Annals of Oncology Advance Access originally published online on March 8, 2006
Annals of Oncology 2006 17(6):920-927; doi:10.1093/annonc/mdl039
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© 2006 European Society for Medical Oncology
Patients with grade 3 follicular lymphoma have prolonged relapse-free survival following anthracycline-based chemotherapy: the Nebraska Lymphoma Study Group Experience
1 Department of Internal Medicine, Division of Oncology/Hematology, 2 Department of Pathology and Microbiology and 3 Department of Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, NE; 4 Department of Internal Medicine, Omaha VA Medical Center, Omaha, NE, USA
* Correspondence to: A. K. Ganti, Department of Internal Medicine, 987680 Nebraska Medical Center, Omaha, NE 68198-7680, USA. Tel: +1-402-559-5520; Fax: +1-402-559-6520; E-mail: aganti{at}unmc.edu
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Abstract |
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Background: The aim of the study was to determine the outcome and clinical features predictive of survival in patients with follicular lymphoma (FL) treated aggressively and to determine the rate of disease-specific mortality in patients with grade 3 FL (FL3).
Materials and methods: Four hundred and twenty-one patients with FL who were treated with various anthracycline-based chemotherapy regimens were included in this retrospective study.
Results: Patients with FL3 and a diffuse component of >50% had the worst outcome, with a hazard ratio of dying of 2.2 (95% CI 1.4–3.4) compared with patients with FL1 or FL2, and a ratio of 1.6 (95% CI 1.02–2.5) compared with FL3 with a diffuse component of 
50% by multivariate analysis (P = 0.0026). Patients with FL3a had an outcome similar to those with FL3b. In patients with FL3 and a diffuse component of 50%, the overall and event-free survival curves showed a plateau for patients younger than 60 years of age. However, there were no differences in the cumulative incidence of relapse/progression or lymphoma-specific/treatment-related mortality between the two age groups.
Conclusions: Less than half of the patients with FL3 and a diffuse component of 50% treated with anthracycline-based combination chemotherapy will relapse and relapses are uncommon after 6 years. Older patients should be offered the same aggressive chemotherapy as younger patients.
Key words: age, anthracyclines, grade 3 follicular lymphoma, outcomes, therapy
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introduction |
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TopAbstractintroductionmaterials and methodsresultsdiscussionReferences |
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Follicular lymphoma (FL) is the most common indolent lymphoma, comprising 35% of adult non-Hodgkin's lymphoma (NHL) in the United States and 22% worldwide [1
, 2]. The most accepted method of grading FL, as described by Mann and Berard [3] and subsequently adopted by the WHO [4], is based on counting the number of centroblasts in 10 neoplastic follicles and expressing this as the average number per 40x high power field (hpf).
Clinically, the behaviour and outcome of grade 1 and grade 2 FL (FL1, FL2) is similar and both are considered indolent lymphomas [5]. In contrast to FL1 and FL2, some authors believe that FL3 behaves more aggressively and, therefore, needs to be treated accordingly [4, 6–10]. However, there is a controversy regarding the curability of FL3. Some studies have shown that the outcome of FL3 following aggressive therapy with anthracycline-based regimens is similar to that of diffuse large B-cell lymphoma (DLBCL), with prolonged survival in a substantial number of patients [10–13]. However, other studies have reported that despite aggressive therapy, there is no evidence of prolonged disease-free survival in FL3 [14, 15]. Miller et al. [15] found no plateau in the overall survival curve of patients with FL3. In their series, the survival curves for all three grades of FL appeared similar. The reasons for this variation in outcome for patients with FL3 are not clear, but may have to do with the relatively small numbers of patients in most of these studies. Another reason may be variation in the criteria used for identification of cases with FL3, as only three studies [7, 8, 10] used the criteria described by the WHO [3, 4]. Also, some studies included only patients with advanced stage disease [15], and others did not limit cases to those with a diffuse component of 50%. As a result, the outcome of patients with FL3 who are treated with aggressive therapy is not well defined.
