ALBERT

Description: Abstract 2724 Background: The NHL 1 study, a prospective, multicenter, randomized, phase 3 study which compared B-R and CHOP-R as first-line treatment in indolent lymphomas and mantle cell lymphoma (MCL), demonstrated a significant benefit in progression-free survival (PFS) as well as improved tolerability for B-R compared with CHOP-R. Here we present an analysis of the impact of response quality on outcome. Methods: 514 patients (pts) with indolent or MCL were randomized to receive B-R or CHOP-R for a maximum of 6 cycles. Results: The overall response rate in the 514 pts (261 B-R; 253 CHOP-R) was 92.7% and 91.3% in the B-R and CHOP-R arms, respectively (as presented at the last ASCO meeting, J Clin Oncol 30, 2012 (suppl; abstr 3). A complete response (CR) was observed in 39.8% in the B-R arm and in 30% in the CHOP-R arm (p=0.021). The achievement of CR was associated with a significantly prolonged PFS and overall survival (OS) (Table 1). Analysis by treatment arm revealed a trend for superior PFS and a significantly improved OS for patients achieving CR following treatment with B-R. In the CHOP-R arm, patients in CR had a significantly superior PFS compared to those in PR with a trend to superior OS. Regardless of the quality of response, PFS was superior with B-R versus CHOP-R: For patients in CR, the median PFS was not reached with B-R, whereas for CHOP-R it was 53.7 months (p=0.0204). In patients achieving PR, treatment with B-R resulted in a median PFS of 57.2 months, and this was 30.9 months with CHOP-R (p=0.0002). We noted a statistically significant difference in CR rates between male (n=272, median age 63 years) and female (n=242, median age 64 years) patients. The CR rate was 28.6% in male patients and 42.1% in female patients (p=0.0016). Female patients had a longer median PFS (51.4 months) compared to male patients (38.6 months), however, this difference was not statistically significant (p=0.0866). Conclusions: Patients in CR following first-line treatment in our study had a significantly longer PFS and OS compared to those achieving a PR. Therefore, our results strongly suggest an association between quality of response and outcome. Disclosures: No relevant conflicts of interest to declare.

Description: 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.

Description: 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

Description: 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

Description: Abstract 3434 Introduction: Several clinical trials established treatment with horse ATG (hATG) and cyclosporine A (CsA) as standard treatment of AA in patients (pts) who are not candidates for stem cell transplantation (SCT). In 2007 the hATG brand Lymphoglobulin® was withdrawn from the market. As the hATG brand ATGAM®, is not approved in Europe, hATG was replaced by rabbit ATG (rATG). Recently a large prospective randomized one-center study from NIH, USA comparing hATG ATGAM®/CsA and rATG Thymoglobulin®/CsA in untreated AA showed significantly lower response rates and survival with rATG. To obtain further information on rATG treatment in an unselected AA population, especially with a higher median of age and use of different rATG dosages we performed a retrospective data collection of first line rATG therapy on several centers. This shall reflect outcome after rATG in a real-world situation. Methods: Retrospective data collection and analysis of first line rATG treatment of AA after approval by Ethical Committee. Results: Up to now retrospective data of 64 pts from 18 centres in Germany were analysed. Characteristics of the pts: 30 male, 34 female; median age at time of therapy 54 years (6–80 years); 87.5% of pts had idiopathic AA. 51.6% of pts had severe AA, 32.8% very severe AA and 15.6% non-severe AA. Median granulocyte count was 0.3 G/l. 86% of the pts required red blood cell and 92% platelet transfusions. 56 of the evaluable pts received Thymoglobulin® and 5 pts Fresenius ATG S®. 52 of the 56 Thymoglobulin®-treated pts got this therapy in the years 2007–2011, i.e. not as deliberate primary choice of rATG but because hATG was no longer available. Median daily dose of Thymoglobulin® was 3.5 mg/kg (range from 2.5 – 3.75 mg/kg) for 5 days. 62 of 64 pts received additional immunosuppressive therapy with CsA and 19 of 64 pts received G-CSF. The median follow-up for surviving pts was 558.5 days (range, 78–3800 days). Response rates at time of best response of pts were CR in 10/58 pts (17%), PR in 18/58 pts (31%) and NR in 30/58 pts (52%) (only surviving patients with a minimum follow-up of 120 days were analyzed). Median interval to best response was 217 days. Response rate (PR+CR) was 16/33 (48.5%) in pts who received a Thymoglobulin® dose of 〉 3.5 –3.75 mg/kg/day versus only 4/14 (28.6%) group of 14 pts with a dose of 〉 2.5 to 〈 3.5 mg/kg/day (p=0.17; Fisher`s exact test). Relapses occurred in 3/28 responders and clonal evolution was observed in 3 pts (2 PNH, 1 MDS). Eighteen of 63 evaluable pts received allogenic SCT after ATG-therapy and were censored at the date of SCT. 23% of 44 pts without SCT died. In 6 of these 10 pts death was caused by infections. Other causes of death were bleeding, cardiac event, acute respiratory distress syndrome, adynamia. Overall probability of survival at 3 years was 75.8% (95% confidence interval (CI): 61.8 – 89.9%) and survival censored for SCT was 79.9% (CI: 66.0–92.8%). Survival was significantly better in responders (PR and CR) (94.1% at 3 years; CI: 82.9–100%) than in non-responders (58.0% at 3 years; CI 34.0 – 81.3%) (p=0.04; log-rank test). Adverse events were reported in 79.4% of 63 evaluable pts consisting of anaphylaxis/allergy in 27.3%, serum sickness in 12.7%, fever/chills in 34.5%, and bacterial/viral/fungal infections in 54.5% of pts. Conclusion: Response rate and survival after rATG+CsA in this retrospective analysis is lower than in historical controls (e.g. hATG+CsA treatment in previous controlled studies of the German AA Study Group and the EBMT AA Working Party; Frickhofen et al., Blood 2003; Tichelli et al., Blood 2011) and rate of (early) infections seem to be high. Our results are in accordance with recent reports from other groups. Additionally the results of this retrospective data analysis suggest a benefit for the patient group treated with a Thymoglobulin® dosage of 〉 3.5 –3.75 mg/kg/day compared to lower doses (〈 3.5 mg/kg/day). There is growing evidence that best results in terms of response and survival are obtained by hATG-based immunosuppression. hATG can not be replaced by rATG without negative impact on patient outcome. There is need for action to achieve availability of hATG worldwide. If hATG is not available, treatment with rATG should be considered instead of no treatment or treatment with CsA alone since still about half of the patients respond to rATG. Disclosures: Höchsmann: Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Genzyme: Consultancy, Honoraria, Research Funding. Off Label Use: The use of the horse ATG ATGAM in Aplastic Anemia is off-label in Europe. At the moment no horse ATG with approval is available in Europe. Schrezenmeier:Genzyme: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria; Novartis: Consultancy, Research Funding.

