1 Department of Hematology and Hematopathology Unit, Hospital Clínic, IDIBAPS, Barcelona; 2 Department of Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
* Correspondence to: Dr A. López-Guillermo, Department of Hematology, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain. Tel: +34-93-227-5575; Fax: +34-93-227-5428; Email: alopezg{at}clinic.ub.es
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Abstract |
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Patients and methods: One hundred and three patients (55 male, 48 female; median age 59 years) with FL in first relapse/progression after an initial response to therapy (50 complete responders/ 53 partial responders) were included in the study.
Results: Five-year survival from progression (SFP) was 55% (95% confidence interval 44%66%). The distribution according to the FLIPI at relapse was 39% good prognosis, 24% intermediate prognosis and 37% poor prognosis. Five-year SFP for these groups were 85%, 79% and 28%, respectively (P < 0.0001). Other variables at relapse with prognostic significance for SFP were age, presence of B symptoms, performance status, bulky disease, number of involved nodal sites, lactate dehydrogenase level, hemoglobin level, histological transformation, the Italian Lymphoma Intergroup prognostic index for FL and the International Prognostic Index for aggressive lymphomas. In the multivariate analysis bulky disease (P=0.01), presence of B symptoms (P=0.03) and FLIPI at relapse (P=0.0003) were the most important variables for predicting SFP.
Conclusions: In patients with FL at first relapse/progression, the FLIPI, along with the presence of bulky disease and B symptoms, are features that predict SFP and thus could be useful to select candidates for experimental treatments.
Key words: FLIPI, follicular lymphoma, prognosis, progression
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Introduction |
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Several papers analyzing prognostic factors for FL patients have been published [2, 9
13
]. In addition, various attempts to build a prognostic index for these patients have been made [3
, 14
]. Recently, an international multicenter study including data from more than 4000 patients resulted in a new prognostic index, the Follicular Lymphoma International Prognostic Index (FLIPI), specifically designed for FL patients [15
]. The FLIPI distinguishes three groups of patients with around one-third of cases each, with overall survivals at 10 years of 70%, 50% and 35%.
In contrast with the many studies dealing with initial prognostic factors in FL after diagnosis, there are few studies addressing the outcome of patients with FL at relapse or progression [4, 16
19
]. We hypothesized that the newly developed FLIPI might be useful to identify patients with different prognoses in such a situation. Towards this aim, the potential usefulness of FLIPI in a series of FL patients at first relapse/progression was analyzed.
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Patients and methods |
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CR was defined as the disappearance of tumor masses and disease-related symptoms, as well as the normalization of the initially abnormal tests and/or biopsies lasting for at least 1 month. PR was considered to be achieved when measurable lesions decreased by at least 50%. Patients not included in these categories, as well as those who died before completing treatment, were considered as non-responders [22].
The follow-up surveillance policy after treatment consisted of physical examination, blood counts and biochemistry, and chest roentgenogram (if initially abnormal) every 3 months during the first year, every 4 months during the second year, every 6 months during the next 3 years and once a year thereafter. Abdominal CT scans were performed every 6 months during the first year and yearly for the following 5 years when abdomen was the principal involved site. The molecular follow-up assessment was only performed systematically from 1998 onwards.
Disease relapse or progression was defined as the appearance of new symptoms or signs of the disease as demonstrated by lymph node biopsy or other appropriate studies. At the time of relapse or progression, besides a new lymph node biopsy, CT scans of thorax, abdomen and pelvis, as well as a bone marrow biopsy, were performed whenever possible.
