Monday, September 22, 2014

Rituximab monotherapy in follicular lymphoma

When patients are diagnosed with follicular lymphoma, the treating doc often uses the “eye ball” test on the CT scans, blood work, and physical exam to figure out whether or not a patient has “a lot” or “a little” follicular lymphoma.

While the “eyeball test” is an approximation that requires individual physician judgment (ie. subject to considerable error), such measurements have been codified by what we call the “GELF criteria” which is a French acronym for “groupe d’Etude des lymphomes folliculaires” (ie. French study group of follicular lymphoma).
You are considered “low tumor burden” provided you lack any node > 7cm, have less than three nodes areas > 3cm each, no B symptoms (night sweats, fever, weight loss), spleen below the belly button, circulating follicular lymphoma, or bone marrow dysfunction from involvement (and a few others).
The distinction between “low tumor burden” and “high tumor burden” is relevant because clinical trials often distinguish between such patients in terms of the appropriateness of certain therapies (see: how I treat follicular lymphoma part 1 and part 2).  Patients with “low tumor burden” follicular lymphoma have been studied in studies such as “rituximab vs watch and wait” or the Resort trial (how much rituxan alone do you need), or even the SAKK study (some rituxan vs some plus more rituxan) whereas patients with high tumor burden are more likely to be studied in chemotherapy type studies such as bendamustine-rituximab vs R-CHOP type studies or perhaps other new study designs.
I wanted to focus on the “low tumor burden” population because I was preparing a talk and thought there were a number of important statistics that such patients should be aware of.  I want to simply list them here for your consideration.  They are drawn from three main studies linked here:
Resort Trial (Induction and Maintenance vs Induction and Retreatment when needed)
SAKK Trial (Four doses in one month vs eight doses in nine months)
From the study of “rituximab vs watch and wait”
Approximately 20% of patients with asymptomatic advanced stage disease can be followed for over 10 years without requiring treatment
Thus far NO study has shown that starting treatment EARLIER (ie immediately at diagnosis vs when needed) improves overall survival (very few studies have ever tried to prove this point
Patients who undergo watchful waiting may experience spontaneous regression in 12% of patients by two year mark evenly split between ones that completely disappear from CT scans and ones that partially disappear (in no case do we think the body has “cured” it, we just can’t detect it on scan
40% of patients with low tumor burden follicular lymphoma on watchful waiting will have growth of their lymphoma by two year mark.
Between 80-90% of patients with low tumor burden follicular lymphoma who receive rituximab will experience a response when evaluated several months post treatment
Between 10-30% of patients suitable for watch and wait yet receive rituximab will experience progression within 24 months (partially depends on how much rituximab is given)
Despite responses seen following rituximab, after following patients on average four years after randomization there is no apparent difference in overall survival or rates of histologic transformation between patients assigned to watch and wait versus rituximab (perhaps will change when data more mature?)
The average time a between diagnosis and disease progression when following watch and wait is approximately two years.
The patients who have most emotionally stable reaction to their lymphoma are patients who start rituximab and then continue on maintenance compared to those who take four doses and stop or those on watch and wait.
From the RESORT study (Rituxan followed by rituxan maintenance versus four doses or rituxan and rituxan re-use when needed)
In the average patient with low tumor burden indolent lymphoma who starts rituximab (whether with maintenance or reuse) it will work for about four years before something new is needed.
Patients who stay on maintenance rituxan are less likely to have disease progression, but those patients who “reuse” rituxan are often able to keep the disease under control for about same amount of time and use less rituxan (about 75% less rituxan)
From the SAKK study (which compared four doses of rituximab over one month versus eight doses over nine months in both previously treated and untreated follicular lymphoma)
If you don’t respond initially to rituxan, continuing it for four more doses doesn’t help
In previously untreated follicular lymphoma patients who respond to rituxan and get total of eight doses, almost half have not experienced any progression by 8 years compared to about a quarter of patients who only get four doses
There is a trend that does not reach the level of “statistical proof” that any patient with follicular lymphoma who gets eight doses compared to four might have better overall survival.  Caution here – not clear if this is real or statistical chance just making it look better

Long story short, you can slice and dice this info to do just about anything you want it to mean.  In my own practice, I generally start with rituximab once per week for four weeks then give one dose every other month for four more doses if I am starting rituximab alone in previously untreated patients.  I would not strenuously argue with others if they did it differently.  Here are a few key slides that come from the representative papers as well as a beautiful view of Mt. Washington in the Cascades east of Eugene