Monday, January 2, 2017

ASH: Bendamustine and Toxicity

We're going back to the ASH conference, looking a little deeper into one of the presentations that delivered some good news. The session discussed results of the GALLIUM study, which showed that in some situations, Obinutuzumab (an anti-CD20 monoclonal antibody) worked better that Rituxan.

However, the data from the study also delivered some bad news -- about Bendamustine. It wasn't the focus of the ASH session, but it got some people talking, and made them very surprised.

I've been hesitating to write about this for a couple of weeks until I worked through it, but now I have and I'm ready to write. But because Bendamustine is a popular treatment for Follicular Lymphoma, I'm asking you to PLEASE read all the way through. I think the best discussion of the bad news about Bendamustine comes from the article "Bendamustine Toxicity in FL Raises Eyebrows -- and Questions" from Medscape Medical News. Read all of that article as well. (You might need a password to get in, but the account is free.)

So here's the deal:

In the GALLIUM study reported at ASH, 1202 patients were given either Rituxan + chemo, followed by Rituxan maintenance, or Obinutuzumab + chemo, followed by Obinutuzumab maintenance. Overall, the study found that patients in the Obinutuzumab arm had a higher Progression-Free Survival -- significantly higher. One of the big problems with Obinutuzumab was that it had higher toxicity that Rituxan, so patients had more side effects and more problems overall, in addition to having a longer PFS.

But then they broke things down a different way, looking at the different chemotherapies that were combined with Obinutuzumab and Rituxan. They found that of the three, patients who took Bendamustine with either O or R had a higher instance of death that with the other chemotherapies (CHOP or CVP).

This is what "raised eyebrows" at ASH -- a treatment that has been very popular in the last few years has an increased death rate over other options. Researchers reported 19 deaths for patients taking Obinutuzumab + Bendamustine (about 5.6% of that group in the study), and 15 deaths for patients taking R + Bendamustine (4.4%). For those taking CHOP or CVP, only 9 deaths occurred.

 Definitely not what we want to hear. HOWEVER, this is why that Medscape Medical News article is so good -- they interview some very smart people who have lots of experience with Bendamustine, to get an explanation and to find out how this new data will affect the way they treat patients.

In a nutshell, it doesn't change things in a really drastic way. The experts interviewed will either continue using Bendamustine the way they have been using it, and/or will be more careful about how they use it.

For example, one of the experts interviewed is Dr. Bruce Cheson (lots of you know how much I respect Dr. Cheson and his work). Here's what he has to say about the study:

"I was quite surprised by the toxicity [reported for the bendamustine arms in the GALLIUM study]. It has not been my experience," Bruce D. Cheson, MD, professor of medicine, head of hematology and deputy chief of hematology-oncology at the Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC, told Medscape Medical News.
Dr Cheson uses bendamustine for most patients with previously untreated FL. Although the data from the GALLIUM study are compelling and support use of obinutuzumab because of the advantage in PFS, its efficacy is counterbalanced by a higher level of toxicity, he noted.
"There may be a select patient population, such as the younger, fit patient, in whom I may use G-bendamustine in preference to R-bendamustine," Dr Cheson said. "However, for most, R-bendamustine remains my standard," he said.
For patients in whom there is a suspicion of occult transformation, Dr Cheson uses R-CHOP as induction in preference to R-bendamustine.

Some things worth noting here: In his experience, Dr. Cheson has not seen this kind of problem with Bendamustine. I think that's important. A clinical trial like the GALLIUM trial provides important, controlled data to help us understand how a treatment works in a large group. But it also controls the circumstances under which it is used. In this case, the GALLIUM study uses Bendamustine with a monoclonal antibody, and THEN follows that up with 6 months of maintenance.

At least one expert thinks that it is the maintenance that might create the problem. Bendamustine suppresses the immune system, and when you follow that up with an antibody that kills immune cells, it makes sense that there is a greater chance for infections. (Although not all of the deaths occurred because of infections.)

So some of the experts interviewed won't change the way they do things, and will keep giving patients R-Bendamustine, but perhaps without maintenance. Others will focus more closely on the individual patient, and what his or her body might be able to handle. Some may use CHOP or CVP if they plan to use maintenance, while others may use O + Bendamustine for the initial treatment,but then Rituxan for maintenance.

For me, I'm getting two big lessons from this.

First, Bendamustine is still on the table. My old oncologist, Dr. R, had always said that Bendamustine was going to be a consideration if and when I needed treatment again. This hasn't scared me off. I trust the experts that were interviewed, and none of them announced that they were giving up on Bendamustine, only that they were going to ask more questions about it.

Second, I think this will slow things down. As one of the experts noted, Bendamustine was pretty quickly adopted as a preference over CHOP, based on one particular study. Other studies backed up its effectiveness and safety. But maybe there needs to be more nuanced examination of who will benefit from the treatment. Maybe this will slow things down a little, and force patients (like me) from being so enthusiastic about it. That doesn't mean I wouldn't take it -- it just means I need to have a longer conversation with my oncologist about whether it's right for me, given whatever circumstances lead me to need treatment.

I'm sorry I couldn't start the New Year of with something more positive. It seems like everyone I know is looking for something to be positive about in 2017. But if nothing else, this is a good reminder -- and a good time for it -- that we should be active patients who take as much control of our own treatment as we can, asking questions and demanding answers, and not accepting what we hear about or read about online (including this blog).

Stay healthy everyone, and have a great New Year.


Marcela, canary islands said...

Happy New Year Bob !! Always reading your blog, is my orientation in my follicular lymphoma disease. Thank you for helping us understand and bring us news and knowledge. Health and Peace for you and your family.

Shelly said...

