The Follicular Lymphoma International Prognostic Index (FLIPI) Can Be a Useful Prognostic Indicator for Patients with Follicular Lymphoma Treated with Combination of Rituximab and Epratuzumab.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4796-4796
Author(s):  
Sandra J. Strauss ◽  
Franck Morschhauser ◽  
Martin Gramatzki ◽  
Philippe Solal-Celigny ◽  
Pier L. Zinzani ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
International Prognostic Index ◽  
Objective Response ◽  
Prognostic Index ◽  
Response Duration ◽  
Rank Test ◽  
P Value ◽  
Open Label ◽  
Median Response ◽  
The Impact

Abstract Background: FLIPI has been proposed as an accurate, simple, and validated prognostic index on the basis of routinely performed tests (age > 60 yrs, Ann Arbor stage III-IV, serum LDH level increased, Hg < 12g/dL, and more than four nodal areas involved (Solal-Céligny et al., Blood2004; 104: 1258–1265). FLIPI has reliably predicted outcome for many follicular lymphoma (FL) patients (pts) treated with chemotherapy and rituximab. Currently, monoclonal antibody (Mab) therapy and a number of radioimmunoconjugates are considered important components of the treatment of FL; therefore, evaluating FLIPI in clinical trials of these modalities is of interest for optimizing therapy. Methods: A subset analysis was performed to assess the impact of FLIPI on the outcome of patients with relapsed/refractory FL enrolled in a larger, multi-center, open label, single-arm study of epratuzumab (humanized anti-CD22 Mab) in combination with rituximab (chimeric anti-CD20 Mab) (Strauss et al., ASCO 2004). Results: A total of 32 pts with FL were treated according to this protocol (4 weekly infusions at full dose of each agent), including 16 pts who had received > 2 prior chemotherapy regimens and 11 pts who had previously received rituximab. Twenty pts (62%) achieved an objective response (OR), including 8 pts (25%) with complete responses (CR, CRu) and 12 (37%) with partial responses, with a median response duration of 16.5 months (95% CI: 6.3 - 25.4) and median time-to-progression (TTP) of 11 months (95% CI: 9.9 - 19.2). Conclusion: Our data indicate that high OR rates and durable CR/CRu’s can be achieved with a combination of rituximab and epratuzumab in pts with low- (0–1) and intermediate-risk (2) FL, who failed multiple prior therapies. OR, CR rates and TTP are similar to rituximab front-line therapy for pts with low tumor burden FL (Solal-Céligny et al., Blood104: 169a, 2004). The combination of rituximab and epratuzumab was significantly less efficacious for pts with high-risk (3–5) FLIPI (P=.0.0023 for TTP). This small Phase-II study supports the prognostic value of FLIPI for pts with recurrent FL who are treated with MAbs. Prospective use of FLIPI may facilitate the optimal design of randomized trials using rituximab in combination with epratuzumab in pts with FL. Results stratified by FLIPI risk groups FLIPI score (No. of pts) OR (%) CR/CRu (%) Median Duration in months (95% CI) Median TTP in months (95% CI) TTP P-value* N/A - Not available due to patients with long TTPs that are still censored (i.e. not reached progression of disease). * - Patients with high (3–5) FLIPI scores versus others, based on the log-rank test. 0–1 (11) 9 (82) 4 (36) 15.7 (N/A) 19.2 (10.3 – 21.3) 0.0023 2 (9) 6 (67) 3 (33) 18.3 (17.2 – 25.4) 18.8 (10 – 26.7) 3–5 (12) 5 (42) 1 (8) 6.3 (N/A) 7.7 (7.1 – 10.2)

High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma

Blood ◽  
2006 ◽  
Vol 108 (9) ◽  
pp. 2957-2964 ◽  
Author(s):  
Joaquim Carreras ◽  
Armando Lopez-Guillermo ◽  
Bridget C. Fox ◽  
Lluis Colomo ◽  
Antonio Martinez ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
Regulatory T Cells ◽  
Follicular Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
Specific Cell ◽  
First Relapse ◽  
The Impact

