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OBJECTIVE A post hoc subgroup analysis of two phase III trials (NCT00416273, NCT00416208) was carried out to investigate the influence of 100/140 and 200 mg/m² melphalan as well as single/double autologous stem cell transplantation (ASCT) on progression-free survival (PFS). Additionally, the effect of bortezomib consolidation on PFS was analyzed. METHODS Following induction therapy and high-dose melphalan with subsequent ASCT, patients with newly diagnosed multiple myeloma (NDMM) were randomized 1:1 to either four 35-day cycles of bortezomib consolidation (1.6 mg/m² IV on days 1, 8, 15, 22) or observation. RESULTS Of the 340 patients included in this analysis, 13.5% received 1 × MEL100/140, 22.9% 2 × MEL100/140, 31.2% 1 × MEL200, and 32.4% 2 × MEL200. With higher cumulative melphalan dose, PFS improved (P = .0085). PFS curves of patients treated with 2 × MEL100/140 and 1 × MEL200 were very similar. The superior dose effect of MEL200 over MEL100/140 was non-existent in the bortezomib consolidation arm but pronounced in the observation arm (P = .0015). Similarly, double ASCT was only beneficial in patients without bortezomib consolidation (P = .0569). CONCLUSIONS Full dose melphalan and double transplantation seem advantageous only as long as patients are not receiving bortezomib consolidation afterwards.

No abstract available.

The prospective randomized Positron Emission Tomography (PET)-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial was designed to test the ability of interim PET (iPET) to direct therapy. As reported previously, outcome remained unaffected by iPET-based treatment changes. In this subgroup analysis, we studied the prognostic value of baseline total metabolic tumor volume (TMTV) and iPET response in 76 patients with T-cell lymphoma. TMTV was measured using the 41% maximum standardized uptake value (SUV41max) and SUV4 thresholding methods. Interim PET was performed after two treatment cycles and evaluated using the ΔSUVmax approach and the Deauville scale. Because of significant differences in outcome, patients with anaplastic lymphoma kinase (ALK)-positive lymphoma were analyzed separately from patients with ALK-negative lymphoma. In the latter, TMTV was statistically significantly correlated with progression-free survival, with thresholds best dichotomizing the population, of 232 cm3 using SUV41max and 460 cm3 using SUV4. For iPET response, the respective thresholds were 46.9% SUVmax reduction and Deauville score 1-4 vs 5. The proportion of poor prognosis patients was 46% and 29% for TMTV by SUV41max and SUV4, and 29% and 25% for iPET response by ΔSUVmax and Deauville, respectively. At diagnosis, the hazard ratio (95% confidence interval) for poor prognosis vs good prognosis patients according to TMTV was 2.291 (1.135-4.624) for SUV41max and 3.206 (1.524-6.743) for SUV4. At iPET, it was 3.910 (1.891-8.087) for ΔSUVmax and 4.371 (2.079-9.187) for Deauville. On multivariable analysis, only TMTV and iPET response independently predicted survival. Patients with high baseline TMTV and poor iPET response (22% of the population) invariably progressed or died within the first year (hazard ratio, 9.031 [3.651-22.336]). Due to small numbers and events, PET did not predict survival in ALK-positive lymphoma. Baseline TMTV and iPET response are promising tools to select patients with ALK-negative T-cell lymphoma for early allogeneic transplantation or innovative therapies.

Early results of the randomized placebo-controlled SORAML trial showed that, in patients with newly diagnosed acute myeloid leukaemia (AML), sorafenib led to a significant improvement in event-free (EFS) and relapse-free survival (RFS). In order to describe second-line treatments and their implications on overall survival (OS), we performed a study after a median follow-up time of 78 months. Newly diagnosed fit AML patients aged ≤60 years received sorafenib (n = 134) or placebo (n = 133) in addition to standard chemotherapy and as maintenance treatment. The 5-year EFS was 41 versus 27% (HR 0.68; p = 0.011) and 5-year RFS was 53 versus 36% (HR 0.64; p = 0.035). Allogeneic stem cell transplantation (allo SCT) was performed in 88% of the relapsed patients. Four years after salvage allo SCT, the cumulative incidence of relapse was 54 versus 35%, and OS was 32 versus 50%. The 5-year OS from randomization in all study patients was 61 versus 53% (HR 0.82; p = 0.282). In conclusion, the addition of sorafenib to chemotherapy led to a significant prolongation of EFS and RFS. Although the OS benefit did not reach statistical significance, these results confirm the antileukaemic activity of sorafenib.

Objective A post hoc analysis of two phase III trials was carried out to explore the influence of age and treatment factors on the effect of bortezomib consolidation on progression-free survival (PFS) post autologous stem cell transplantation (ASCT). Methods Patients with newly diagnosed multiple myeloma were assigned to one of two trials (ClinicalTrials.gov IDs: NCT00416273, NCT00416208), which were conducted in parallel, based on age (18-60 or 61-75 years, respectively). Following induction and ASCT, patients were randomized 1:1 to four 35-day cycles of bortezomib consolidation (1.6 mg/m2 IV on days 1, 8, 15, 22) or observation only. Results Median PFS with bortezomib consolidation vs observation was 33.6 vs 29.0 months (P = 0.3599) in patients aged 18-60 years (n = 202), and 33.4 vs 26.4 months (P = 0.0073) in patients aged 61-75 years (n = 155), respectively. Bortezomib consolidation post-ASCT appeared to equalize outcomes between older and younger patients who received prior treatment of differing intensity. This suggests that the effect of consolidation may be relative and may depend on the composition and intensity of induction and high-dose therapy. Conclusion Older patients receiving less intensive prior treatment could experience a larger PFS benefit from bortezomib consolidation.