Hi Bob, I was dx in 2015 with an aggressive form of fNHL, so treatment had to start immediately. R-Bendamustine was induced - treatment was supposed to be 6 cycles, 28 days apart. I reacted to the R on first induction, so it was stopped and reintroduced the second cycle more slowly, Bendamustine was continued as prescribed. By end of third cycle start of 4th cycle I was diagnosed with pnuemonitis and put on steroids and antibiotics which cleared the issue. They blamed the infection on Rituxin and decided to stop it altogether, but continued with the B for the last two cycles. In 2016 scans showed CR. No maintenance was prescribed. I'm at one year anniversary for ending treatment and will have another scan in Feb. Anyway, long-story but after reading this I'm wondering if they jumped to blame Retuxin for my infection without considering the B could be the cause? From reading the entire article it appears there is a relationship to the maintenance component and the doctors are reconsidering prescribing maintenance only when there is a PR. So far, I am doing very well, no longer anemic as of last blood work and hope that I have been cured. I am so grateful to have found your blog during my treatments - you give me and so many others hope and of course scientific finding on fL. Watching you continue to live well and thrive this new year is all I need. Thank you! Shelly, Cape Cod

Mylegacy said...

Bob, I was told, in a letter from my Unc that - pending an unexpected result from my chest scan or my bone biopsy - that I would be a "Watch and Wait" with my FL. I was given a date five months(ish) off for my "next appointment." As a quite healthy, very active, 69 year old, I was delighted.

The very next day my Unc phoned - change of plan - "Your bone marrow is 95% involved with Lymphoma. We have to start immediately".

"Immediately" was to be a six month set of two day treatments of Rhythm and Blues (as I called them) or Rituximab and Bendamustine as most call them. I was to get B 12 times and R six times (R & B on the second of each set of two days and B only on the first day of each set).

The day before my first "set" I met with my Unc. Change of plan. Because of the 95% involvement they were concerned that "statistically" they might actually kill all my healthy B cells and also they might create a TLS situation where the toxic substances from the dead cancer cells (and the healthy B cells killed by R) overwhelmed the bodies ability to deal with it. SO - I got B the first day (to try and just knock back the cancer) and they skipped the second day (B & R) all together.

Last week I finished my third set of treatments. The second and third have both been the full two day doses.

During infusion - to me, sitting in the chair - B seems not unlike saline. I have no noticeable reaction of any kind. AFTER, there appeared to be almost no negative situations.

R however has been a beast of a very different colour. During my first infusion (this would be the second day of my second set) I got waves of slipping, sliding, itching and skin flushing on my head - then on/in my chest, then deep up in my armpits. My "Team" reduced and raised the feed, I ended up getting about 85% to 90% of the R in the bag.

Last week, the second time I got R, it started the same - my head began to itch and flush. Then BANG (literally BANG) I felt (what felt like) a blast of hot air go from the outside of both ears into my sinuses. My upper mouth felt very hot and sore (almost like a chemical burn), my tongue swelled up, it affected my speech and my breathing. To breath (adequately) I had to take deep breaths. As I did it felt like a pair of hands were holding my lungs and only slowly letting them expand as I breathed in. There was (as there had been in my mouth) reasonably significant pain in my chest. They switched me to saline until the symptoms subsided and then restarted the R.

As you will have no doubt noticed - I survived (so far).

NOW - B - to me like water - ends up perhaps having deadly "later" side effects. While R - which seems to hate me, and all I stand for, - may be the longer term "no problem" chemical.

My question(s) is/are: Is the problem with (R & B) Chemo the "short term" side effects (like I'm getting with R) of the chemicals during infusion OR some "longer term" effects that I have yet to encounter? I now know some of R's short term effects but are there "known" longer term effects of B & R who's joys I've still to look forward to?

To quote the yellow press tabloid: "Enquiring minds want to know."

Lymphomaniac said...

Hi Shelly. I hope things are going well on Cape Cod -- I grew up in Massachusetts, and have some great memories of the Cape. And congratulations on your year-long CR. As for the Bendamustine, it's hard to say if it was the B or the R that gave you problems. They work differently, but both can have some effect on the immune system, so I guess either could explain an infection. But it seems like they guessed right with the Rituxan -- you're a year out with a CR! I'd say that's the most important thing. I hope it continues for you. And thanks for reading.

Lymphomaniac said...

Hello Mylegacy.
First off, this is a good time to remind you (and anyone else reading) that I'm not a doctor, or a cancer researcher, or anything else that involves medical or science training. I'm just a guy who reads a lot. So anything I say is just speculation.
Second -- really nice description of your symptoms. Very vivid. I'm sorry you had to go through them, but you really paint a picture.
It does sound to me like you were dealing with short-term symptoms from the Rituxan. A good chunk of people have allergic reactions to Rituxan, and the thinking is that it comes from the murine (mouse-originated) parts of the Rituxan. I had some of the same symptoms as you when I had R -- itching and burning, but also some chills (rigor), plus horrible stomach pains for a few hours after the infusion. Those problems are all fairly easy to deal with in most people.
As for the Bendamustine, when it was first approved, it was praised for having fewer side effects than CHOP, which it was compared to for effectiveness. But again, those were relatively short-term side effects. We're seeing longer-term effects now, and I think researchers are going to have enough data to start thinking in more nuanced ways about the best way to sue Bendamustine (for example, NOT in combination with long-term maintenance, at least for some populations).
In short, in my non-expert opinion, I don't think Rituxan or Bendamustine are going anywhere, but they might be used differently. Both have been successful for a lot of people. And Bendamustine has been used in Europe for a long-time, so there has to be some long-term data there, too. We're using them in new ways, in new combinations, so we have to expect some new problems.