Description: Abstract 335 Purpose. Standard chemotherapy for elderly patients with acute myeloid leukemia (AML) results in a median overall survival of only 60 years) patients with relapsed AML and shows low cardiac toxicity. The purpose of the randomized phase II study reported here was to compare the antileukemic activity of a standard combination of ara-C (100 mg/m2/day c.i., days 1–7) and DNR (60 mg/m2 i.v., on days 3–5) (7+3) versus ara-C plus GO (6 mg/m2 i.v. on days 1 and 8) (7+GO) as the first course of induction therapy in AML patients at the age of 60 years and older. Patients and Methods. On the basis of the data from the AMLCG (JCO 27: 61–69, 2009) the study was powered to detect an increase of median event free survival (EFS) from 90 to 160 days and a prolongation of the median overall survival (OS) from 9 to 〉16 months with a power of 80% (alpha= .05), in order to obtain information as a basis for potential further phase III randomized studies. Primary objectives of the study were the achievement of blast clearance (〈 5%) on day 16 after induction therapy onset and EFS. OS, complete response (CR) and tolerability were among the secondary objectives. 112 pts. entered the study, suffering from de novo AML, treatment-related secondary AML, AML with a history of MDS, and high-risk MDS. Median age of the patients was 69 years (range 60–83). Study protocol outlined a second induction course 7+3 in those pts. without blast clearance on day 16 and 2 courses of consolidation therapy with high-dose ara-C (1 g/m2 q 12 hours i.v., days 1, 3, 5) for patients in CR. We looked for balance of AML standard risk factors between both arms of the study. Results. The study was approved by the Ethical Board of the University of Muenster and the other participating institutions and written informed consent was obligatory by every pt. prior to entry on study. 58 pts. were randomized to induction therapy with 7+3 as the first course, whereas 54 pts. were randomized to receive 7+GO. All parameters evaluated are for the intent-to-treat population. There were no statistically significant differences between treatment arms in blast clearance (〈 5%) on day 16 after treatment onset (7+3: 18 pts., 7+GO: 19 pts.), complete response (CR) rate (7+3: 53.5%, 7+GO: 61.1%), EFS (median for 7+3: 67 days, median for 7+GO: 172 days), or OS (median for 7+3: 9 months, median for 7+GO: 15 months). Toxicity profiles of the protocols were different with 4 pts. developing severe veno-occlusive disease in the 7+GO group. Conclusion. The study did not show a significant advantage of 7+GO over 7+3 as the first course of induction treatment in elderly pts. with AML. Ara-C and GO and ara-C and DNR have comparable antileukemic activity as the first course of induction. Ara-C and GO may represent an alternative, replacing non-targeted anthracyclines for induction therapy of elderly AML patients e.g. with significant cardiac comorbidities. Disclosures: Berdel: Wyeth: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Mylotarg as first-line treatment in AML.