ALBERT

Beschreibung: Background: Promising results have been observed in our previous phase-II study evaluating the combination of Bendamustine plus Rituximab (B-R) in patients with relapsed/refractory indolent or mantle cell lymphomas. An overall response rate (ORR) of 90%, including a 60% rate of complete remissions (CR) was documented. Objective: In October 2003, we initiated a multicenter randomized phase-III study to compare efficacy and safety of the combination B-R versus CHOP plus Rituximab (CHOP-R) as first-line therapy for follicular, indolent and mantle cell lymphomas. Methods: Patients (pts) were randomized to receive Rituximab 375 mg/qm (day 1) plus either Bendamustine 90 mg/qm (days 1+2) every 28 days or the standard CHOP regimen every 21 days for a maximum of 6 cycles. The primary endpoint was event-free survival (EFS). The trial was calculated to power the study to demonstrate a non-inferior EFS associated with B-R treatment, as defined by a difference in EFS between the two regimes of less than 10% after 3 years. An event was defined by a response less than a partial response, disease progression, relapse, or death from any cause. The study is closed according to the planned recruitment schedule. Results: 546 patients have been randomized. For this second interim analysis, 437 patients are evaluable for response (B-R: n=221; CHOP-R: n=212). Median patient age is 64 years. Histologies are equally distributed between arms: follicular 52%, mantle cell 20%, and other indolent lymphomas 28% in both treatment groups, each. The ORR for pts treated with B-R was similar to that associated with CHOP-R (94% vs 93%, respectively). CR was also similar at 41% for B-R compared to 33% for CHOP-R. The median follow-up time for both groups is 28 months. Thus far, 50 deaths have been observed (B-R: 25; CHOP-R: 25). Progressive or relapsed disease has been documented during the follow-up period: 58 in pts treated with B-R and 75 in the CHOP-R group. The median EFS for B-R is not yet reached, the median EFS for CHOP-R is 39 months with no statistical significant difference for the EFS between both groups. The B-R regimen appears to have a better toxicity profile, as evidenced by a lower rate of total alopecia (0% with B-R vs. 89% CHOP-R) and a lower number of infectious complications (number of patients with infections of any grade were 56 (25%) in the B-R group vs. 78 (37%) in CHOP-R group). Correlating, the CHOP-R regimen was more hematotoxic: WHO grade 3/4 leukocytopenia was reported in 36% CHOP-R treated pts compared with 19% in pts treated with B-R, while in the CHOP-R group more frequently G-CSF was used. Conclusions: In this second interim analysis, the combination of Bendamustine plus Rituximab appears to be non-inferior to the standard CHOP-R while showing a better tolerability profile. Further updated results will be presented at this time.

Beschreibung: 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

Beschreibung: Introduction. Autologous stem cell transplantation (ASCT) after cytoreductive induction is considered standard of care for younger patients (pts) with multiple myeloma (MM). However, 40% of pts fail to achieve remission to standard cytotoxic regimens obviously necessitating improvement. Bortezomib (Vel) is considered the most potent single agent MM therapy. Bortezomib-containing induction treatments have already been shown to be superior to vincristine, adriamycine, and dexamethasone. Methods. As previously reported, 30 pts were included in the dose finding study to determine the optimum dose of intravenous cyclophosphamide (C) in conjunction with Vel and dexamethasone (D). Here we report on the results of the planned interim analysis with an additional 70 pts up to 60 years of age with untreated MM. They were enrolled between 03/2006 and 03/2008 to receive a maximum of 3 three-week cycles of induction treatment with Vel 1.3 mg/m2 IV d1,4,8,11; D 40 mg/d d1,2,4,5,8,9,11,12; and C 900mg/m2 IV d1 before scheduled ASCT as a consolidation. Primary study objective is response rate (≥ PR) to VelCD before ASCT according to the stringent EBMT criteria. Results. Data from the first consecutively completed 100 pts (mean age, 52 years; 78% stage III) from 22 German centers were analyzed. Molecular cytogenetic analysis was available for 79% with the most frequent cytogenetic abnormalities being 13q− (34%), 17p− (14%) and t[4;14] (8%). All 100 pts (84% of whom completed three cycles) were included in the intent-to-treat analysis. Overall response rate was 79% with 11% CR and 68% PR + VGPR; only 2 subjects (2%) progressed. Typically VAD induces app. 60% response. Additionally, response by cytogenetic risk group was assessed. Response was documented in 73.5% of the subjects with 13q−, in 100% with t(4;14) and in 57.1% with 17p−. 42 SAEs were reported: 18 pts had a SAE associated with Vel, 17 had a SAE associated with C, and for 10 pts SAE associated with D was established. One patient died due to gastric hemorrhage possibly related to dexamethasone. This is a remarkably low rate of early deaths (1%) in this setting. 53% of the patients experienced grade 3 + 4 AE with leucopenia (34%), thrombocytopenia (6%), neutropenia (5%), anaemia (4%), nausea (3%) and bone pain (3%) being the most frequent. Infections of grade 3 and 4 have been reported in 2% and a low incidence of grade 3 (2%) but no grade 4 paraesthesia occurred while 13% of pts developed peripheral neuropathy (only of grades 1 and 2). Conclusion. This analysis demonstrates Bortezomib combined with D and intravenous C is a highly effective treatment regimen regardless of cytogenetic risk factors for newly diagnosed MM with acceptable toxicity. Given the importance of high-quality response prior to ASCT, VelCD is considered a very active induction regimen. Table 1. Response to study therapy (intent-to-treat set, n=100) Response to VelCD n (%) CR 11 PR + VGPR 68 MR 8 SD 11 PD 2 Table 2. Response by result of cytogenetic analysis (intent-to-treat set, n=100) Responding patients (≥ PR) N % No FISH abnormality 15/17 88.2 13q− 25/34 73.5 t(4;14) 8/8 100 17p− 8/14 57.1 Other 26/29 89.7