scholarly journals Progression-Free Survival as a Surrogate End Point for Overall Survival in First-Line Diffuse Large B-Cell Lymphoma: An Individual Patient–Level Analysis of Multiple Randomized Trials (SEAL)

2018 ◽  
Vol 36 (25) ◽  
pp. 2593-2602 ◽  
Author(s):  
Qian Shi ◽  
Norbert Schmitz ◽  
Fang-Shu Ou ◽  
Jesse G. Dixon ◽  
David Cunningham ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Threshold Effect ◽  
First Line ◽  
Free Survival ◽  
Patient Level ◽  
Randomized Controlled ◽  
End Point ◽  
Large B Cell Lymphoma ◽  
Surrogate Threshold Effect

Purpose Overall survival (OS) is the definitive and best-established primary efficacy end point to evaluate diffuse large B-cell lymphoma (DLBCL) therapies, but it requires prolonged follow-up. An earlier end point assessed post-treatment would expedite clinical trial conduct and accelerate patient access to effective new therapies. Our objective was to formally evaluate progression-free survival (PFS) and PFS at 24 months (PFS24) as surrogate end points for OS in first-line DLBCL. Patients and Methods Individual patient data were analyzed from 7,507 patients from 13 multicenter randomized controlled trials of active treatment in previously untreated DLBCL, published after 2002, with sufficient PFS data to predict treatment effects on OS. Trial-level surrogacy examining the correlation of treatment effect estimates of PFS/PFS24 and OS was evaluated using both linear regression ( R2WLS) and Copula bivariable ( R2Copula) models. Prespecified criteria for surrogacy required either R2WLS or R2Copula ≥ 0.80 and neither < 0.7, with lower-bound 95% CI > 0.60. Results Trial-level surrogacy for PFS was strong ( R2WLS = 0.83; R2Copula = 0.85) and met the predefined criteria for surrogacy. At the patient level, PFS strongly correlated with OS. The surrogate threshold effect had a hazard ratio of 0.89. Surrogacy was consistent across comparisons with or without rituximab and with rituximab maintenance trials. Trial-level surrogacy for PFS24 was relatively strong ( R2WLS = 0.77; R2Copula = 0.78) but did not meet prespecified criteria. At the patient level, PFS24 significantly correlated with OS. The surrogate threshold effect had an odds ratio of 1.51. Conclusion This large pooled analysis of individual patient data supports PFS as a surrogate end point for OS in future randomized controlled trials evaluating chemoimmunotherapy in DLBCL. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before OS results are mature.

scholarly journals A Prognostic Nomogram and Survival Analysis in Relapsed or Refractory Diffuse Large B-Cell Lymphoma Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2994-2994
Author(s):  
Shiyu Jiang ◽  
Yan Qin ◽  
Peng Liu ◽  
Jiangliang Yang ◽  
Sheng Yang ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Entire Group ◽  
First Line ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
Line Setting ◽  
Ecog Ps

Abstract Background The clinical course of diffuse large B-cell lymphoma (DLBCL) is variable. Although the prognostic markers and models have been developed and adapted in DLBCL, prognostic indices in relapse and refractory (r/r) DLBCL remain unclear. In order to better guide clinical practice, this study aimed to develop a prognostic nomogram in r/r DLBCL. Patients and methods Among 1858 DLBCL patients treated in National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital in China, between 2006 and 2016, 682 were r/r DLBCL, of which 573 patients were treated with enough cycles of first-line anthracycline-based chemotherapy. The clinical data were reviewed and evaluated. Progression free survival (PFS) was defined as the time from first treatment administration to disease progression/relapse. Relapse was defined as progression after initial complete or partial remission, and refractory disease was defined as achieving less than a partial response in the first-line setting. Cell of origin (COO) was assessed at diagnosis via Hans algorithm. The concordance index (C-index) and a calibration curve were used to determine and compare their predictive and discriminatory capacity. Results Overall, the median age at diagnosis was 54 (range 10-91) years old. Among all the patients, 325 (56.7%) were male and 248 (43.3%) were female. There were 255 (45.1%) patients categorized as stage I-II and 310 (54.9%) categorized as stage III-IV at diagnosis. Of all the patients, 145 (27.0%) were germinal center B-cell-like (GCB) and 393 (73.0%) were non-GCB. According to the Eastern Cooperative Oncology Group (ECOG) performance status (PS) score, the majority of patients had a good performance, with 457 (79.8%) of cases presenting with an ECOG PS score of 0-1; 89 (15.5%) presenting with ECOG PS of 2; 27(4.7%) scored ≥3. In the entire group, 563 (98.3%) patients received CHOP or CHOP-like regimen and 301 (52.5%) received rituximab treatment in the first-line setting. There were 200 patients (34.9%) had refractory disease; 203 (35.4%) had relapse in the first year from treatment commence; 91 (15.9%) had relapse in the second year; and 79 (13.8%) had relapse after the first 2 years. The median overall survival (OS) from diagnosis were 12, 17, 46 and 66 months, respectively in the above four groups, and OS in the entire group was shown in Figure 1. A total of 437 patients with complete clinical information were further divided into the primary (n=300) and validation (n=137) cohorts. Based on a multivariate analysis of the primary cohort, four independent prognostic factors including lactate dehydrogenase (LDH) level at diagnosis; response to the first-line treatment (CR with not CR); progression free survival and recurrence location (original with new with both) were identified and entered the nomogram (Figure 2). The calibration curve showed the optimal agreement between nomogram prediction and actual observation. In addition, the C-index of the nomogram for OS prediction was 0.743. The area under the receiver operating characteristic (ROC) curve (AUC) was 0.75 in the internal validation and 0.84 in the external validation. Four risk groups depending the nomogram were further developed and OS were presented in Figure 3. Conclusions Independent predictors of survival in r/r DLBCL have been identified and 4 indicators were used to create a nomogram. This proposed nomogram help with assess individual risks and decide on second-line treatment in clinical practice. Disclosures No relevant conflicts of interest to declare.

