Long Term Results for Cladribine Induction and Interferon Maintenance Treatment in Previous Untreated Indolent Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4596-4596
Author(s):  
Michael A. Fridrik ◽  
Keyword(s):  
Remission Rate ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Long Term Results ◽  
Induction Treatment ◽  
Indolent Lymphoma ◽  
Incurable Disease ◽  
Significant Difference ◽  
Mantel Cell Lymphoma ◽  
Indolent Lymphomas

Abstract Indolent lymphoma in advanced stage is an incurable disease. The main treatment goal is palliation with low treatment related toxicity. In a multicenter setting we prospectively treated 91 previous untreated indolent lymphomas with intravenous cladribine 0.12 mg/kg body weight for 4 or 5 consecutive days every 4 weeks for 4 cycles. Following the cladribine induction treatment an interferon-2c maintenance therapy was started until progression. Median age was 59 years (range 25–79). All patients had stage 3 or 4 disease. Overall remission rate was 70% with 23% complete remissions. We found no significant difference in remission rate between the 4 or 5 day regimen. The remission rate was not different between follicular lymphoma, mantel-cell lymphoma, or Waldenstrom’s disease. Neither did the international prognostic index influence the rate of remission. Median observation was 60 months for living patients. Median time to progression and survival was 22 and 69 months respectively. At 5 years 23% and 57% were progression free and alive respectively. Transformation in a high-grade lymphoma occurred in 11/91 patients. A secondary cancer was observed in 4/91 patients. Toxicity was mainly hematologic for cladribine. Interferon maintenance was poorly tolerated, 27% of patients did not complete the therapy. Four months of cladribine seems to have similar results as conventional therapy with chlorambucil for 6 to 12 months.

R-CHOP Versus (vs) CHOP Followed by Maintenance Rituximab (MR) Vs Observation In Older Diffuse Large B-Cell Lymphoma (DLBCL) Patients (pts): Long-Term Follow-up of Intergroup E4494/C9793

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 589-589 ◽  
Author(s):  
Vicki A. Morrison ◽  
Fangxin Hong ◽  
Thomas M. Habermann ◽  
Richard I. Fisher ◽  
Bruce D. Cheson ◽  
...  
Keyword(s):  
High Risk ◽  
Induction Therapy ◽  
Cox Regression ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Induction Treatment ◽  
Time To Failure ◽  
Significant Difference

