Outcomes of Treatment in Slovene Follicular Lymphoma Patients

Original Study Outcomes of Treatment in Slovene Follicular Lymphoma Patients Tanja Juznic Setina, Simona Borstnar, Barbara Jezersek Novakovic Abstract The treatment outcomes of follicular lymphoma (FL) patients have been positively influenced by the introduction of rituximab in the last 2 decades. A retrospective analysis of progression-free survival and overall survival of 278 routinely treated Slovene FL patients confirmed the significant benefit of adding rituximab to chemotherapy and into the maintenance setting outside clinical studies. Background: The outcome of follicular lymphoma (FL) patients has dramatically improved over the last 2 decades by introduction of rituximab in combination chemotherapy and into maintenance setting. We retrospectively analyzed the treatment outcomes in Slovene FL patients in the era of rituximab and compared them to the results reported by pivotal clinical studies. Patients and Methods: Two hundred seventy-eight patients with FL treated in Slovenia between 2000 and 2010 with a median follow-up of 5.7 years were included in our retrospective analysis. One hundred ninety-three (69%) received systemic treatment (ST). Results: With a median follow-up of 5.7 years, the 5- and 10-year overall survival (OS) rates for the whole series were 77% and 53%, respectively. The 5-year progression-free survival (PFS) for 193 FL patients treated with ST was 37%. Patients treated with rituximab chemotherapy had a significantly better OS than patients treated with chemotherapy alone, with a 5-year OS of 79% versus 53% (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.22-0.67; P ¼.001). Adding rituximab to the first-line chemotherapy significantly improved PFS compared to chemotherapy alone (HR, 0.26; 95% CI 0.18-0.36; P <.001). Maintenance rituximab after immunochemotherapy in first-line treatment reduced the risk for progression by 61% and significantly prolonged the time to progression (HR, 0.39; 95% CI 0.20-0.73; P <.003). Conclusion: The outcomes in our routinely treated FL patients confirm the benefit of adding rituximab to chemotherapy and are comparable to the results of pivotal clinical studies. The outcome of our FL patients was improved in terms of both PFS and OS. Clinical Lymphoma, Myeloma & Leukemia, Vol. 15, No. 10, 586-91 ª 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Keywords: Chemotherapy, Follicular lymphoma, Overall survival, Progression-free survival, Rituximab Introduction Follicular lymphoma (FL) is the second most common subtype of non-hodgkin lymphoma, comprising 20% to 30% of all lymphomas and approximately 70% of indolent lymphomas. The median age at diagnosis is 60 years. Clinically, the disease is characterized by an indolent course, with waxing and waning lymphadenopathy, slowly progressing over the years. Most patients are diagnosed with advanced-stage disease; despite the major progress that has been made in the management of the disease, it is still considered incurable. 1,2 Division of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia Submitted: Apr 23, 2015; Accepted: Jul 22, 2015; Epub: Aug 3, 2015 Address for correspondence: Barbara Jezersek Novakovic, MD, PhD, Department of Medical Oncology, Institute of Oncology Ljubljana, Zaloska 2, 1000 Ljubljana, Slovenia Fax: þ386 15879 305; e-mail contact: bjezersek@onko-i.si The optimal management strategy of FL has not yet been defined. Current treatment approaches vary from watchful waiting to combination chemotherapy and allogeneic transplantation. 3 The watch-and-wait strategy remains a safe option for patients without disease-related symptoms because randomized studies have not demonstrated a survival benefit with early application of systemic therapy. 4 With the introduction of the anti-cd20 monoclonal antibody rituximab, the prognosis of FL patients has dramatically changed over the past 2 decades. The benefit ofaddingrituximabto combination chemotherapy has been proved in multiple randomized trials, all of which demonstrated improvement in response rates, time to progression, and improvement in survival. 5-9 Additional benefit in the outcome of FL patients has been proven by introduction of rituximab in the maintenance setting. Several prospective randomized studies have shown the beneficial effect of rituximab maintenance therapy in patients with previously untreated and relapsed FL. 10-14 The results of the PRIMA study established rituximab maintenance 586 - Clinical Lymphoma, Myeloma & Leukemia October 2015 2152-2650/ª 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.clml.2015.07.631

