1 Clinical Hematology Division, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona; 2 Hematology Department, Institut Clínic de Malalties Hemato-oncológiques, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona; 3 Hematology Department, Hospital Durán i Reynals, Institut Català d'Oncologia, Ciutat Sanitaria i Universitaria de Bellvitge (Hospitalet de Llobregat); 4 Clinical Hematology Division, Hospital Germans Trias i Pujol, Badalona; 5 Clinical Hematology Division, Hospital del Mar, Barcelona; 6 Hematology Department, Hospital de Mataró, Mataró; 7 Hematology Department, Hospital Mútua de Terrassa, Terrassa, Spain
* Correspondence to: Dr G. Perea, Department of Hematology, Hospital de la Santa Creu i Sant Pau, C/ Sant Antoni Maria Claret 167, 08025 Barcelona, Spain. Tel: +34-93-291-93-96; Fax: +34-93-291-94-66; Email: gperea{at}hsp.santpau.es
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patients and methods: Three indexes, IPI [age >60 years, extranodal involvement two or more sites, elevated lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group performance status 2, stage
3], ILI (age >60 years, extranodal involvement two or more sites, elevated LDH, male sex, B symptoms, erythrocyte sedimentation rate
30 mm first hour) and FLIPI (age >60 years, stage
3, elevated LDH, nodal involvement five or more, haemoglobin level
12 g/dl) were calculated in 411 patients with FL.
Results: Overall concordance between the three indexes was 54%. A total of 126 (31%) patients were included in the high-risk group according to IPI, 131 (32%) according to ILI and 157 (38%) after FLIPI application. Ten-year overall survival rates after applying the prognostic indexes (IPI, ILI and FLIPI) were, respectively: 72%, 71% and 72%, in the low-risk group; 51%, 60% and 49% in the intermediate-risk group; and 24%, 16% and 31% in the high-risk group.
Conclusions: In this series, all three indexes, IPI, ILI and FLIPI, were useful to classify FL patients into differentiated risk groups, although the FLIPI identified a larger proportion of high-risk patients than the IPI and ILI.
Key words: follicular lymphoma, prognostic index, survival
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
The ILI index was calculated as detailed by the Italian Lymphoma Intergroup [14]. Six variables were used to construct this index, three of them also being included in IPI (age, extranodal involvement and LDH level). The other three variables considered were presence of B-symptoms, male sex and erythrocyte sedimentation rate
30 mm/h. Depending on the number of adverse prognostic factors (01, 2 or
3), patients were classified into low-, intermediate- or high-risk groups.
The FLIPI was calculated according to the Follicular Lymphoma International Prognostic Project [15]. The variables used to classify patients according to the FLIPI index were age
60, advanced stage (IIIIV), increased serum LDH, haemoglobin level <12 g/dl and nodal involvement (five or more sites). Three risk groups were considered: score 01, low-risk; score 2, intermediate-risk; and score
3, high-risk.
Statistical analysis
CR was defined as the disappearance of tumour masses and disease-related symptoms, as well as normalisation of the initially abnormal tests and/or biopsies, for at least 1 month. PR was considered when measurable lesions decreased by at least 50%. Disease was considered stable when there was no clinical response or evidence of progression. Disease progression during or after treatment was also taken into account [18].
OS and PFS curves were calculated for each risk category according to the KaplanMeier method. OS was calculated from the date of diagnosis to the last follow-up or death regardless of the cause. PFS was calculated for all treated patients from the onset of therapy until disease progression, relapse or death. Survival curves were compared using the log-rank test. All data were analysed using Statistical Package for the Social Sciencies software (SPSS®). The limit of statistical significance for all analyses was defined as P 0.05.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Of patients aged 60 years or younger (n=249), 36 (14%) were classified in the high-risk group according to the IPI, 39 (16%) according to the ILI and 50 (20%) according to the FLIPI.
Survival
Survival data for the whole population and for each risk group are summarised in Table 3, and OS and PFS curves according to the IPI, ILI and FLIPI are shown in Figures 1, and 3, respectively. Using the IPI system, three groups of patients with statistically different OS and PFS were distinguished. The 5- and 10-year OS rates were 88% and 72%, respectively, in the low-risk group, 78% and 51% in the intermediate-risk group, and 47% and 24% in the high-risk group (log-rank test 71.7; P <0.0001). Five-year PFS was 53% for the low-risk group, 31% for the intermediate-risk group and 17% for the high-risk group (log-rank test 53.5; P <0.0001).
|
|
|
Finally, according to the FLIPI, the 5- and 10-year OS rates were 89% and 72% for low-risk patients, 78% and 49% for the intermediate-risk group and 54% and 31% for the high-risk group, respectively (log-rank test 48.6; P <0.0001). The 5-year PFS for the different risk groups defined by the FLIPI were 50%, 37% and 22%, respectively (log-rank test 32.5; P <0.0001).