Abstract Abstract 589 Background: The initial results of this intergroup trial with median follow-up of 3.5 years (yrs) were previously reported (J Clin Oncol 24:3121, 2006). We present updated results with median follow-up of 9.4 yrs from induction therapy randomization, and 9.0 yrs from maintenance randomization. Methods: 632 patients (pts), age >60 yrs, with DLBCL were randomized to CHOP+rituximab 375 mg/m2 IV, administered Day -7, -3, and two days before cycles 3/5/7 (if given) (R-CHOP), versus CHOP, for two cycles beyond best response for 6–8 cycles total. Pts were stratified by the International Prognostic Index (IPI) (<3 vs >3). 415 pts responding to R-CHOP or CHOP were then randomized to maintenance rituximab 375 mg/m2 weekly times 4, every 6 months for 2 yrs starting 4 weeks after the last chemotherapy (MR, n=207), or observation (OBS, n=208). Results are presented for the 546 (267 R-CHOP; 279 CHOP) pts for induction, and 352 (174 MR; 178 observation) evaluable, centrally reviewed, maintenance pts. Failure-free survival (FFS) was the primary endpoint. The stratified weighted Cox regression was used to remove the effect of MR in comparing induction treatment, and stratified log-rank test used to assess maintenance effect. Results: Baseline characteristics and response to induction were balanced. 9-yr FFS and OS) are 35% and 44% for R-CHOP, and 25% and 37% for CHOP. Compared with CHOP, R-CHOP significantly prolonged FFS (p=.008), but not OS (p=.11). Pts were categorized into low-risk (LR) and high-risk (HR) groups according to their IPI (<3 or 33) (LR, n=217; HR, n=327). A significant difference in the effect of induction therapy was observed for high-risk patients only for FFS (p=0.02, HR=0.61, 95% CI, 0.51 to 0.93) but not for OS. MR significantly prolonged FFS (log-rank p=0.018, HR=0.71, 95%CI, 0.54 to 0.94), but not OS (p=0.44, HR=0.89, 95%CI, 0.65 to 1.20). A significant interaction between maintenance and induction therapies was observed in that MR significantly prolonged FFS after CHOP (p=0.003, HR=0.56, 95%CI, 0.38 to 0.82), but not after R-CHOP (p=0.89, HR=0.97, 95% CI, 0.64 to 1.47). There was no OS difference with MR after CHOP (p=0.19, HR=0.76, 95% CI. 0.50 to 1.15) or R-CHOP (p=0.77, HR=1.07, 95% CI, 0.68 to 1.68). Median time to failure after maintenance randomization following CHOP+MR was 9.5 yrs vs 2.0 yrs for CHOP+OBS (p=0.003) and following R-CHOP+MR was 8.5 yrs vs 7.5 yrs for R-CHOP+OBS (p=NS). Proportionately more treatment failures occurred within 2 yrs after CHOP+OBS (73%) compared to CHOP+MR (47%), p=0.01. In contrast, the proportion of failures within 2 yrs was similar for R-CHOP+OBS (38%) and R-CHOP+MR (36%), p=NS. Conclusions: Initial R-CHOP therapy, as compared with CHOP, resulted in improved DFS and FFS for older DLBCL pts. MR after CHOP, but not after R-CHOP, significantly prolonged time to failure but did not prolong OS. However, FFS was 42% at 9 yrs among R-CHOP responders, with or without MR. Future treatment strategies should build upon these findings in this older patient population, often with significant co-morbidities. Disclosures: Morrison: merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Speakers Bureau; amgen: Consultancy, Speakers Bureau; genentech: Speakers Bureau; pfizer: Speakers Bureau. Fisher:roche: Consultancy. Horning:Genentech: Employment.

Randomized Comparison of ACVBP and m-BACOD in the Treatment of Patients With Low-Risk Aggressive Lymphoma: The LNH87-1 Study

2000 ◽  
Vol 18 (6) ◽  
pp. 1309-1315 ◽  
Author(s):  
Hervé Tilly ◽  
Nicolas Mounier ◽  
Pierre Lederlin ◽  
Josette Brière ◽  
Brigitte Dupriez ◽  
...  
Keyword(s):  
Group Performance ◽  
Remission Rate ◽  
Performance Status ◽  
International Prognostic Index ◽  
Eastern Cooperative Oncology Group ◽  
Prognostic Index ◽  
Tumor Burden ◽  
Low Risk ◽  
Aggressive Lymphoma ◽  
Standard Regimen

PURPOSE: To compare a short intensified regimen followed by sequential consolidation therapy (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone [ACVBP]) to the standard regimen of methotrexate, bleomycin, cyclophosphamide, and etoposide (m-BACOD) in patients with low-risk aggressive lymphoma. PATIENTS AND METHODS: A total of 752 patients with intermediate- or high-grade lymphoma and no adverse prognostic factors (Eastern Cooperative Oncology Group performance status of 2 to 4, ≥ two extranodal sites of disease, tumor burden ≥ 10 cm in largest dimension, bone marrow or CNS involvement, Burkitt’s or lymphoblastic subtypes) were registered. Of 673 eligible patients, 332 received ACVBP and 341 received m-BACOD. RESULTS: The complete remission rate was identical (86%) in the two groups. With a median follow-up duration of 7 years, the 5-year failure-free survival (FFS) rate was 65% in the ACVBP group and 61% in the m-BACOD group (P = .16). The 5-year overall survival rate was 75% in the ACVBP group and 73% in the m-BACOD group (P = .47). ACVBP was responsible for more severe and life-threatening infections (P < .01), but m-BACOD caused more pulmonary toxicity (P < .001). The number of treatment-related deaths did not differ between the two regimens. A multivariate analysis indicated that ACVBP was associated with a longer FFS in patients with two or three risk factors of the International Prognostic Index. CONCLUSION: In this population of patients with low-risk aggressive lymphoma, toxicities of the regimens are different, but the rates of response and survival are identical. The survival advantage of ACVBP over standard regimen in patients with advanced disease is suggested by this analysis but remains to be assessed in prospective studies specifically designed for this purpose.

