Bendamustine Plus Rituximab Versus Fludarabine Plus Rituximab In Patients with Relapsed Follicular, Indolent and Mantle Cell Lymphomas – Final Results of the Randomized Phase III Study NHL 2–2003 on Behalf of the StiL (Study Group Indolent Lymphomas, Germany)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 856-856 ◽  
Author(s):  
Mathias J Rummel ◽  
Ulrich Kaiser ◽  
Christina Balser ◽  
Martina Beate Stauch ◽  
Wolfram Brugger ◽  
...  
Keyword(s):  
Overall Survival ◽  
Maintenance Therapy ◽  
Conflicts Of Interest ◽  
International Prognostic Index ◽  
Phase Iii ◽  
Rituximab Maintenance ◽  
Mantle Cell ◽  
Phase Iii Study ◽  
Grade 3 ◽  
Indolent Lymphomas

Abstract Abstract 856 Introduction: Promising results have been observed in two phase II studies evaluating the combination of bendamustine plus rituximab (B-R) in patients (pts) with relapsed/refractory follicular, other indolent or mantle cell lymphomas (MCL) (Rummel et al. JCO 2005; Robinson et al. JCO 2008). Fludarabine plus rituximab (F-R) is an established treatment option in this setting. Therefore, we initiated in 2003 a multicenter, randomized phase III study to compare the efficacy and safety of B-R versus F-R for pts with relapsed follicular (FL), indolent or MCL. Patients and methods: 219 pts with relapsed FL, indolent or MCL in need of treatment were randomized to rituximab 375 mg/m2 (day 1) plus either bendamustine 90 mg/m2 (days 1+2) or fludarabine 25 mg/m2 (days 1–3) q 28 days for a maximum of 6 cycles. Prophylactic use of antibiotics or granulocyte-colony stimulating factor (G-CSF) was not generally recommended; however in cases of severe granulocytopenia, G-CSF use was permitted. The primary endpoint was progression-free survival (PFS). The protocol was amended in 2006 to allow rituximab maintenance therapy (rituximab 375 mg/m2 q 3 months for up to 2 years) in both arms, following regulatory approvals in this setting. Results: 11 pts were not evaluable due to protocol violations, and were not followed further. A total of 208 pts were evaluable for the final analysis (109 B-R; 99 F-R). There were no significant differences between arms for patient characteristics, including age, stage, LDH, International Prognostic Index (IPI), follicular IPI (FLIPI), bone marrow infiltration and extranodal involvement. Most pts had stage IV (71.6% B-R; 60.6% F-R) or stage III disease (21.1% B-R and 25.3% F-R, respectively). Median patient age was 68 yrs (range 38–87). Patients had received a median of 1 prior therapy (range 1–7). Histological subtypes were distributed equally between the B-R and F-R arms: follicular 45.9 % and 47.5%, respectively; immunocytoma 11.9% and 11.1%; MCL 20.2% and 21.2%; other indolent lymphomas 23% and 20.2%. A median number of 6 cycles were given in both treatment arms, with 75.2% of B-R pts and 53.4% of F-R pts receiving 6 cycles, respectively. At the time of this analysis (June 2010), the median observation time was 33 months. Median PFS was significantly prolonged with B-R compared with F-R (30 vs 11 months; hazard ratio [HR] 0.51, 95 % confidence interval [CI] 0.34–0.67; p<0.0001). The overall response rate was significantly higher with B-R than with F-R (83.5 vs 52.5%, respectively; p< 0.0001). The CR rate with B-R was also significantly higher than that with F-R (38.5 vs 16.2%; p=0.0004). Overall survival did not differ significantly between arms, with 42 and 46 deaths documented in the B-R and F-R arms, respectively. There were no significant differences in the rates of alopecia, stomatitis, erythema, allergic reactions, peripheral neuropathy or infectious episodes between groups. Hematologic toxicities were also similar between arms: 8.9% grade 3/4 neutropenia with B-R vs 9.1% with F-R; 11.8% grade 3/4 leukocytopenia with B-R vs 12.4% with F-R. The overall incidence of serious adverse events was similar for the B-R and F-R groups (17.4 and 22.2%, respectively). An unplanned subanalysis showed that rituximab maintenance therapy significantly prolonged overall survival (HR 0.21, 95% CI 0.22–0.67; p=0.0008) and PFS (HR 0.27, 95% CI 0.27–0.59; p< 0.0001) in the small group of 40 pts who received this treatment (23 B-R, 17 F-R), compared with those who did not. Although the numbers are too small in this non-randomized comparison to draw some validated conclusions, these results appear to confirm the favorable role of rituximab maintenance. Conclusions: These data confirm the efficacy of B-R in pts with relapsed FL, indolent or MCL, and, in this setting, demonstrate a superior PFS benefit for this regimen in comparison with F-R. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Bendamustine Plus Rituximab Versus Fludarabine Plus Rituximab in Patients with Relapsed Follicular, Indolent, or Mantle Cell Lymphomas – 8-Year Follow-up Results of the Randomized Phase III Study NHL 2-2003 on Behalf of the StiL (Study Group Indolent Lymphomas, Germany)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 145-145 ◽  
Author(s):  
Mathias J. Rummel ◽  
Christina Balser ◽  
Ulrich Kaiser ◽  
Hans Peter Böck ◽  
Martina Beate Stauch ◽  
...  
Keyword(s):  
Overall Survival ◽  
Maintenance Therapy ◽  
Response Rate ◽  
Complete Response ◽  
Phase Iii ◽  
Rituximab Maintenance ◽  
Mantle Cell ◽  
Phase Iii Study ◽  
Grade 3 ◽  
Indolent Lymphomas