Abstract The tumor microenvironment plays an important role in the biologic behavior of follicular lymphoma (FL), but the specific cell subsets involved in this regulation are unknown. To determine the impact of FOXP3-positive regulatory T cells (Tregs) in the progression and outcome of FL patients, we examined samples from 97 patients at diagnosis and 37 at first relapse with an anti-FOXP3 monoclonal antibody. Tregs were quantified using computerized image analysis. The median overall survival (OS) of the series was 9.9 years, and the FL International Prognostic Index (FLIPI) was prognostically significant. The median Treg percentage at diagnosis was 10.5%. Overall, 49 patients had more than 10% Tregs, 30 between 5% to 10%, and 19 less than 5%, with a 5-year OS of 80%, 74%, and 50%, respectively (P = .001). Patients with very low numbers of Tregs (< 5%) presented more frequently with refractory disease (P = .007). The prognostic significance of Treg numbers was independent of the FLIPI. Seven transformed diffuse large B-cell lymphomas (DLBCLs) had lower Treg percentages (mean: 3.3%) than FL grades 1,2 (mean: 12.1%) or 3 (mean: 9%) (P < .02). In conclusion, high Treg numbers predict improved survival of FL patients, while a marked reduction in Tregs is observed on transformation to DLBCL.

scholarly journals Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab

2014 ◽  
Vol 32 (10) ◽  
pp. 1020-1030 ◽  
Author(s):  
Suzanne L. Topalian ◽  
Mario Sznol ◽  
David F. McDermott ◽  
Harriet M. Kluger ◽  
Richard D. Carvajal ◽  
...  
Keyword(s):  
Overall Survival ◽  
Randomized Clinical Trials ◽  
Objective Response ◽  
Response Duration ◽  
Advanced Melanoma ◽  
Immune Memory ◽  
Drug Discontinuation ◽  
Median Response ◽  
The Impact

PurposeProgrammed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued.Patients and MethodsPatients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation.ResultsMedian overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative.ConclusionOverall survival following nivolumab treatment in patients with advanced treatment–refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.

Phase III Study of R-CVP Compared With Cyclophosphamide, Vincristine, and Prednisone Alone in Patients With Previously Untreated Advanced Follicular Lymphoma

2008 ◽  
Vol 26 (28) ◽  
pp. 4579-4586 ◽  
Author(s):  
Robert Marcus ◽  
Kevin Imrie ◽  
Philippe Solal-Celigny ◽  
John V. Catalano ◽  
Anna Dmoszynska ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Response Duration ◽  
Complete Response ◽  
Phase Iii ◽  
Term Outcome ◽  
Bulky Disease ◽  
Long Term Outcome ◽  
Trial Treatment

PurposeTo compare the long-term outcome of patients with previously untreated follicular lymphoma (FL) needing therapy, after treatment with cyclophosphamide, vincristine and prednisone (CVP) versus CVP plus rituximab (R-CVP) and to evaluate the predictive value of known prognostic factors after treatment with R-CVP.Patients and MethodsPatients with previously untreated CD20-positive stage III/IV FL were randomly assigned to eight cycles of R-CVP (n = 159) or CVP alone (n = 162). The median follow-up period was 53 months.ResultsThe primary end point—time to treatment failure (TTF), which included patients without a response after four cycles as an event—was significantly prolonged in patients receiving R-CVP versus CVP (P < .0001). Improvements in all other end points, including overall and complete response rates (P < .0001), time to progression (TTP; P < .0001), response duration (P < .0001), time to next antilymphoma treatment (P < .0001), and overall survival (OS; P = .029; 4-year OS: 83% v 77%;) were achieved with R-CVP versus CVP alone. Univariate analyses demonstrated an improvement in TTP with R-CVP versus CVP irrespective of the Follicular Lymphoma International Prognostic Index (FLIPI) subgroup, the International Prognostic Index (IPI) subgroup, baseline histology, and the presence or absence of B symptoms or bulky disease. By multivariate analysis, FLIPI retains a strong predictive power for TTP in the presence of the trial treatment effect.ConclusionAnalysis of all outcome measures, including OS, confirm the benefit of adding R to CVP in the front-line treatment of FL.

