Is the International Prognostic Index for aggressive lymphomas useful for low-grade lymphoma patients? Applicability to stage 111-IV patients

Annals of Oncology 8 (Suppl. I): S49-S52, 1997. i 1997 Kluwer Academic Publishers Printed in the Netherlands.

Original article Is the International Prognostic Index for aggressive lymphomas useful for low-grade lymphoma patients? Applicability to stage HI-TV patients C. Foussard,1 B. Desablens,2 L. Sensebe,3 S. Fransois,1 N. Milpied,4 E. Deconinck,5 V. Delwail,6 J. Dugay,7 T. Lamy,8 C. Ghandour,9 A. Le Mevel,10 H. Maisonneuve,11 P. Casassus12 & P. Colombat13 for the GOELAMS Group, France

Summary Background: The International Prognostic Index (IPI) is widely used to predict outcome of patients with aggressive lymphomas. Our goal was to assess the prognostic value of this index for low-grade lymphoma. Patients and methods: One hundred eighty-two patients with disseminated (stage III or IV) low-grade lymphoma were enrolled in a prospective multicenter trial. According to the initial features, treatment either was started immediately or was deferred until indicated by disease progression. Patients received the same polychemotherapy regimen, given monthly for six cycles. They were assigned to one of four risk groups according to the number of presenting risk factors: low-risk

Introduction

(0 or 1), low-intermediate-risk (2), high-intermediate-risk (3), high-risk groups (4). Results: Survival curves (Kaplan-Meier method) demonstrated a high significant difference for the four groups (logrank: P < 0.0001). Median survival for the low-risk group has yet to be reached, while that for the three other groups are, respectively, 65, 34, and 12 months. Conclusions: In this study, the IPI has been found to be an important prognostic tool in low-grade lymphoma and may be used in the selection of appropriate therapeutic approaches for individual patients.

Key words: index, lymphoma, low grade, prognostic factors

Patients and methods Patients and treatment

The low-grade non-Hodgkin's lymphomas (LG NHLs), generally characterized by indolent clinical outcome, may not require treatment for years and are often easily controlled by chemotherapy. But even though most patients respond to this therapy, complete responses (CRs) are rare and relapses occur frequently [1-3]. Recurrence or progression makes death from lymphoma almost inevitable, regardless of whether histologic transformation has occurred [4]. Therefore, new therapeutic approaches, such as intensive chemotherapy with hematopoietic support, have to be attempted [5]. A reliable prognostic system would be useful to select patients for intensive therapies. The International Prognostic Index (IPI), based on age, disease stage, serum lactic dehydrogenase (LDH) level, performance status (PS), and number of extranodal sites of disease, is a universally recognized prognostic factor model for aggressive non-Hodgkin's lymphomas (NHLs) [6]. These parameters also have predictive value in low-grade lymphomas [1, 7, 8]. They were applied to 182 patients with LG NHL, prospectively studied.

The GOELAMS group initiated a program of conservative conventional management for diffuse-stage LG NHL (Ann Arbor stages III and IV), not previously treated. Adult patients were eligible for this study if they had folhcular NHL and were older than 60 years or if they had other LG NHLs (International Working Formulation categories A, B, C, and E). No treatment was required for asymptomatic patients and low tumor burden until progression. Treatment was started in symptomatic patients because of the presence of one of the following parameters: disease-related B symptoms, peripheral lymph node with diameter of more than 5 cm, serious effusion, compression syndrome, symptomatic splenomegaly, or cytopenia (hemoglobin level < 100g/l, granulocyte count < 1.5 x 109/l, platelets < 100 x 109/!). All patients received the same chemotherapy regimen, consisting of cyclophosphamide at a dose of 750 mg per square meter of body-surface area (or 300 mg per square meter by mouth for 5 days), epirubicin at a dose of 30 mg per square meter, and vindesine at 3 mg per square meter, all given intravenously on day 1, as well as prednisone at a daily dose of 50 mg per square meter, given orally on days 1 to 5 (mini-CEEP). Treatment was repeated every 28 days for six cycles. Of 220 patients included between July 1987 and December 1993,182 provided data appropriate for completion of the IPI. The distribution of the histologic subtypes according to the Working Formulation was as follows: small lymphocytic, 54 patients (29%); follicular small cleavedcell and mixed, 56 patients (31%), diffuse small cleaved-cell, 51 patients (28%); and others, 21 patients (11%). Of the 182 patients, 134 were older than 60 years, and ranging in age from 35 to 81 years (median 65). Their clinical characteristics at diagnosis are shown in Table 1. Among treated