Background: Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) helps to prevent excess toxicity. Patients (pts) from two prospective trials were analyzed, provided postinduction (PInd) restaging was performed. Pts received three cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex, VCD) or btz, lenalidomide (len), and dex (VRd) or len, adriamycin, and dex (RAD). The minimum required estimated glomerular filtration rate (eGFR) was &gt, 30 mL/min. We analyzed the percent change of the renal function using the International Myeloma Working Group (IMWG) criteria and Kidney Disease: Improving Global Outcomes (KDIGO)-defined categories. Results: Seven hundred and seventy-two patients were eligible. Three hundred and fifty-six received VCD, 214 VRd, and 202 RAD. VCD patients had the best baseline eGFR. The proportion of pts with eGFR &lt, 45 mL/min decreased from 7.3% at baseline to 1.9% PInd (p &lt, 0.0001). Thirty-seven point one percent of VCD versus 49% of VRd patients had a decrease of GFR (p = 0.0872). IMWG-defined “renal complete response (CRrenal)” was achieved in 17/25 (68%) pts after VCD, 12/19 (63%) after RAD, and 14/27 (52%) after VRd (p = 0.4747). Conclusions: Analyzing a large and representative newly diagnosed myeloma (NDMM) group, we found no difference in CRrenal that occurred independently from the myeloma response across the three regimens. A trend towards deterioration of the renal function with VRd versus VCD may be explained by a better pretreatment “renal fitness” in the latter group.

Korrektur zu 10.1038/s41375-020-0826-9

© 2018 The Authors., [Background]: The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients. [Patients and Methods]: Adult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months., [Results]: A total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide., [Conclusion]: The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits., Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc.

Summary We assessed the safety and efficacy of bortezomib, cyclophosphamide and dexamethasone (VCD) induction therapy in previously untreated multiple myeloma patients. A total of 414 patients received three 21-day cycles of VCD prior to autologous stem-cell transplantation (ASCT). Most common grade ≥3 adverse events were leucopenia (31·4%) and thrombocytopenia (6·8%). The overall response rate (ORR) by investigator-based assessment was 85·4%. Most patients (74%) underwent successful central laboratory-based molecular cytogenetic analysis. No clinically relevant differences in ORR post-induction were seen between patients with or without high-risk cytogenetic abnormalities (86·2% vs. 84·3%). Further follow-up data are available for 113 patients receiving ASCT who were included in a prospective consolidation trial (median follow-up, 55·5 months); median progression-free survival (PFS) was 35·3 months and median overall survival (OS) was not reached. In patients with high-risk versus standard-risk cytogenetics, median PFS was 19·9 vs. 43·6 months (P

Response-adapted consolidation with bortezomib after ASCT improves progression-free survival in newly diagnosed multiple myeloma

Introduction High-dose chemotherapy and stem cell transplant (SCT) remains a standard of care in medically fit patients (pts) with newly diagnosed (ND) MM. Induction triplets with at least one of the newer compounds are recommended. Bortezomib (V), lenalidomide (R) and dexamethasone (D; VRD) ranks among the most effective regimens and VRD/SCT was superior to VRD alone in an RCT. In a phase 2 study, we demonstrated RAD induction (lenalidomide 25 mg d1-21; Adriamycin 9 mg/m2 iv d1-4; dexamethasone 40 mg d 1-4 and 17-20 every 4 weeks) followed by SCT to be safe and effective (Knop et al., Leukemia 2017). Therefore, we decided to compare RAD versus (vs) VRD (lenalidomide 25 mg, d1-14; subcutaneous bortezomib 1.3 mg/m2 d 1, 4, 8, 11; dexamethasone 20 mg d 1+2, 4+5, 8+9, 11+12 every 3 weeks) induction (3 cycles each) in an RCT. MethodsThe current study was set up according to a double 2x2-factorial design to enrol transplant-eligible pts up to 65 years. The post-induction (PI) complete response (CR) rate as per IMWG criteria was the efficacy co-primary endpoint. We hypothesized the CR rate following RAD to be non-inferior to VRD which was estimated to be 20%. The study was powered to confirm non-inferiority of RAD at a margin of 10% with a one-sided alpha level of .05. Cytogenetic characterization was performed by fluorescence in situ hybridization (FISH) from CD138-enriched plasma cells. Minimal residual disease (MRD) was assessed by second-generation eight-color flow cytometry (FC; EuroFlow protocol). Bone marrow (BM) samples from baseline and defined restaging time points were analyzed for an acquisition of ⩾107cells/sample. In a subgroup of 103 pts, we evaluated the applicability of comprehensive immunoglobulin (Ig) amplicon next generation sequencing (NGS) to detect molecular MRD markers and to compare the results with FC. NGS-based marker screening was performed in baseline BM. Sequencing libraries were prepared using 2-step PCR employing multiplex primer sets for IGH V-D-J (FR1, FR2 and FR3), IGH D-J and IGK loci (V-J and KDe). For MRD detection, we used 1-step library preparation with the same primer sets. Results476 pts with a median age of 55 (range, 32-65) years were randomized between 05/2012 and 06/2016 and 469 received at least one dose of study drug. High-risk (HR) FISH abnormalities comprised del17p (11.3% of pts); t(4;14) (11.7%); and t(14;16) (4.5%). 232 pts were randomized to receive RAD, and 237 to VRD, respectively. 90.5% of RAD vs 93.7% of VRD pts completed all 3 cycles. PI CR rate was 13.5% (95% CI, 9.4%-18.7%) with RAD vs 13.4% (95% CI, 9.3-18.5) with VRD, (P=.971). Rates of ≥VGPR were 40.6% (50% CI, 34.2%-47.3%) with RAD vs 48.9% (95% CI, 42.3-55.6%) with VRD (P=.076). In pts with HR cytogenetics, rates of ≥VGPR were 43.3% (RAD) vs. 59.3% (VRD; P=.096). From 317 pts with paired samples, 33/151 (21.9%) of RAD vs 45/166 (27.1%) of VRD pts were FC MRD negative (P=.169) following induction at a median sensitivity level of 6.73x10-6. 197/239 positive pts (82.4%%) had MRD levels above 0.01%, and 42 (17.6%), between 0.0001 and 0.01%. Flow MRD negativity as per IMWG MRD criteria (Kumar et al, Lancet Oncol 2016) was seen in 8/151 (5.2%) pts with RAD vs 6/166 (3.6%) with VRD (P=.27). The remainder of pts did not (yet) fulfil IMWG CR for various reasons. NGS marker screening identified at least 1 Ig marker in 98/103 evaluable patients. To date, 47/98 pts were analyzed for NGS MRD following induction. Four out of 47 (8.5%) subjects were sequencing negative (3/4 post-VRD) with all of them also being IMWG FC MRD negative. One VRD patient died during induction for a mortality rate of 0.2 %. 62.1% of RAD vs 55.3% of VRD pts experienced at least one serious adverse event (SAE; p=.16). SAEs with relationship to study drugs of at least °3 severity occurred in 26.3% (RAD) vs 23.6% (VRD) pts (p=.523). ConclusionsTo the best of our knowledge, this is the first RCT to compare two R-based triplets in SCT-eligible pts. The co-primary efficacy endpoint was met with identical PI CR rates of around 13% for RAD and VRD, respectively. However, a trend emerges to favor VRD over RAD in terms of at least VGPR including HR FISH subjects. Analysis of MRD by multicolor FC showed 5% of pts to be already IMWG flow MRD-negative. Results for all 98 pts evaluable for NGS MRD will be presented. As of yet, too few progression events have occurred to estimate the second co-primary endpoint, 3-year progression-free survival. Longitudinal response and MRD analysis are ongoing. Disclosures Langer: Celgene: Consultancy. Mügge:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Honoraria. Blau:Amgen: Other: Advisory board; BMS: Other: Advisory board; Novartis: Other: Advisory boards; Takeda: Other: Advisory board; Janssen: Other: Advisory board, Research Funding; Celgene: Other: Advisory board, Research Funding. Rollig:Janssen: Research Funding; Bayer: Research Funding. Dechow:AMGEN: Consultancy; Celgene: Honoraria. Gramatzki:Affimed: Research Funding. Brümmendorf:Merck: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Schmidt:Gilead: Honoraria, Other: Travel Grants; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Honoraria. Knop:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