Little data regarding the clinical features of patients with FL3 have been published since the acceptance of the WHO criteria for FL3. Although patients with FL3 having a diffuse component of >50% have an inferior survival, similar to that of patients with DLBCL [16], the clinical prognostic factors for FL3 have not been clearly defined. Hence, we performed a retrospective analysis of our patients with FL3 who were treated with anthracycline-based chemotherapy regimens, to determine the outcome and identify clinical features predictive of survival.
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materials and methods |
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Adult patients who were diagnosed with FL and initially treated with an anthracycline-based chemotherapy regimen by the Nebraska Lymphoma Study Group between June 1983 and January 2001 were included in this analysis. Four hundred and twenty-one patients diagnosed with FL during the study period were identified. The subclassification of FL was performed using the method of Mann and Berard [3
], which was subsequently adopted by the WHO Classification [4]. The grading is based on counting the number of centroblasts in 10 neoplastic follicles, and expressed as the average number per 40x high power field (hpf): grade 1 is 0–5 centroblasts/hpf, grade 2 is 6–15 centroblasts/hpf and grade 3 is >15 centroblasts/hpf. The FL3 cases were then subclassified as grade 3a (FL3a) if the follicular component contained >15 centroblasts/hpf in a background of small cleaved cells (centrocytes) or grade 3b (FL3b) if there were solid sheets of centroblasts without small centrocytes. All cases were reviewed by two haematopathologists (DDW, CPH) to confirm the diagnosis.
Data collected at the time of diagnosis included age, gender, stage of the disease based on the Ann Arbor system, presence of B symptoms, Karnofsky performance score, serum lactate dehydrogenase (LDH) level, International Prognostic Index (IPI) score [17], Follicular Lymphoma International Prognostic Index (FLIPI) score (poor prognostic factors: age >60 years, Ann Arbor stage III/IV, haemoglobin <12 g/dl, more than four nodal areas and elevated LDH level) [18], therapeutic regimen, response to therapy, survival and cause of death.
All patients received one of the following anthracycline-based chemotherapy regimens: cyclophosphamide, mitoxantrone or doxorubicin, procarbazine, bleomycin, vincristine and prednisone or dexamethasone (CAP/BOP) [19]; cyclophosphamide, mitoxantrone, vincristine and prednisone (CNOP) [20]; or cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) [21]. None of these patients received rituximab as initial therapy. Patients with stage I or II disease received radiation therapy to the involved fields following two to four cycles of chemotherapy. Patients with stage III or IV disease were treated to a complete response followed by two additional cycles of chemotherapy (five to 12 cycles in total).
Patient characteristics were compared using the chi-squared test. The Kaplan–Meier method was used to estimate overall and event-free survival distributions [22]. Overall survival (OS) was defined as the time from the date of first treatment to death from any cause or the date of last contact. Event-free survival (EFS) was defined as the time from the date of first treatment to relapse, progression or death, or the date of last contact. Cumulative incidence methods were used to estimate the distributions of relapse/progression and lymphoma-specific/treatment-related deaths. Comparisons of survival distributions were made using the log-rank test. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for risk factors of OS and EFS. Cox regression with stepwise selection was used for multivariate analysis. Variables included in the multivariate analysis were age, gender, number of extranodal sites, LDH level, Karnofsky score, stage, B symptoms, haemoglobin and the number of nodal sites. Stepwise selection was used with a significance level of P = 0.05.
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results |
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Four hundred and twenty-one patients with FL diagnosed between 1983 and 2001 were included in this study, including 208 males and 213 females. The clinical features of the patients are shown in Table 1. The median age of the patients was 60 years (range 23–88 years) and 36% of the patients presented with low-stage (I or II) disease. Nineteen per cent of the patients had B symptoms and 20% had an elevated LDH level at diagnosis. A significant number of patients had a low FLIPI score (46%) or IPI score (54%) at diagnosis. At the time of analysis, with a median follow-up of 9 years for all surviving patients (range 0.5–20.2 years), 214 patients (51%) had died and 207 patients (49%) were alive at last contact.