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Departments of Hematology of ^Angers, 2Amiens, Brest, ^Nantes, 5Besancon, 6Poitiers, sRennes, nBobigny, ^Tours; Departments of Oncology of ''Le Mans, 9Rennes, i0Nantes, uLa Roche, France

50 Table 1. Characteristics of 182 patients assigned to International Pronostic Index groups; median agep 65 years; >60 years: 134; median follow-up: 54 months; range: 24-105. Characteristic

Present (%)

Absent (%)

B symptoms Performance status 2 or > LDH > N Sites of disease Mass > 10 cm Splenomegaly* Bone marrow Extranodal 2 or > (32-microglobulin > N

30 34 34

70 66 66

16 20 73 39 57

84 80 27 61 43 (no. = 107)

* > 5 cm below left costal margin.

Statistical methods The characteristics of the patients before treatment and their response rates were compared with the chi-square test. Actuarial survival analysis was performed according to the method described by Kaplan-Meier, and the curves were compared using the log-rank test [10]. Endpoints were response to therapy and survival. Univariate analysis was performed for each of the parameters indicated earlier. All significant prognostic parameters in the univariate study and the IPI were considered for multivariate analysis performed by Cox's model [11].

Results

International Prognostic Index

International Prognostic Index distribution

As detailed by the Internationa] Non-Hodgkin's Lymphoma Prognosic Factors Project [6], variables used in the IPI are age ( < 6 0 vs. >60 years), performance status (ECOG 0 or 1 vs. 2 to 4), Ann Arbor stage (I or II vs. II or IV), serum LDH level (normal vs. high) and extranodal involvement for patients older than 60 years. As all our patients had stage III or IV disease, only the other criteria were applied. Patients with none or one unfavorable variable were considered to be of low risk, those with two to be of low-intermediate risk, those with three to be of high-intermediate risk, and those with four to be of high risk.

After applying the IPI, we established four groups of patients according to risk factors: low, 78 cases (43%); low-intermediate, 44 cases (24%); high-intermediate, 45 cases (25%); and high, 15 cases (8%). Patients whose treatments were deferred were in the low (27 cases) and in the low-intermediate risk groups (7 cases).

Parameters evaluated

According to the IPI, CR was achieved in 40, 36, 25, and 14%; PR in 49, 53, 44, and 50%; failure or death in 11, 10, 30, and 36% (P = 0.04) for patients in the low-, lowintermediate-, high-intermediate-, and high-risk groups, respectively (Figure 1). Nontreated patients were only in the low (15 cases) and low-intermediate (3 cases) groups. The following parameters also had prognostic value: PS (P = 0.02), extranodal involvement (P = 0.009), presence of bulky disease (P < 0.0001), histologic subtype (P 0.002), bone marrow involvement (P = 0.008), and 02microglobulin level (P = 0.03).

In addition to the IPI, the following initial data were evaluated: presence of B symptoms, PS, histologic subtype, hemoelobin value. WBC count.

70

Response to therapy

Survival

2 years

5 years

Group*. • • o •

Low risk low-intermediate risk high-intermediate risk high risk

Figure 1. Complete response and overall survival at 2 and 5 years.

Survival was strongly correlated with IPI (P < 0.0001) as shown in Figure 2. The overall survival was 96, 84, 50, and 32% at two years and 84, 60, 24, and 0% at five years for low-, low-intermediate-, high-intermediate-, and highrisk groups, respectively (Figure 1). The median survival from diagnosis for each IPI group was not reached for low risk, 65 months for low-intermediate risk, 34 months for high-intermediate risk, and 12 months for high risk. When the IPI was included in a multivariate analysis, IPI {P < 0.0001), presence of bulky disease (P - 0.03), and histologic subtype (P - 0.05) were independant prognostic parameters for survival. For 107 patients with 02microglobulin level data, only IPI (P-0.02) and 02-

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patients, 33% had a complete response (CR), and 49% a partial response (PR). Thirty-four patients (19%) had deferred treatment, and 18 were not yet treated. No differences were observed between patients older than 60 years and younger patients. The median follow-up duration was 54 months, and overall survival duration 71 months.

