Wednesday, March 22, 2017

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.

Saturday, March 18, 2017

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.