A lot has changed in follicular lymphoma in the past few years. Quite a few items considered standard of care just a few years ago have been replaced by new standards. I thought it might be worth while putting forward my take on all of it. For the purposes of this post, I want to talk about patients with follicular lymphoma and "low risk" disease.
In order for us all to be on the same page about what constitutes "low risk" disease, I need to immediately introduce a scoring system called the FLIPI scale. It stands for "follicular lymphoma international prognostic index"
Follicular Lymphoma International Prognostic Index
This scale uses age > 60, stage III-IV, hemoglobin < 12, number of nodal areas > 4, elevated LDH. Patients with 0-1, 2, 3, 4-5 are grouped together in risk strata. Lower scores are better and higher scores are worse.
A good starting place for patterns of care in follicular lymphoma is the "lymphocare" study published in 2009. What is startling is how much has changed in the last three years.
Follicular Lymphoma in the United States: First Report of the National LymphoCare Study
The punch line from the paper is that in a mix of community practice sites (80%) and academic sites (20%), about 2800 patients were enrolled at diagnosis and followed in order to characterize treatment choices and outcomes. 18% were placed on "watch and wait," 14% were given rituximab alone, 52% were given rituxan with chemotherapy. When R-Chemo was given R-CHOP was given to about half, R-CVP to about a quarter, and R-Fludarabine to about 15%.
I find it unusual that so much has changed so quickly. For a disease like follicular lymphoma, this treatment mix has been turned on it's head by several high profile publications.
Let's start with "Watch and wait." For many patients, the idea of "watchful waiting" is a tough recommendation. I completely understand the sentiment that if you have cancer you ought to do something about it. The problem from a historical perspective is that we didn't necessarily have anything that really changed the long term prognosis. That historical precident was established for quite a few years by the BNLI study which started accruing patients a LONG TIME ago. In this study patients with advanced stage FL were randomized to watch and wait vs immediate chlorambucil.
Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial.
This study found that with long term follow up, the folks who went on "watch and wait" actually did a little better than patients who got up front chlorambucil (keep in mind that chlorambucil is an "alkalating" agent which causes DNA damage). A generation of oncologists followed this paradigm for nearly 20 years. Unfortunately, chlorambucil is such a lousy drug (I only use it in the "very unfit patient population"). One point to highlight for later is that the average survival of either arm on this study was only between 5-6 years. Furthermore, this wasn't terribly different than the overall natural history of the disease.
The natural history of initially untreated low-grade non-Hodgkin's lymphomas.
Over time however, more effective regimens such as CVP, or CHOP came along. With more effective regimens, watch and wait remained a good option, but the pendulum moved back toward combination therapy. By the time of the lymphocare study in the mid 2000's watch and wait was a distinctly small minority. Having done my fellowship at Stanford with Ron Levy and even Saul Rosenburg, I have certainly watched and waited on quite a few patients.
The biggest change to this equilibrium has been the introduction of rituximab. Rituximab is not chemotherapy - it is "immunotherapy." It is an "engineered antibody." You make antibodies to flu, e. coli, etc. This is just an antibody against the lymphoma. I tell patients it coats the outside of the cancer cell and "focuses" the immune system. There may even be some degree to which it helps "train" the immune system to fight the lymphoma.
There are several important studies that have made this option more welcome in the minds of physicians. The first was a single arm phase 2 study of four doses of rituxan which showed an overall response rate of 70% with complete response of 30%.
Rituximab therapy for patients with newly diagnosed, advanced-stage, follicular grade I non-Hodgkin's lymphoma: a phase II trial in the North Central Cancer Treatment Group.
The second paper was a plenary session at ASH in 2010 which was a redo of the original chlorambucil study but was "watch and wait" versus rituxan. This study remains quite "young" so we do not have good long term data. We cannot yet say whether patients live longer etc. What we can conclude however is that giving rituximab certainly delays the need for subsequent chemotherapy.
An Intergroup Randomised Trial of Rituximab Versus a Watch and Wait Strategy In Patients with Stage II, III, IV, Asymptomatic, Non-Bulky Follicular Lymphoma (Grades 1, 2 and 3a). A Preliminary Analysis.
Finally, the Resort study presented at ASH 2011 was significant. This study took "low risk" patients and randomized to four doses of Rituximab versus four doses followed by one dose every three months forever. In the patients who only got four doses, they could get four more doses if their disease came back. Only those patients who had an initial response were followed long term (70%). So the study design is more about the best way to maintain long term benefit from rituximab with either "re-treatment" or "maintenance" in rituximab sensitive patients.
Results of Eastern Cooperative Oncology Group Protocol E4402 (RESORT): A Randomized Phase III Study Comparing Two Different Rituximab Dosing Strategies for Low Tumor Burden Follicular Lymphoma
The key findings was there was very little difference between the two arms in terms of how long a patient was sensitive to rituximab. There was a slight increase in patients needing chemotherapy in the re-treatment arm but not enough to really make thought leaders think that maintenance was the winner. Perhaps the most significant secondary finding though was that there were more patients doing well in either arm of this study than compared to historical controls by a long shot. There is danger in this sort of comparison because that is not what the study was designed to answer.
With these three studies however, you see more and more editorials asking if "watch and wait" is an outdated strategy. I don't think it is just yet, but I admit, my threshold for giving single agent rituximab is a lot lower than it was before and I think that is reflected in national practice patterns as well. If we swing back to the lymphocare study, I think the impact here has been that single agent rituximab use has gone up quite a bit. Instead of the 14% reported previously, I would wager it is somewhere between 25-35% of patients. This strategy has probably stripped out more of the "watch and wait" group as well as some of the other folks who would have previously gotten R-Chemo.
I think that "watch and wait" was probably underutilized in the lymphocare observational study and probably more so now. A lot of patients are less comfortable with extra CT scans due to the radiation concerns.
I think that rituxan monotherapy opens up a lot of interesting research options. It may prove to be a useful platform for new drug combinations in research. I am particularly excited by a study (which sadly I am not a part of) where it is revlimid-rituxan versus investigator choice of R-chemo regimen. I hope to see studies soon in which the design is rituxan versus rituxan / new agent.
In our next follicular lymphoma post, I will talk about what sorts or R-Chemo regimens I give when I need to reach for chemotherapy regimens.