Background: The addition of sorafenib to standard induction and consolidation therapy in newly diagnosed patients (pts) ≤60 years (yrs) with acute myeloid leukemia (AML) led to significant prolongation of event-free survival (EFS) and relapse-free survival (RFS) in the randomized placebo-controlled SORAML trial (NCT00893373). After a median follow-up of 3 yrs, a benefit for sorafenib treated pts was observed also in overall survival (OS), but this difference was not significant. Here, we present updated survival data and information on relapse treatment and outcome. Methods: In the SORAML trial, 267 newly diagnosed untreated fit AML pts up to 60 yrs of age and irrespective of FLT3 mutation status received two cycles of induction chemotherapy with DA (daunorubicin 60 mg/m2 days 3-5 plus cytarabine 100 mg/m2 cont. inf. days 1-7), followed by three cycles of high-dose cytarabine consolidation (3 g/m2 b.i.d. days 1, 3, 5). Allogeneic stem cell transplantation (SCT) was scheduled for all intermediate-risk pts in first complete remission (CR) with a sibling donor and for all high-risk pts with a matched related or unrelated donor. At study inclusion, pts were randomized to receive either sorafenib (2x400 mg/day) or placebo as add-on to standard treatment in a double blinded fashion. Study medication was given on days 10-19 of DA I+II, from day 8 of each consolidation until 3 days before the start of the next consolidation and as maintenance for 12 months (mos) after the end of consolidation. The primary endpoint of the trial was EFS. The results after follow-up of 3 yrs were presented at ASH 2014 (Röllig et al., Blood 2014; 124: 6) and fully published (Röllig et al., Lancet Oncol 2015; 16: 1691-9). Here, we present the results after prolonged follow-up. For this analysis, information on remission and survival status, mode and outcome of relapse treatment including SCT were collected for all randomized pts and analyzed by standard statistical methods. Results: Of 267 treated pts, 134 were randomized in the sorafenib arm and 133 in the placebo arm with a resulting CR rate of 60% and 59%, respectively. After a median observation time of 78 mos, the primary study endpoint EFS in the placebo vs sorafenib arm was 9 mos vs 26 mos (HR 0.68, p=0.01) in univariate Kaplan Meier analysis. The beneficial effect of sorafenib on EFS was confirmed in multivariate Cox regression analysis with a HR of 0.61 (p=0.005). Median RFS in the placebo vs sorafenib arms was 22 vs 63 mos, corresponding to a HR of 0.64 (p=0.033). Exploratory analyses were performed in the 70 relapsing pts (40 after placebo vs 30 after sorafenib treatment). Among relapsing pts, 82% vs 73% achieved a second CR. In these two groups, 88% and 87% of pts received a SCT as part of salvage treatment. A lower proportion of pts in the placebo arm received a second SCT as salvage treatment (5% vs 13%). In the context of salvage SCT, the proportion of haploident donors in the placebo and sorafenib group was 3% vs 15% and the incidence of Grade 3/4 GVDH was 17% vs 0%. SCT-related non-relapse mortality (NRM) was similar in both groups, but the cumulative incidence of second relapse (CIR) was higher in the sorafenib group (35% vs 54% after 48 mos). Therefore, median OS from relapse in the placebo vs sorafenib groups were 27 mos vs 10 mos, corresponding to a HR of 1.68 (p=0.098). The projected median OS from randomization is 83 mos in the placebo arm and was not reached for the sorafenib arm, corresponding to a 5-year OS of 52% vs 61% (HR 0.81, p=0.263). Conclusion: Mature follow-up data confirms the antileukemic efficacy of sorafenib in younger AML pts with and without FLT3 mutation. The addition of sorafenib to standard chemotherapy resulted in a significantly longer EFS and clinically relevant 36% risk reduction for relapse or death. Five pts need to be treated (NNT) to prevent one relapse or death at 3 years and six pts at 5 yrs. Exploratory analyses in relapsing pts show that survival after relapse is shorter after sorafenib which might be due to i) a higher rate of second SCTs and a higher incidence of haploidentical SCT despite the lower frequency of severe GVHD, most likely by chance and not explainable by systematic reasons and ii) a lower response to salvage treatment after sorafenib therapy. Despite these observations, primary sorafenib treatment led to an OS benefit with a 19% risk reduction for death which was not statistically significant since this phase II trial was not adequately powered to detect OS differences. Figure Figure. Disclosures Rollig: Bayer: Research Funding; Janssen: Research Funding. Hüttmann: Gilead, Amgen: Other: Travel cost; Bristol-Myers Squibb, Takeda, Celgene, Roche: Honoraria. Giagounidis: Acceleron: Consultancy; Celgene: Consultancy. Mackensen: AMGEN: Research Funding. Hänel: Roche: Honoraria; Novartis: Honoraria. Thiede: Roche: Consultancy; Novartis: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Agendix: Employment. Schetelig: Sanofi Aventis: Consultancy, Research Funding; Roche: Honoraria; Abbvie: Honoraria; Janssen: Consultancy, Honoraria.