Cell of origin, germinal center versus nongerminal center, determined by immunohistochemistry on tissue microarray, does not correlate with outcome in patients with relapsed and refractory DLBCL

Blood ◽  
2005 ◽  
Vol 106 (10) ◽  
pp. 3383-3385 ◽  
Author(s):  
Craig H. Moskowitz ◽  
Andrew D. Zelenetz ◽  
Tarun Kewalramani ◽  
Paul Hamlin ◽  
Simone Lessac-Chenen ◽  
...  
Keyword(s):  
De Novo ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Second Line ◽  
Cell Of Origin ◽  
Free Survival ◽  
Significant Difference ◽  
The Common

AbstractA number of prognostic factors affect outcome in patients with relapsed or primary refractory diffuse large B-cell lymphoma (DLBCL), including refractory disease and the second-line age-adjusted international prognostic index. In de novo DLBCL, the cell of orgin, as determined by expression microarray analysis or immunohistochemistry (IHC), predicts event-free survival (EFS). We evaluated the cell of origin, as well as other pathologic markers of outcome, on the repeat biopsy specimen of 88 transplantation-eligible patients undergoing ifosfamide, carboplatin, etoposide (ICE) second-line chemotherapy (SLT) followed by high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) to see if were they prognostic in the salvage setting. Pretreatment clinical factors were well balanced between the cohorts. There was no significant difference in response to SLT, HDT, event-free or overall survival based on the cell of origin or any of the common pathologic markers examined. The cell of origin as determined by IHC does not predict outcome in transplantation-eligible patients with relapsed or primary refractory DLBCL.

Treatment of Indolent B-Cell Nonfollicular Lymphomas: Final Results of the LL01 Randomized Trial of the Gruppo Italiano per lo Studio dei Linfomi

2003 ◽  
Vol 21 (8) ◽  
pp. 1459-1465 ◽  
Author(s):  
Luca Baldini ◽  
Maura Brugiatelli ◽  
Stefano Luminari ◽  
Marco Lombardo ◽  
Francesco Merli ◽  
...  
Keyword(s):  
B Cell ◽  
Univariate Analysis ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Progression Free Survival ◽  
Serum Lactate ◽  
Serum Lactate Dehydrogenase ◽  
High Dose ◽  
Free Survival ◽  
Significant Difference

Purpose: To evaluate the effect of epirubicin on therapeutic response and survival in patients with indolent nonfollicular B-cell lymphomas (INFL) treated with pulsed high-dose chlorambucil. Patients and Methods: A total of 170 untreated patients with advanced/active INFL were randomly assigned to receive either eight cycles of high-dose chlorambucil (15 mg/m2/d) plus prednisone (100 mg/d) for 5 days (HD-CHL-P; arm A) or eight cycles of HD-CHL-P plus epirubicin 60 mg/m2 intravenous on day 1 (arm B). The responding patients were randomly assigned to either maintenance therapy with interferon alfa (IFNα-2a; 3 MU, three times weekly) for 12 months or observation. Results: There were 160 assessable patients (82 males, 78 females; median age, 63 years; range, 33 to 77 years); 77 patients were assigned to arm A, and 83 were assigned to arm B. Induction therapy led to 47 complete responses (CRs; 29.4%) and 68 partial responses (PRs; 42.5%), with no significant difference between the two arms (60 CR + PR in arm A [77.9%] and 55 CR + PR in arm B [66.3%]; P = .07). After a median follow-up of 38 months (range, 2 to 103 months), there was no between-group difference in overall survival (OS; P = .45), failure-free survival (P = .07), or progression-free survival (PFS; P = .5). Eighty-eight patients were randomly assigned to either IFNα-2a (n = 43) or observation (n = 45), without any difference in 3-year PFS (44% and 42%, respectively). Univariate analysis showed that OS was influenced by age, anemia, serum lactate dehydrogenase levels, and International Prognostic Index distribution; multivariate analysis identified age and anemia as having influence on OS. Conclusion: HD-CHL-P treatment outcome in INFL patients was good (50% 3-year PFS, minimal toxicity, and low costs); epirubicin did not add any advantage. One-year IFNα maintenance treatment did not prolong response duration.

