Saturday, August 8, 2015

A More Accurate FLIPI?

Fascinating article soon to be published by Lancet Oncology: "Integration of Gene Mutations in Risk Prognostication for Patients Receiving First-Line Immunochemotherapy for Follicular Lymphoma: A Retrospective Analysis of a Prospective Clinical Trial and Validation in a Population-Based Registry."

Basically, this is all about improving FLIPI, so let's start there.

FLIPI stands for Follicular Lymphoma International Prognostic Index. It was developed by an international team of FL specialists as a way of deciding how aggressively to treat the patient by (essentially) guessing what the patient's 5 year survival will be.

I'm trying to be really careful here, as I am whenever I bring up FLIPI. It's kind of controversial, because it does pretty much make a guess, based on statistics from how FL patients have done in the past. Here is how FLIPI works -- each one of these factors gives you a point:
  • Patient is over 60 years of age
  • has stage III or IV disease
  • has five or more nodules or tumors, or more than four lymph node groups involved
  • has serum hemoglobin less than 12 g/dL
  • has elevated levels of LDH
Having 0-1 points makes you low risk; having two makes you intermediate risk; and 3 or more makes you high risk. The "risk" here is related to 5 year survival -- the higher the number, the greater the risk that you won't reach 5 years.

Let's be clear about this, though -- as says in its discussion of FLIPI,

"physicians may sometimes use FLIPI to guide treatment selection and possibly timing of treatment, but FLIPI is not predictive of outcomes in individual cases - or predictive of outcomes with specific therapies."

Having a score of 1 doesn't mean you'll necesssary live longer, and having a 5 doesn't mean you'll die in five years. This is based on statistics of how well patients did in the past -- in other words, old statistics.

There's a FLIPI-2 index, too, that used different measures and updated statistics. But it's also controversial, since it works on the same assumption -- comparing patients from the past to patients right now will allow us to make guesses about their survival. Not only are you looking at statistics from the past, you're also looking at some pretty general information. (Age, for example.)

That's where the Lancet Oncology study comes in. By looking at newer statistics and some different factors, they think they have been able to improve on FLIPI and FLIPI-2. It's the new factors that are the big change here -- their research looked at 7 different genes associated with Follicular Lymphoma, and whether they have mutated. (In case you are curious, the genes are EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11.) Those genes are associated with different levels of aggression in Follicular Lymphoma.

They call the new index m7-FLIPI, and after they developed it, they tested it on a different group of patients, and found that it was a more accurate predictor of 5 year survival.

So what does all of this mean?

Well, first the positive -- no version of FLIPI will predict how well an individual patient will do, but the fact that this group has been able to work genetic mutations into a new FLIPI says a lot about where we are in understanding Follicular Lymphoma. It wasn't long ago that we had no idea what kind of influence genetic mutations had on the disease. the fact that we can now identify them and use them in a prediction model is huge in showing how far we've come. It will only get better from here, as we are able to identify more genetic influences on our disease, and figure out how to use them to treat it.

Now, the less positive. Even though it's an improvement on the old FLIPIs, it still is far from perfect -- it was accurate about three-fourths of the time, at best. 25% inaccurate is still a pretty big number. In some ways, it's not surprising -- there are so many other factors, even beyond things like age and LDH and FOXO1 mutations -- that influence how well we do, that it's going to be almost impossible to make any kind of 100% accurate prediction. Cancer is just too unpredictable, and Follicular Lymphoma seems even less predictable than others. Then there's the basic question of what value a predictor even has -- if I know I am "intermediate risk," as my FLIPI score of 2 would suggest, what does that really even matter? I was treated fairly non-aggressively, watching and waiting for two years, and then getting Rituxan. Would things have been done differently if I was a 1 or a 3 at diagnosis? Probably not.

So I'm taking the positive big picture look at all of this -- it's a nice snapshot of where we are right now, in terms of understanding Follicular Lymphoma.

And it's only going to get better.


Anonymous said...

Another great blog. I, too, am risk factor 2. Watching and waiting with large tumor load and largest retro peritoneal mass of 10cm...
Doc mentioned R + B when it's time. How does one decide if it's only R or a combo?

William May said...

You can determine your m7-FLIPI score by knowing your genetic testing results for EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP and CARD11. See the m7-FLIPI tool at:

Lymphomaniac said...

Very interesting link. I don't have my own genetic results handy, though I'm pretty sure they've been done (I don't think it was done routinely 8 years ago, when I was diagnosed, but the director of the hospital I went to has stated that he wants every cancer patient tested).

Thanks for reading. Interesting question about how one decided. I think a lot of oncologists rely on NCCN guidelines ( -- my new onc seems pretty into them. But they don't say much about initial treatment in the guidelines, which might be why there are so many options. NCCN has recommended B + R, especially as an alternative to CHOP. I guess what it comes down to is your doctor's preference. Some might suggest Rituxan in your case, since you are watching and waiting, and therefore moving slowly. But the doctor might also see that bulky disease and think slightly more aggressive is better. If you have a preference for Rituxan, I'd ask the doctor why B + R, and see what he or she says. Maybe ask if you can try Rituxan first, and then add Bendamustine if it doesn't do the job? Whatever the case, certainly value your doctor's knowledge on this, but use your own knowledge to ask some informed questions about the choice.
Good luck -- when the time comes.

Anonymous said...

Thanks for your lengthy reply!
I will ask about R only...but I suspect my very large tumor load and large tumor masses, plus stage 4 may be the factor for adding B. I'm lucky my oncologist is also a hematologist, and he's young so I'm hoping up on all the latest!

Lymphomaniac said...

Sounds like Dr. R, my first oncologist. He was young, and did a fellowship in hematology at Yale, and he was up on (and excited about) newer stuff. My new oncologist is more of a generalist, kind of old school, and more of a rule follower (NCCN guidelines). We'll see how it goes.