Annals of Oncology Advance Access published online on December 13, 2007
Annals of Oncology, doi:10.1093/annonc/mdm511
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© 2007 European Society for Medical Oncology
The addition of rituximab to CHOP chemotherapy improves overall and failure-free survival for follicular grade 3 lymphoma
1 Department of Gastrointestinal Medical Oncology
2 Department of Biostatistics and Applied Mathematics
3 Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
4 Hospital Auxilio Mutuo Cancer Center, San Juan, Puerto Rico
* Correspondence to: Dr L. E. Fayad, Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Unit 429, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Tel: +1-713-792-2860; Fax: +1-713-794-5656; E-mail: lefayad{at}mdanderson.org
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Abstract |
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Background: The benefit of adding rituximab to anthracycline-based therapy for follicular lymphoma grade 3 has not been studied.
Patients and methods: We retrospectively reviewed the records of 45 patients with follicular grade 3 lymphoma who were treated with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) at The University of Texas MD Anderson Cancer Center. Response rate, failure-free survival (FFS), and overall survival (OS) were estimated and a historical comparison to CHOP-only-treated patients was made.
Results: The International Prognostic Index (IPI) distribution was 47% low, 36% low intermediate, 13% high intermediate, and 4% high risk. The complete response rate was 96%. Forty-four of 45 patients are still alive. Median follow-up for the alive patients is 3.5 years. The 3-year FFS rate according to the IPI was 80% [95% confidence interval (CI) 64% to 100%] in low, 81% in low intermediate (95% CI 64% to 100%), and 50% (95% CI 25% to 100%) in high-intermediate/high-risk patient group. The addition of rituximab to CHOP improved both 5-year FFS, 71% (95% CI 58% to 87%) compared with 44% (95% CI 36% to 55%) with P value of 0.019, and 5-year OS, 98% (95% CI 93% to 100%) compared with 75% (95% CI 67% to 84%) with P value of 0.0034.
Conclusion: The addition of rituximab to CHOP provided a high response rate and excellent early survival. Poor-risk patients continue to demonstrate a high rate of failure despite the use of rituximab.
CHOP, follicular lymphoma grade 3, outcome, rituximab, therapy
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introduction |
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The follicular lymphomas (FLs) are indolent lymphomas representing 35% of all non-Hodgkin's lymphomas [1]. The median survival for FL is
9 years but there are significant variabilities in aggressiveness and outcomes of these diseases [2]. Current treatment approaches vary from watchful waiting to combination chemotherapy to allogeneic transplantation. The most notable attempts to develop clinically useful algorithms for decisions regarding patient care have included pathological grading and the creation of the International Prognostic Index (IPI) or the Follicular Lymphoma International Prognostic Index (FLIPI) [2–4]. Both the International Working Formulation and the Revised European–American Lymphoma classification have relied primarily upon the presence of large cells to subdivide FL [5, 6]. More recently, the classification scheme adopted by the World Health Organization (WHO) defined three pathological grades of FL on the basis of the number of large noncleaved cells, or centroblasts, per x40 high power field (hpf) [7]. Grade 3 follicular lymphoma (FLG3), defined as >15 centroblasts per hpf, was further subdivided into grades 3A or 3B on the basis of the presence or absence of centrocytes. This subdivision was based on recent molecular and cytogenetic work, suggesting a biological difference between these two subtypes [8]. In contrast to follicular grades 1 and 2 lymphoma, FLG3 has a more aggressive natural history and a relapse pattern that is more similar to those observed with diffuse large B-cell lymphoma [4, 9–11]. Multiple investigators have demonstrated that there is a benefit in the early use of an aggressive anthracycline-based chemotherapy as initial treatment of FLG3 [12–15], and use of certain regimens has resulted in a plateau in the relapse rate, suggesting the possibility of cure with intensive therapy of this disease [13, 16].
Rituximab is an active agent in treatment of both diffuse large B-cell lymphoma and FL grades 1 and 2. In a large randomized phase III study, the German Low-Grade Lymphoma Study Group demonstrated improvements in both progression-free survival and overall survival (OS) rates with the addition of rituximab to combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy for FL grades 1 and 2 [17]. Other studies evaluating rituximab included FLG3, but due to the small sample size of patients in these studies, it has been difficult to interpret the benefit of rituximab in this subgroup [18–20].