Age as a potential new prognostic indicator in primary cutaneous B-cell lymphoma (PCBCL).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e19034-e19034
Author(s):  
Poorvi Kirit Desai ◽  
Magali Van den Bergh ◽  
Xiaohui Zhang ◽  
Hailing Zhang ◽  
Braydon Schaible ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Age Groups ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Prognostic Indicator ◽  
Rank Test ◽  
Cancer Center ◽  
Significant Difference

e19034 Background: PCBCL is a group of rare lymphoproliferative disorders, with an estimated annual incidence of 2.5 per 1,000,000 persons. Indolent subtypes include Primary Cutaneous Marginal Zone Lymphoma (PCMZL) and Primary Cutaneous Follicular Center Lymphoma (PCFCL). Primary Cutaneous Diffuse Large B-cell Lymphoma (PCDLBCL) is an aggressive subtype with a fatality rate of 50%. The Cutaneous Lymphoma International Prognostic Index (CLIPI) can risk-stratify indolent subtypes, but age is not considered. Here we present our single-institutional analysis of clinicopathologic features and outcomes of patients with PCBCL. Methods: This is a retrospective study of patients evaluated at Moffitt Cancer Center between 01/1990 and 12/2016. Patients were identified using our PCBCL database and diagnosis was verified by independent hematopathologists and dermatopathologists. Staging was determined by ISCL/EORTC criteria. Demographics, subtype, stage, disease course, and CLIPI scores were collected. Continuous and categorical values were tested using Kruskal-Wallis ANOVA method and Fisher’s Exact Test, respectively. Kaplan-Meier curves were produced to determine PFS. Results: We identified 37 patients who met diagnostic criteria for PCBCL (35% PCFCL, 40.5% PCMZL, 13.5% PCDLBCL, and 11% indolent, unspecified). Male:female ratio was 2.4:1. 51% of patients were ≥ 60 years old (yo), and 49% were < 60 yo. 54% had stage T1 disease, 27% T2, and 19% T3. Median PFS for patients <60 was 1.1 years, but was not reached for those ≥60. Mean follow-up time was 2.6 years for all patients. Log-rank test showed a statistically significant difference in PFS between the two age groups (p=0.01). PFS for stage of indolent subtypes showed marginal significance (p <0.06). CLIPI for indolent subtypes did not show a significant difference in PFS. Conclusions: We found that age is a highly statistically significant prognostic parameter in PCBCL, as patients ≥ 60 yo had a longer PFS compared to younger patients, even after adjusting for stage and CLIPI. These results are promising for age as a possible prognostic indicator for PCBCL, but validation is needed with a larger sample size.

scholarly journals Maintenance Rituximab After Cyclophosphamide, Vincristine, and Prednisone Prolongs Progression-Free Survival in Advanced Indolent Lymphoma: Results of the Randomized Phase III ECOG1496 Study

2009 ◽  
Vol 27 (10) ◽  
pp. 1607-1614 ◽  
Author(s):  
Howard Hochster ◽  
Edie Weller ◽  
Randy D. Gascoyne ◽  
Thomas M. Habermann ◽  
Leo I. Gordon ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Residual Disease ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Progression Free Survival ◽  
Tumor Burden ◽  
Phase Iii ◽  
Indolent Lymphoma ◽  
Free Survival ◽  
Rank One