scholarly journals Addition of Rituximab Significantly Improves Outcomes in Patients with Diffuse Large B-cell Lymphoma – a Single-center, Retrospective Study

2007 ◽  
Vol 50 (2) ◽  
pp. 113-118
Author(s):  
David Belada ◽  
Lukáš Smolej ◽  
Monika Hrudková ◽  
Pavla Štěpánková ◽  
Alice Sýkorová ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Single Center ◽  
Chop Chemotherapy ◽  
First Line ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
Large B Cell

CHOP chemotherapy has been used as a standard first-line treatment for diffuse large B-cell lymphoma since the 1970s. Phase III trials have shown that the addition of rituximab (R) to CHOP chemotherapy leads to significant improvements in response rate, progression-free survival and overall survival. This single-center, retrospective study was performed to evaluate the role of the addition of R to chemotherapy (CHT) in a real-world clinical setting. Outcomes were assessed in 85 patients with newly diagnosed DLBCL treated with CHT alone (n=38) and R-CHT (n=47). Complete response (CR) rates were significantly higher after R-CHT than CHT (93 % vs. 73 %; p=0.02). The relapse rate was significantly higher after CHT compared with R-CHT (38 % versus 12 %; p=0.01). Progression-free survival was significantly extended by the addition of R (median not reached versus 26.1 months; p=0.04). These data bring further support for rituximab- based immunochemotherapy as a standard first-line therapy for patients with DLBCL.

The impact of Epstein-Barr virus status on clinical outcome in diffuse large B-cell lymphoma

Blood ◽  
2007 ◽  
Vol 110 (3) ◽  
pp. 972-978 ◽  
Author(s):  
Sarah Park ◽  
Jeeyun Lee ◽  
Young Hyeh Ko ◽  
Arum Han ◽  
Hyun Jung Jun ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Free Survival ◽  
Barr Virus ◽  
Large B Cell Lymphoma ◽  
Epstein Barr

AbstractTo define prognostic impact of Epstein-Barr virus (EBV) infection in diffuse large B-cell lymphoma (DLBCL), we investigated EBV status in patients with DLBCL. In all, 380 slides from paraffin-embedded tissue were available for analysis by EBV-encoded RNA-1 (EBER) in situ hybridization, and 34 cases (9.0%) were identified as EBER-positive. EBER positivity was significantly associated with age greater than 60 years (P = .005), more advanced stage (P < .001), more than one extranodal involvement (P = .009), higher International Prognostic Index (IPI) risk group (P = .015), presence of B symptom (P = .004), and poorer outcome to initial treatment (P = .006). The EBER+ patients with DLBCL demonstrated substantially poorer overall survival (EBER+ vs EBER− 35.8 months [95% confidence interval (CI), 0-114.1 months] vs not reached, P = .026) and progression-free survival (EBER+ vs EBER− 12.8 months [95% CI, 0-31.8 months] vs 35.8 months [95% CI, 0-114.1 months], respectively (P = .018). In nongerminal center B-cell–like subtype, EBER in situ hybridization positivity retained its statistical significance at the multivariate level (P = .045). Nongerminal center B-cell–like patients with DLBCL with EBER positivity showed substantially poorer overall survival with 2.9-fold (95% CI, 1.1-8.1) risk for death. Taken together, DLBCL patients with EBER in situ hybridization+ pursued more rapidly deteriorating clinical course with poorer treatment response, survival, and progression-free survival.

scholarly journals Risk-Adapted Dose-Dense Immunochemotherapy Determined by Interim FDG-PET in Advanced-Stage Diffuse Large B-Cell Lymphoma