therapy as a new standard of care for the first-line treatment of patients who experience remission after immunochemotherapy. 15 With the modern rituximab chemotherapeutic regimens, the median survival of FL patients has been prolonged from 8 to 10 years to 12 to 15 years. 3,16-18 Hence, the introduction of rituximab into therapy represents an important step forward in the management of this disease and has become the standard of care in firstline, relapse, and maintenance treatment of FL patients. 19 According to cancer registry data, Slovenia has about 65 new cases of FL per year, with an incidence rate of 2.8 per 100,000 persons for both men and women, which represents approximately 20% of all non-hodgkin lymphoma cases in Slovenia. 20 The aim of our retrospective study of 278 FL patients was to analyze the treatment outcome in Slovene FL patients, to evaluate the benefit of adding rituximab to combination therapy, and to compare the results to the outcomes of FL patients reported by major clinical studies. Patients and Methods Patients Two hundred seventy-eight patients diagnosed with FL treated at the Institute of Oncology and other Slovene hospitals between 2000 and 2010 were included in our retrospective analysis. Methods Treatment decisions were based primarily on consensus recommendations at the time. After the completion of primary treatment, patients underwent regular follow-up examinations at our institute. Patient and disease characteristics, treatment, and survival outcomes were evaluated retrospectively from patients records. All procedures were compliant with the ethical standards of the local institutional ethical committee. Statistical Analysis The outcome variables analyzed were progression-free survival (PFS) and overall survival (OS), defined according to the criteria of Cheson et al. 21 The PFS was calculated from the date of starting treatment to the first occurrence of relapse, disease progression or death, or last follow-up. OS was defined as the time interval between the date of diagnosis of lymphoma and last follow-up or death. Survival curves were plotted by the Kaplan-Meier method, and the log rank test was applied to analyze statistical differences in survival. 22 Cox multivariate hazard models were used to calculate the hazard ratios (HR) and their 95% confidence intervals (CI) in the analysis of PFS and OS. All reported P values are 2-tailed. SPSS version 19.0 was used for all statistical analysis (IBM, Armonk, NY). Results Patient Characteristics and Treatment Baseline characteristics are presented in Table 1. A total of 278 patients with FL were included in our analysis. The median age was 58 years; 128 patients (46.1%) were older than 60 years. There were 59.4% women and 40.6% men included. Thirty-four percent of the patients had limited-stage disease, and almost 65% had advancedstage disease at the time of diagnosis. According to histopathologic grade, 50% had low-grade FL (grade 1 or 2), 27.3% were grade 3, and 5% were combined FL and diffuse large B-cell lymphoma. In Table 1 Characteristic Patient Characteristics All Patients (n [ 278) Patients With ST (n [ 193) Age (Years) 60, n (%) 128 (46.1) 87 (45.0) Median (range) 58 (20-90) 57 (20-90) Gender, n (%) Male 113 (40.6) 78 (40.0) Female 165 (59.4) 115 (60.0) Stage, n (%) I 53 (19.1) 15 (7.7) II 43 (15.5) 27 (14.0) III 53 (19.1) 36 (18.6) IV 127 (45.7) 114 (59.0) Not determined 2 1 Grade, n (%) 1 35 (12.6) 24 (12.4) 2 105 (37.8) 68 (35.2) 3 76 (27.3) 53 (27.4) FL þ DVCBL 14 (5.0) 14 (7.2) Not determined 48 (17.3) 34 FLIPI Score, n (%) Low (0-1) 125 (44.9) 62 (32.0) Intermediate (2) 72 (25.9) 59 (30.5) High (3-5) 74 (26.6) 67 (34.7) Not determined 7 5 Abbreviations: FL þ DLBCL ¼ follicular lymphoma þ diffuse large B cell lymphoma; FLIPI ¼ Follicular Lymphoma International Prognostic Index; ST ¼ systemic treatment. 