A new prognostic index for follicular lymphoma, based on easily attainable clinical data and focused on progression-free survival appears to be a good tool for making treatment decisions in the immunochemotherapy age. So concludes a study in the September 20 issue of the Journal of Clinical Oncology (2009;27:4555–4562).
Previous indexes, including the Follicular Lymphoma International Prognostic Index 1 (FLIPI-1), were developed based on patient populations treated before the advent of monoclonal antibodies, explained lead study author Massimo Federico, MD, of the Department of Oncology and Hematology at the University of Modena and Reggio Emilia in Italy. The new system—Follicular Lymphoma International Prognostic Index 2 (FLIPI-2)—is valuable in the rituximab era, he said.
FLIPI-2 will help oncologists choose initial treatment according to the risk of disease progression in individual patients, said another of the coauthors, Barbara Pro, MD, Associate Professor in the Department of Lymphoma/Myeloma at the University of Texas M. D. Anderson Cancer Center.
One of the greatest strengths of FLIPI-2 is that it is based on prospective data, commented Andrew D. Zelenetz, MD, PhD, Chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center. “This is incredibly important and the authors should be applauded for putting together a very large-scale study.”
However, the model also has a number of limitations, said Dr. Zelenetz. Moreover, there may not be a reason to implement a new index when FLIPI-1 already works in clinical practice and is well accepted.
To determine whether a prospective study would result in a more accurate prognostic index using progression-free survival as a primary endpoint, researchers registered 1,093 patients with newly diagnosed follicular lymphoma between January 2003 and May 2005. A total of 942 patients receiving lymphoma treatment were assessable, and 832 were retained for model development. Of 826 patients who received systemic therapy, 559 had rituximab, while 267 did not.
The researchers recorded 261 progression-free survival events after a median follow-up of 38 months. Independent predictive factors of PFS were a beta2-microglobulin (B2M) higher than the upper limit of normal, longest diameter of the largest involved node (LoDLIN) of more than 6 cm, bone marrow involvement, hemoglobin level less than 12 g/dL, and age over 60.
These variables were used to develop a prognostic model to identify three different risk levels. The three-year progression-free survival rate was 91% for individuals at low risk of disease progression, 69% for those at intermediate risk, and 51% for patients at high risk.
The three-year survival rates was 99%, 96%, and 84% for patients at low, intermediate, and high risk, respectively. FLIPI-2 was also predictive in patients treated with rituximab, with survival rates of 89%, 73%, and 57% for patients at low, intermediate and high risk, respectively.
The Question of PFS
The researchers originally identified overall survival as the primary endpoint. However, after data accrual, the study population was “characterized by an actuarial five-year survival rate of 89% and not the assumed 70%,” the authors wrote, deciding, therefore, to adopt progression-free rather than overall survival as the main efficacy endpoint.
With the advent of monoclonal antibodies, the prognosis of follicular lymphoma has greatly improved, and “with this very promising scenario, overall survival seemed to us not to be an appropriate and clinically relevant endpoint,” Dr. Frederico said.
Progression-free survival also made sense as a primary outcome because of the indolent nature of the disease and the multiple relapses patients are likely to experience, Dr. Pro added. Moreover, if patients are diagnosed later in life, the disease itself may not affect their lifespan. Overall survival can also be affected by a salvage regimen and progression-free survival cannot, she added.
Additionally, said Dr. Federico, PFS is currently accepted as the principal endpoint in clinical trials, especially those designed for indolent lymphomas, such as follicular lymphoma.
“I don't think PFS has been universally accepted as an endpoint in indolent lymphoma,” Dr. Zelenetz countered. With follicular lymphoma, physicians might be able to get a better PFS with more aggressive treatment upfront, but this isn't always the right answer, he said. “It's not the optimal endpoint. Overall survival is important, and FLIPI-1 was very good at predicting overall survival.”
Also of note is that one of the side effects of using PFS is that it excludes patients who were initially observed. The study excluded 115 patients because they were in the watch-and-wait category, he said.
Can't Wait 10-15 Years
Another reason that evaluating progression-free survival may make sense is that researchers can't wait 10 to 15 years to assess the effect of new treatments on overall survival, noted Anas Younes, MD, Professor of Medicine and Director of the Clinical Investigation and Translational Research Department of Lymphoma/ Myeloma at the University of Texas M. D. Anderson Cancer Center. Dr. Younes, who was not involved in the study, was asked for his opinion for this article.
However, if PFS is the primary outcome, researchers need to eliminate variables that may influence this endpoint, especially therapy, said Dr. Younes, adding that to accurately assess the impact of a specific therapy on PFS, patients should receive the same treatment regimens.
However, patients analyzed in the FLIPI-2 project received a wide variety of treatments including single agents and multiple combinations with and without rituximab, Dr. Younes said.
“In other words, prognostic factors reflect the outcome of very specific treatments, and as treatment changes, prognostic factors change. When you include patients who did not receive uniform therapy, prognostic factor analysis and the impact on PFS may not be accurate.”
While incorporating progression-free survival into the prognostic index is problematic, including serum B2M into FLIPI-2 is valuable, said Dr. Younes, adding that data for this factor was not available for the original FLIP-1 project. “It's legitimate to prospectively collect data and to question whether a new variable has an added value.”
In the past, B2M was routinely excluded from indexes based on retrospective data collection, Dr. Federico said, noting that his research team worked diligently to define B2M's independent prognostic role. Although B2M partially overlaps the prognostic significance of serum lactate dehydrogenase, the former predicts outcome to a wider extent, he said.
One of the problems associated with serum B2M is that it is very sensitive, and levels can be affected by renal function, Dr. Zelenetz said.
LoDLIN Easy to Evaluate
The longest diameter of the largest involved node (LoDLIN) is also a valuable measurement, and as defined in the study represents a surrogate of nodal tumor burden that can very easily be assessed, Dr. Federico said. Using LoDLIN, the researchers were able to acquire the same information that used to be gathered through counting a number of nodal sites, which wasn't always recorded correctly or completely, he explained.
LoDLIN is a single measurement that is a useful surrogate for having to register nodal sites, agreed Dr. Zelenetz.
However, Dr. Younes cautions that LoDLIN is an arbitrary measurement that does not reflect the true biology of the disease and it may also be measured inaccurately.
Bone Marrow Involvement Refines Staging
Bone marrow involvement has already been documented as valuable in determining the prognosis of different types of lymphomas, Dr. Federico said. “In our model, bone marrow involvement retained its independent prognostic role and is likely to reflect the extent of extranodal disease.”
In the past, Stages 3 and 4 follicular lymphoma had the same outcome, but now bone marrow involvement distinguishes the two stages from each other, Dr. Pro explained.
Future studies of FLIPI-2 need to have longer follow-up and evaluate overall survival, Dr. Zelenetz said.
Additionally, an external validation of FLIPI-2 could help assess its value. In the meantime the research group is considering using FLIPI-2 for patient stratification in future clinical trials.
Further research should also focus on biologically driven prognostic biomarkers that may predict resistance and sensitivity to certain regimens so physicians can move forward with truly personalized cancer therapy, Dr. Younes said.
“We ideally want an index that integrates people's outcomes over multiple therapies,” Dr. Zelenetz concluded.