Abstract Introduction: Fludarabine plus rituximab (F-R) is an established treatment option for patients (pts) with relapsed/refractory follicular lymphoma (FL), other indolent lymphoma, or mantle cell lymphoma (MCL). To further improve the treatment in this setting we initiated in 2003 a multicenter, randomized phase III study to compare the efficacy and safety of bendamustine plus rituximab (B-R) versus F-R for pts with relapsed FL, other indolent lymphomas or MCL. Patients and Methods: 230 pts in need of treatment were randomized to rituximab 375 mg/m² (day 1) plus either bendamustine 90 mg/m² (days 1+2) or fludarabine 25 mg/m² (days 1–3) q 28 days for a maximum of 6 cycles. Prophylactic use of antibiotics or granulocyte-colony stimulating factor (G-CSF) was not generally recommended; however, in case of severe granulocytopenia, G-CSF use was permitted. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), overall response rate (ORR), and complete response rate (CR). The protocol was amended in 2006 to allow rituximab maintenance therapy (rituximab 375 mg/m2 q 3 months for up to 2 years) in both arms, following regulatory approvals in this setting. Results: A total of 219 pts were evaluable for the analysis (114 B-R; 105 F-R). There were no significant differences between arms for patient characteristics, including age, stage, LDH, IPI, FLIPI, bone marrow infiltration, and extranodal involvement. Most pts had stage IV (71.6% B-R; 60.6% F-R) or stage III disease (21.1% B-R; 25.3% F-R). Median patient age was 68 yrs (range 38–87). Patients had received a median of 1 prior therapy (range 1–7). Histological subtypes were distributed equally between the B-R and F-R arms: follicular, 45.9% and 47.5%, respectively; Waldenström’s Macroglobulinemia, 11.9% and 11.1%; MCL, 20.2% and 21.2%; other indolent lymphomas, 23% and 20.2%. A median of 6 cycles were given in both treatment arms, with 75.2% and 53.4% of B-R and F-R pts receiving 6 cycles, respectively. At the time of this analysis (June 2014), the median observation time was 96 months. The ORR was significantly higher with B-R than with F-R (83.5% vs. 52.5%, respectively; p< 0.0001). The CR rate with B-R was also significantly higher than that with F-R (38.5% vs. 16.2%; p=0.0004). Median PFS was significantly prolonged with B-R compared with F-R (34 vs. 12 months; hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.38–0.72; p<0.0001). The longer PFS translated into a survival benefit with a significantly longer median overall survival in the B-R group than in the F-R group (110 vs. 49 months; HR 0.64, 95% CI 0.45–0.91; p=0.0125) comprising 55 and 71 deaths in the B-R and F-R groups, respectively. There were no significant differences in the rates of alopecia, stomatitis, erythema, allergic reactions, peripheral neuropathy, or infectious episodes between groups. Hematologic toxicities were also similar between arms: 8.9% grade 3/4 neutropenia with B-R vs. 9.1% with F-R; 11.8% grade 3/4 leukocytopenia with B-R vs. 12.4% with F-R. The overall incidence of serious adverse events was similar for the B-R and F-R groups (17.4% and 22.2%, respectively). 17 pts (14.9%) developed a secondary neoplasia after B-R compared with 16 pts (15.2%) after F-R. Of these, 5 pts in the B-R group, and 3 pts in the F-R group developed a secondary hematological neoplasia (2 AML [1 AML M4], 1 CML, 1 DLBCL, and 1 HD after B-R; and 2 AML M4, and 1 MDS after F-R). An unplanned subanalysis showed that rituximab maintenance therapy significantly prolonged overall survival (HR 0.38, 95% CI 0.32-0.71; p=0.0003) and PFS (HR 0.35, 95% CI 0.31-0.62; p< 0.0001) in the small group of 40 pts who received this treatment (23 B-R, 17 F-R) compared with those who did not. Although the numbers are too small in this non-randomized comparison to draw validated conclusions, these results appear to confirm the favorable role of rituximab maintenance. Conclusions: B-R was more effective than F-R in this setting of relapsed FL, other indolent lymphomas and MCL due to higher overall and complete response rates, a longer PFS, and an improved OS. These data confirm the high anti-lymphoma activity of B-R. Disclosures Off Label Use: Indication and dosage of bendamustine.