The Clinical Impact of Minimal Bone Marrow Involvement on the Outcome of Patients with Follicular Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2966-2966
Author(s):  
Daisuke Kato ◽  
Satoshi Yoshioka ◽  
Tomohiro Yabushita ◽  
Yoshimitsu Shimomura ◽  
Yuichiro Ono ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Follicular Lymphoma ◽  
Bone Marrow Involvement ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Morphological Evidence ◽  
Stage Disease ◽  
Igh Rearrangement ◽  
The Impact ◽  
Index Table

Abstract Introduction: Follicular lymphoma (FL) is the second most common type of non-Hodgkin cell lymphoma, and usually manifests as a disseminated disease. Bone marrow (BM) involvement, which occurs in 40-70% of cases, is often seen in follicular lymphoma and thought to be associated with less favorable prognosis. Diagnosis of BM involvement has traditionally been based on morphological findings, and BM involvement has been determined using histology alone in most clinical trials. Immunocytologic or molecular studies, such as flow cytometry (FCM) and polymerase chain reaction (PCR), have become more readily available, and their usage has clearly documented minimal BM involvement reproducibly. In this study, we evaluated the impact of BM involvement detected by FCM and PCR on the outcome of patients treated for FL. Methods: Patients who were diagnosed with biopsy-proven FL between 2004 and 2015 at our institution were included in the study. All patients had received a staging bone marrow examination before treatment with immunotherapy-based regimen. Immunocytologic [FCM] and/or molecular [PCR] studies were always performed if the patients did not have morphological BM involvement. We used 4- or 6- color FCM, and performed PCR analysis of Bcl-2/IgH rearrangement and/or IgH rearrangement detected by modified BioMed-2 protocol. A total of 90 patients were included, and the median follow-up duration was 36 months (range, 6|122 months). The BM status was classified using into 3 categories: morphological, minimal, and negative BM involvement. Minimal BM involvement was defined as BM involvement detected by FCM or PCR without morphological evidence. Morphological and minimal BM involvements were detected in 37 (41%) and 38 (42%) patients, respectively. The primary outcome measure was progression-free survival (PFS). PFS curves were plotted using the Kaplan-Meier method and compared by the log-rank test. Multivariate analyses were performed using a Cox linear regression model. There were significant differences in gender, LDH levels, stage, nodal sites, and FL International Prognostic Index (FLIPI) between patients with and without morphological BM involvement (Table1). Results: The 3-year PFS rate for patients with negative BM involvement was significantly better than that for patients with minimal or morphological BM involvement (84.8% vs. 40.3% vs. 60.5%; p= 0.043) (Figure 1). There was no statistical difference in 3-year PFS between patients with morphological BM involvement and those with minimal BM involvement. The difference of 3-year PFS rate between patients with minimal BM involvement and those with negative BM involvement was significant for patients with FLIPI low-intermediate risk (88.9% vs. 51.5%; p= 0.032) and those with advanced stage disease (90.0% vs. 33.6%; p= 0.027), but there were no significant differences in patients deemed FLIPI high risk and those with limited stage disease. Multivariate analysis revealed that BM involvement, including morphological and minimal involvement, was a significant poor prognostic factor (hazard ratio 4.885 [95% confidence interval 1.16-20.56], p = 0.0305). Conclusion: At the start of treatment, bone marrow involvement was seen in most FL patients. Patients without any BM involvement had an excellent prognosis. Patients with minimal BM involvement had an equally poor prognosis as those with morphologic BM involvement. Table 1 FLIPI: Follicular Lymphoma International Prognostic Index Table 1. FLIPI: Follicular Lymphoma International Prognostic Index Table 2 BM state positive: including morphological and minimal bone marrow involvement. Table 2. BM state positive: including morphological and minimal bone marrow involvement. Figure Figure. Disclosures Ishikawa: Mundipharma KK: Research Funding.