48 patients, the grade was not defined. According to Follicular Lymphoma International Prognostic Index (FLIPI) score, 45% were considered low risk, 26% intermediate risk, and 26.6% high risk. One hundred ninety-three of all patients who needed therapy received systemic treatment (ST). The induction regimen was R- CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in 54.4%, 4 patients received R-CVP (rituximab, cyclophosphamide, doxorubicin, vincristine), and 2 patients received rituximab combined with other chemotherapy regimens. The other 82 patients (42.5%) received chemotherapy alone as an induction regimen, with CHOP (n ¼ 26) and CVP (n ¼ 39) being the regimens most often provided. Seventeen patients received chlorambucil. Among 111 patients who received rituximab chemotherapy as firstline treatment, 66 continued with maintenance rituximab. There were no statistically significant differences regarding grade, stage, and FLIPI between the maintenance rituximab and observation groups. Altogether, 163 FL patients received rituximab chemotherapy at least once in their lifetime during the course of their disease as firstline treatment or in a relapse setting, and only 30 patients had never been treated with rituximab. Disease Outcomes OS of All Patients (n ¼ 278) and OS of Patients Treated With Systemic Therapy (n ¼ 193). With a median follow-up of 5.7 years (range, 2-11 years), the estimated 5- and 10-year OS rates for the Clinical Lymphoma, Myeloma & Leukemia October 2015-587

Slovene Follicular Lymphoma Patients whole series were 77% and 53%, respectively. The median OS has not yet been reached. The respective OS rates of 193 patients treated with ST were 75% and 48%, with a median OS of 9.43 years (Figure 1). Figure 2 Progression-Free Survival of 193 Follicular Lymphoma Patients Treated With Systemic Therapy PFS of Patients Treated With Systemic Therapy (n ¼ 193). The 3- and 5-year PFS of 193 patients treated with first-line ST were 47% and 37%, respectively. The median PFS was 2.3 years (95% CI, 1.4-3.1) (Figure 2). PFS and OS of FL Patients According to Rituximab in First-Line Therapy (n ¼ 193). The 3- and 5-year PFS rates of 82 patients treated with chemotherapy alone in first-line treatment were 20% and 14%, respectively. The 3- and 5-year PFS of the 111 patients treated with rituximab chemotherapy in first-line were 69% and 54%, respectively. The median survival has not yet been reached in the rituximab chemotherapy group and was 12 months in the chemotherapy-alone group. The risk of progression of FL in patients treated with rituximab chemotherapy was reduced by 74% compared to patients treated with chemotherapy alone (HR, 0.26; 95% CI, 0.18-0.36; P <.001) (Figure 3A). The 3- and 5-year OS rates of 193 patients according to first-line rituximab treatment was 82% for both for the rituximab chemotherapy group, and 82% and 68% for the chemotherapy-alone group. The difference was not statistically significant (HR, 0.76; 95% CI, 0.45-1.27; P ¼.29) (Figure 3B). PFS of FL Patients According to Maintenance Rituximab Versus Observation in First-Line Immunochemotherapy (n ¼ 111). The 3- and 5-year PFS rates of 66 patients treated with maintenance rituximab in first-line immunochemotherapy were 77% and 64%, respectively, whereas the respective PFS rates for the observation Figure 1 Overall Survival of All Patients and Patients Treated With Systemic Therapy (ST) group were 50% and 39%. The median PFS has not been reached in the maintenance rituximab group and was 3.2 years in the observation group. Treatment with maintenance rituximab after immunochemotherapy reduced the risk of progression for 61% compared to the observation group (HR, 0.39; 95% CI, 0.20-0.73; P ¼.003) (Figure 4). OS of FL Patients Treated With Rituximab Chemotherapy as First- Line Treatment or in Relapse Versus Chemotherapy Alone (n ¼ 193). The estimated 5- and 10-year OS rates of 163 FL patients treated with rituximab chemotherapy