A Shot in the Arm for Rituxan

The title of this post is a bad pun that I think is funny, that most of you won't, and that those of you who are reading this by using Google Translate won't understand:

An FDA committee has recommended that subcutaneous Rituxan be approved.

Subcutaneous -- "under the skin" -- Rituxan is given by an injection rather than through an IV. A shot in the arm (though I guess it could be a shot somewhere else).

The subcutaneous Rituxan should take about 5-7 minutes to administer, rather than the 90 minutes it takes for IV Rituxan. (And that 90 minutes assumes that everything is going well. When I had it, I had an allergic reaction, so the first infusion took about 4 or 5 hours.)

The recommendation comes because of results from 5 clinical trials that used subcutaneous Rituxan, and found that the results were very similar to IV Rituxan. For example, in the phase III SABRINA trial, patients were given R + Chemo, with some patients getting Rituxan through an IV and some getting the Rituxan in subcutaneous form.The results were almost identical -- an Overall Response of 89.9% for the IV and 89.4% for subcutaneous, with Complete Response rates of 32.2% for both.

About 50 countries already use subcutaneous Rituxan (so if you didn't get the "shot in the arm" joke, all of this is probably old news to you.) It saves time, saves money, and generally makes a bad thing just a little less bad.

One question I have about all of this: does a subcutaneous administration re-start the clock on the manufacturer's proprietary ownership of Rituxan? In other words, other companies are allowed to make biosimilars of Rituxan now, which will mean fewer people will use actual Rituxan. Can those companies immediately start making or using biosimilar subcutaneous Rituxan, too? Or is this a new treatment altogether, and they'll have to wait a while, giving subcutaneous Rituxan no competition? If anyone has an answer, I'd appreciate it.

The FDA will make a final decision on approving subcutaneous Rituxan by June 26.  I hope none of us need it any time soon, but it will be nice to know that it's there if we do.

The phase III SABRINA trial compared the rituximab formulations in combination with CHOP or CVP chemotherapy in previously untreated patients with FL. The ORR was 84.9% in the IV arm (205 patients) and 84.4% in the SC arm (205 patients; P = 0.8911). The CR rates were 32.2% versus 32.2%, respectively. The HR for PFS was 0.84 (95% CI, 0.57-1.23; P = 0.3696) and the HR for OS was 0.81 (95% CI, 0.42-1.57; P = 0.5398). - See more at: http://www.onclive.com/web-exclusives/fda-panel-supports-subcutaneous-rituximab-for-blood-cancers#sthash.eNwNMEeQ.dpuf

Clinical Trial Stopped

Some bad news last week in The Lancet Haematology: a trial that looked at the combination of Idelalisib, Lenalidomide, and Rituxan was stopped because the side effects were just too much for patients (including some with Follicular Lymphoma). It's bad news, but not horrendous news, in my opinion.

The article is called "Safety and Tolerability of Idelalisib, Lenalidomide, and Rituximab in Relapsed and Refractory Lymphoma: The Alliance for Clinical Trials in Oncology A051201 and A051202 phase 1 Trials."

Basically, they took R-squared [Lenalidomide/Revlimid] and added Idelalisib to the mix. In theory, this should work. You have three agents that attack the cancer cells in different ways. If one or two don't do the job, then maybe the third one will.

The problem, of course, is that all three agents attack the cancer in different ways, they also all have side effects. Some are only found in one of the three agents, but some come from all three. And there's the problem.

There were 11 patients in the trial -- 8 of them had Follicular Lymphoma.(That's a very small number, but this is a phase 1 trial, so that's pretty typical). Over 28 days, patients were given Lenalidomide for 21 days, Idelalisib for all 28 days, and then had a Rituxan infusion once a week. Things seemed to go pretty well until patients received the Rituxan, and then symptoms of the side effects started to show up. The researchers stopped giving Rituxan, but a few patients continued to have symptoms. They decided at that point to stop the trial completely.

Specifically, the side effects were ALT elevation (a sign that the liver was being damaged) and rash for the Mantle Cell Lymphoma patients, and neutropenia (very low white blood cell count) and rash for the FL patients. (I know I don't talk about side effects enough when I discuss research -- I'm too focused on the positive -- but it's important to point them out here because it's the whole point of the article).

