International Prognostic Index
Follicular Lymphoma (FL) is the second most frequently diagnosed Lymphoma in the United States and Western Europe. It accounts for approximately 15–20% of all Non-Hodgkin Lymphomas (NHLs) and 50% of indolent Lymphomas. The clinical course of FL is usually characterized by a good response to initial treatment followed by frequent relapses, which can be associated with histologic transformation into an aggressive NHL. Treatment options for patients with naïve or recurrent FL are still controversial, ranging from a "watch and wait" policy to Hematopoietic Stem Cell Transplantation (HSCT). The availability of rituximab (R) has substantially changed FL therapeutic approaches, to such an extent that R-chemo is now the standard induction treatment. The introduction of rituximab is considered to be at least partly responsible for the improved median overall survival (OS).1–4
The Follicular Lymphoma International Prognostic Index (FLIPI) was proposed as a suitable prognostic tool for patients with FL.5 The index was developed following a retrospective analysis of data collected from over 4,000 patients with FL diagnosed between 1985 and 1992. The FLIPI includes five adverse prognostic factors:
- Age (≥60 vs<60 years),
- Ann Arbor stage (III–IV vsI–II),
- Hemoglobin level (<120 vs≥120 g/L)
- Number of nodal areas involved (>4 vs≤4)
- Serum Lactate Dehydrogenase (LDH) level (above normal vsnormal or below)
Risk groups were graded by comparing the relative risk of death across patients presenting with a number of risk factors (from 0 to 5). Therefore, three risk groups were defined according to the number of adverse factors:
- Low risk (0–1 adverse factor)
- Intermediate risk (2 adverse factors)
- High risk (≥3 adverse factors)
The FLIPI was validated in an independent cohort of 919 patients with FL. The FLIPI is also considered to be highly predictive of Progression Free Survival (PFS) and can thus be used clinically to identify patients with a poor prognosis who may better benefit from experimental treatments.6 In 2009, the FLIPI was validated outside the clinical trial setting in a population-based study that used the data recorded in a cancer registry.7
In 2003, the International Follicular Lymphoma Prognostic Factor Project launched the F2-study, which aimed to verify whether a prospective collection of data would enable a better definition of prognostic factors and the development of a more accurate prognostic index. Assessment of β2-microglobulin (β2M) and Erythrocyte Sedimentation Rate (ESR) were also included among study procedures.8 Thus, in 2009, the same working group proposed the FLIPI2 as a prognostic index with improved clinical utility.
The FLIPI2 derives from a prospective multivariate analysis of PFS in 832 patients who received treatment for FL between 2003 and 2005 and were followed for a median of 38 months. PFS is now considered the preferred endpoint in Lymphoma clinical trials, in particular those involving indolent subtypes such as FL. The FLIPI2 consists of five adverse prognostic factors including two (hemoglobin level and age) retained from the FLIPI. The newer prognostic parameters are β2M (>Upper Limit Normal [ULN] vs ≤ULN), largest involved node (>6 vs ≤6 cm), and bone marrow involvement (presence vs absence). Using these parameters, a prognostic model was devised to identify three groups with different risk levels.
The website below calculates the FLIPI value from a patient’s age, number of involved nodes, LDH and hemoglobin levels, and FL stage.
- Marcus R. et al. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. Journal of Clinical Oncology. 2008 Oct; 26(28):4579–4586. doi: 10.1200/JCO.2007.13.5376. Epub 2008 Jul 28.
- Herold M. et al. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. Journal of Clinical Oncology. 2007 May; 25(15):1986–1992. Epub 2007 Apr 9.
- Salles G. et al. Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 study. Blood. 2008 Dec; 112(13):4824–4831. doi: 10.1182/blood-2008-04-153189. Epub 2008 Sep 17.
- Hiddemann W. et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2005 Dec; 106(12):3725–3732. doi: 10.1182/blood-2005-01-0016. Epub 2005 Aug 25.
- Solal-Céligny P. et al. Follicular lymphoma international prognostic index. Blood. 2004 Sep; 104(5):1258–1265. Epub 2004 May 4.
- Montoto S. et al. Predictive value of Follicular Lymphoma International Prognostic Index (FLIPI) in patients with follicular lymphoma at first progression. Annals of Oncology. Oct 2004; 15(10):1484–1489. doi: 10.1093/annonc/mdh406.
- van de Schans S.A. et al. Validation, revision and extension of the Follicular Lymphoma International Prognostic Index (FLIPI) in a population-based setting. Annals of Oncology. 2009 Oct; 20(10):1697–1702. doi: 10.1093/annonc/mdp053. Epub 2009 Jun 23.
- Federico M. et al. Follicular Lymphoma International Prognostic Index 2: A new prognostic Index for follicular Lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol. 2009 Sep; 27(27):4555–4562. doi: 10.1200/JCO.2008.21.3991. Epub 2009 Aug 3.