Bendamustine Plus Rituximab Is Superior in Respect of Progression Free Survival and CR Rate When Compared to CHOP Plus Rituximab as First-Line Treatment of Patients with Advanced Follicular, Indolent, and Mantle Cell Lymphomas: Final Results of a Randomized Phase III Study of the StiL (Study Group Indolent Lymphomas, Germany).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 405-405 ◽  
Author(s):  
Mathias J Rummel ◽  
Norbert Niederle ◽  
Georg Maschmeyer ◽  
Andre Banat ◽  
Ulrich von Gruenhagen ◽  
...  
Keyword(s):  
Early Death ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Phase Iii ◽  
First Line ◽  
Free Survival ◽  
Mantle Cell ◽  
Phase Iii Study ◽  
Grade 3 ◽  
Indolent Lymphomas

Abstract Abstract 405 Introduction: Promising results have been observed in two phase-II studies evaluating the combination of Bendamustine plus Rituximab (B-R) in patients with relapsed/refractory indolent or mantle cell lymphomas (Rummel et al., JCO 2005; Robinson et al., JCO 2008). In order to further investigate the role of the combination B-R we initiated a multicenter randomized phase-III study in October 2003 to compare efficacy and safety of B-R versus CHOP plus Rituximab (CHOP-R) as first-line therapy for patients with follicular (FL), indolent and mantle cell lymphomas (MCL). Patients and Methods: 549 patients (pts) in need of treatment for their disease were randomized to receive Rituximab 375 mg/m2 (day 1) plus either Bendamustine 90 mg/m2 (days 1+2) every 28 days or the standard CHOP regimen every 21 days for a maximum of 6 cycles. The primary endpoint was progression-free survival (PFS). Patients characteristics, including age, stage, LDH, IPI, FLIPI, bone marrow infiltration and extranodal involvement did not statistically significant differ between both arms. The median patient age was 64 years (range 31-83) (64 yrs for B-R and 63 yrs for CHOP-R). Most patients were in stage IV (76,9% in BR and 77,5 in CHOP-R) and stage III (19,2% in B-R and 18,6% in CHOP-R). Histologies were distributed equally between B-R and CHOP-R: follicular 55% and 56%, mantle cell 18% and 19%, and other indolent lymphomas 27% and 24%, respectively. Prophylactic use of antibiotics or growth factors were not generally recommended in this protocol. Results: Of the 549 pts 36 pts were not evaluable: 10 did not receive any study medication, 9 due to withdrawal of consent, 13 due to incorrect diagnosis (4 × DLBCL, 3 × CLL, 2 × MM, 1 × HD, 3 × solid tumors), and 4 for other reasons. 513 randomized pts are evaluable for the final analysis (B-R: n=260; CHOP-R: n=253). Out of these 9 pts were not evaluable for response evaluation: 4 pts (3 × CHOP-R, 1 × B-R) due to early death in neutropenic sepsis, 3 pts due to a subsequent change of therapy after severe toxicity in 1st cycle of CHOP-R, 1 B-R pt due to progress of disease, and 1 B-R due to early death. All patients were counted for evaluation of PFS, overall survival (OS), event-free survival (EFS; an event was defined by a response less than a partial response, disease progression, relapse, or death from any cause), and for time to next treatment (TTNT). A median number of 6 cycles was given in both treatment arms each. 82% of B-R pts and 86% of CHOP-R pts received 6 cycles. At the time of analysis in August 2009, the median observation time was 32 months. Overall response rate for pts treated with B-R was similar to the CHOP-R group (93,8% vs 93,5%, respectively). The CR rate was significantly higher with 40,1% for B-R compared to 30,8% for CHOP-R (p=0.0323). The median PFS, EFS and TTNT were significantly longer after B-R compared to after CHOP-R: PFS 54,8 months for B-R versus (vs) 34,8 months for CHOP-R (p=0.0002), Hazard Ratio (HR) 0.5765 (95% confidence interval (CI) 0.4292 to 0.7683); EFS 54 months for B-R vs 31 months for CHOP-R (p=0.0002, HR 0.6014 (95% CI 0.4515 to 0.7845); and TTNT median not yet reached in the B-R group vs 40,7 months in the CHOP-R group (p=0.0002; HR 0.5416, 95% CI 0.3897 to 0.7491). OS did not differ between both groups at this point of time. Thus far, 67 deaths have been observed (B-R: 34; CHOP-R: 33). CHOP-R treatment was more frequently associated with serious adverse events (SAE) (n=49 in B-R vs n=74 in CHOP-R). Significant differences in hematologic toxicities were observed for neutropenia grade 3+4 (BR 10,7% vs CHOP-R 46,5%; p<0.0001) and for leukocytopenia grade 3+4 (BR 12,1% vs CHOP-R 38,2%; p<0.0001). G-CSF was more often used in CHOP-R treated pts (20,0% of all cycles) than it was used in the B-R group (4,0%) (p<0.0001). The B-R regimen was better tolerated by the pts as evidenced by a lower rate of alopecia (15% (only grade 1) in B-R vs 62% CHOP-R), a lower number of infectious complications (95 in BR vs 121 in CHOP-R, p=0.0403), a lower incidence of peripheral neuropathy (B-R n=18; CHOP-R n=73; p<0.0001), and fewer episodes of stomatitis (B-R n=16; CHOP-R n=47; p<0.0001). Only drug-associated erythematous skin reaction (urticaria, rash) was more often seen with B-R (n=42) than with CHOP-R (n=23) (p=0.0122). Conclusions: In this final analysis the combination of Bendamustine plus Rituximab improves PFS and CR rates while showing a better tolerability profile. These promising results suggest that B-R does have the potential to become a new standard first-line treatment option for patients with FL, MCL, and indolent lymphomas. Disclosures: Rummel: Roche Pharma AG: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Amgen: Honoraria. Maschmeyer:OrthoBiotech: .

Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non–Small-Cell Lung Cancer

2008 ◽  
Vol 26 (21) ◽  
pp. 3543-3551 ◽  
Author(s):  
Giorgio Vittorio Scagliotti ◽  
Purvish Parikh ◽  
Joachim von Pawel ◽  
Bonne Biesma ◽  
Johan Vansteenkiste ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Group Performance ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Phase Iii Study ◽  
Grade 3

PurposeCisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non–small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting.Patients and MethodsThis noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m2on day 1 and gemcitabine 1,250 mg/m2on days 1 and 8 (n = 863) or cisplatin 75 mg/m2and pemetrexed 500 mg/m2on day 1 (n = 862) every 3 weeks for up to six cycles.ResultsOverall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common.ConclusionIn advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

A Phase IIIb Study of Rituximab Maintenance Therapy in Patients with Follicular Non-Hodgkin’s Lymphoma Who Have Responded to Induction Therapy - MAXIMA-Protocol.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4706-4706 ◽  
Author(s):  
Manfred Hensel ◽  
Mathias Witzens-Harig ◽  
Peter Dreger ◽  
Anthony D. Ho ◽  
Daniel Thurley ◽  
...  
Keyword(s):  
Overall Survival ◽  
Complete Remission ◽  
Maintenance Therapy ◽  
Follicular Lymphoma ◽  
Induction Therapy ◽  
Randomized Trials ◽  
Phase Iii ◽  
First Line ◽  
Free Survival ◽  
Rituximab Maintenance

Abstract Five randomized trials (four Phase III and one phase II) have confirmed that rituximab maintenance therapy provides clinical meaningful improvements in terms of Progression Free Survival, Event Free Survival and response duration for patients. Two studies have also found an overall survival advantage for rituximab maintenance therapy (Hoechster et al. 2005, van Oers et al. 2005) and a third study could demonstrate a strong trend towards overall survival advantage (Dreyling et al. 2006). A Cochrane meta-analysis of several randomised Phase III trials (Schulz et al. 2005) demonstrated that rituximab plus-chemotherapy for first-line treatment of Follicular Lymphoma is superior to chemotherapy alone and significantly prolongs overall survival. To further broaden the available basis for maintenance treatment in the first-line and relapsed setting, the MAXIMA (MAintenance rituXImab in Follicular LymphoMA) trial has been started in August 2006 and will last 5 years. Patients with first line or relapsed/refractory advanced Follicular Lymphoma are included in this trial. In total 500 patients are planned for this international trial running in 23 countries. Patients who achieve a Complete Remission, Complete Remission unconfirmed or Partial Remission after rituximab containing induction therapy (rituximab with or without chemotherapy) are eligible to enter the study to receive rituximab maintenance therapy administered at the standard dose of 375 mg/m2 every 2 months for 2 years. This regimen is also investigated in the ongoing PRIMA study, and also in an ongoing SAKK study which investigates the benefit of rituximab maintenance therapy for up to five years. The previous five randomized trials did not detect significant safety issues for rituximab maintenance therapy. The main objective of the MAXIMA trial is to confirm this safety data in a wider patient population. Secondary objectives of the study include standard time dependent parameters (PFS, EF, OS). In addition, the effect of rituximab maintenance therapy on improving response quality (PR =&gt;CR) after induction therapy will be evaluated.