2010 ◽  
Vol 28 (11) ◽  
pp. 1896-1903 ◽  
Author(s):  
Craig H. Moskowitz ◽  
Heiko Schöder ◽  
Julie Teruya-Feldstein ◽  
Camelia Sima ◽  
Alexia Iasonos ◽  
...  
Keyword(s):  
Fdg Pet ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Pet Scan ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
Positive Biopsy ◽  
Fdg Pet Scan ◽  
Dose Dense ◽  
Pet Scans

Purpose In studies of diffuse large B-cell lymphoma, positron emission tomography with [18F]fluorodeoxyglucose (FDG-PET) performed after two to four cycles of chemotherapy has demonstrated prognostic significance. However, some patients treated with immunochemotherapy experience a favorable long-term outcome despite a positive interim FDG-PET scan. To clarify the significance of interim FDG-PET scans, we prospectively studied interim FDG-positive disease within a risk-adapted sequential immunochemotherapy program. Patients and Methods From March 2002 to November 2006, 98 patients at Memorial Sloan-Kettering Cancer Center received induction therapy with four cycles of accelerated R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by an interim FDG-PET scan. If the FDG-PET scan was negative, patients received three cycles of ICE (ifosfamide, carboplatin, and etoposide) consolidation therapy. If residual FDG-positive disease was seen, patients underwent biopsy; if the biopsy was negative, they also received three cycles of ICE. Patients with a positive biopsy received ICE followed by autologous stem-cell transplantation. Results At a median follow-up of 44 months, overall and progression-free survival were 90% and 79%, respectively. Ninety-seven patients underwent interim FDG-PET scans; 59 had a negative scan, 51 of whom are progression free. Thirty-eight patients with FDG-PET–positive disease underwent repeat biopsy; 33 were negative, and 26 remain progression free after ICE consolidation therapy. Progression-free survival of interim FDG-PET–positive/biopsy-negative patients was identical to that in patients with a negative interim FDG-PET scan (P = .27). Conclusion Interim or post-treatment FDG-PET evaluation did not predict outcome with this dose-dense, sequential immunochemotherapy program. Outside of a clinical trial, we recommend biopsy confirmation of an abnormal interim FDG-PET scan before changing therapy.

Inferior progression-free survival for Thai patients with diffuse large B-cell lymphoma treated under Universal Coverage Scheme: the impact of rituximab inaccessability

2012 ◽  
Vol 54 (1) ◽  
pp. 83-89 ◽  
Author(s):  
Tanin Intragumtornchai ◽  
Udomsak Bunworasate ◽  
Noppadol Siritanaratkul ◽  
Archrob Khuhapinant ◽  
Weerasak Nawarawong ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Universal Coverage ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
The Impact ◽  
Universal Coverage Scheme ◽  
Large B Cell

scholarly journals Paclitaxel, Ifosfamide, and Cisplatin Efficacy for First-Line Treatment of Patients With Intermediate- or Poor-Risk Germ Cell Tumors

2016 ◽  
Vol 34 (21) ◽  
pp. 2478-2483 ◽  
Author(s):  
Darren R. Feldman ◽  
James Hu ◽  
Tanya B. Dorff ◽  
Kristina Lim ◽  
Sujata Patil ◽  
...  
Keyword(s):  
Overall Survival ◽  
Germ Cell ◽  
Germ Cell Tumors ◽  
Progression Free Survival ◽  
Collaborative Group ◽  
Intermediate Risk ◽  
First Line ◽  
Free Survival ◽  
Poor Risk ◽  
End Point

Purpose Paclitaxel, ifosfamide, and cisplatin (TIP) achieved complete responses (CRs) in two thirds of patients with advanced germ cell tumors (GCTs) who relapsed after first-line chemotherapy with cisplatin and etoposide with or without bleomycin. We tested the efficacy of first-line TIP in patients with intermediate- or poor-risk disease. Patients and Methods In this prospective, multicenter, single-arm phase II trial, previously untreated patients with International Germ Cell Cancer Collaborative Group poor-risk or modified intermediate-risk GCTs received four cycles of TIP (paclitaxel 240 mg/m2 over 2 days, ifosfamide 6 g/m2 over 5 days with mesna support, and cisplatin 100 mg/m2 over 5 days) once every 3 weeks with granulocyte colony-stimulating factor support. The primary end point was the CR rate. Results Of the first 41 evaluable patients, 28 (68%) achieved a CR, meeting the primary efficacy end point. After additional accrual on an extension phase, total enrollment was 60 patients, including 40 (67%) with poor risk and 20 (33%) with intermediate risk. Thirty-eight (68%) of 56 evaluable patients achieved a CR and seven (13%) achieved partial responses with negative markers (PR-negative) for a favorable response rate of 80%. Five of seven achieving PR-negative status had seminoma and therefore did not undergo postchemotherapy resection of residual masses. Estimated 3-year progression-free survival and overall survival rates were 72% (poor risk, 63%; intermediate risk, 90%) and 91% (poor risk, 87%; intermediate risk, 100%), respectively. Grade 3 to 4 toxicities consisted primarily of reversible hematologic or electrolyte abnormalities, including neutropenic fever in 18%. Conclusion TIP demonstrated efficacy as first-line therapy for intermediate- and poor-risk GCTs with an acceptable safety profile. Given higher rates of favorable response, progression-free survival, and overall survival compared with prior first-line studies, TIP warrants further study in this population.