Fluorouracil, Doxorubicin, and Streptozocin in the Treatment of Patients With Locally Advanced and Metastatic Pancreatic Endocrine Carcinomas

2004 ◽  
Vol 22 (23) ◽  
pp. 4762-4771 ◽  
Author(s):  
Maria A. Kouvaraki ◽  
Jaffer A. Ajani ◽  
Paulo Hoff ◽  
Robert Wolff ◽  
Douglas B. Evans ◽  
...  
Keyword(s):  
Response Rate ◽  
Objective Response ◽  
Locally Advanced ◽  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Response Duration ◽  
Response To Treatment ◽  
Rank Test ◽  
Median Response ◽  
Log Rank Test

Purpose The role of systemic chemotherapy in the management of pancreatic endocrine carcinoma (islet cell carcinoma; PEC) is an area of considerable controversy. Response rates ranging from 6% to 69% have been reported for streptozocin-based chemotherapy. We retrospectively studied 84 patients with locally advanced or metastatic PEC who had been treated with fluorouracil, doxorubicin, and streptozocin (FAS) to determine the objective response rate, duration of progression-free survival (PFS), and duration of overall survival (OS). Patients and Methods Eligible patients had histologic or cytologic confirmation of their tumor and measurable disease on computed tomography or magnetic resonance imaging scans. Response to treatment was evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors Committee. Results Sixty-one of the patients were male and 23 were female, with a median age of 54 years (range, 24 to 78 years). The response rate (RR) to FAS was 39%, with a median response duration of 9.3 months. The 2-year PFS rate was 41%, and the 2-year OS rate was 74%. The extent of liver metastatic disease correlated with a worse PFS (P = .01 by log-rank test) and a worse OS (P < .0001 by log-rank test). Analyses showed that metastatic replacement of more than 75% of the liver and prior chemotherapy were independently associated with inferior PFS. Conclusion Patients with locally advanced or metastatic PEC who are treated with FAS may have a reasonable RR, and responders may experience longer PFS and OS. The volume of metastases in the liver is the most important predictor of outcome.

Impact Of Pre-Transplant Rituximab Sensitivity In Relapsed Follicular Lymphoma On Outcome After Autologous Transplant

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3365-3365
Author(s):  
Colin Phipps ◽  
Ajay K. Gopal ◽  
Barry E. Storer ◽  
Ryan D. Cassaday ◽  
Oliver W. Press ◽  
...  
Keyword(s):  
Stem Cell ◽  
Follicular Lymphoma ◽  
Cumulative Incidence ◽  
International Prognostic Index ◽  
Single Agent ◽  
Conditioning Regimen ◽  
Prognostic Index ◽  
Risk Of Death ◽  
Multivariate Adjustment ◽  
The Impact

