Follicular lymphoma international prognostic index.

TL;DR: The Follicular Lymphoma International Prognostic Index was designed from the data recorded over 8 years of nearly 5000 patients registered worldwide to help provide an optimal treatment option for patients with follicular lymphoma.

About: This article is published in Blood.The article was published on 2004-09-01 and is currently open access. It has received 1459 citations till now. The article focuses on the topics: International Prognostic Index & Follicular lymphoma.

Summary

Introduction

• Follicular lymphomas (FLs) account for one third of nonHodgkin lymphomas (NHLs) in adults.
• Several retrospective analyses have also suggested that the International Prognostic Index (IPI) initially designed for aggressive NHLs could also be used in indolent NHLs.15-20However, some important prognostic factors may have been missed since the IPI was not designed to investigate prognostic factors in FL.
• An Inside Blood analysis of this article appears in the front of this issue.
• Therefore, and solely to indicate this fact, this article is hereby marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.

Patients

• The following inclusion criteria were used: (1) Follicular lymphoma according to the Working Formulation for Clinical Usage21 and/or the Kiel classification,22 which were in use at the time of the period of inclusion.
• All cell types (small-cell, mixed, or large-cell FL) could be included in the study.
• Consent for this study was part of the informed consent given for these trials.

Data collection

• Nodal areas considered were cervical, axillary, inguino-crural, para aortic and/or iliac, celiac and/or mesenteric, and other ancillary nodal sites.
• As in the International Prognostic Index for aggressive NHLs2 the spleen was considered as an extra nodal site.
• The following clinical and biologic characteristics were related to disease extension and/or tumor bulk: cell type, Ann Arbor stage, serum LDH, and 2 microglobulin levels (expressed as the ratio of the measured value to the upper limit of normal for the center).
• The following clinical and biologic characteristics were related to the effects of FL on the host: performance status according to the Eastern Cooperative Oncology Group scale, presence or absence of any B symptoms, anemia, lymphocytopenia, decreased serum albumin level, increased erythrocyte sedimentation rate (ESR), thrombocytopenia.

Statistical analysis

• Overall survival was the end point of all statistical analyses.
• BNLI indicates British National Lymphoma Intergroup; EORTC, European Organization for the Treatment of Cancer; GELF, Groupe d’Etude des Lymphomes Folliculaires; GOELAMS, Groupe Ouest-Est des Leucémies Aiguës et Autres Maladies du Sang; SNLG, Scotland and Newcastle Lymphoma Study Group; and SWOG, SouthWest Oncology Group.
• A prognostic model was built fitting a proportional hazard model with all variables that significantly influenced the overall survival at a level of P values less than or equal to .05 in the univariate analysis (full model).
• Then, categories were combined according to the number of patients within each category, the combination producing the smallest loss of information in terms of loglikelihood, and clinical consideration in order to obtain 3 categories of approximately equal size.

External validation

• The data of 1101 other cases of patients with FL were received from 10 groups or centers in the United States and Europe.
• Of these, 92 were not analyzed because of missing values and/or inconsistencies.
• The distribution of the 5 parameters of the FLIPI among these 919 patients, the distribution among the 3 FLIPI groups, and the hazard ratios are shown in Table 7. upper limit of normal; Ann Arbor stage III-IV; and age greater than 60 years.

Patient characteristics

• Overall, 5120 patients from 27 centers or groups have been registered (Table 1).
• There were 4167 cases included in the final analysis.
• The median follow-up of surviving patients was 7.5 years and the overall survival of these patients is shown in Figure 2.
• Treatment modalities varied over time and according to the institutions.

Univariate analysis

• The correlations between the clinical characteristics at diagnosis and overall survival are shown in Table 2.
• Given the size of the study population, all the listed characteristics (except cell type) were significantly associated with outcome.
• In order to propose a simple and accurate index, the clinical and statistical committees decided not to include all of these parameters in the multivariate analysis.

Prognostic model

• Based on clinical relevance and availability of the information, 12 pretreatment characteristics were included in the multivariate RR indicates relative risk (of death); CI, confidence interval; PB, peripheral blood; LDH, lactate dehydrogenase; and ULN, upper limit of normal.
• RR indicates relative risk (of death); CI, confidence interval; LDH, lactate dehydrogenase; and ULN, upper limit of normal.
• *Factors adversely affecting survival in the FLIPI include age greater than 60 years;.
• Both complete model and forward analyses retained 8 variables independently associated with the prognosis in a model established on 1795 patients for whom these parameters were available (Table 3).

Prognostic index

• This sample of 1795 patients comprised the population used to build the FLIPI.
• In the 100 resamples of the original data set, this 5-parameter model was classified 24 times with the best score and 59 times as one of the 3 highest scoring models.
• The FLIPI index was thus created with 3 risk groups: low (0-1 risk factor), intermediate (2 risk factors), high ( 3 risk factors).
• The distribution of patients into these 3 groups and hazard ratios are shown in Table 5.