Retherapy with Bendamustine-Containing Regimens in Patients with Relapsed/Refractory CLL and Indolent Lymphomas Achieves High Response Rates

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1615-1615
Author(s):  
Rudolf Weide ◽  
Stefan Feiten ◽  
Vera Friesenhahn ◽  
Jochen Heymanns ◽  
Kristina Kleboth ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Overall Response Rate ◽  
Conflicts Of Interest ◽  
Response Rates ◽  
High Response ◽  
B Cell Malignancies ◽  
The Mean ◽  
Grade 3 ◽  
Indolent Lymphomas

Abstract Abstract 1615 Purpose: Bendamustine-containing regimens have shown high response rates and long lasting remissions in relapsed/refractory indolent B-cell-malignancies. Here we have evaluated the efficacy of Bendamustine-containing regimens as retherapy in this patient population. Patients and methods: Patients with CLL or indolent B-cell-malignancies (NHL) who previously had been treated with Bendamustine and were retreated with either Bendamustine (90mg/m2, day 1+2, q day 29 (1–6 cycles)) (B) or Bendamustine (90mg/m2, day 1+2) + Mitoxantrone (6–10mg/m2, day 1), q day 29 (1–4 cycles) (BM) or Bendamustine (90mg/m2, day 1+2) + Rituximab (375mg/m2, day 1), q day 29 (1–6 cycles) (BR) or Bendamustine (90mg/m2, day 1+2) + Mitoxantrone (6mg/m2 day 1) + Rituximab (375mg/m2, day 8,15,22,29) (BM was repeated on day 36 × 1–3 every 4 weeks) (BMR) between 2000–2010 were analyzed retrospectively. Data were collected from patient files into a database and analyzed statistically using SPSS. Results: 88 patients (57 CLL, 31 NHL) received a Bendamustine-retherapy-regimen. The median age at the first Bendamustine retherapy was 72 years (50–88). The mean number of therapies per patient was 6.0 in CLL and 7.0 in NHL; the mean number of Bendamustine therapies was 3.0 in CLL and 2.6 in NHL. Bendamustine-containing retherapy consisted of B in 4%, BM in 12%, BR in 29% and BMR in 55%. The overall response rate of Bendamustine retherapy was 79% (9% CR, 70% PR). ORR according to regimen was as follows: B: 57% (14% CR, 43% PR), BM: 70% (4% CR, 66% PR), BR: 55% (10% CR, 45% PR), BMR: 84% (7% CR, 78% PR). Main toxicity was a reversible grade 3 or 4 hematotoxicity in 35% of retherapies! No therapy associated death was observed. Overall survival since first diagnosis was 134 months in CLL (23–187) and 131 months in NHL (20–339). Overall survival since start of Bendamustine-containing retherapy was 33 months in CLL (2–129+) and 23 months in NHL (2–62+). Conclusion: Bendamustine-containing retherapy-regimens achieve high response rates in patients with relapsed/refractory CLL and NHL. Hematotoxicity is relevant but reversible. Disclosures: No relevant conflicts of interest to declare.

Bendamustin-Rituximab Induction Followed by Observation or Rituximab Maintenance for Newly Diagnosed Patients with Waldenström's Macroglobulinemia: Results From a Prospective, Randomized, Multicenter Study (StiL NHL 7–2008 –MAINTAIN-; ClinicalTrials.gov Identifier: NCT00877214).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2739-2739 ◽  
Author(s):  
Mathias J. Rummel ◽  
Christian Lerchenmüller ◽  
Richard Greil ◽  
Martin Görner ◽  
Manfred Hensel ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Primary Treatment ◽  
Newly Diagnosed ◽  
Rituximab Maintenance ◽  
Efficacious Treatment ◽  
Mantle Cell ◽  
Indolent Lymphomas ◽  
The Impact ◽  
Initial Results