Abstract Purpose Prior to the introduction of modern induction and maintenance regimens, autologous stem cell transplantation (ASCT) improved outcomes in chemotherapy-sensitive, relapsed follicular lymphoma (FL). We re-evaluated the impact of Rituximab (R) sensitivity on ASCT for relapsed FL in the current Rituximab era. Methods 194 consecutive patients with a confirmed diagnosis of relapsed, grade 1, 2 or 3A FL underwent ASCT at our center from April 1993 to October 2011. They were categorized as R-sensitive, R-refractory, or no R (NoR) if transplanted prior to use of Rituximab. Rituximab refractoriness was defined as failure (at any point in treatment) to achieve at least a PR or documented disease progression within 6 months of receiving the first dose of a full course of single-agent rituximab (³ 4 doses of 375mg/m2 weekly), getting rituximab maintenance (R-maintenance) or completing 2 courses of Rituximab combined with chemotherapy (R-chemotherapy). The statistical significance of differences in event rates was evaluated with the proportional hazards regression model. Two-sided p-values less than 0.05 were considered statistically significant. Kaplan-Meier (K-M) curves were used to estimate the probabilities of overall survival (OS) and progression-free survival (PFS). Cumulative incidence of relapse was calculated in a competing risk data analysis considering non-relapse mortality as a competing event. Results There were 65 rituximab-refractory (RR), 35 rituximab-sensitive (RS) and 94 NoR patients. RS (11%) and RR (12%) patients received R-maintenance. High-risk FL international prognostic index (FLIPI) scores at the time of ASCT was imbalanced between the groups: RS 3%, RR 23% and NoR 26% (P = .009). Baseline characteristics were otherwise comparable between the 3 groups. Median follow-up from ASCT to time of last contact or death was 64 months (range 10-169), 42 months (range 1-157) and 91 months ( range 0.5-231) in the RS, RR and NoR groups, respectively. Univariate analyses showed significantly better OS (P = .003) and PFS (P = .0004) in RS patients with 3-year OS and PFS (Figure 3) of 97% and 85% compared with 63% and 35% in RR and 73.4% and 49% in NoR patients, respectively (Figures 1 & 2). Time to next treatment in relapsing patients was significantly shorter in the RR group compared to the RS and NoR groups. We performed multivariate adjustment for pre-ASCT factors that could affect outcomes i.e. age ≥ 50, FLIPI score ≥ 3, # prior chemotherapy regimens ≥ 3, chemo-resistance, elevated lactate dehydrogenase, prior radiation therapy, bone marrow stem cell source, and remission quotient ≥ 6 (defined as the months from diagnosis to ASCT divided by number of prior therapies). Multivariate adjustment showed OS to be significantly affected only by rituximab sensitivity, with a lower risk of death in RS patients (HR 0.24, P = .01). PFS was also significantly affected by pre-ASCT rituximab sensitivity (HR 0.35, P = .006). Cumulative incidence of relapse was increased in RR patients (HR 2.11, P = .01). The differences in post-ASCT OS, PFS, and relapse rates between the RS and RR patients were maintained independent of transplant conditioning regimen. There were no differences in OS, PFS or relapse whether RR patients were refractory to single-agent rituximab, R-maintenance, or R-chemotherapy. Conclusions Pre-transplant rituximab sensitivity in relapsed FL is a strong independent predictor of post-ASCT outcome. For RR FL patients with limited effective options, nearly half were alive and progression-free at 3 years after ASCT. Disclosures: Shustov: Seattle Genetics, Inc.: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Multicenter Phase II Trial of Immunotherapy With the Humanized Anti-CD22 Antibody, Epratuzumab, in Combination With Rituximab, in Refractory or Recurrent Non-Hodgkin's Lymphoma

2006 ◽  
Vol 24 (24) ◽  
pp. 3880-3886 ◽  
Author(s):  
Sandra J. Strauss ◽  
Frank Morschhauser ◽  
Juergen Rech ◽  
Roland Repp ◽  
Philippe Solal-Celigny ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Hodgkin’S Lymphoma ◽  
International Prognostic Index ◽  
Objective Response ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Hodgkin's Lymphoma ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma

Purpose A multicenter, single-arm study examining efficacy and toxicity of epratuzumab combined with rituximab was conducted in patients with recurrent or refractory non-Hodgkin's lymphoma. Patients and Methods Sixty-five patients were enrolled; 34 patients with follicular lymphoma (FL), 15 patients with diffuse large B-cell lymphoma (DLBCL), and 16 patients with other lymphomas. The patients had received a median of two prior therapies (range, 1 to 4); 23% had received rituximab. Epratuzumab was given at 360 mg/m2 intravenously over 60 minutes followed by infusion of 375 mg/m2 rituximab, weekly for 4 consecutive weeks. Results Combination therapy was well tolerated without greater toxicity than rituximab alone. The objective response (OR) rate was 47% (30 of 64) in assessable patients (46%; 30 of 65 in all patients), being highest in FL (64%; 21 of 33) and DLBCL (47%; seven of 15), and with 24% (eight of 33) and 33% (five of 15) achieving complete response (CR) or complete response unconfirmed (CRu) in these two groups, respectively. Two of six patients with marginal zone lymphoma responded to treatment (one CR). There was a trend for the response rates to be higher in patients with low prognostic index scores (statistically significant with respect to the Follicular Lymphoma International Prognostic Index score in FL patients), with 12 FL patients and three DLBCL patients in groups 0 to 1 having OR (CR/CRu) rates of 83% (33%) and 100% (100%), respectively. The median duration of response was 16 months for FL, with five patients currently progression free for 18 months to 30 months, and 6 months for DLBCL, with two patients currently progression free for 12 months and 18 months. Conclusion Epratuzumab combined with rituximab was well tolerated, demonstrating promising antilymphoma activity that warrants additional study.