at least once during the course of disease were 79% and 52%, respectively. The 5- and 10-year OS estimates for 30 patients who had never received rituximabcontaining therapy were 53% and 29%, respectively. The risk of dying was reduced by 61% in the rituximab-treated group (HR, 0.39; 95% CI, 0.22-0.67; P ¼.001) (Figure 5). Discussion FL is an indolent disease, so patients may have a long life expectancy, but it is still considered incurable in its advanced stage. Patients usually respond well to initial therapy, but relapses are common, leading to recurrent therapeutic interventions. Despite decades of study, no uniformly accepted standard initial treatment has emerged for patients with FL. For patients without disease-related symptoms, a watch-and-wait strategy is still a safe option. Those who develop systemic symptoms or have high tumor burden need to initiate treatment. With the introduction of the anti-cd20 monoclonal antibody rituximab into therapy, the clinical outcome of FL patients has markedly improved. The clinical characteristics of our patients do not differ from those described in other studies and from the report of a LymphoCare study. 3 The median age of our patients was 58 years, and 588 - Clinical Lymphoma, Myeloma & Leukemia October 2015

Tanja Juznic Setina et al Figure 3 Progression-Free Survival (A) and Overall Survival (B) According to Rituximab in First-Line Therapy we observed a slight female predominance. Most of the patients (65%) were diagnosed with advanced-stage disease, which is a little less frequently than what is described in the literature. The distribution of FLIPI groups was similar to that described in other studies, with most patients being in low and intermediate FLIPI risk groups. At a median follow-up of 5.7 years, the 5-year OS of the whole group was 77% and is similar to the data of the EUROCARE-5 study from the period 1997 to 2008, with a reported 5-year survival rate of 74.3% (72.9%-75.5%). 23 On the other hand, the analysis by Fisher et al 16 describes a 4-year survival rate of 69% for CHOP and up to 91% for the R-CHOP studies, yet the outcomes are given only for the patients treated with systemic therapy and not for the complete cohort of FL patients. In 193 patients, ST was implemented. Those patients differed from the whole group of 278 patients in that more patients had stage IV disease and more patients had intermediate and high FLIPI scores. Interestingly, the OS rates of the whole group and the group receiving ST were very similar. The PFS curve of the patients who received ST, 57% of them with rituximab, is consistent with the progressing course of the disease. Still, the 5-year PFS of 37% is in concordance with the 40% 5-year PFS reported for 832 patients in the observational study conducted to develop the FLIPI 2 prognostic index, where 68% of patients received a rituximab chemotherapyebased regimen. 24 Several randomized phase 3 trials have demonstrated improved survival rates by adding rituximab to standard chemotherapy in frontline treatment of FL patients. Almost all of them demonstrated improved PFS with rituximab plus chemotherapy, with some of them also experiencing improved OS. 5-9,25 Most of these trials applied R-CHOP, R-CVP, or R-FM (rituximab, fludarabine, mitoxantrone) as front-line chemotherapy. Other chemotherapy drugs, such as bendamustine plus rituximab, have been evaluated in a randomized trial with significantly improved PFS and proven noninferiority to previously mentioned regimens but with no difference in OS. 25 A recently published randomized trial demonstrated the superiority of Figure 4 Progression-Free Survival According to Maintenance Rituximab Versus Observation in First-Line Immunochemotherapy Clinical Lymphoma, Myeloma & Leukemia October 2015-589