We undertook this analysis to evaluate the benefit of adding rituximab to combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for FLG3. From 1999 to 2004, 45 patients with FLG3 have been treated at the University of Texas MD Anderson Cancer Center (UTMDACC) with R-CHOP chemotherapy. This report represents the single-institution largest series of FLG3 patients treated with rituximab-based therapy.
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patients and methods |
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We identified all patients with FLG3 who received therapy before 2005 from the UTMDACC lymphoma database. Only patients who received R-CHOP as frontline therapy and had a review of their pathologic biopsy at UTMDACC were included in this study. Pathologic grading was based on the WHO classification [7]. We recorded information regarding demographic data, tumor characteristics, treatment, treatment response, survival, and staging upon the Ann Arbor classification. All patients had undergone evaluations by computed tomography and bone marrow aspirations and biopsies. Eastern Cooperative Oncology Group (ECOG) performance status, extranodal involvement, presence of B symptoms, presence of bulky disease, and IPI category were defined at diagnosis in all the patients. Assignment to the FLIPI category required retrospective review to gather information regarding involved nodal stations. This study was carried out in accordance with the institutional review board guidelines.
For comparative purposes, we collected a historical cohort of previously reported patients with follicular grade 3 lymphoma treated with CHOP-based therapy as initial treatment at UTMDACC. CHOP-based therapy consisted of CHOP alone in 47 patients, CHOP combined with bleomycin in 53 patients, and CHOP combined with melatonin or placebo in 11 patients [14, 16, 21, 22].
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statistical analysis |
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Descriptive statistics were used to describe the basic features of the data in the study. The chi-square test or the Fisher's exact test was used to evaluate associations between categorical variables. Kaplan–Meier estimates were calculated to plot event-free curves for each outcome. The log-rank test was used to compare the differences in the event-free survival between the patient groups. Cox proportional hazards model was used for multivariate analysis. Step-wise model selection method was carried out to obtain the best subset of variables in the final model. The hazard ratios with the 95% confidence intervals (CIs) and the P values were also determined. P values were derived from two-sided tests and the statistical analyses were performed using SAS 9.1 (SAS Institute Inc., 2002–2003) and Splus 7.0 (MathSoft, Inc., 2005). OS was defined from the time to start treatment until death of any cause. Failure-free survival (FFS) was measured from the time to start treatment to the time of failure for any reason or death. Complete remission (CR) and partial remission criteria were used following the response criteria for malignant lymphoma [23].
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results |
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patients
Baseline characteristics of both cohorts, R-CHOP-treated and CHOP-treated patients, are shown in Table 1. For the R-CHOP-treated group, the median age was 58 years (range 37–83 years) and 49% were women. In the R-CHOP-treated patients, 87% of the patients were classified as having follicular grade 3B. As expected, these patients had few poor prognostic factors with ECOG performance status of more than one in only 2%, elevated lactate dehydrogenase in 24%, more than one extranodal disease site in 13%, B symptoms in 11%, and bulky disease defined as tumor size >7 cm in 11%. Eighty percent, however, had stages 3 and 4 disease and 56% had elevated serum beta-2 microglobulin, a previously described poor prognostic factor. According to the FLIPI scoring system, 33% were classified as having disease compared with only 17% according to the IPI.
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Other characteristics between the two groups were well matched, except that there were significantly more patients with bone marrow involvement in the R-CHOP-treated group, 31% compared with 12%, P = 0.004. In addition, there was a trend for more early-stage patients in the CHOP-treated cohort, 31% versus 20%, P = 0.14. Consolidation radiation therapy was used following R-CHOP for 12 patients (27%) and following CHOP for 27 patients (24%).
results with R-CHOP
The CR rate to R-CHOP was 96% and 44 of the 45 patients are still alive. Two patients who had PR had residual radiographic abnormalities following eight cycles of R-CHOP. In each case, biopsy of the residual mass revealed transformation to large B-cell lymphoma and both cases are currently in CR following autologous transplant. The CR rate was higher in the R-CHOP-treated patients (96%) compared with the CHOP-treated patients (86%), but this difference was not statistically different (P = 0.15).
At a median follow-up of 3.5 years, 12 patients (27%) relapsed and one patient died. The 3-year OS and FFS rates were 97.6% (95% CI 93% to 100%) and 75% (95% CI 63% to 89%), respectively. FFS results stratified by the IPI and FLIPI status are shown in Figure 1. Both the IPI and FLIPI prognostic systems stratified patients into two subgroups with different FFS results (Figure 1). According to the FLIPI, patients with low- and intermediate-risk disease (zero to two factors) had statistically better FFS than did those patients with three to five risk factors (P = 0.024), whereas stratification by the IPI was not statistically significant (P = 0.096). Many patients also had high-risk disease according to the FLIPI than by the IPI.
