells have been decimated over time.

I've only had one 6 month R/B dance so far but just now (6 months after my final 2 day adventure) I'm in the 19th day of a cold. I'm 71, had a few colds in my time, but NEVER have I had one last this long. I'm beginning to think I understand what my future might look like. To make this journey even more interesting - I've already had pneumonia once about 15 years ago.

Intuitively, why wouldn't B maintenance (just killing Cancer cells) make more sense than reducing generations of adult B cells and diminish our bodies immune system being able to find and identify the bad guys for or T cells to kill? 

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OK, lots to respond to. (And it's just a response. I don't think I've given anyone a "smack down" since I was on the wrestling team in high school....)

We'll start with how we die -- that's the thing that caught my eye first.

I'm not a big fan of talking about death (I'm sure not too many of us are), though it's certainly in the back of our minds as cancer patients (and maybe the front).

I think the description of FL patients dying of infection is accurate for some patients, but I'm not sure I'd commit to "most" patients.

And before we go any farther, I want to remind everyone about what I wrote a couple of weeks ago about Overall Survival. Death is always part of the equation for cancer, but the median OS for FL patients is close to 20 years, and statistics don't say anything about individuals. Keep reminding yourself of that.

There has actually not been a lot of research on how FL patients die, though earlier in the year, there was a presentation at the Lugano Conference called "Cause of Death in Follicular Lymphoma in the Rituximab Era: A Pooled Analysis of French and US Cohorts." There were 1643 patients in the study, who were diagnosed from 2001 onward. The median OS for the patients was about 80% at 10 years.

The median follow-up for the patients was about 85 months, or about 7 years. In that time, the OS was about 83% -- 283 of 1643 patients had died.

(Let's repeat that, since we're talking about death here -- 83% of the FL patients in this study lived.)

Of those 283 patients, 49% of them died of Lymphoma. Another 15% died of treatment-related causes, including infection, heart problems, and Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) -- basically side effects of the treatment, whatever the treatment was. Another 12% developed and died from a different cancer, and a final 12% didn't have a cause of death listed for the study.

Of that 49% (about 140 of the 1643 patients) who died of Lymphoma, about 55% of them died from Transformed FL.

Now, even though "infection" is listed as part of that 15% treatment-related cause, Mylegacy's comment seems to be including "infection" in a broader way, one that would make it part of the "Lymphoma" cause. It certainly is the case that for some cancer patients, a weakened immune system leads to infection, including pneumonia. But that's not the case for everyone.

I think the important thing here is to understand that 1) Follicular Lymphoma doesn't kill everyone who has it -- it's a fairly small percentage, and 2) the cause of death varies.

That's important to make clear, given the second part of the comment.

Rituxan Maintenance does indeed kill mature B cells. But I don't think the immune system works in such a way that we end up with only immature B cells as our only defense. For one thing, not all B cells express CD20. And for those that do, not all of them are killed by Rituxan.

Stepping back a little -- Follicular Lymphoma is a B cell lymphoma. It affects a particular type of white blood cell called a B cell. B cells go through a a series of steps before they are "mature" -- able to do their job of finding invaders in the blood. If you want an explanation of how B cells develop, this video does a decent job of explaining. B cells start out in the bone marrow, and over time become differentiated -- the body sends signals that let the stem cell know which type of blood cells they need to develop into. So they develop into a form of B cell that is able to accept an antigen -- the thing that lets them fight a specific type of invader.

In the scenario described in the comment, Rituxan would wipe out all of those later-stage B cells that are able to accept an antigen, leaving only B cells that can't fight off invaders.

I don't think it works that way. Bone marrow produces new stem cells all the time. (I read somewhere that it is several million every day, but I can't find that source again.) Some of those cells will move on down the chain that eventually leads them to develop into mature B cells. The point is, the body has a supply of them ready to go when signals come that an invader needs to be fought. It's an ongoing process.