Single 4-Dose Rituximab Treatment for Low-Tumor Burden Follicular Lymphoma (FL): Survival Analyses with a Follow-Up (F/Up) of at Least 5 Years.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 585-585 ◽  
Author(s):  
Philippe Solal-Celigny ◽  
Gilles Andre Salles ◽  
Nicole Brousse ◽  
Patricia Franchi-Rezgui ◽  
Pierre Soubeyran ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Risk Group ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Progression Free Survival ◽  
Tumor Burden ◽  
Rank Test ◽  
Induction Treatment ◽  
Relapse Free Survival ◽  
Free Survival

Abstract Rituximab alone may be given as initial treatment for FL either as a single treatment or as an induction treatment followed by a maintenance. In 2002, we have reported the response rates and progression-free survival (PFS) of 49 patients (pts) treated with 4 weekly 375 mg/m² doses of rituximab (Blood2002; 97: 101–6). All patients had FL and a low-tumor burden according to the GELF criteria. These pts have been followed during at least 5 years. According to the Follicular Lymphoma International Prognostic Index (Blood, in press). 22 pts were in the low-risk group (45%), 20 (41%) in the intermediate risk group and 7 (14%) in the poor risk group. Best response rate was 80% with 49% CR/CRu and 31% PR, and response was maintained in 34% without further treatment after at least 5 years. Median F/Up was 60 months. The median PFS was 18 months. Among these 49 pts, only 3 pts died (2 from NHL, 1 from lung carcinoma). Among the 32 pts who were bcl-2 positive in the blood and/or the bone marrow before treatment with rituximab, 10 (33%) became negative and 20 (67%) remained positive at d50. 6 (60%) relapsed among the former and 15 (75%) among the latter. Median PFS was 37 months for pts who became bcl-2 negative and 14 months for those who remained positive (p[log-rank test] = 0.10). Among the 4 patients who had information on molecular biology who did not relapse after a 5-year F/Up, 3 were bcl-2 negative and 1 was bcl-2 positive. The long F/Up of these pts (i) confirms the median PFS of 18 months for all pts and the median relapse-free survival of 27 months for best responders (ii) shows that some patients (i.e. 28% of all pts and 34 % of responders) may have a relapse-free survival longer than 5 years after a single first line treatment with rituximab in monotherapy ; (iii) shows an excellent overall survival (only 3 death (6%) during the study) in these FL pts. These results confirm the relevance of on-going trials comparing a maintenance treatment with rituximab and treatment at the time of relapse.

TIVO-3: A phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 541-541 ◽  
Author(s):  
Brian I. Rini ◽  
Sumanta K. Pal ◽  
Bernard Escudier ◽  
Michael B. Atkins ◽  
Thomas E. Hutson ◽  
...  
Keyword(s):  
Adverse Event ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Phase Iii ◽  
Rank Test ◽  
Tyrosine Kinase Receptor ◽  
P Value ◽  
Risk Category ◽  
Open Label