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In addition to the FLIPI score, other variables significantly associated with improved FFS were bone marrow involvement and performance status (Table 2).Twenty-five patients who had an ECOG performance status of zero had an excellent 3-year FFS of 92% (95% CI 82% to 100%). Those with the presence or absence of bone marrow involvement had a 3-year FFS of 50% (95% CI 30% to 84%) and 87% (95% CI 75% to 100%), respectively (P = 0.009).
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R-CHOP compared with CHOP
The CR rate was higher in the R-CHOP-treated patients (96%) compared with the CHOP-treated patients, (86%) but this difference was not statistically different (P = 0.15).
FFS results were better following the use of R-CHOP (Figure 2, P = 0.019). Five-year results were 71% (95% CI 58% to 87%) following R-CHOP and 44% (95% CI 36% to 55%) for those following CHOP treatment. Stratification into low (low and low-intermediate IPI) and high-risk (high-intermediate and high) categories by the IPI is shown in Figure 2b. Interestingly, high-risk patients, as defined by the IPI, appeared to have a similar rapid rate of relapse whether treated with CHOP or R-CHOP.
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OS, shown in Figure 3, is improved with the use of R-CHOP, P = 0.0034. At 5 years, OS for the R-CHOP- and CHOP-treated groups are 98% (95% CI 93% to 100%) and 75% (95% CI 67% to 84%), respectively. Despite the high rate of relapse in the R-CHOP-treated patients with high-risk IPI, three or more risk factors, OS is improved in comparison to high-risk CHOP-treated patients. Comparison of R-CHOP patients with CHOP-based treatment using FLIPI was not possible due to incomplete information about the number of involved sites in the CHOP-treated cohort.
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R-CHOP relapse and disease transformation
The median failure survival time was not reached for the group of patients treated with R-CHOP. For the 12 patients who had relapses, the median time from treatment start date to relapse date is 17.3 months (range 5.8–40.4 months). Five relapses occurred in 30 patients with low-risk FLIPI, zero to two risk factors, and seven relapses occurred in 15 patients with high-risk FLIPI, three to five risk factors. Transformation to diffuse large B-cell lymphoma occurred in four patients at first relapse and in six patients overall. Patients with transformation at first relapse relapsed faster than those not transforming, 10 months versus 20.7 months. No relapses occurred in the five patients with FL grade 3A.
Salvage therapy consisted of chemotherapy alone in five patients, radiation therapy followed by rituximab in one patient, chemotherapy followed by autologous transplant in four patients, and chemotherapy followed by allogeneic transplant in two patients. All patients treated with transplantation are currently alive without evidence of disease.
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discussion |
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This data support the use of rituximab in the treatment of FLG3. The excellent early survival demonstrated in this study is highly encouraging. Our data, however, clearly show that despite the use of rituximab, a significant number of relapses continue to occur in high-risk patients.
In 1984, Kantarjian et al. [14] reported improved outcomes with anthracycline use in follicular large-cell lymphoma. Subsequent studies have found a similar benefit from anthracycline use with a 5-year FFS of 52%–67% [12, 16]. Whether anthracycline-based therapy results in long-term ‘cures’ or a plateau in relapse-free survival is controversial [24]. A number of studies with a long-term follow-up have shown a 10-year relapse-free survival of 31%–42% [12, 13, 16]. Other studies, however, have demonstrated a lower 10-year FFS, 22%–29%, and no evidence for a plateau in the rate of relapse [25, 26]. These survival rates for anthracycline-treated patients from the literature are similar to our CHOP-treated cohort, in which a 10-year OS is 58% (95% CI 48% to 69%) and a 10-year FFS is 35% (95% CI 27% to 46%).
Due to the limited follow-up in our study, no definitive conclusions regarding the potential effect of rituximab on long-term disease control can be made at this time. With early follow-up, however, R-CHOP treatment clearly demonstrates a lower rate of early relapse when compared with the CHOP treatment. When stratified by risk, this benefit appears limited to those patients with good prognosis disease.
The addition of rituximab to CHOP chemotherapy for DLBCL has improved the CR rate by 17%–21%, reduced relapses by 27%–58%, and improved survival by 10%–19% [27, 28].