Rituxan goes after those B cells -- they have a protein on their surface called CD20 that Rituxan attaches to. It goes after them whether they are cancerous or not. That is certainly true. And while people are taking Rituxan, they are, for that reason, more susceptible to infection.Their B cell counts are lowered. But it's important to note that Rituxan doesn't wipe out the entire immune system. Some B cells remain in the blood, and stem cells go untouched, and they keep differentiating into B cells. 

The next question is, how long is the patient affected by this?

Well, Rituxan works slowly. It can take a couple of months for it to really start to bring the size of tumors down. And then Rituxan's effects can go for up to 6 months. It could be a full year before the immune system is back to "normal" again.

(By the way, I'm getting a  lot of what I'm giving here from the Lymphomation.org page on Rituxan. They're my go-to for all things Lymphoma-related.)

With Rituxan Maintenance, that period could extend for up to a year after the maintenance is finished (so if we're talking about the standard 2 year maintenance, then you'd have a good 3 years before the Rituxan's effects were finished.)

Next important question: are there any long-term negative effects from Rituxan?

Yes, for some patients. Again, Lymphomation.org helps us here, citing some studies that show that "Late Onset Neutropenia" is a side effect for 5% to 27% of patients who received Rituxan. For as much as a year after treatment, patients can have abnormally low levels of neutraphils, a type of white blood cell. I haven't seen anything to suggest that it's a chronic condition brought on by Rituxan. My understanding is that it is treatable.

So, again, the important point here is, Rituxan does a good job of taking out cancerous B cells, and does result in some side effects, including making patients more prone to infection. But those don't seem to be long-term. The idea that Rituxan Maintenance might have a negative effect on our immune systems over the long term just doesn't seem to be the case.

And further evidence about a lack of long-term side effects comes from the study that Mylegacy was commenting on. Both the maintenance group and the non-maintenance group in that study had about the same median Overall Survival rate -- about 80% after 10 years. If there was a negative long-term result from Ritiuxan Maintenance, I assume we would see a difference there, with a lower OS for the maintenance group.

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So let's sum all of this up.

Rituxan Maintenance is controversial. Given how it works -- finding and killing off B cells, whether they are cancerous or not, and lasting for up to a year -- it makes sense that it prolongs Progression Free Survival, when compared to patients who had a similar initial treatment but no Maintenance. 

However, while it does increase the risk for infection (given that it weakens the immune system), there does not seem to be a long-term negative affect. Patients who had maintenance after immunochemotherapy had the same Overall Survival rate as those who didn't have maintenance. The controversy comes when you ask whether the short-term risks are worth it, given the same long-term result in OS. Lots of different answers to that question.

Now, as far as causes of death, there's no question that infection (in some form) is a cause of death for some FL patients (as it is for other cancers). Many different treatments affect our immune systems -- including Rituxan.

But long term? The evidence that I found does not suggest that Rituxan or Rituxan Maintenance plays a role in long-term infections. If anything, experts agree that Rituxan has extended Overall Survival. Since the beginning of the "Rituxan Era" in the late 1990's, OS for Follicular Lymphoma has about doubled. 

And as for the last question in the comment -- why wouldn't Bendamustine Maintenance work better? Well, Bendamustine is a chemotherapy, and its side effects would probably cause much more damage through repeated use over the long term than Rituxan would. But the point is well-taken -- treatments that target the cancer cells, and not healthy cells as well, make a lot more sense.

And that's exactly what more recently-developed treatments are trying to do. We know so much more about the genetics of cancer cells now than we ever did, enough to know how to find particular biomarkers -- clues that let us know which cells need to be killed and which can be left alone, and which treatments can find distinguish between them. 

That's the future. And partly the present. Lots of treatments in different stages of development that will find cancer cells and get rid of them as needed. Researchers are still working on those.

But until that's all perfected, we could do a lot worse than Rituxan.

Thanks for the comment, Mylegacy. I hope that answered your questions. And I'll close out by saying, once again, that I'm not an oncologist or other expert in this area. I'm confident in the numbers I give, and what they have to say, but I know I oversimplified the biology. If anyone has a better explanation for all of this, please let us know.