Summary Background Preclinical data and results from non-randomised trials suggest that the multikinase inhibitor sorafenib might be an effective drug for the treatment of acute myeloid leukaemia. We investigated the efficacy and tolerability of sorafenib versus placebo in addition to standard chemotherapy in patients with acute myeloid leukaemia aged 60 years or younger. Methods This randomised, double-blind, placebo-controlled, phase 2 trial was done at 25 sites in Germany. We enrolled patients aged 18–60 years with newly diagnosed, previously untreated acute myeloid leukaemia who had a WHO clinical performance score 0–2, adequate renal and liver function, no cardiac comorbidities, and no recent trauma or operation. Patients were randomly assigned (1:1) to receive two cycles of induction therapy with daunorubicin (60 mg/m 2 on days 3–5) plus cytarabine (100 mg/m 2 on days 1–7), followed by three cycles of high-dose cytarabine consolidation therapy (3 g/m 2 twice daily on days 1, 3, and 5) plus either sorafenib (400 mg twice daily) or placebo on days 10–19 of induction cycles 1 and 2, from day 8 of each consolidation, and as maintenance for 12 months. Allogeneic stem-cell transplantation was scheduled for all intermediate-risk patients with a sibling donor and for all high-risk patients with a matched donor in first remission. Computer-generated randomisation was done in blocks. The primary endpoint was event-free survival, with an event defined as either primary treatment failure or relapse or death, assessed in all randomised patients who received at least one dose of study treatment. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00893373, and the EU Clinical Trials Register (2008-004968-40). Findings Between March 27, 2009, and Nov 28, 2011, 276 patients were enrolled and randomised, of whom nine did not receive study medication. 267 patients were included in the primary analysis (placebo, n=133; sorafenib, n=134). With a median follow-up of 36 months (IQR 35·5–38·1), median event-free survival was 9 months (95% CI 4–15) in the placebo group versus 21 months (9–32) in the sorafenib group, corresponding to a 3-year event-free survival of 22% (95% CI 13–32) in the placebo group versus 40% (29–51) in the sorafenib group (hazard ratio [HR] 0·64, 95% CI; 0·45–0·91; p=0·013). The most common grade 3–4 adverse events in both groups were fever (71 [53%] in the placebo group vs 73 [54%] in the sorafenib group), infections (55 [41%] vs 46 [34%]), pneumonia (21 [16%] vs 20 [14%]), and pain (13 [10%] vs 15 [11%]). Grade 3 or worse adverse events that were significantly more common in the sorafenib group than the placebo group were fever (relative risk [RR] 1·54, 95% CI 1·04–2·28), diarrhoea (RR 7·89, 2·94–25·2), bleeding (RR 3·75, 1·5–10·0), cardiac events (RR 3·46, 1·15–11·8), hand-foot-skin reaction (only in sorafenib group), and rash (RR 4·06, 1·25–15·7). Interpretation In patients with acute myeloid leukaemia aged 60 years or younger, the addition of sorafenib to standard chemotherapy has antileukaemic efficacy but also increased toxicity. Our findings suggest that kinase inhibitors could be a useful addition to curative treatment for acute myeloid leukaemia. Overall survival after long-term follow-up and strategies to reduce toxicity are needed to determine the future role of sorafenib in treatment of this disease. Funding Bayer HealthCare.

Purpose The aim of this multicenter-study was to evaluate the progression-free survival, response rate and toxicity of the combination of bendamustine and rituximab (BR) in patients with mantle cell or low-grade lymphomas in first to third relapse or refractory to previous treatment. Patients and Methods A total of 245 courses (median, four courses per patient) were administered to 63 patients. Bendamustine was given at a dose of 90 mg/m2 as a 30-minute infusion on days 1 and 2, combined with 375 mg/m2 rituximab on day 1, for a maximum of four cycles every 4 weeks. Histologies were 24 follicular, 16 mantle cell, 17 lymphoplasmacytoid, and six marginal zone lymphoma. Results Fifty-seven of 63 patients responded to BR, corresponding to an overall response rate of 90% (95% CI, 80% to 96%) with a complete remission rate (CR) of 60% (95% CI, 47% to 72%). The median time of progression-free survival was 24 months (range, 5 to 44+ months), and the median duration of overall survival has not yet been reached. In mantle cell lymphomas, BR showed a considerable activity, achieving a response rate of 75% (95% CI, 48% to 93%) with a CR rate of 50%. Myelosuppression was the major toxicity, with 16% grade 3 and 4 leukocytopenia. Thrombocytopenia was rare, with only 3% grade 3 and 4. Conclusion These results demonstrate that the BR combination is a highly active regimen in the treatment of low-grade lymphomas and mantle cell lymphomas.