platelet count, splenomegaly, presence of bulky disease, bone marrow infiltration, treatment deferred or not and its result, relapse, and death. Only 107 patients registered p2-microglobutin level. Previously reported age ( < 60 vs. > 60 years), B symptoms, PS (0 or 1 vs. > 1), extranodal involvement, tumor mass size (tumor diameter > 10 cm), serum levels of LDH ( < N vs. > N) and p2-microglobulin, histologic subtype (follicular vs. nonfollicular lymphoma) were factors significantly correlated with survival [9],

51 Logimnk P cOOOl

low risk group

£ -

low inlenncdiate risk group high iutermediatt risk group high ntk group

o 20

60 80 Time (months )

100

120

Figure 2. The overall survival curves of 182 patients according to risk groups.

Discussion In our study, 182 patients, with disseminated low-grade lymphoma, had data suitable to complete the IPI. According to the initial features, treatment either was immediately started or was deferred until progression. Patients received the same polychemotherapy regimen, given monthly for six cycles. After applying the IPI, the distribution of patients in the four groups, according to risk factors, were as follows: low-risk group, 78 cases; lowintermediate-risk group, 44 cases; high-intermediate-risk group, 45 cases; and high-risk group, 15 cases. CR was achieved in 40%, 36%, 25%, and 14% of cases for each of these risk groups, respectively. The median survival from diagnosis for each IPI group was not reached for low risk, 65 months for low-intermediate risk, 34 months for highintermediate risk, and 12 months for high risk. In our study cohort, all histologic subtypes of LG NHL were included. Thus, this population was more heterogeneous than those in most of the other studies, exclusively or mainly conducted on follicular lymphoma [8, 12]. In terms of survival, prognosis was significantly (log-rank test P = 0.02) better for nodular lymphoma than for other categories. According to a review of most of the histologic data, mantle-cell lymphoma (REAL classification) has worse prognostic value according to the same criteria (i>=0.01). On the other hand, our patients had the same treatment policy. Inclusion criteria focused our study on advanced-stage and old patients. However, survival is significantly different for age (P = 0.03), PS (P < 0.0001), extranodal sites of disease {P < 0.0001), and LDH (P < 0.0001) in univariate analysis. This is where the IPI may be used. In developing new treatment strategies, the relative indolence of the disease and the knowledge that some

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microglobulin level (P = 0.05) were significant. When response to therapy (CR, PR, and failure) was also included in in the analysis, response (P < 0.0001) and IPI (P < 0.0001) were the most important prognostic factors for survival. In including relapse in the model, only IPI (P = 0.0002) and relapse (P = 0.001) had prognostic value for survival.

patients will survive for long periods despite incomplete remission make the identification of subgroups with a less favorable prognosis important. If trials are to be designed with a realistic chance of showing an improvement in survival, patients will have to be selected on the basis of those characteristics that predict for a poor outcome with current approaches. Investigators have analyzed several features to better predict survival among patients with LG NHL [7, 8, 13, 14]. These prognostic models have not been validated in other large sets of patients and are not easy to calculate. Serum levels of LDH and p2-microglobulin seem to be major prognostic factors, and Bastion and Coiffier [15] found them very powerful in the stratification of follicular lymphoma patients. Developed for aggressive lymphomas, the IPI is widely used. Prognostic value of all parameters included in this model has been demonstrated in LG NHL. Bastion, Lopez-Guillermo and Hermans and colleagues found good prognostic power for the IPI in their series [8, 12, 16]. In the first study, 107 of 125 patients had follicular lymphoma and in the second, all patients had follicular lymphoma. Although all our patients had stage III or IV, the IPI was very powerful in discriminating the four prognostic groups. As in the other studies, few patients had high risk in our study (8%). In summary, the IPI identifies four different groups with discriminated response rates and overall survival curves. A powerful prognostic index is needed to identify a greater proportion of patients with high risk factors and to allocate them for intensive treatments. It is likely that IPI, combined with other variables, could be improved to provide this tool.

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15. Bastion Y, Coiffier B. Is the International Prognostic Index for aggressive lymphoma patients useful for follicular lymphoma patients? J Clin Oncol 1994; 12:1340-2 (Editorial). 16. Hermans J, Krol ADG, Van Groningen F et al. International Prognostic Index for aggressive non-Hodgkin's lymphoma is valid for all malignancy grades. Blood 1995, 86:1460-3. Correspondence to: Dr C. Foussard Department of Hematology CHU Angers 49033 Angers Cedex 01 France

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