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By univariate analysis, age
60 years, advanced stage (III/IV), presence of B symptoms, involvement of more than four nodal sites, haemoglobin <12 g/dl, an elevated LDH level, poor performance status (Karnofsky score <70) and high FLIPI or IPI scores, were found to predict for adverse OS and EFS (Table 2). In addition, patients with FL1 and FL2 had a significantly better OS, but not EFS than those with FL3. The median OS for patients with FL1 and FL2 was 11 years compared with 9.4 years for patients with FL3 and a diffuse component 50% and 5 years for patients with FL3 and a diffuse component of >50% (P = 0.0018) (Figure 1).
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However, by multivariate analysis, gender, the FLIPI score and the grade of follicular lymphoma were the only significant predictors of OS. Females had a hazard ratio of death of 0.6 (95% CI 0.5–0.9; P = 0.0025) compared with males. Patients with two adverse risk factors on the FLIPI score had a 1.8-fold increased risk of death (95% CI 1.2–2.6), whereas those with three or more adverse factors had a hazard ratio of dying of 3.4 (95% CI 2.7–5.4) compared with patients with 0 or 1 risk factors (P < 0.0001). FL grade was also a significant predictor of OS in the multivariate model (P = 0.0026). Patients with FL3 and a diffuse component of >50% had the worst outcome, with a hazard ratio of death of 2.2 (95% CI 1.4–3.4) compared with patients with FL1 and FL2 (P = 0.0008). Patients with FL3 and a diffuse component
50% had a hazard ratio of death of 1.3 (95% CI 1.0–1.8) compared with patients with FL1 and FL2 (P = 0.054). When we evaluated FL3 specifically, patients with FL3a had an outcome similar to those with FL3b (Figure 2). However, patients with FL3 and a diffuse component >50% had a significantly worse outcome compared with those with a diffuse component of 50%, with a hazard ratio of death of 1.6 (95% CI 1.02–2.5; P = 0.039).
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Given these results and our previous observation that patients with FL3 and a diffuse component of >50% have a significantly worse survival [16
], we then specifically looked at patients with FL3 and a diffuse component 50% to try and identify the clinical prognostic factors in this select group of patients. One hundred and seventy-seven patients with either pure FL3 or FL3 with a diffuse component of 50% were identified among the 421 patients with FL. The 10-year OS for this group of patients was 45% (95% CI 37% to 53%) and the corresponding EFS was 31% (95% CI 24% to 39%). The clinical features of these patients are shown in Table 3. There have been 96 deaths in this group of patients and the median follow-up of the remaining patients is 9.3 years (range 0.5–19.5 years). The relapse rate at 10 years in this group was 48% (95% CI 31% to 66%).
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Factors that predicted for adverse OS and EFS in this group of patients were B symptoms, haemoglobin level of <12 g/dl, and high FLIPI and IPI scores (Table 4). In addition, age
60 years and an elevated LDH level predicted for poor OS, whereas advanced stage (stage III/IV) and involvement of more than four nodal sites predicted for poor EFS. However, by multivariate analysis, only low haemoglobin level (HR 1.8, 95% CI 1.1–2.9, P = 0.025; HR 1.9, 95% CI 1.2–2.9, P = 0.0048) and the presence of B symptoms (HR 2.2, 95% CI 1.3–3.7, P = 0.0027; HR 1.7, 95% CI 1.1–2.7, P = 0.028) predicted for both adverse OS and EFS. In addition, age 60 years (HR 2.7, 95% CI 1.7–4.3, P < 0.0001) predicted for adverse OS and advanced stage (HR 1.8, 95% CI 1.2–2.7, P = 0.0084) predicted for adverse EFS. Of the 177 patients, 25 underwent high-dose chemotherapy with stem cell transplantation for relapse. We found that undergoing transplantation was not a significant predictor of overall survival (HR = 0.8, 95% CI 0.4–1.6, P = 0.57).