Parameters evaluated
In each patient the following data were recorded and evaluated for prognosis: (i) initial variables: age (<60 versus 60 years), gender, Eastern Cooperative Oncology Group (ECOG) performance status, B symptoms, histological subtype, hemoglobin (Hb), lymphocyte count, serum lactate dehydrogenase (LDH) and serum ß2-microglobulin (ß2M) levels, number of nodal and extranodal involved sites, Ann Arbor stage, bulky disease (defined as a tumor diameter
10 cm), bone marrow infiltration, the International Prognostic Index (IPI) for aggressive lymphomas and the FLIPI. (ii) Treatment: monotherapy with alkylating agents versus combination chemotherapies without doxorubicin versus doxorubicin-containing regimens. (iii) Response to initial therapy: CR versus PR versus no response. (iv) Response duration (RD): defined as the time from the response assessment to the relapse/progression. (v) Variables at relapse: clinical data (age, performance status, presence of B symptoms), histological subtype (FL versus transformed into high-grade lymphoma), tumor extension data (bulky disease, Ann Arbor stage, number of involved nodal sites, bone marrow involvement, Hb, lymphocyte count, LDH, ß2M), IPI [23
], Italian Lymphoma Intergroup prognostic index (ILI) and FLIPI (as described below). (vi) Salvage treatment and response to salvage treatment.
Follicular Lymphoma International Prognostic Index
Age 60 years, advanced stage (IIIIV), increased serum LDH level, Hb level <120 g/l and more than five involved nodal sites were the variables used to classify patients according to the FLIPI as patients with good, intermediate or poor prognosis, depending on the number of adverse prognostic factors (01, 2 and
3, respectively) [15
].
Statistical analysis
Overall survival was defined as the time between the date of diagnosis and the date of last follow-up or death. Survival from progression (SFP) for responding patients (CR or PR) was defined as the time from the relapse or progression assessment to the date of last follow-up or death.
The main end point of the study was SFP. In addition, overall survival was also analyzed. Actuarial survival analysis was performed according to the method described by Kaplan and Meier [24], and the curves were compared by the log-rank test [25
]. The univariate analysis was carried out for each of the parameters indicated above. All significant prognostic factors in the univariate study, as well as some clinically relevant variables, were included in a multivariate analysis performed by Cox's stepwise proportional hazard regression method [26
].
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Results |
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Treatment at progression varied over the study period and consisted of: monotherapy with alkylating agents, 23 patients (22%); combination chemotherapy (including doxorubicin in 16 cases and ifosfamide/etoposide-containing regimens in 24 cases), 47 patients (46%); purine analogs alone or in combination, 18 patients (17%); and other treatments, 15 patients (15%). Among the latter, three patients were observed without treatment until further progression and four patients in localized stage received radiotherapy as salvage therapy. Treatment at progression for transformed patients consisted of combination chemotherapy, including doxorubicin in three cases and ifosfamide/etoposide-containing regimens in eight cases. Autologous SCT was performed in 22 patients at first relapse as part of the salvage treatment because of the following reasons: RD <2 years in 17 patients; disease transformation in six; and both causes in three. Seventeen of 58 (29%) patients with an RD <2 years were submitted to SCT at first relapse, whereas this proportion was 12% in those cases with a RD 2 years (P=0.03). SCT was performed at first relapse as part of the salvage therapy in 30%, 39% and 14% of patients with good, intermediate and poor prognosis according to the FLIPI, respectively (P not significant). One patient received an allogeneic SCT with reduced-intensity conditioning.
Forty-three of 93 assessable patients achieved CR (46%) after salvage therapy, 31 (33%) achieved PR and 19 patients (21%) were considered as non-responders.
Survival from progression
The median SFP was 5.4 years, with a 5-year SFP of 55% [95% confidence interval (CI) 44%66%] (Figure 1). The most important variables predicting SFP are listed in Table 2. First-line treatment (monotherapy with alkylating agents versus combination chemotherapies without doxorubicin versus doxorubicin-containing regimens) did not significantly correlate with SFP. No statistical differences in SFP were found between patients achieving CR after initial therapy and patients in PR.