Background: We investigated the combination of docetaxel and cisplatin as first-line chemotherapy in patients with metastatic esophageal cancer. Patients and Methods: 16 chemotherapy-naive patients with distant metastases were included in the study (15 male, 1 female; median age: 58.5 years (range 37-69); median ECOG performance status: 1). 11 patients (69%) had esophageal cancer, and 5 patients (31%) had cancer of the gastroesophageal junction. Patients received docetaxel 75 mg/m2 and cisplatin 80 mg/m2 on day 1 every 3 weeks. A total of 55 chemotherapy cycles was administered. The median number of cycles was 3 (range 1-6). Results: The overall response rate was 31.3%. 4 out of 10 patients (40%) with squamous cell carcinoma and 1 out of 5 patients (20%) with adenocarcinoma responded to chemotherapy. The median overall survival was 29.6 weeks, and the median progression-free survival was 18.6 weeks. Hematological and non-hematological toxicities were moderate (neutropenia WHO grade III/IV: 42.9%, alopecia grade II/III: 64.3%, nausea/vomiting grade II/III: 57.2%, neurotoxicity grade II: 14.3%). Conclusion: The combination of docetaxel and cisplatin is an active regimen with moderate toxicity in the treatment of patients with metastatic esophageal cancer. This pilot study demonstrates the feasibility of a combination treatment containing a taxane and cisplatin in metastatic esophageal cancer.

The aim of this pilot study was to evaluate the activity and toxicity of docetaxel plus carboplatin as second-line treatment in patients with metastatic non-small cell lung cancer (NSCLC). Patients received docetaxel 75 mg/m 2 followed by carboplatin AUC 5 on day 1 every 3 weeks in an out-patient setting. Twenty-six patients were enrolled; 23 patients were diagnosed stage IV disease and three patients had a IIIB disease with malignant pleural effusion. The median interval from first to second-line treatment was 3.5 months (range 1–13). Patients received a total of 101 cycles with a median number of four cycles per patient (range 1–6). Five patients achieved a partial remission (19.23%; 95% confidence interval (CI) 6.55–39.35%), 11 had stable disease (42.31%) and ten progressed (38.46%) after initiation of second-line therapy. Median survival was 243 days (95% CI 182–336 days), the median progression-free survival was 118 days (95% CI 89–170 days), and the 1-year survival rate was 25.98% (95% CI 6.33–45.63%). Moderate haematological and mild nonhaematological toxicities were observed. No treatment-related death occurred. In conclusion, docetaxel plus carboplatin as second-line regimen has a reasonable activity with good tolerance and encouraging survival data.

The purpose of this phase II trial was to investigate the efficacy and safety of a combination chemotherapy with gemcitabine, vinorelbine and cisplatin in the first-line treatment of advanced non-small cell lung cancer (NSCLC). Patients with NSCLC stage IIIB or IV disease received 1000 mg/m 2 gemcitabine and 25 mg/m 2 vinorelbine on days 1 and 8 and 75 mg/m 2 cisplatin on day 2, every 3 weeks. From December 1998 to May 1999, 31 patients (21 stage IV and 10 stage IIIB disease), with a median age of 59 years (range 40–72 years) were enrolled. The overall intent-to-treat response rate was 45% (95% confidence interval (CI): 27–64%) with 2 complete responders (CR) and 12 partial responders (PR), 7 patients had stable disease and 10 progressed. Median survival was 12.8 months (95% CI: 6.5–12.8+ months), median time to progression was 5.1 months (95% CI: 3.5–7.7 months), and the 1-year survival rate was 52.9% (95% CI: 36.7–76.2%). Patients with stage IIIB disease had a significantly longer overall survival than patients with stage IV disease ( P =0.05). Transient World Health Organization (WHO) grade IV leucopenia, anaemia and thrombocytopenia occurred in 3 (10%), 2 (6%) and 3 (10%) patients, respectively. The predominant non-haematological toxicities were alopecia and nausea/vomiting. 15 patients (48%) had WHO grade II and III alopecia and 14 patients (45%) nausea/vomiting. The combination of gemcitabine, vinorelbine and cisplatin has demonstrated major antitumour efficacy in advanced NSCLC with a manageable toxicity profile.

7501 Background: This multicenter, randomized, phase III study compared B-R and CHOP-R as first-line treatment in patients (pts) with indolent lymphomas or mantle cell lymphoma and was first published in The Lancet in 2013. The final analysis demonstrated a significantly prolonged progression-free survival (PFS) in the B-R group compared to the CHOP-R group, with a median PFS of 69.5 vs. 31.2 months, respectively. In the current analysis, we present updated results for overall survival (OS), time-to-next-treatment (TTNT), and secondary malignancies (sNPL) with a median follow-up of 113 months for patients with indolent lymphomas (excluding MCL). Methods: 447 pts with indolent lymphomas were randomized to receive B-R or CHOP-R for a maximum of 6 cycles. The primary endpoint was PFS; secondary endpoints included OS, TTNT, and sNPL. Results: Patient characteristics were well balanced between arms; median age was 64 years. The difference in OS between the two treatment arms was not statistically significant, with 60 deaths in the B-R group vs 68 deaths with CHOP-R (HR 0.82, 95% CI 0.58 – 1.15, p = 0.249). The estimated 10-year survival rates were 71% for B-R and 66% for CHOP-R. TTNT was significantly prolonged with B-R compared with CHOP-R (HR 0.52, 95% CI 0.38 – 0.69, p < 0.001). Median TTNT was not yet reached in the B-R group (95% CI 124.9 – n.y.r) vs. 56 months in the CHOP-R group (95% CI 39.1 – 82.0). Patients treated initially with B-R needed fewer second-line treatments due to disease progression compared to CHOP-R treated pts: 73 pts (34%) in the B-R group received salvage treatment compared with 106 pts (52%) in the CHOP-R group. For B-R pts, CHOP-R was used as second-line therapy 26 times (36%), whereas B-R was used for pts initially treated with CHOP-R 49 times (46%). 36 pts with sNPL were observed in the B-R group compared with 39 in the CHOP-R group, with 7 hematological malignancies in both groups to date. Conclusions: In pts with previously untreated indolent lymphomas, B-R demonstrates a PFS and TTNT benefit over CHOP-R. Clinical trial information: NCT00991211.