Purpose To determine if maintenance rituximab (MR) after standard chemotherapy improves progression-free survival (PFS) in advanced-stage indolent lymphoma. Patients and Methods Patients with stage III-IV indolent lymphoma with responding or stable disease after cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy were stratified by initial tumor burden, residual disease after CVP (minimal or gross), and histology, and randomly assigned to observation (OBS) or MR 375 mg/m2 once per week for 4 weeks every 6 months for 2 years. PFS was the primary end point. Results Three hundred eleven (282 with follicular lymphoma) evaluable patients who received CVP were randomly assigned to OBS (n = 158) or MR (n = 153). Best response improved in 22% MR versus 7% OBS patients (P = .00006). Toxicity was minimal in both study arms. Three-year PFS after random assignment was 68% MR versus 33% OBS (hazard ratio [HR] = 0.4; P = 4.4 × 10−10 [all patients]) and 64% MR v 33% OBS (HR = 0.4; P = 9.2 × 10−8 [patients with follicular lymphoma]). There was an advantage for MR regardless of Follicular Lymphoma International Prognostic Index score, tumor burden, residual disease, or histology. In multivariate analysis of MR patients, minimal disease after CVP was a favorable prognostic factor. OS at 3 years was 92% MR versus 86% OBS (HR = 0.6; log-rank one-sided P = .05) and, among patients with follicular lymphoma, OS was 91% MR versus 86% (HR = 0.6; log-rank one-sided P = .08). A trend favoring MR was observed among patients with high tumor burden (log-rank one-sided P = .03). Conclusion The E1496 study provides the first phase III data in untreated indolent lymphoma that MR after chemotherapy significantly prolongs PFS.

scholarly journals Comparing the Outcome of Diffuse Large B-Cell Lymphoma in Very Elderly Patients (age greater than 80 years) with Elderly Patients (age between 65 to 79 years)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5072-5072
Author(s):  
Charalampos S. Floudas ◽  
Ajay Dhakal ◽  
Sunjay Neupane ◽  
Pouyan Gohari ◽  
Abhinav B Chandra
Keyword(s):  
Elderly Patients ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Elderly Group ◽  
Very Elderly ◽  
Free Survival ◽  
Significant Difference ◽  
Ecog Ps

Abstract Background Diffuse large B-cell lymphoma (DLBCL) is the most frequent NHL subtype and the risk for it increases with age. At the same time, in advanced countries, the population over 65 years old is increasing because of the continuous increase in life expectancy and as a result the incidence of DLBCL is increasing as well. Increasing age is a major determinant of therapeutic decisions since it is associated with the presence of concomitant diseases, however elderly (over 65 years old) and very elderly (>80 years old) patients are not often included in clinical trials. Consequently, the optimal management of patients in the very elderly has not been identified. We conducted a single-center retrospective study with the objective to compare the comorbidity profiles, chemotherapy offered and tolerance, as well as outcome between elderly and very elderly DLBCL patients. Method A chart review of patients diagnosed with DLBCL in our center from January 2008 to January 2014 identified 33 patients aged between 60 to 79 years (elderly group, EG) and 30 patients aged 80 or more (very elderly group, VEG). We analyzed the clinical and laboratory characteristics (gender, extranodal disease presence, International Prognostic Index (IPI) factors, ECOG performance status (PS), Charlson comorbidity index, B-symptoms, hemoglobin, serum albumin), Progression Free Survival (PFS) and Overall Survival (OS) in comparison between the two groups. Furthermore, we studied the percentage of patients that were offered chemotherapy in each group, the regimen that was offered and the completion of chemotherapy as planned. Results: Median age for the EG was 72 years and for the VEG was 84 years (80 - 93). Significant differences between EG and VEG were found in mean serum albumin concentration at diagnosis (3.48 vs. 2.77, p=0.008), ECOG PS (0.91 vs. 2.36, p=0.000), and International Prognostic Index (IPI) (1.76 vs. 2.54, p=0.023) between EG and VEG. Compared to EG, VEG patients were more likely to have comorbidities (100 vs. 81.8%, p=0.025) and extra-nodal disease (93.3% vs. 66.7%, p=0.012). Though there was no statistically significant difference in percent of patients receiving chemotherapy, greater percent of EG (60.6) received R-CHOP regimen compared to VEG (20.0, p=0.001). There was no significant difference in therapy related toxicity, but fewer patients in the VEG (60 vs. 90.5%, p=0.039) were able to complete the course of chemotherapy planned and fewer achieved CR (35.7% vs. 68.2, p=0.036). Median overall survival was 762 vs. 650 days (p=0.793) and median progression free survival was 704 vs. 331 days (p= 0.180) for EG versus VEG. Conclusion: Very elderly DLBCL patients may differ from elderly patients in ECOG PS, comorbidity profile and chemotherapy regimen. These patients were less likely to complete the course of chemotherapy and fewer achieved complete response compared to the elderly group. There were no statistically significant differences in outcomes between the two groups. Disclosures No relevant conflicts of interest to declare.