scholarly journals Rituximab-CHOP With Early Rituximab Intensification for Diffuse Large B-Cell Lymphoma: A Randomized Phase III Trial of the HOVON and the Nordic Lymphoma Group (HOVON-84)

2020 ◽  
Vol 38 (29) ◽  
pp. 3377-3387
Author(s):  
Pieternella Johanna Lugtenburg ◽  
Peter de Nully Brown ◽  
Bronno van der Holt ◽  
Francesco A. D’Amore ◽  
Harry R. Koene ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Standard Of Care ◽  
Phase Iii ◽  
Free Survival ◽  
Intention To Treat ◽  
Large B Cell Lymphoma ◽  
Large B Cell

PURPOSE Immunochemotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has become standard of care for patients with diffuse large B-cell lymphoma (DLBCL). This randomized trial assessed whether rituximab intensification during the first 4 cycles of R-CHOP could improve the outcome of these patients compared with standard R-CHOP. PATIENTS AND METHODS A total of 574 patients with DLBCL age 18 to 80 years were randomly assigned to induction therapy with 6 or 8 cycles of R-CHOP-14 with (RR-CHOP-14) or without (R-CHOP-14) intensification of rituximab in the first 4 cycles. The primary end point was complete remission (CR) on induction. Analyses were performed by intention to treat. RESULTS CR was achieved in 254 (89%) of 286 patients in the R-CHOP-14 arm and 249 (86%) of 288 patients in the RR-CHOP-14 arm (hazard ratio [HR], 0.82; 95% CI, 0.50 to 1.36; P = .44). After a median follow-up of 92 months (range, 1-131 months), 3-year failure-free survival was 74% (95% CI, 68% to 78%) in the R-CHOP-14 arm versus 69% (95% CI, 63% to 74%) in the RR-CHOP-14 arm (HR, 1.26; 95% CI, 0.98 to 1.61; P = .07). Progression-free survival at 3 years was 74% (95% CI, 69% to 79%) in the R-CHOP-14 arm versus 71% (95% CI, 66% to 76%) in the RR-CHOP-14 arm (HR, 1.20; 95% CI, 0.94 to 1.55; P = .15). Overall survival at 3 years was 81% (95% CI, 76% to 85%) in the R-CHOP-14 arm versus 76% (95% CI, 70% to 80%) in the RR-CHOP-14 arm (HR, 1.27; 95% CI, 0.97 to 1.67; P = .09). Patients between ages 66 and 80 years experienced significantly more toxicity during the first 4 cycles in the RR-CHOP-14 arm, especially neutropenia and infections. CONCLUSION Early rituximab intensification during R-CHOP-14 does not improve outcome in patients with untreated DLBCL.

scholarly journals Real-world practice patterns and outcomes in Veterans with relapsed/refractory diffuse large B-cell lymphoma

2020 ◽  
Author(s):  
Hsu-Chih Chien ◽  
Deborah Morreall ◽  
Vikas Patil ◽  
Kelli M Rasmussen ◽  
Chunyang Li ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Line Treatment ◽  
Electronic Health Record Data ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Aim: To describe practices and outcomes in veterans with relapsed/refractory diffuse large B-cell lymphoma. Patients & methods: Using Veteran Affairs Cancer Registry System and electronic health record data, we identified relapsed/refractory diffuse large B-cell lymphoma patients completing second-line treatment (2L) in 2000–2016. Treatments were classified as aggressive/nonaggressive. Analyses included descriptive statistics and the Kaplan–Meier estimation of progression-free survival and overall survival. Results: Two hundred and seventy patients received 2L. During median 9.7-month follow-up starting from 2L, 470 regimens were observed, averaging 2.7 regimens/patient: 219 aggressive, 251 nonaggressive. One hundred and twenty-one patients proceeded to third-line, 50 to fourth-line and 18 to fifth-line treatment. Median progression-free survival in 2L was 5.2 months. Median overall survival was 9.5 months. Forty-four patients (16.3%) proceeded to bone marrow transplant. Conclusion: More effective, less toxic treatments are needed and should be initiated earlier in treatment trajectory.

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