In FL, the use of R-CHOP in follicular grades 1 and 2 lymphoma reduced the 18-month relapse rate by 55% and the improved 2-year OS from 90% to 95% [18]. The largest study that investigated rituximab treatment in FLG3 patients compared the combination of cyclophosphamide, vincristine, and prednisone to RCVP treatment [20]. Out of a total of 162 RCVP-treated advanced staged FL patients, 19 had FL grade 3. The addition of rituximab increased the overall response rate from 57% to 81%, reduced the 18-month relapse rate by 55%, and improved the 4-year OS from 81% to 90%. In our study, the addition of rituximab to CHOP improved complete response rate from 86% to 96% (P = 0.15), the 5-year FFS from 44% to 71% (P = 0.019), and the 5-year OS from 75% to 98% (P = 0.0034).
Prognostic stratification by the FLIPI classified more patients as high risk when compared with the IPI. This applied whether high risk was defined as either four to five risk factors or three to five risk factors (data not shown). In patients treated with R-CHOP chemotherapy, the FLIPI was able to successfully stratify patients according to the relapse risk. Those patients with zero to two risk factors had a 86% 3-year FFS and those with three to five risk factors had a 53% 3-year FFS, P = 0.024. Our classification of low-risk patients as zero to two FLIPI risk factors is similar to a recent report evaluating the applicability of the FLIPI in rituximab-treated FL patients [29]. In this report of 362 advanced FL patients treated with R-CHOP, low risk, zero to one risk factors, and intermediate risk, two risk factors, demonstrated equivalent 2-year time to treatment failure.
The significance of subdividing follicular grade 3 lymphoma into 3A and 3B is controversial. Recent molecular and cytogenetic data have supported this differentiation with immunohistochemical/cytogenetic studies demonstrating a bcl-2+/t(14;18) pattern being highly representative of 3A cases and a bcl-6+/3q27 pattern being highly representative of 3B cases [8, 30]. The rarity of FLG3 has limited evaluations on the clinical outcomes of these two subtypes. Two recent studies have, however, indicated no differences in the clinical outcomes between 3A and 3B FL [13, 26]. The small number of 3A patients in this study precludes any conclusion regarding the possible outcome differences between 3A and 3B FL. We believe that the low numbers of FLG3 in this study reflect a selection bias favoring the use of more aggressive R-CHOP-based therapy in patients with greater large-cell predominance, histological grade 3B. Recent data have indicated that in diffuse large B-cell lymphoma patients, those patients who express bcl-6 do not appear to gain added benefit from the addition of rituximab to standard chemotherapy [31]. This observation in theory suggests that follicular grade 3A lymphoma may derive the greatest benefit from rituximab-based therapy.
We encountered certain limitations in our analysis of this data. This was a retrospective study with a potential for both selection and interpretation bias. Despite representing a rather large cohort of FLG3 patients, interpretation of variables within this dataset is limited by its small sample size. Follow-up is also short, with only a limited number of events so far. Our comparison to prior CHOP-treated patients represents a cross-study comparison and should be interpreted as hypothesis generating and not demonstrative of a conclusive benefit for the addition of rituximab to CHOP. Significant differences exist in regard to the supportive care and salvage therapy administered to the CHOP- and R-CHOP-treated cohorts. All R-CHOP-treated patients received therapy after 1999, whereas >80% of the CHOP-treated patients received therapy before this date.
This data demonstrate a high response rate and promising survival rates with the addition of rituximab to CHOP chemotherapy. In good-risk patients, defined by either the IPI or FLIPI prognostic indices, relapses are rare at this early evaluation. In high-risk patients, the high relapse rate despite the addition of rituximab to CHOP suggests that further optimization of therapy is required for this group of FLG3 patients.
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This paper contains original work not previously published. A previous presentation of this material was given at the American Society of Hematology meeting 2006, abstract #2770.
Received for publication September 28, 2007. Accepted for publication October 2, 2007.
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References |
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1. Armitage JO, MP, Harris NL, et al. Non-Hodgkin's Lymphoma (2001) Philadelphia, PA: Lippincott Williams and Wilkins.
2. Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood (2004) 104:1258–1265.
3. A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project [editorial]. N Engl J Med (1993) 329:987–994.
4. Martin AR, Weisenburger DD, Chan WC, et al. Prognostic value of cellular proliferation and histologic grade in follicular lymphoma. Blood (1995) 85:3671–3678.
5. National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project [editorial]. Cancer (1982) 49:2112–2135.[CrossRef][Web of Science][Medline]
6. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood (1994) 84:1361–1392.