What are the challenges for building real world comparative cohorts in oncology?

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e19285-e19285
Author(s):  
Nikita Jeswani ◽  
Amanda McDonell ◽  
Finlay MacDougall ◽  
Jeff Paul Hodge
Keyword(s):  
Language Processing ◽  
Real World ◽  
International Prognostic Index ◽  
Evaluation Criteria ◽  
Prognostic Index ◽  
Cost Effective ◽  
Patient Characteristics ◽  
Outcome Evaluation ◽  
Real World Data ◽  
Indolent Lymphomas

e19285 Background: There has been a proliferation of single arm trials in oncology being presented to regulators. An external comparator using real world data (RWD) can help establish context to trial results and direct comparison to the treatment arm by mirroring the inclusion/exclusion criteria for the trial and examining trial outcomes in an RWD external comparator cohort. RWD has successfully supported some regulatory submissions, although there have been failures as well, with comparability of patients and endpoints under scrutiny. Methods: IQVIA has partnered with life sciences companies on > 20 external comparator projects from 2017-present using a mix of data acquisition strategies (e.g., chart review, database extraction) and methods (e.g., real-world cohort vs. real-world benchmark, propensity matching vs. inverse probability treatment weighting). We collated, reviewed, and synthesised the challenges and risk mitigations documented throughout study execution in aggressive and indolent lymphomas, multiple myeloma, Merkel cell carcinoma, and synovial sarcoma. Results: Patient characteristics used to assess trial eligibility (e.g., biomarker expression, International Prognostic Index, ECOG status) and outcomes (e.g., response rate) are not often captured in a structured format in RWD or recorded in routine clinical practice. As a result, there is a greater reliance on chart reviews today over database extractions to fulfil external comparator requirements, though in some diseases, databases have proven to be a faster and more cost-effective solution. Conclusions: To improve the success of external comparator studies, trial design should be informed by existing RWD so that relevant real-world endpoints and outcome evaluation criteria are included alongside RCT standards. Advances are needed to facilitate RWD capture that matches trial data more closely. This could include bespoke data collaborations, biobank linkage, and natural language processing to drive study execution in databases in the future.

Phase II/III Study of Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone with Rituximab (R-CHOP) Versus Biweekly CHOP with Rituximab (R-Bi-CHOP) In Untreated Advanced-Stage Indolent B-Cell Lymphoma: Japan Clinical Oncology Group (JCOG) 0203 Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 431-431
Author(s):  
Takashi Watanabe ◽  
Yasuo Morishima ◽  
Taro Shibata ◽  
Nobuo Maseki ◽  
Tomohiro Kinoshita ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Phase Iii ◽  
Advanced Stage ◽  
Significant Difference