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Interestingly, we found that the OS and EFS curves showed a plateau for patients younger than 60 years of age at diagnosis, but not for older patients (Figures 3 and 4). Therefore, we decided to study these two subgroups of patients further to see which clinical features predicted an adverse outcome. The clinical features of our patients by age group are shown in Table 5. We found that there were more males among the younger group of patients (55% versus 39%, P = 0.036) and that more patients in the older age group had an elevated LDH level at diagnosis (29% versus 13%; P = 0.014). However, there were no other differences in the clinical features of these two groups that could account for the difference in outcome.
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We then analysed the cumulative incidence of disease-specific events for each age group to see if the difference in outcome was due to lymphoma or other causes. However, we did not find any difference in the cumulative incidence of relapse/progression in the two groups (Figure 5). The risk of relapse at 5 years in the younger group was 46% (95% CI 30% to 61%) compared with 37% (95% CI 21% to 53%) in the older group. The corresponding 10-year rates were 53% (95% CI 29% to 76%) and 44% (95% CI 19% to 69%), respectively. We found that relapse/progression was unusual after 6 years. Similarly, when we analysed the lymphoma-specific/treatment-related mortality for the two age groups, there was no difference in the incidence of disease-specific deaths (Figure 6), thereby showing that the decreased survival in older patients was due to other unrelated causes.
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discussion |
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Grade 3 follicular lymphoma (FL3) is a relatively common lymphoma accounting for 6.4% of all NHL and 29% of all FL using the new WHO classification criteria [23
]. Although FL1 and FL2 are generally considered to have an indolent behaviour [5], the clinical course of FL3 is a subject of intense debate. The clinical behaviour and outcome of this disease when treated with aggressive therapy are not well defined. Therefore, we decided to study our patients with FL3 in order to define the clinical course of this disease better.
One of the major reasons for the controversy regarding the behaviour of patients with FL3 has been the lack of a uniform classification system. In a collaborative study between the Repository Center for Lymphoma Clinical Studies and members of the pathology subcommittees of the major cooperative oncology groups, 105 patients with follicular lymphoma were subclassified by seven haematopathologists [24]. Great variability in diagnosis was noted due to difficulties inherent in the accurate determination of cell size and the precise percentages of different cells. In order to make the classification more objective, the WHO has recommended the grading of FL based on the number of centroblasts, as described by Mann and Berard [3, 4].
The various clinical studies that have been published to date evaluating the behaviour of FL3 are shown in Table 6 [7–15, 25–29]. The median survival ranges from 25 months in the study by Stewart et al. [27] to 266 months in the study by Chau et al. [29]. Similarly, there is wide variation in the OS, ranging from 35% at 4.5 years in the Stanford study by Jones et al. [25] to 72% at 5 years as reported by Rodriguez et al. [9]. A closer look at these studies, however, may help explain these wide disparities. The older studies demonstrated that the outcome of these patients was intermediate between those with low grade nodular (FL1 and FL2) and diffuse lymphomas (DLBCL) [11, 12, 25]. The results of our study confirm these observations. Patients with FL1 and FL2 had a median OS of 11 years compared with 9.4 years for patients with FL3 and a diffuse component 50% and 5 years for those with FL3 and a diffuse component >50% (P = 0.0018). These observations also confirm our previous finding that patients with FL3 and a diffuse component >50% have a worse outcome than other patients with FL3 [16]. Also, similar to our previous observation, we did not find any difference in outcome when patients with FL3 were subclassified as FL3a and 3b.