No differences were observed between treatments received by patients included in each high-risk group according to the three prognostic indexes. Fifty-five per cent (n=227) of FL patients in this series were treated uniformly with chemotherapy regimens including an anthracycline (CHOP/CNOP), and 28% of these patients were included in the high-risk group according to the IPI, 33% according to the ILI and 38% according to the FLIPI. The 5-year OS and PFS rates were 74% and 38%, respectively. No differences were observed in OS and PFS rates when these patients were classified according to the three prognostic indexes.
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In this report we have compared the three prognostic indexes for FL most commonly employed (i.e. the IPI, ILI and FLIPI) in an attempt to determine the merits of each one of these prognostic models. The IPI, initially designed for use in aggressive lymphomas, is easily applicable in clinical practice [11], and is also valuable in low-grade lymphomas [12
, 13
]. A major setback with the IPI is that only a small percentage (
811%) of patients with FL are included in the high-risk group. The ILI and FLIPI indexes, specifically designed for FL, also include variables that are easy to calculate, and separate patients into different risk groups. Both the IPI and the ILI have been applied in a series of FL patients. Maartense et al. [16
] found that the ILI index fitted grade III FL patients better, while the IPI showed a better discrimination among grade III FL patients. In our experience, we did not observe significant differences regarding the discriminating value between IPI and ILI indexes in a series of grade III FL patients [17
].
Regarding the FLIPI, patients from the current series were distributed in three different survival groups, with an OS probability at 5 and 10 years very similar to those previously showed by Solal-Céligny et al. [15], although in our series a higher proportion of patients were included in the high-risk group (38% versus 27%). The FLIPI seems to classify a larger number of patients into the high-risk group than IPI and ILI, even when only younger patients (
60 years old) are considered: 14%, 16% and 20% of patients were included in the high-risk group after applying IPI, ILI and FLIPI indexes, respectively. According to these results, all three systems are useful to distribute FL patients into different risk groups, although the ILI index was especially valuable to separate high-risk patients, because in contrast with the other two indexes, differences in survival between low-risk and intermediate-risk patients were less significant. Of note, median survival of patients in the high-risk group is quite long (3034 months) whatever the prognostic system employed. Because of this, it could be argued that prognostic indexes for FL, as currently devised, are not useful for making treatment decisions, particularly if the therapy proposed conveys important morbo-mortality. The prognostic assessment of patients with FL could be improved by using other variables [23
27
]. In addition, the prognostic impact of genomic aberrations in patients with FL has also been investigated and a negative impact has been described for deletions of 6q [28
, 29
]. The whole-genome microarray analysis of gene expression has also been applied in FL and a survival predictor model constructed according to the gene expression signatures derived from non-malignant immune cells presents in the tumour at diagnosis [30
]. These biological findings may contribute significantly to risk assessment in patients with FL.
In conclusion, all three prognostic systems investigated (IPI, ILI and FLIPI) were useful to identify patients with FL and different survival probabilities. In our series, however, the FLIPI identified a larger number of patients in the high-risk category. Future research should aim at improving the prognostic assessment of patients with FL by combining clinical variables with recently discovered biological variables.
|
![]() |
Acknowledgements |
---|
Received for publication February 21, 2005. Revision received April 18, 2005. Accepted for publication April 20, 2005.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Decaudin D, Lepage E, Brousse N et al. Low-grade stage IIIIV follicular lymphoma: multivariate analysis of prognostic factors in 484 patientsA study of the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 1999; 17: 24992505.
3. Bierman PJ, Vose JM, Anderson JR et al. High dose therapy with autologous hematopoietic rescue for follicular low-grade non-Hodgkin's lymphoma. J Clin Oncol 1997; 15: 445450.
4. McLaughlin P, Hagemeister FB, Romaguera JE et al. Fludarabine, mitoxantrone and dexamethasone: an effective new regimen for indolent lymphomas. J Clin Oncol 1996; 14: 1262.
5. López R, Martino R, Sureda A et al. Autologous stem cell transplantation in advanced follicular lymphoma. A single center experience. Haematologica 1999; 84: 350355.[ISI][Medline]
6. Mahé B, Milpied N, Mellerin MP et al. PCR detection of residual Bcl-2/IgH-positive cells after high-dose therapy with autologous stem cell transplantation is a prognostic factor for event-free survival in patients with low-grade follicular non-Hodgkin's lymphoma. Bone Marrow Transplant 2003; 31: 467473.[CrossRef][ISI][Medline]
7. Seymour JF, Pro B, Fuller LM et al. Long-term follow-up of a prospective study of combined modality therapy for stage III indolent non-Hodgkin's lymphoma. J Clin Oncol 2003; 21: 21152122.