541 Background: Tivozanib (T) is a biochemically potent and highly selective VEGF tyrosine kinase receptor inhibitor in clinical development in RCC. The TIVO-1 trial in treatment naïve or prior cytokine-treated subjects with metastatic (m) RCC showed a median progression free survival (mPFS) of 11.9 months (mos) for T compared to 9.1 mos for sorafenib (S) (p = 0.042, HR = 0.797). However, overall survival (OS) favored sorafenib, likely due to imbalanced crossover to active treatments. TIVO-3 was conducted to confirm the PFS results from TIVO-1. Methods: Subjects with mRCC who failed 2 or 3 prior systemic regimens, one of which included a VEGFR TKI other than S or T, were stratified by IMDC risk category and type of prior therapy (two TKIs; TKI plus checkpoint; TKI + other) then randomized in a 1:1 ratio to T or S. The primary objective was to compare PFS by blinded independent radiological review. 350 subjects were enrolled to yield 244 events with ~88% power to detect a difference of 6 mos vs. 4 mos with a two-sided p-value of 0.05 by the log-rank test. Secondary endpoints were OS, safety, objective response rate (ORR), and duration of response. Results: The two arms were well balanced for demographics and prior cancer history.60% of subjects had 2 prior lines of therapy and 40% had 3 prior lines. 28% had prior treatment with a checkpoint inhibitor. T demonstrated a statistically significant improvement in mPFS compared to S, 5.6 (95% CI 7.3-5.3) v. 3.9 mos (95% CI 5.6-3.7; HR 0.73; p=0.02). PFS rate at 2 years was 18% for T compared to 5% for S. ORR was 18% for T compared to 8% for S. 44% of T treated subjects experienced a grade 3 treatment-related adverse event compared to 55% for S. Subjects on T were less likely to require a dose reduction (24% v. 38%), interruption (48% v. 63%), or discontinuation (21% v. 29%) due to an adverse event than subjects on S. Conclusions: T is superior to S as measured by PFS; 2-year PFS, and ORR in this pre-treated population and is better tolerated than S. OS data will be updated prior to presentation. Clinical trial information: NCT02627963.

Confirmation of Safety, Efficacy and Response Duration in Non-Hodgkin Lymphoma Patients Treated with 60 μg/m2/d of BiTE® Antibody Blinatumomab.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2723-2723 ◽  
Author(s):  
Dirk Nagorsen ◽  
Gerhard Zugmaier ◽  
Andreas Viardot ◽  
Mariele Goebeler ◽  
Richard Noppeney ◽  
...  
Keyword(s):  
Adverse Events ◽  
Follicular Lymphoma ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Response Duration ◽  
Single Chain ◽  
Employment Equity ◽  
Median Response ◽  
Equity Ownership

Abstract Abstract 2723 Poster Board II-699 Indolent and mantle cell lymphoma (MCL) are predominantly treated with chemotherapy or a combination of chemotherapy with monoclonal antibodies. Despite high initial response rates, eventually almost all patients however relapse, leaving the disease incurable. Moreover, with increasing numbers of regimens administered, the responsiveness of patients is reduced. Blinatumomab is a single-chain bispecific antibody construct with specificity for CD19 and CD3, belonging to the class of bispecific T cell engager (BiTE®). Here, we report on patients in an ongoing phase 1 trial treated at a dose of 60 μg/m2/d for 4–8-week by continuous i.v. infusion with single-agent blinatumomab. In total, 12 patients with indolent mainly follicular lymphoma or MCL were treated at 60 μg/m2/d during the first treatment cycle. 11/12 patients showed an objective response (7 PR and 4 CR). As of July 2009, median response duration was 12 months with 6 out of 11 responses still ongoing. The single non-responding patient experienced a reversible, neurological adverse event leading to early discontinuation of treatment. Of the 11 responders, one patient developed a port infection and 4 patients showed neurological symptoms, which were all fully reversible. In order to mitigate neurological adverse events during first dosing, which can occur in a defined subset of patients, patients were treated for 1–2 weeks with a lower initial dose (5 and/or 15 μg/m2/d) followed by a maintenance dose of 60 μg/m2/d. A lower starting dose appeared to ameliorate initial adverse events to an extent that treatment could be continued without interruption. Taken together, our data confirm a high single-agent activity of 60 μg/m2/d blinatumomab infused for 4–8 week with long lasting remissions and a favorable risk/benefit profile. The confirmed dose will be considered for further clinical development of blinatumomab in follicular lymphoma and MCL. New data on patients treated with a dose of 90 μg/m2/d will be presented. Disclosures: Nagorsen: Micromet: Employment, Equity Ownership. Zugmaier:Micromet: Employment, Equity Ownership. Schmidt:Micromet: Employment, Equity Ownership. Klappers:Micromet: Employment, Equity Ownership. Baeuerle:Micromet: Employment, Equity Ownership. Kufer:Micromet: Employment, Equity Ownership, Patents & Royalties. Bargou:Micromet: Consultancy, Patents & Royalties.

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