Abstract Abstract 431 Introduction: There has been no standard treatment for untreated advanced-stage indolent B-cell lymphoma, including follicular lymphoma (FL). However, cyclophosphamide, doxorubicin, vincristine, and prednisolone with rituximab (R-CHOP) is regarded as one of the most effective frontline therapies. Granulocyte colony-stimulating factor (G-CSF) has been often used to shorten CHOP intervals, and it potentiates the antibody-dependent cell-mediated cytotoxicity of rituximab. Methods: To improve the outcome of R-CHOP, we conducted a phase II/III trial comparing R-CHOP with biweekly CHOP with rituximab (R-Bi-CHOP). Patients with previously untreated stage III/IV indolent B-cell lymphoma were randomized to receive 6 cycles of R-CHOP or R-Bi-CHOP. All patients received a total of 6 doses of rituximab, 2 days prior to each cycle of CHOP. In the R-Bi-CHOP arm, during each cycle patients received G-CSF for 6 days until the next cycle's rituximab was given. Maintenance use of rituximab was not allowed. The primary endpoint of the phase II portion was complete response rate (%CR). The primary and secondary endpoints of the phase III study were progression-free survival (PFS), and overall survival (OS) and safety, respectively. Age, bulky disease, and institution were used as dynamic allocation adjustment factors. The sample size was determined with a one-sided alpha of 0.05 and beta of 0.2. All the histopathologic specimens were reviewed by 3 hematopathologists. In the phase II portion, the response was judged according to the International Workshop Criteria by the Central CT Review Committee. Results: For the 73 patients enrolled in the phase II portion, the %CR of the R-CHOP and R-Bi-CHOP arms were 60% vs. 72%, both of which were above the threshold value, and consequently this study continued to the phase III portion. Between September 2002 and February 2007, 300 patients were enrolled in the study overall. The median age of all patients was 54 years. Baseline characteristics were well balanced between the 2 arms except for B symptoms and the number of extranodal sites (R-CHOP < R-Bi-CHOP). FL (G1 to G3) was seen in 88%. The delivered doses were exactly the same in both arms except for vincristine (R-CHOP > R-Bi-CHOP). Excluding 1 patient with histologic transformation, 299 patients were eligible for survival analysis. The median follow-up time for all randomly assigned patients was 4.7 years at the planned analysis time point 3 years after the last patient enrollment. Of note, most of the enrolled patients were followed up for more than 3 years. There was no significant difference in PFS between the R-CHOP and R-Bi-CHOP arms: median, 3.6 y [95% confidence interval (CI), 3.0–5.1 y] vs. 4.2 y [95%CI, 3.1–5.4 y]; 40% [95%CI, 31–49%] vs. 40% [95%CI, 30–50%] at 6 y (HR=0.94, stratified log-rank p=0.35). The median survival time was not reached in either arm and there was no significant difference in 6-y OS: 85% [95%CI, 75–92%] vs. 87% [95%CI, 77–92%] (p=0.53). No difference was found in either 6-y PFS or 6-y OS in any of the 3 risk groups defined by the Follicular Lymphoma International Prognostic Index. Moreover, the 2 arms did not differ in PFS or OS in the 2 International Prognostic Index risk categories (low/low-intermediate and high-intermediate/high) or in groups based on patient age (above or below 60 years). As for FL patients, there was no significant difference in PFS between R-CHOP (n=133) and R-Bi-CHOP (n=132): median, 3.7 y vs. 4.2 y; 42% vs. 40% at 6 y (p=0.45). Of 134 patients in the R-CHOP arm, 7 (5.2%) developed interstitial pneumonitis. Pneumocystis jiroveci was the cause in 6 of these. Because the original protocol stipulated prophylaxis against this organism only for patients assigned to the R-Bi-CHOP arm, it was amended to include both arms. The incidence of G4 neutropenia, G3 infection, and G3 peripheral neuropathy in the R-CHOP and R-Bi-CHOP arms were 85% vs. 37%, 34% vs. 15%, and 2.0% vs. 7.3%, respectively. Conclusion: R-Bi-CHOP, a dose-dense approach, has failed to improve the outcome of R-CHOP treatment for untreated patients with advanced-stage indolent B-cell lymphoma. The long-term PFS with R-CHOP treatment is unsatisfactory, warranting further investigations on post-remission therapy after R-CHOP. Disclosures: Kinoshita: Chugai Pharmaceutical Co., Ltd., Zenyaku Kogyo Co., and Kyowa Hakko Kirin Co., Ltd.: Research Funding.

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