Abstract Abstract 2739 Background: Bendamustine-rituximab (B-R) has demonstrated substantial efficacy in the primary treatment of indolent lymphomas. A multicenter prospective randomized trial was initiated to investigate the impact of adding rituximab maintenance following B-R first-line induction. The trial included patients (pts) with Waldenström's Macroglobulinemia (WM), marginal zone, small lymphocytic and mantle cell lymphomas. Here we present first and preliminary results for pts with WM. Methods: Treatment consisted of a maximum of 6 cycles of B-R (bendamustine 90 mg/m2, rituximab 375 mg/m2) administered every 28 days plus 2 cycles of rituximab every 4 weeks. Responding pts (≥ PR) were eligible for further treatment and were randomized to observation or 2 years of rituximab maintenance every two months. The primary endpoint is PFS. Results: From April 2009 to July 2012, 57 centers included a total of 162 pts with newly diagnosed WM with a median age of 67 years (31% < 60 years, 69% > 60 years). At baseline/inclusion/screening, the median values for b2-microglobulin (b2M), hemoglobin and IgM were 3.3 mg/L, 10.1 g/dL and 2110 mg/dL (max. 13400 mg/dL), respectively. To date (Aug 2012) 116 pts are evaluable for response (43 women [37%] and 73 men [63%]). 100 pts have responded to B-R leading to an overall response rate (ORR) of 86%. At the time of response evaluation, the median Hb was 12.6 g/dl and the median IgM was 380 mg/dl. 90 pts have undergone randomization to date, 43 to observation and 47 to maintenance. Randomization is ongoing. No results can be reported from that ongoing part of the trial. No uncommon toxicities were observed during B-R induction. Conclusion: Initial results of our trial confirm that for patients with Waldenström's macroglobulinemia, treatment with B-R is an efficacious treatment with a manageable safety profile. The role of rituximab maintenance in this disease is under investigation. Disclosures: No relevant conflicts of interest to declare.

Final Results of the BP22333 Study Demonstrate Non-Inferior Pharmacokinetics (PK) and Safety of Subcutaneous (SC) Administration of Rituximab Compared with Intravenous (IV) Administration As Maintenance Therapy in Patients with Follicular Lymphoma (FL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1641-1641 ◽  
Author(s):  
Antonio Salar ◽  
Irit Avivi ◽  
Jean-Francois Larouche ◽  
Andrea Janikova ◽  
Juliana Pereira ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Phase Iii ◽  
Employment Equity ◽  
Advisory Committees ◽  
Rituximab Maintenance ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 1641 Rituximab has proven efficacy and tolerability for treating B-cell malignancies. IV rituximab administration can take several hours, consuming considerable healthcare resources. A SC rituximab formulation has been developed which may shorten administration time, increase patient (pt) convenience, and potentially reduce IV administration-associated costs. Rituximab efficacy depends on CD20 binding, and Ctrough rituximab levels reflect rituximab exposure throughout the therapy cycle; therefore, achieving a non-inferior Ctrough level with SC dosing is expected to provide comparable efficacy to IV dosing. BP22333 (NCT00930514) is a two-stage phase Ib study assessing PK and tolerability of SC vs IV maintenance rituximab in pts with first-line or relapsed FL. Stage 1 dose-finding results (Salar et al, ASH 2010, abstract 2858; Salar et al, EHA 2012, abstract 0794) identified a fixed dose of 1400 mg for formal Ctrough non-inferiority testing in Stage 2. We report Stage 2 data. The Stage 2 objective was to demonstrate non-inferiority of simulated Ctrough of rituximab SC and IV, using a non-inferiority test with a lower boundary of 0.8 for the 90% confidence interval (CI). Secondary endpoints include SC vs IV rituximab safety and area under the serum concentration-time curve. Eligible pts (N = 157) were aged ≥18 years with an ECOG performance status of ≤ 2, and histologically confirmed CD20-positive grade 1, 2, or 3a FL requiring treatment. Eligible pts must have achieved a complete or partial response following IV rituximab-based induction therapy for FL and have received ≥1 cycle of IV rituximab maintenance within 16 weeks of completing induction. Pts (N = 154) were randomized 1:1 to receive SC rituximab (1400 mg) or IV rituximab (375 mg/m2) for their remaining maintenance cycles, stratified by 2-monthly (q2m) vs 3-monthly (q3m) regimen. Study arms were balanced for age, sex, body surface area, FL grade at diagnosis, induction therapy and number of maintenance doses prior to study entry. As of May 11, 2012, 13 SC pts had withdrawn (7 for progressive disease [PD], 4 for AEs, 1 at investigator's decision, 1 for ineligibility) and 17 IV pts had withdrawn (10 for PD, 4 for AEs, 3 for ineligibility). Median treatment duration on-study was 14.8 months (range, 0–19) in the SC arm and 13.8 months (range, 0–19) in the IV arm. The primary endpoint of the study was met. Geometric mean Ctrough,SC:Ctrough,IV ratios were 1.24 and 1.12, respectively, for q2m and q3m, and lower limits of the two-sided 90% CI (1.02 and 0.86, respectively) exceeded the protocol-specified non-inferiority limit (Ctrough,SC:Ctrough,IV ratio of 0.8). Therefore, 1400 mg SC rituximab was concluded to be non-inferior to 375 mg/m2 IV rituximab administration. AE incidence and intensity were generally balanced; 79% of pts in each arm experienced AEs. Serious AEs were observed in 12% and 14% of pts in the SC and IV arms, respectively; none occurred in > 1 pt in either arm. Grade 3/4 AEs occurred in 18% and 17% of pts in the SC and IV arms, respectively; the only grade 3/4 AEs occurring in > 1 pt in either arm were neutropenia (2 pts in each arm) and arthralgia (2 pts in the IV arm). Administration-related reactions (ARRs) were the most frequent AE and had a higher incidence in the SC arm (reported in 31% of SC vs 4% of IV pts). ARRs were mostly local reactions; the most common in the SC arm were: erythema (13%), injection site erythema (5%), and myalgia (5%). Further safety data will be presented. PK data for SC and IV rituximab administration demonstrate non-inferiority of 1400 mg rituximab SC administration to that of the approved IV rituximab maintenance regimen for both q2m and q3m schedules. The overall AE profiles were similar for SC and IV rituximab administration, with the exception of local ARRs, which had a higher incidence in the SC arm compared with the IV arm, reflecting the expected change in the ARR profile with SC administration. Induction and maintenance therapy using the 1400 mg SC rituximab dose is being assessed in the phase III BO22334 study. Disclosures: Salar: Roche: Consultancy. Off Label Use: Subcutaneous (SC) administration of rituximab as maintenance therapy in patients with follicular lymphoma (FL). Larouche:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Brewster:Roche: Employment, Equity Ownership. Catalani:Roche: Employment, Equity Ownership. McIntyre:Roche: Employment. Sayyed:Roche: Employment. Haynes:Roche: Consultancy, Honoraria.