The purpose of this phase II study was to investigate the efficacy and safety of gemcitabine plus vinorelbine as first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Eligibility criteria included cytologically or histologically confirmed NSCLC (stage IIIB or IV), no previous chemotherapy, and bidimensionally measurable disease. Patients received 1000 mg/m2 gemcitabine and 30 mg/m2 vinorelbine on days 1, 8 and 15 every 4 weeks up to eight courses. From December 1997 to November 1998, 70 patients (59 stage IV and 11 stage IIIB disease), with a median age of 59 years (range 38–74 years) were enrolled. The intent-to-treat response rate was 41% (95% confidence interval (CI) 30–54%) with 1 complete responder (CR) and 28 partial responders (PRs), 15 patients had stable disease (SD) and 26 progressed (PD). Median survival was 8.3 months (95% CI 6.0–9.9 months), median progression-free survival (PFS) was 4.8 months (95% CI 3.9–5.5 months), and 1-year survival rate was 33.5% (95% CI 24.0–46.8%). Patients received a total of 229 cycles. Haematological and non-haematological toxicities were moderate. Transient World Health Organization (WHO)-grade IV leucopenia and thrombocytopenia occurred in 13 (6%) and two (1%) cycles, respectively. The predominant non-haematological toxicity was local reactions of the veins in 19 (27%) patients (WHO-grade II and III). Neurotoxicity was infrequent, non-cumulative, and reversible. The combination of gemcitabine and vinorelbine has demonstrated activity in metastatic NSCLC, with response and survival rates similar to those of cisplatin-based regimens and a more favourable toxicity profile that is well tolerated in an outpatient setting.

Background High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the established standard-of-care for patients with newly diagnosed multiple myeloma (NDMM) who are young and/or fit. The number of older patients receiving HDT-ASCT is increasing, although they often receive lower-intensity treatment. Novel agent-based consolidation therapy can be used to improve responses following ASCT and prolong progression-free survival (PFS). The proteasome inhibitor bortezomib, given as post-ASCT consolidation therapy, resulted in an improved PFS compared with observation alone (median 33.6 vs 27.8 months, adjusted hazard ratio [HR] 0.70, p=0.0058) in a combined analysis of two phase 3 trials (MMY3012 [DSMM XIb; NCT00416273] and MMY3013 [DSMM X; NCT00416208]; JCO 2015;33:8511). These studies enrolled 222 patients aged ≤60 years and 158 aged >60 years. In this post-hoc analysis we investigated the effect of age and related treatment factors on PFS in more detail. Methods In both trials, 371 patients were randomized 1:1 following ASCT to receive four 35-day cycles of bortezomib consolidation (n=186; bortezomib 1.6 mg/m2 IV administered on days 1, 8, 15, and 22) or observation (n=185; no treatment). The primary endpoint was PFS from the start of induction chemotherapy. Response and progression were assessed at the start of each bortezomib cycle and at the end-of-treatment/observation visit (week 25), as well as during the follow-up period of 30-60 months. Patient characteristics and treatments were compared between trials; PFS following randomization was assessed separately for each study. Univariate, bivariate, and multivariate Cox regressions were conducted to evaluate the impact of treatment group, age (≤60 vs >60 years), single vs tandem ASCT, melphalan conditioning dose (MEL Results A number of relevant factors were different between age groups (median age in ≤60 group 53 years vs 66 years in >60 group), including the HDT regimen received (MEL100 7% vs 10%; MEL140 3% vs 59%; MEL200 88% vs 31%). The rate of double transplantation was similar for the younger and older cohorts (55% vs 59%), likely due to the older patients receiving age-adjusted high-dose melphalan with a lower toxicity, allowing a similar rate of double transplantation as younger patients receiving MEL200. Among the 357 patients included in these analyses, median PFS from start of induction was 33.6 vs 27.8 months with bortezomib consolidation vs observation (log-rank p=0.0243). Median PFS for bortezomib vs observation was 33.6 vs 29.0 months (HR 0.86; p=0.3599) in the younger cohort and 33.4 vs 26.4 months (HR 0.60; p=0.0073) in the older cohort. PFS for older patients who received bortezomib consolidation was very similar to PFS in younger patients (p=0.861); survival curves were superimposable despite the older patients having received less intensive pretreatment. Univariate analysis demonstrated that treatment group (bortezomib vs observation) had an effect on PFS (HR 0.75; exploratory p-value 60 vs ≤60 years; HR 1.30), melphalan dose (200 vs Conclusions For patients with NDMM, bortezomib consolidation post-ASCT appeared to equalize the outcome for older patients who had received less intensive pretreatment than younger patients prior to randomization. A consistent PFS benefit was demonstrated with bortezomib consolidation vs observation in the context of other prognostic factors. In a multivariate analysis, the use of tandem transplantation retained independent prognostic relevance, whereas MEL200 as first HDT did not. Table. Table. Disclosures Straka: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel/Accommodation/Expenses, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel/Accommodation/Expenses; Chugai: Research Funding. Knop:Takeda: Consultancy. Vogel:Janssen-Cilag GmbH: Employment. Kropff:Celgene: Consultancy, Other: Travel/Accommodation/Expenses, Speakers Bureau; Janssen: Consultancy, Other: Travel/Accommodation/Expenses, Speakers Bureau; Onyx: Consultancy, Speakers Bureau. Metzner:Amgen: Consultancy; Sanofi: Consultancy; Celgene: Other: Travel/Accommodation/Expenses; Takeda: Other: Travel/Accommodation/Expenses. Langer:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Sayer:Riemser Pharma: Consultancy. Bassermann:Celgene: Other: Travel/Accommodation/Expenses. Gramatzki:Janssen: Other: Travel/Accommodation/Expenses, Research Funding. Rösler:Janssen: Consultancy, Other: Travel/Accommodation/Expenses. Engelhardt:MSD: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel/Accommodation/Expenses , Research Funding. Fischer:Novartis: Consultancy, Honoraria. Einsele:Celgene: Consultancy, Honoraria, Other: Travel/Accommodation/Expenses , Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel/Accommodation/Expenses , Research Funding, Speakers Bureau; Novartis: Consultancy, Other: Travel/Accommodation/Expenses , Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