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Many studies have consistently found that a proportion of patients with FL3 have prolonged disease-free survival following treatment with aggressive combination chemotherapy [6
, 8–10, 12, 13, 27]. The role of anthracyclines/anthracenediones in the therapy of FL3 was controversial in the past. However, anthracycline-containing regimens are now considered the standard treatment for patients with advanced-stage follicular lymphomas. In the study by Bartlett et al. [10], the 10-year freedom from progression was 55% for patients treated with a doxorubicin-containing regimen compared with only 25% for patients treated with other regimens. Recently, the Italian Lymphoma Intergroup conducted a retrospective study of patients with follicular lymphoma treated in various trials between 1985 and 1996. They found that patients treated with anthracyclines had a better 5-year OS compared with patients treated without anthracyclines (80% versus 67%, P = 0.0004) [30]. However, the role of anthracyclines in the management of FL3 has recently been challenged. A study of 231 patients by Chau et al. [29] found that anthracyclines did not appear to influence survival or disease relapse when given as front-line therapy. A closer look at this study, however, shows that there was a plateau in the overall and failure-free survival curves after 5 years in the group that received anthracyclines, and the lack of a significant difference may have been due to the small number of patients. In contrast, we found a 10-year EFS of 32% and a 10-year OS of 45% for our patients with FL3 and a diffuse component of 50%, who were treated with anthracycline/anthracenedione-based chemotherapy regimens. Although the median age of our patients was higher than that in the other reported series, our patients appeared to have a better median survival than most previous reports [6, 11, 15, 27], with a few exceptions [9, 27, 28]. Our results are similar to those of the International Study that found an 8-year OS of approximately 65% and failure-free survival of 45% [31]. When we looked at outcomes following transplantation, we found that patients who received high-dose chemotherapy followed by haematopoietic stem cell transplantation had a similar OS to those who did not undergo a transplant. However, the number of patients who received a transplant was too small to make any meaningful recommendations based on our data.
Based on these results, we believe that aggressive anthracycline-based chemotherapy should be offered to all suitable patients with FL3. One aspect of therapy that our study did not address was the role of rituximab in the treatment of FL3. The German Low Grade Lymphoma Study Group recently presented the findings of a randomized trial comparing CHOP with R-CHOP (CHOP and rituximab) [32]. They found that the addition of rituximab reduced the relative risk for treatment failure by 60% and significantly prolonged the time to treatment failure. They also found a significantly higher overall response rate, prolonged duration of remission and superior OS for patients in the R-CHOP arm. This suggests that adding rituximab would improve the outcome of patients with FL3 to an even greater extent than with anthracycline-based therapy alone.
Interestingly, we found that there was a plateau in the survival curves for patients <60 years of age at diagnosis, suggesting a prolonged disease-free survival in approximately 40%–50% of these patients. These findings are similar to those reported by Maartense et al. [33]. In their study of 214 patients with FL, they found that patients with FL3 had a worse OS than patients with FL1 or FL2, but the cause-specific survival curve in patients with FL3 had a plateau (approximately 25%). They also found that survival was lower in older patients due to the increasing influence of concomitant disease on the death rate, especially among FL3 patients older than 70 years of age. We evaluated the relapse/progression rates and the lymphoma-specific/treatment-related death rates among our younger (<60 years) and older (60 years) patients, but did not find any significant differences. There was also no difference in the response to initial treatment between these two groups. Therefore, we believe that the behaviour of this disease does not depend on the age of the patient. The worse EFS and OS seen in our older patients was due to the increased frequency of co-morbid conditions and not due to any difference in either the behaviour of the lymphoma or the response to therapy. Also, there was a plateau in the cumulative incidence curves for both relapse/progression and disease-specific death rates, thereby indicating that approximately half of all patients with FL3 have a prolonged disease-free survival following aggressive therapy with an anthracycline-based regimen.
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Acknowledgements |
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The authors wish to acknowledge Martin C. Bast, Lead Coordinator, Nebraska Lymphoma Study Group, for his invaluable assistance with the data collection.
Received for publication March 22, 2005. Revision received February 3, 2006. Accepted for publication February 6, 2006.
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