The researchers say that, obviously, this combination is too toxic to use. More broadly, they say that we need to bee more careful about the kinds of combinations that we attempt in fighting lymphoma.

A couple of observations, for what they are worth, from this non-expert:

First, I think our future as patients will continue to depend on combination treatments like this one. The whole idea just makes sense -- cancer cells seem to find ways around our ways of fighting them, so we need to keep finding new ways to fight. It's kind of like keeping mice out of your house -- you find the hole that they are coming in and block it, and then when they keep coming in, you look for another hole. Keep blocking the holes until they stop coming in.

(Unless the mice were used to help create Rituxan. Then they can come in any time they want....)

The trick, obviously, is going to be to find the right combinations -- the ones that are effective and safe. Every treatment is going to have side effects. We'll need to determine whether the side effects are worth it.

Second -- I sad this was bad news, but not horrendous news. What I mean is, this combination didn't work. But the three things that make up the combination do work. All as individual agents, and in other combinations (R-squared still gets lymphoma experts very excited, and Rituxan + Idelalisib is very effective in CLL -- no word on FL yet). It's easy to be alarmed at a headline and start to get worried about different agents, but there is still a lot to be hopeful about with these three, alone, together, and combined in other ways.

The real lesson here, though, is to thank the heroes who took part in the trial. Nothing happens without trials, and trials don't happen without patients who are willing to participate in them. So here's another reminder to think about being a participant, with another link to Lymphomation.org's page on Clinical Trials -- how to find them, how they work, why you should participate, and things to think about before you do. Good stuff.

So, bottom line -- a set-back for us, but I think something good will come from it in the end.

Venetoclax Phase 1

The Journal of Clinical Oncology has published the results of a phase 1 study of Venetoclax, in an article called "Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma." The article reports on a phase 1 study, which means it is very early on in the process, but it is promising.

The treatment being studied in Venetoclax (also known as Venclexta and Venclyxto and ABT-199). Venetoclax is a Bcl-2 inhibitor. That probably requires some explanation.

Bcl-2 stands for "B-Cell Lymphoma 2," and describes a particular gene that controls a particular protein. These proteins are important because they help tell a cell when to die. Too much Bcl-2 means the cells don't know they are supposed to die, which, of course, causes cancer.

(OK, it's slightly more complicated than that. Keep reading if you want the complicated version:
Bcl-2 becomes a problem when two chromosomes switch places -- number 14 and number 18. This switch is one of the genetic mutations that define Follicular Lymphoma. You might see it written as t(14;18) or translocation of chromosomes 14 and 18. That's a problem because when those chromosomes are switched, it puts the Bcl-2 from 18 next to something from 14, and when they combine, the Bcl-2 becomes a problem, and shuts off apoptosis -- the natural signal that tells a cell to die. No dying = cancer cell.)

The important thing is, too much Bcl-2 means the B cells don't die.

Venetoclax turns off the Bcl-2 gene, so the cells know that they are supposed to die.

Venetoclax  has been around for a little while. It's one of the treatments that the FDA approved as a Breakthrough Therapy in 2015, for relapsed and refractory Chronic Lymphocytic Lymphoma.

This phase 1study looked at a bunch of NHL types besides CLL, including Follicular Lymphoma. There were 106 patients in the whole study, and 29 of them had FL.

Of the 29 with FL, 11 had a response (4 Complete Response and 7 Partial Response) and another 17 had Stable Disease. Only 1 of the 29 got worse.

There are more details in the article about important parts of phase 1 trials: how much of a dose that certain patients were given (that was especially important for the Follicular Lymphoma patients), and what kind of side effects patients had (and there were a bunch, but they were seen as manageable).

The researchers think that while Venetoclax going to be effective on its own, it will probably be even more effective when it is combined with some other treatment.

But that's something for the future. For now, this seems promising. The results, once again, are very early, and there will need to be a lot of work until Venetoclax is ever approved. But it's something else to look forward to. We'll definitely keep an eye on this one.