Slovene Follicular Lymphoma Patients Figure 5 Overall Survival According to Treatment With or Without Rituximab-Containing Regimen R-CHOP and R-FM over R-CVP in terms of response rates and time to treatment failure (3-year time to treatment failure 60%, 57%, and 47%, respectively). 26 After stratification of our group of patients into rituximab chemotherapy and chemotherapy-alone groups to determine the impact on PFS of adding rituximab, the difference between the 2 treatments was significant. The median PFS in our patients in chemotherapy-alone arm was approximately 12 months, which is quite short and even worse than in some of the aforementioned trials. Marcus et al 5 reported the median time to progression in the CVP arm to be 15 months, and Hiddemann et al 8 reported a median PFS of 28 months but with the CHOP regimen, which is proven to be more effective than nonanthracycline regimens. The short median PFS of our patients is probably due to the fact that most in the chemotherapyalone group received nonanthracycline chemotherapy as front-line treatment. For rituximab chemotherapy regimens, the median PFSs are longer. For example, in the R-CVP group, the median time to progression was 32 months in one study, 5 while in other studies where R-CHOP was provided, the median time has not yet been reached. 8,9 This is similar to our analysis, with R-CHOP being by far the most used induction regimen in the rituximab chemotherapy group, with a median PFS that has not yet been reached. Actually, the risk for progression in the rituximab chemotherapy group was reduced by 74% compared to the chemotherapy-only group (HR, 0.26; 95% CI, 0.18-0.36; P <.001). In the randomized study by Hiddemann et al, 8 which compared R-CHOP with CHOP in front-line treatment, there was a 60% reduction of risk for treatment failure (P <.001) in favor of R-CHOP regimen. The data from the LymphoCare study confirm R- CHOP to be the most frequently used rituximab-based regimen in front-line FL therapy, which has also become the standard of care for front-line treatment. 3 Some of the randomized studies mentioned above demonstrated a significant benefit not only in terms of PFS but also OS when comparing rituximab chemotherapy with chemotherapy alone in front-line treatment and in the relapse setting. 5-8,27 A meta-analysis of 7 randomized trials involving 1943 patients with previously untreated or treated FL demonstrated that patients treated with rituximabcontaining regimens, compared to those treated with the same regimens but without rituximab, had significantly improved OS (HR, 0.63; 95% CI, 0.51-0.79). 28 Herold et al 7 randomized previously untreated patients to R-MCP (rituximab, mitoxantrone, chlorambucil, prednisolone) versus MCP with a 4-year follow-up difference in OS of 87% versus 74% in favor of R-MCP (P ¼.0096). In a randomized study by Marcus et al, 6 the patients in the R-CVP group had significantly higher rates of 4-year OS (83% vs. 77%; P ¼.029). In addition, the study of Overman et al 29 showed a benefit in OS for follicular grade 3 lymphoma patients, with R-CHOP chemotherapy versus CHOP alone with a 5-year OS of 98% versus 75% in favor of R-CHOP (P <.0034). In our analysis, no difference in OS between the rituximab chemotherapy and chemotherapy-alone groups in firstline treatment was observed. The 5-year OS was 82% for the rituximab chemotherapy group and 68% for the chemotherapy-alone group (HR, 0.76; 95% CI, 0.45-1.27; P ¼.29). The reason for this lack of significance in OS is probably that 63% of the patients who did not receive rituximab and/or CHOP regimen in induction therapy, crossed over to R-CHOP therapy subsequently at progression or in case of relapsed disease. We have no data about how many patients crossed over to rituximab therapy in the previously mentioned studies. However, there was a significant difference in the OS when we compared the group of 163 patients who received rituximabcontaining therapy at least once during the course of their disease to a small group of 30 FL patients who had never received rituximab as a part of their ST (5-year OS 79.2% vs. 50.8%). The risk of dying in the rituximab group was actually reduced by 61% (HR, 0.39; 95% CI, 0.22-0.67; P ¼.001). The use of maintenance rituximab after immunochemotherapy has been examined in several large randomized trials. 