Introduction: The PETAL trial is a multicenter randomized controlled study for patients with aggressive lymphomas of diverse histologies (EudraCT 2006-001641-33, NCT00554164). In the study population as a whole interim PET (iPET) reliably predicted time to treatment failure (TTTF) and overall survival (OS). Interim PET-based treatment changes, however, had no impact on outcome (ASH 2014, abstract 391). Here we report the exploratory analysis for peripheral T cell lymphomas (PTCL). Methods: Pts. aged 18 to 80 yrs. with newly diagnosed aggressive lymphomas and a positive baseline PET received 2 cycles of rituximab (R), cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) followed by iPET. R was omitted in pts. with CD20-negative lymphomas. The conditions of iPET were strictly defined: 3-week interval between the 2nd (R-)CHOP cycle and iPET to avoid inflammatory reactions (Eur J Nucl Med Mol Imaging 30:682, 2003), no G-CSF after the 2nd cycle to avoid altered glucose biodistribution (J Nucl Med 47:950, 2006), standardized uptake value (SUV)-based PET interpretation to improve reproducibility (favorable iPET response: reduction of maximum SUV by > 66 % compared to baseline; J Nucl Med 48:1626, 2007). PTCL pts. with CD20-negative lymphomas and a favorable iPET uniformly received 4 additional cycles of CHOP (part A of the trial). Pts. with an unfavorable iPET were randomized to continue CHOP for 6 additional cycles or receive 6 blocks of a more complex methotrexate-, cytarabine- and etoposide-based regimen originally designed for Burkitt lymphoma (Blood 124: 3870, 2014; part B). Sample size of the entire study population was based on the empirically derived assumption that treatment failure after 2 yrs. (progression, relapse, treatment discontinuation due to toxicity, start of alternative therapy, death of any cause) could be improved from 30 % to 45 % in part B (alpha=0.05, power=0.8). Secondary endpoints included OS and toxicity. Results: Fifty-seven oncological centers and 23 nuclear medicine institutions participated in the trial. Between 2007 and 2012 1072 pts. were registered, and 862 (80.4 %) had a positive baseline PET, received 2 cycles (R-)CHOP, underwent iPET and were allocated to one of the post-iPET treatment arms detailed above. Reference pathology was available in 98 %, and median follow-up is 52 months. All in all, there were 76 pts. (8.8 % of all treated pts.) with T-cell lymphomas of whom 21 had ALK+ anaplastic large cell lymphoma (ALCL), 13 ALK- ALCL, 18 angioimmunoblastic T-cell lymphoma (AITL) and 20 PTCL not otherwise specified (NOS). Interim PET was favorable in 57 pts. (75 %) and unfavorable in 19 pts. with T-cell lymphomas (25 %). It was highly predictive of outcome, TTTF and OS being significantly higher in part A than B (2-year probability for TTTF: 63 % vs. 21 %; univariate hazard ratio (HR) for B 3.4, 95 % confidence interval (CI) 1.8 - 6.4, p TTTF (2-year probability: 81 % vs. 46 % vs. 49 % vs. 35 %; p=0.0110) and OS (90 % vs. 69 % vs. 52 % vs. 50 %; p=0.0026) were better in ALK+ ALCL than in ALK- ALCL, AITL or PTCL NOS. In pts. with an unfavorable iPET response, a switch from CHOP to the alternative regimen failed to improve TTTF or OS. The latter was associated with more frequent grade 3/4 neutropenia (40 % vs. 0 % vs. 11 %, p=0.0279), thrombocytopenia (70 % vs. 33 % vs. 23 %; p=0.0106), infection (60 % vs. 44 % vs. 18 %, p=0.0057) and mucositis (40 % vs. 33 % vs. 4 %, p=0.0025) as compared to 6 or 4 post-iPET cycles of CHOP, respectively, but treatment-related mortality was similar in all treatment arms (2 vs. 1 vs. 2 deaths). Conclusion: In this large multicenter trial iPET proved highly predictive of outcome in PTCL. A favorable iPET was found in 75 % of pts., and this was associated with long-term survival in about 70 %. In pts. with an unfavorable iPET response, outcome was dismal and could not be improved by switching to a more aggressive regimen. Novel strategies are required for PTCL pts. failing to respond to the first 2 cycles of CHOP. Disclosures Hüttmann: Gilead, Amgen: Other: Travel cost; Bristol-Myers Squibb, Takeda, Celgene, Roche: Honoraria. Giagounidis:Celgene Corporation: Consultancy. Klapper:Roche, Novartis, Amgen, Takeda: Research Funding. Duehrsen:Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding.