Results of a randomized phase III study to compare the overall survival of gefitinib (IRESSA) versus docetaxel in Japanese patients with non-small cell lung cancer who failed one or two chemotherapy regimens

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. LBA7509-LBA7509 ◽  
Author(s):  
S. Niho ◽  
Y. Ichinose ◽  
T. Tamura ◽  
N. Yamamoto ◽  
M. Tsuboi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Japanese Patients ◽  
Phase Iii ◽  
Significant Difference ◽  
Trial Outcome Index ◽  
Secondary Endpoints ◽  
Phase Iii Study ◽  
Predefined Criterion ◽  
Grade 3 ◽  
Outcome Index

LBA7509 Background: This phase III study (V-15–32) compared gefitinib vs docetaxel on overall survival (OS) in Japanese patients (pts) with pretreated advanced NSCLC. Methods: Pts with advanced or metastatic (Stage IIIb or IV) NSCLC who failed 1 or 2 chemotherapy regimens were randomized to gefitinib (250 mg/day) or docetaxel (60 mg/m2 every 3 weeks). Non-inferiority of the primary endpoint, OS, was assessed by the confidence interval (CI) of the hazard ratio (HR; gefitinib/docetaxel) derived from an unadjusted Cox proportional hazard model. Results: 489 eligible pts were recruited. Non-inferiority in OS was not achieved (HR 1.12; 95.24% CI 0.89, 1.40) according to predefined criterion (upper CI limit for HR <1.25); however, no significant difference in OS (p=0.330) or PFS (p=0.335) was apparent between treatments. Post study, 36% of gefitinib-treated pts received subsequent docetaxel and 40% received no other therapy apart from gefitinib; 53% of docetaxel-treated pts received subsequent gefitinib and 26% received no other therapy apart from docetaxel. Gefitinib significantly improved ORR (22.5% vs 12.8%; p=0.009), TTF (HR 0.63; 95% CI 0.51, 0.77; p<0.001), and QoL (FACT-L trial outcome index 20.5% vs 8.7%; p=0.002; FACT-L 23.4% vs 13.9%; p=0.023), vs docetaxel. Additional subgroup analyses will be presented. Grade 3/4 AEs occurred in 40.6% (gefitinib) and 81.6% (docetaxel) of pts. Incidence of interstitial lung disease (ILD) was 5.7% (n=14) and 2.9% (n=7), respectively. There were 4 deaths due to AEs in the gefitinib arm (3 possibly treatment-related due to ILD; 1 due to pneumonia that was not considered treatment-related) and none in the docetaxel arm. Conclusions: Whilst non-inferiority in OS between gefitinib and docetaxel was not demonstrated according to predefined criteria, there was no statistically significant difference in survival between the two arms. Secondary endpoints largely unaffected by subsequent therapy provide further evidence of clinical efficacy of gefitinib in these pts. AEs were consistent with those previously observed for both treatments. [Table: see text]