8. Leonard RCF, Hayward RL, Prescott RJ, Wang JX. The identification of discrete prognostic groups in low-grade non-Hodgkin's lymphoma. Ann Oncol 1991; 2: 655667.[Abstract]
9. Romaguera JE, McLaughlin P, North L et al. Multivariate analysis of prognostic factors in stage IV follicular low-grade lymphoma: A risk model. J Clin Oncol 1991; 9: 762769.
10. Cameron DA, Leonard RCF, Jian-Hua M, Prescott RJ. Identification of prognostic groups in follicular lymphoma. Leuk Lymph 1993; 10: 8999.[ISI][Medline]
11. The Non-Hodgkin's Lymphoma Prognostic Factors Project. Development of a predictive model for aggressive lymphoma: The International NHL Prognostic Factors Project. N Engl J Med; 329 1993; 987994.
12. López-Guillermo A, Montserrat E, Bosch F et al. Applicability of the International Index for agressive lymphomas to patients with low-grade lymphoma. J Clin Oncol 1994; 12: 13431348.
13. Foussard C, Desablens B, Sensebe L et al. Is the International Prognostic Index for aggressive lymphomas useful for low-grade lymphoma patients? Applicability to stage IIIIV patients. The GOELAM Group, France. Ann Oncol 1997; 8 (Suppl 1): 4952.[Abstract]
14. Federico M, Vitolo U, Zinzani PL et al. Prognosis of follicular lymphoma: a predictive model based on a retrospective analysis of 987 cases. Blood 2000; 95: 783789.
15. Solal-Céligny P, Roy P, Colombat P et al. Follicular lymphoma international prognostic index. Blood 2004; 104: 12581265.
16. Maartense E, le Cessie S, Kluin-Nelemans HC et al. Age-related differences among patients with follicular lymphoma and the importance of prognostic scoring systems: analysis from a population-based non-Hodgkin's lymphoma registry. Ann Oncol 2002; 13: 12751284.
17. Perea G, Altés A, Montoto S et al. International and Italian prognostic indices in follicular lymphoma. Haematologica 2003; 88: 649653.
18. Cheson BD, Horning SJ, Coiffier B et al. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol 1999; 17: 12441253.
19. López-Guillermo A, Montserrat E, Bosch F et al. Low-grade lymphoma: clinical and prognostic studies in a series of 143 patients from a single institution. Leuk Lymphoma 1994; 15: 159165.[ISI][Medline]
20. Bastion Y, Berger F, Bryon PA et al. Follicular lymphomas: assessment of prognostic factors in 127 patients followed for 10 years. Ann Oncol 1991; 2 (Suppl 2): 123129.[Abstract]
21. Coiffier B, Bastion Y, Berger F et al. Prognostic factors in follicular lymphomas. Semin Oncol 1993; 20 (Suppl 5): 8995.[ISI][Medline]
22. Litam P, Swan F, Cabanillas F et al. Prognostic value of serum ß-2 microglobulin in low-grade lymphoma. Ann Intern Med 1991; 114: 855860.[CrossRef][ISI][Medline]
23. López-Guillermo A, Cabanillas F, McDonnell TI et al. Correlation of Bcl-2 rearrangement with clinical characteristics and outcome in indolent follicular lymphoma. Blood 1999; 93: 30813087.
24. López-Guillermo A, Cabanillas F, McLaughlin P et al. Molecular response assessed by PCR is the most important factor predicting failure-free survival in indolent follicular lymphoma: update of the MDACC series. Ann Oncol 2000; 11 (Suppl 1): 137140.[CrossRef][Medline]
25. Zhao WL, Daneshpouy ME, Mounier N et al. Prognostic significance of bcl-xL gene expression and apoptotic cell counts in follicular lymphoma. Blood 2004; 103: 695697.
26. Bilalovic N, Kirsti Blystod A, Golouh R et al. Expression of bcl-6 and CD10 protein is associated with longer overall survival and time to treatment failure in follicular lymphoma. Am J Clin Pathol 2004; 121: 3442.[CrossRef][ISI][Medline]
27. Akasaka T, Lossos IS, Levy R. BCL-6 gene translocation in follicular lymphoma: a harbinger of eventual transformation to diffuse aggressive lymphoma. Blood 2003; 102: 19311932.
28. Viardot A, Möller P, Högel J et al. Clinicopathologic correlations of genomic gains and losses in follicular lymphoma. J Clin Oncol 2002; 20: 45234530.
29. Tilly H, Rossi A, Stamatoullas A et al. Prognostic value of chromosomal aberrations in follicular lymphoma. Blood 1994; 84: 10431049.
30. Dave S, Wright G, Tan B et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 2004; 351: 21595169.
|