10-15 Most of them demonstrated a beneficial effect by prolonging response duration in first remission and in patients with recurrent disease. Hochster et al 13 reported a significantly better 3-year PFS of 64% in the rituximab maintenance group compared to 33% in the observation group after CVP induction chemotherapy (HR, 0.4; P ¼ 9.2 10 8 ). Van Oers et al 14 evaluated rituximab maintenance in relapsed FL patients and demonstrated a significantly improved PFS after CHOP (HR, 0.30; P <.001) as well as after a R-CHOP regimen (HR, 0.54; P ¼.004). A meta-analysis of 9 randomized trials comparing rituximab maintenance with no maintenance found a significant PFS benefit in the rituximab maintenance arm and an improved OS in relapsed patients, whereas the previously untreated patients had no survival benefit (HR, 0.72; 95% CI, 0.57-0.91). This may be due to the longer follow-up needed to demonstrate a survival difference of patients in first remission, whose estimated survival is almost 2 decades. 30 The PRIMA study was the first large phase 3 randomized trial to investigate the potential benefit of 2-year maintenance rituximab therapy in previously untreated FL patients who responded to firstline immunochemotherapy. There were 1019 patients included. With a median follow-up of 36 months from randomization, the 3-year PFS was 74.9% in the rituximab maintenance group compared to 57.6% in the observation group (P <.0001). These 590 - Clinical Lymphoma, Myeloma & Leukemia October 2015

Tanja Juznic Setina et al results demonstrated a significant reduction of risk of progression, with an HR of 0.55 (95% CI, 0.44-0.68; P <.0001) in favor of patients randomized to rituximab maintenance. 15 Our study can fairly compare to the results of the PRIMA study though with less patients included into analysis. The 3-year PFS of our patients was 77% in the maintenance group compared to 50% in the observation only group. There was a significant reduction of risk of progression, with an HR of 0.39 (95% CI, 0.20-0.73; P <.003). In conclusion, the results of our analysis can be related to the results of several larger pivotal studies. Adding rituximab to combination therapy in FL significantly prolonged the PFS and OS of these patients. Furthermore, rituximab maintenance therapy in firstline treatment significantly prolongs the time to disease progression. Clinical Practice Points The treatment outcomes of FL patients have been positively influenced by the introduction of rituximab in the last 2 decades. Our retrospective analysis of PFS and OS in 278 routinely treated Slovene FL patients confirmed the significant benefit of adding rituximab to chemotherapy and into the maintenance setting outside clinical studies. Strict adherence to treatment recommendations and early introduction of rituximab into routine treatment of FL patients assures treatment results that can be related to the results of larger pivotal studies. Acknowledgments This study was partially sponsored by the Ministry of Science and Technology of Slovenia grant P3-0321. Disclosure The authors have stated that they have no conflicts of interest. References 1. Armitage JO, Weisenburger DD. New approach to classifying non-hodgkin s lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin s Lymphoma Classification Project. J Clin Oncol 1998; 16:2780-95. 2. Horning SJ, Rosenberg SA. The natural history of initially untreated low-grade non-hodgkin s lymphomas. N Engl J Med 1984; 311:1471-5. 3. Friedberg JW, Taylor MD, Cerhan JR, et al. Follicular lymphoma in the United States: first report of the national LymphoCare study. J Clin Oncol 2009; 27: 1202-8. 4. Ardeshna KM, Smith P, Norton A, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non- Hodgkin lymphoma: a randomised controlled trial. Lancet 2003; 362:516-22. 5. 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; 105:1417-23. 6. Marcus R, Imrie K, Solal-Celigny P, et al. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol 2008; 26:4579-86. 7. Herold M, Haas A, Srock S, et al. 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Rituximab maintenance for the treatment of patients with follicular lymphoma: an updated systematic review and metaanalysis of randomized trials. J Natl Cancer Inst 2011; 103:1799-806. Clinical Lymphoma, Myeloma & Leukemia October 2015-591