When and How to Treat Follicular Lymphoma

Targeted Oncology published a piece last week, aimed at oncologists, at how and when to treat Follicular Lymphoma. It's called "How to Refine Treatment Choice in Follicular Lymphoma," and while I'm not sure it's a "refinement" as much as a good summary of options, it still does some interesting things that are worth thinking about.

The article opens with the very true idea that there are lots of options for FL patients, and many different variations of the disease -- some of us have a version that's pretty slow-growing, some more aggressive, and some really aggressive. And even within those general categories, we as patients are all a little different. So how does a clinical oncologist (someone who isn't a specialist in blood cancer) think about the best way to treat?

First, the authors say, you should look at some basic tests -- a biopsy of the node (NOT a needle biopsy, which won't tell you enough), a scan, some blood work, maybe a bone marrow biopsy. (I would hope that even the most general oncologist would know enough to do stuff like that). With some data, some analysis can be applied: determining tumor grade through the biopsy, a FLIPI score to determine risk, and a GELF score to determine tumor burden.

[A comment on this analysis: I don't think FLIPI (FLIPI-2) is all that useful for individual patients. (Go to Lymphomation.org to read a little more about why.) And, interestingly, the authors don't mention it for the rest of the article. Ignore your FLIP score; there are lots of other ways to think about your own individual disease.]

With all of that data, an oncologist can figure out the best way to treat. The main point of the article is to offer "an algorithm" for determining treatment, which I have copied below:



There are four factors to deal with: whether the patient is showing symptoms or isn't, and whether the patient has high or low tumor burden.

From there, the article goes through the four possible combinations of those factors, and why one would choose one treatment option over another. For example, a patient who isn't showing any symptoms but has high tumor burden basically has tow choices: watch and wait, or Rituxan + chemo, with or without Rituxan Maintenance.  Watching and waiting might be appropriate if they are on the very low end of the GELF scale, with tumor burden that barely qualifies as "high." But, given the risks that come with high tumor burden, most patients in this group will need treatment. The R-chemo can be given in several ways (CHOP, CVP, or Bendamustine), and maintenance might result in longer times until the next treatment (Progression Free Survival), but it also comes with greater cost, more side effects, and more time commitment for the patient.

In some ways, the article is kind of a narrative form of the NCCN Guidelines for treating Follicular Lymphoma. The "refinement" is providing more detail about why an oncologist might make certain (limited) choices.

But those choices are limited -- the choices laid out are watching and waiting, straight Rituxan, R-chemo, and maybe maintenance. For an article that says there are lots of options out there, it doesn't give too many of them. Even the NCCN guidelines for patients mentions at least a couple of other options: RadioImmunoTherapy and R-Squared (Rituxan + Revlimid).

And I guess this makes sense, thinking about who it is written for: general clinical oncologists who aren't specialists, who are dealing with patients that have one of about 50 different cancers. I get that. They want to do right by every one of their patients, and they don't have time to get into deep study for all 50 of them. This algorithm makes the choices easy, and it's based on what we know has worked in the past. No one is going to go wrong by using it. These treatments have helped a whole bunch of us already.

(But I still like to see more choices.)

I will give them credit for one "refinement," something that very few articles like this recognize -- patient emotion. Most attempts to lay out treatment options are based on clinical trial results -- the higher the percentage of responses, the higher the recommendation for using that treatment. But that's only part of the story. I've said it before, and I'll keep saying it -- Follicular Lymphoma is an emotional disease as much as a physical disease. Going just by the numbers, watch and wait is a great strategy for patients with no symptoms and low tumor burden. But if it means increased anxiety, it might not be the best choice. Most articles on treatment options don't mention that.

But this one does. In their opening, they say "When making therapeutic decisions in FL, it is crucial for practitioners to assess a number of patient-specific factors including age, disease burden, comorbidities, and coping style."  I love that they recognize patient emotion as a factor.

And for me, that makes up for the limited choices that they offer. If an oncologist reads this, and they get the emphasis on patients' emotional needs, that's huge. I like to think that any oncologist would keep an eye out for how a patient is reacting emotionally, but I know from experience that it's not always the case.

It's nice to get a glimpse into how oncologists might think when they consider how to treat us. We can help with one more refinement -- being honest about how we feel at the time, and demanding that they understand it.