7. Nathwani BN, HN, Weisenburger DD, et al. Follicular Lymphoma (1994) Lyon, France: IARC Press.
8. Ott G, Katzenberger T, Lohr A, et al. Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3. Blood (2002) 99:3806–3812.
9. Wendum D, Sebban C, Gaulard P, et al. Follicular large-cell lymphoma treated with intensive chemotherapy: an analysis of 89 cases included in the LNH87 trial and comparison with the outcome of diffuse large B-cell lymphoma. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol (1997) 15:1654–1663.[Abstract]
10. Glick JH, McFadden E, Costello W, et al. Nodular histiocytic lymphoma: factors influencing prognosis and implications for aggressive chemotherapy. Cancer (1982) 49:840–845.[CrossRef][Medline]
11. Osborne CK, Norton L, Young RC, et al. Nodular histiocytic lymphoma: an aggressive nodular lymphoma with potential for prolonged disease-free survival. Blood (1980) 56:98–103.
12. Bartlett NL, Rizeq M, Dorfman RF, et al. Follicular large-cell lymphoma: intermediate or low grade? J Clin Oncol (1994) 12:1349–1357.[Abstract]
13. Ganti AK, Weisenburger DD, Smith LM, et al. Patients with grade 3 follicular lymphoma have prolonged relapse-free survival following anthracycline-based chemotherapy: the Nebraska Lymphoma Study Group Experience. Ann Oncol (2006) 17:920–927.
14. Kantarjian HM, McLaughlin P, Fuller LM, et al. Follicular large cell lymphoma: analysis and prognostic factors in 62 patients. J Clin Oncol (1984) 2:811–819.[Abstract]
15. Rigacci L, Federico M, Martelli M, et al. The role of anthracyclines in combination chemotherapy for the treatment of follicular lymphoma: retrospective study of the Intergruppo Italiano Linfomi on 761 cases. Leuk Lymphoma (2003) 44:1911–1917.[CrossRef][Web of Science][Medline]
16. Rodriguez J, McLaughlin P, Hagemeister FB, et al. Follicular large cell lymphoma: an aggressive lymphoma that often presents with favorable prognostic features. Blood (1999) 93:2202–2207.
17. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood (2005) 106:3725–3732.
18. Czuczman MS, Weaver R, Alkuzweny B, et al. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol (2004) 22:4711–4716.
19. Forstpointner R, Dreyling M, Repp R, et al. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood (2004) 104:3064–3071.
20. Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood (2005) 105:1417–1423.
21. Sarma A, RA, Cabanillas F, et al. A randomized trial of CHOP chemotherapy with or without melatonin in patients with favorable prognosis large B-cell lymphoma. ASCO Annual Meeting Proceedings (Post-Meeting Edition) (2004) 122. Abstr 8066.
22. 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) 9:762–769.[Abstract]
23. Cheson BD, Horning SJ, Coiffier B, et al. Report of an International Workshop to standardize response criteria for non-Hodgkin's lymphoma. J Clin Oncol (1999) 17:1244–1253.
24. Ghielmini M, Mora O. Does the FLIPI apply to grade 3 follicular lymphoma? Blood (2005) 105:4892. author reply 4892–4893.
25. Horning SJ. Something old, something few, something subjective, something deja vu. J Clin Oncol (2003) 21:1–2.
26. Chau I, Jones R, Cunningham D, et al. Outcome of follicular lymphoma grade 3: is anthracycline necessary as front-line therapy? Br J Cancer (2003) 89:36–42.[CrossRef][Web of Science][Medline]
27. Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol (2006) 7:379–391.[CrossRef][Web of Science][Medline]
28. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med (2002) 346:235–242.
29. Buske C, Hoster E, Dreyling M, et al. The Follicular Lymphoma International Prognostic Index (FLIPI) separates high-risk from intermediate- or low-risk patients with advanced-stage follicular lymphoma treated front-line with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with respect to treatment outcome. Blood (2006) 108:1504–1508.
30. Bosga-Bouwer AG, van Imhoff GW, Boonstra R, et al. Follicular lymphoma grade 3B includes 3 cytogenetically defined subgroups with primary t(14;18), 3q27, or other translocations: t(14;18) and 3q27 are mutually exclusive. Blood (2003) 101:1149–1154.
31. Winter JN, Weller EA, Horning SJ, et al. Prognostic significance of Bcl-6 protein expression in DLBCL treated with CHOP or R-CHOP: A prospective correlative study. Blood (2006) 107:4207–4213.
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