Comparison with the International Prognostic Index (IPI)

• This comparison was performed on 1647 of 1795 patients used for building the FLIPI for whom complete information was also available for the parameters of the IPI (age, serum LDH level, performance status, Ann Arbor stage, number of extra nodal sites of disease).
• The distribution of patients into the 4 IPI risk groups and the relative risks of death are shown in Table 6.
• The IPI separates the patients into 4 risk groups with significantly different survivals.
• Meanwhile, the number of patients in “high” and “high-intermediate” risk groups is low (4.7% and 15.5%, respectively).
• Conversely, most of the patients are in the “ low” and “ low-intermediate” risk groups (49% and 31%, respectively).

Age-adjusted model

• The FLIPI was also tested in patients younger than 60 years and in patients 60 years or older.
• As in the IPI study,2 the 4 risk factors other than age were tested within each age group.
• The 4 other identified risk factors (number of nodal sites, Ann Arbor stage, serum LDH level, and hemoglobin level) remained independent prognostic factors.
• Survival curves for these 2 age groups are shown in Figure 6.

Discussion

• Among all NHLs, follicular lymphomas are the second most frequent subtype.
• Several new treatment modalities including combination of chemotherapy and interferon alpha,27 anti-CD20 monoclonal antibodies given alone28 or bound to a radio nuclide,29 intensive therapy with autologous stem cell transplantation,30 or nonmyeloablative allogenic stem cell transplantation31 have recently shown their activity in clinical trials.
• None of the treatments given during the period of inclusion has significantly changed the natural history of the disease.
• In conclusion, the FLIPI is an extremely simple and reproducible prognostic index, based on easily available clinical data, for patients with FL.
• This index may be a useful tool for improving the prognostic assessment of patients with FL.

FLIPI

• LDH indicates lactate dehydrogenase; and ULN, upper limit of normal.
• Figure 7. Overall survival of the 919 patients used for validation of the Follicular Lymphoma International Prognostic Index.
• Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric antiCD20 monoclonal antibody and CHOP chemotherapy.

Figures

Table 6. Outcome and relative risk of death according to risk group as defined by the IPI among the 1647 patients for whom data for the FLIPI and the IPI were available

Figure 4. Survival of the 1795 patients according to risk group as defined by the Follicular Lymphoma International Prognostic Index.

Figure 5. Overall survival of patients with low IPI risk, low-intermediate IPI risk, and high-intermediate plus high IPI risk as determined by the Follicular Lymphoma International Prognostic Index (FLIPI). (A) Low IPI risk. (B) Low-intermediate IPI risk. (C) High-intermediate and high IPI risk. Within each IPI risk group, the FLIPI can discriminate patients in groups with significantly different death risks.

Figure 6. Survival of 1795 patients according to risk group as defined by the Follicular Lymphoma International Prognostic Index. Patients younger than 60 years (A); patients 60 years or older (B).

Table 1. Accrual of patients in the FLIPI study

Figure 1. Mannikin used for counting the number of involved areas. See “Demographic characteristics and initial staging” in the text. Each rectangle corre-

Table 7. Characteristics of the patients studied for the “external” validation of the Follicular Lymphoma International Prognostic Index (FLIPI)

Table 2. Characteristics of the patients and results of the univariate analysis of prognostic factors

Table 4. Results of the Cox regression analysis in 1795 patients who exhibited the 5 parameters retained for building the Follicular Lymphoma International Prognostic Index

Figure 3. Numbers of patients included for designing the FLIPI. From the study population, the remaining number of patients who had information on the 8 significant factors after Cox analysis are mentioned. Note that no data were missing for age and sex.

Table 3. Results of the Cox regression analysis in 1795 patients who exhibited the 8 parameters having significant influence on overall survival

Table 5. Outcome and relative risk of death according to risk group as defined by the Follicular Lymphoma International Prognostic Index

Frequently asked questions

Q1. What have the authors contributed in "Follicular lymphoma international prognostic index" ?

In this paper, the authors proposed a prognostic index for Follicular Lymphoma ( FL ) based on the International Prognostic Index. 

Q2. What were the risk groups for follicular lymphomas?

Three risk groups were defined: low risk (0-1 adverse factor, 36% of patients), intermediate risk (2 factors, 37% of patients, hazard ratio [HR] of 2.3), and poor risk (> 3 adverse factors, 27% of patients, HR 4.3). 

Q3. How many patients were used for the FLIPI?

The size of the high-risk group (27% of patients in the sample used for creating this index and 28% in the sample used for validation) could allow the design of multicenter randomized trials. 

Q4. What is the way to diagnose follicular lymphomas?

2004;104:1258-1265) © 2004 by The American Society of HematologyFollicular lymphomas (FLs) account for one third of nonHodgkin lymphomas (NHLs) in adults. 

Q5. What are the adverse prognostic factors for follicular lymphomas?

Five adverse prognostic factors were selected: age (> 60 years vs < 60 years), Ann Arbor stage (III-IV vs I-II), hemoglobin level (< 120 g/L vs > 120 g/L), number of nodal areas (> 4 vs < 4), and serum LDH level (above normal vs normal or below). 

Q6. How many times was the FLIPI classified?

In the 100 resamples of the original data set, this 5-parameter model was classified 24 times with the best score and 59 times as one of the 3 highest scoring models.