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To assess the importance of the FLIPI in predicting SFP, a multivariate analysis was performed. Besides the FLIPI (good versus intermediate versus poor prognosis) the variables selected for the analysis were as follows: (i) variables with prognostic significance in the univariate analysis (P < 0.05) and a high enough number of assessable cases: B symptoms at relapse (no versus yes), bulky disease at relapse (no versus yes), transformation into a high-risk lymphoma (no transformation versus transformation versus no biopsy); and (ii) RD (<2 versus 2 years). The variables used to calculate the FLIPI were not included in the model. Seventy-four of the 103 study patients were included in the final multivariate analysis for SFP. The variables that retained prognostic significance for SFP were the presence of bulky disease at progression [P=0.005; relative risk (RR) 3.8; 95% CI 2.94.8], the presence of B symptoms at relapse (P=0.03; RR 2.7; 95% CI 1.83.6) and the FLIPI at progression (P=0.002; RR 2.4; 95% CI 1.93). The multivariate analysis was repeated including only the patients in whom a new biopsy was performed at relapse to better analyse the role of histological transformation. In this subset of patients, the variables with prognostic significance for SFP were the presence of B symptoms, histological transformation and the FLIPI.
In Table 3, 5-year SFP according to the FLIPI, the ILI and the IPI is detailed. FLIPI, ILI (low versus intermediate versus high risk) and IPI (0, 1 versus 2 risk factors) were compared by a Cox regression method including these three scores as covariates. In the final model, with 61 cases, the FLIPI retained prognostic importance for SFP (P=0.0001; RR 2.9; 95% CI 2.43.4).
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Discussion |
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The analysis of prognostic factors in patients with FL upon relapse or progression has been addressed in a few studies. Age at relapse [4, 16
], response to first-line therapy [16
], number of previous lines of therapy [4
], response to salvage treatment [17
] and RD [16
, 19
] are factors that have been associated with survival from first progression. However, the prognostic significance of clinical features at relapse has not been fully investigated. Spinolo et al. [18
] reported that the number of prior failures, as well as B symptoms, Hb level and number of extranodal sites at relapse, were associated with outcome after progression, but in this study survival was analyzed after several relapses.
In the present series, poor prognosis according to the FLIPI, as well as the presence of bulky disease and B symptoms, were the factors at relapse that allowed the discrimination of patients with a shorter survival from progression. In line with some other studies [4, 16
], in the current series the 5-year SFP was significantly shorter in older patients in the univariate analysis, but this variable was not included in the multivariate analysis since it is incorporated in the FLIPI. The prognostic value of the presence of bulky disease is consistent with the findings from a previous study by our group [19
]. In the present series, the 5-year SFP of patients with good, intermediate or poor prognosis according to the FLIPI was 85%, 79% and 28%, respectively (P < 0.0001). In the multivariate analysis the FLIPI emerged as one of the variables with prognostic value for SFP. Of note, the RD was also included in the multivariate analysis and did not achieve prognostic importance. Moreover, when we compared the FLIPI, the ILI and the IPI by a Cox regression, only the FLIPI retained prognostic significance. These results support the predictive value for SFP of FLIPI at relapse, and suggest that this index may be more accurate than other scores to select FL patients according to their risk.
In contrast to the report by Weisdorf et al. [16], response to first-line therapy did not predict SFP in the present series. RD, another variable with important prognostic value for SFP in the Weisdorf et al. [16
] paper, did not correlate with survival in the current study. In fact, although in a previous report from our group [19
] RD maintained its prognostic value for SFP, in the current series the median SFP was 4.9 and 6 years for patients with RD <2 and
2 years, respectively. Since, according to our previous results, patients with RD <2 years were submitted to autologous SCT, this may have overcome the negative impact of a shorter initial response on overall survival (data not shown).
In conclusion, this study shows that the clinical characteristics of the disease at relapse as assessed by the FLIPI are the crucial factor in the outcome of patients with FL after progression. Consequently, FLIPI may be employed to identify patients in progression who have an especially unfavorable outcome, and because of this, are reasonable candidates for experimental therapies.
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Acknowledgements |
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Received for publication March 22, 2004. Revision received May 27, 2004. Accepted for publication July 2, 2004.
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