scholarly journals Rituximab Maintenance Versus Wait and Watch after Four Courses of R-DHAP Followed By Autologous Stem Cell transplantation in Previously Untreated Young Patients with Mantle Cell Lymphoma: First Interim Analysis of the Phase III Prospective Lyma Trial, a Lysa Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 146-146 ◽  
Author(s):  
Steven Le Gouill ◽  
Catherine Thieblemont ◽  
Lucie Oberic ◽  
Krimo Bouabdallah ◽  
Emmanuel Gyan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Maintenance Therapy ◽  
Mantle Cell Lymphoma ◽  
Interim Analysis ◽  
Cell Lymphoma ◽  
Young Patients ◽  
Phase Iii ◽  
Rituximab Maintenance ◽  
Mantle Cell

Abstract The LyMa (ClinicalTrials.gov, NCT00921414) is a prospective randomised phase III trial conducted by the LYSA group (GOELAMS and GELA groups) and that assessed the potential benefit of Rituximab maintenance after autologous stem cell transplantation (ASCT) in young previously untreated Mantle Cell Lymphoma (MCL) patients (<66y). Patients were enrolled at times of diagnosis. All patients received 4 courses of R-DHAP followed by ASCT (patients who did not reach at least a PR after these 4 courses could receive 4 additional courses of R-CHOP). The conditioning regimen of ASCT was Rituximab (500mg/m2) plus BEAM. Patients achieving a complete or partial response after ASCT were then randomly assigned to receive 3 years of Rituximab maintenance therapy (375mg/m2, one injection every two months) or wait and watch (WW) (1:1). The primary endpoint was EFS at 4 years after randomization, EFS being defined as death of any cause, disease progression, severe allergic reaction to Rituximab or severe infection. PFS and OS were secondary objectives. Herein, we present the first planned interim analysis. Analysis was performed by intention to treat. From September 2008 to August 2012, 299 patients were included (one patient withdrawn his consent, data of one patient with incomplete data at time of the present analysis). Median age at registration was 57y (27-65) and 236 (78,9%) patients were male. MIPI score was low in 53,2% (n=159), intermediate in 27,4% (n=82) and high in 19,4% (n=58). In all, 257 (86%) patients proceeded to ASCT. The CR/CRu rates before and after ASCT were 81,4% and 92%, respectively. At the time of the present interim analysis, 58 patients died. With a median follow-up calculated from time of inclusion of 35.8 months, median PFS and OS are not reached. The estimates 3y-PFS and -OS are 73.7% (95%CI ; 67.8-78.7) and 82.6% (95%CI ; 77.3-86.8), respectively. Last randomization was done in February 2013. Two hundred and thirty eight patients were randomised: 119 patients were assigned to rituximab maintenance and 119 to WW. The mFU (n=238) calculated from date of randomization is 29.7 months. Median EFS and PFS are not reached : the 2y-EFS is 87.5% (95%CI ; 82.4-91.2) and 2y-PFS is 87.5% (95%CI ; 82.4-91.2). The EFS and PFS are statistically different between the treatment arms (p=0.015 for both) : the 2y-EFS is 93.2% (95%CI, 86.9-96.6) in the Rituximab arm versus 81.5% (95%CI, 72.7- 87.7) in the WW arm (HR=2.1). OS does not differ between the two groups. The 2y-OS is 93.4% (95%CI, 86.6-96.9) in the Rituximab arm versus 93.9% (95%CI, 86.7-97.3) in the WW arm. This planned interim analysis of the LyMa trial shows that a 3 years of rituximab maintenance after R-DHAP plus ASCT as first-line treatment for young patients with MCL significantly improves both EFS and PFS. Thus, as reported in elderly MCL, the Lyma trial demonstrates that Rituximab should be used in maintenance therapy after ASCT and provides the rational for a new standard of care in MCL. Disclosures Le Gouill: pfizer: Honoraria; mundipharma: Honoraria; roche: Honoraria; celgene: Consultancy, Honoraria; janssen-cilag: Honoraria.

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