Rituximab plus chemotherapy, most often CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is the first-line standard of care for patients with advanced indolent lymphoma, and for elderly patients with mantle-cell lymphoma. Bendamustine plus rituximab is effective for relapsed or refractory disease. We compared bendamustine plus rituximab with CHOP plus rituximab (R-CHOP) as first-line treatment for patients with indolent and mantle-cell lymphomas.We did a prospective, multicentre, randomised, open-label, non-inferiority trial at 81 centres in Germany between Sept 1, 2003, and Aug 31, 2008. Patients aged 18 years or older with a WHO performance status of 2 or less were eligible if they had newly diagnosed stage III or IV indolent or mantle-cell lymphoma. Patients were stratified by histological lymphoma subtype, then randomly assigned according to a prespecified randomisation list to receive either intravenous bendamustine (90 mg/m(2) on days 1 and 2 of a 4-week cycle) or CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1.4 mg/m(2) on day 1, and prednisone 100 mg/day for 5 days) for a maximum of six cycles. Patients in both groups received rituximab 375 mg/m(2) on day 1 of each cycle. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival, with a non-inferiority margin of 10%. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00991211, and the Federal Institute for Drugs and Medical Devices of Germany, BfArM 4021335.274 patients were assigned to bendamustine plus rituximab (261 assessed) and 275 to R-CHOP (253 assessed). At median follow-up of 45 months (IQR 25-57), median progression-free survival was significantly longer in the bendamustine plus rituximab group than in the R-CHOP group (69.5 months [26.1 to not yet reached] vs 31.2 months [15.2-65.7]; hazard ratio 0.58, 95% CI 0.44-0.74; p0.0001). Bendamustine plus rituximab was better tolerated than R-CHOP, with lower rates of alopecia (0 patients vs 245 (100%) of 245 patients who recieved ≥3 cycles; p0.0001), haematological toxicity (77 [30%] vs 173 [68%]; p0.0001), infections (96 [37%] vs 127 [50%]); p=0.0025), peripheral neuropathy (18 [7%] vs 73 [29%]; p0.0001), and stomatitis (16 [6%] vs 47 [19%]; p0.0001). Erythematous skin reactions were more common in patients in the bendamustine plus rituximab group than in those in the R-CHOP group (42 [16%] vs 23 [9%]; p=0.024).In patients with previously untreated indolent lymphoma, bendamustine plus rituximab can be considered as a preferred first-line treatment approach to R-CHOP because of increased progression-free survival and fewer toxic effects.Roche Pharma AG, Ribosepharm/Mundipharma GmbH.

Five magnetic resonance (MR) studies of the lower leg were performed in three patients with eosinophilia-myalgia syndrome (EMS). The 1H spectroscopic and imaging findings were compared with seven examinations of age-matched healthy controls. Standard imaging with proton density-, T1-, and T2-weighted spin-echo (SE) sequences at 1.5 T showed marked atrophy of the calf muscles and slightly increased signal strength of muscle tissue in T2-weighted SE images. The application of frequency selective chemical shift imaging (SENEX) exhibited skin changes similar to those of scleroderma with increased water content and thickened cutis in the water selective images. In one patient the tibialis muscles showed irregular structures, but no fatty degeneration as demonstrated in the fat selective images. Proton signals from volume elements of (20 mm)3 within the soleus and gastrocnemius muscle were recorded by the PRESS localization method. A reduction of the creatine/water and the choline/water ratios was found in the 1H spectra from the EMS patients compared to the controls. Localized 1H spectroscopy exhibited modified distributions of the lipid signals in two EMS patients with slightly elevated signals from unsaturated fatty acids. The transverse relaxation of choline and creatine signals was accelerated in both examinations of one patient compared with the healthy controls.

Background Chemotherapy for elderly patients with acute myeloid leukemia (AML) results in a median overall survival (OS) of ≤1 year. Elderly patients often present with cardiac comorbidity. Gemtuzumab ozogamicin (GO) is active in elderly (≥60 years) patients with relapsed AML with low cardiac toxicity. Patients and methods This randomized phase II study compared a standard combination of ara-C and daunorubicin (DNR; 7+3) versus ara-C plus gemtuzumab ozogamicin (7+GO) as the first course of induction therapy. Primary objectives were comparison of blast clearance on day 16, event-free survival (EFS), and remission duration. OS, complete remission (CR), and tolerability were secondary objectives. Results One hundred and nineteen patients with de novo AML, treatment-related AML, AML with a history of myelodysplastic syndrome (MDS), or high-risk MDS entered the study. Median age of 115 patients (intent-to-treat population) was 69 years. Protocol outlined a second course 7+3 for patients without blast clearance and two courses of high-dose ara-C consolidation upon CR. Both treatments were equally effective in blast clearance, CR, EFS, remission duration, or OS (median: 7+3, 9 months; 7+GO, 10 months). Induction death rate was higher in the GO group due to veno-occlusive disease. Conclusion The study did not show significant superiority of 7+GO over standard 7+3.

Treatment standards are changing as a result of new findings in the therapy of multiple myeloma. So far, prednisone, dexamethasone and interferon-a have mainly been used as maintenance therapy after achieving remission or stable disease. At present, thalidomide is being considered as a new therapeutic option in several studies investigating maintenance therapy. As a result of the dose dependence of adverse effects such as neuropathy, constipation, sedation/vertigo and bradycardia, individual adjustment of the thalidomide dose is recommended. Only isolated cases of thrombosis occurred in the maintenance phase of therapy, and discontinuation of therapy is generally not necessary. While important study results on the efficacy of thalidomide following conventional chemotherapy are still awaited, it is the best documented drug so far for maintenance therapy following autologous stem cell transplantation. An upgrade of the response was seen in 22-73% of patients, as well as a significant prolongation of progression-free survival. For the first time, maintenance therapy with thalidomide showed a significant improvement in overall survival in a phase III study published recently. The tolerability of thalidomide could be further improved by including the option of intermittent administration of the drug.

8511 Background: Following ASCT, consolidation therapy including novel agents can improve outcomes in pts with MM. Here we report the combined outcomes of two large randomized phase III studies inv...

Background: This multicenter, randomized, phase III study compared B-R and CHOP-R as first-line treatment in patients (pts) with indolent lymphomas or MCL and was presented at ASH 2009, ASCO 2012, and published in The Lancet in 2013. The final published analysis at a median follow-up of 45 months demonstrated a significantly prolonged progression-free survival (PFS) in the B-R group, compared to the CHOP-R group (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.44–0.74; p Methods: 549 pts with indolent lymphomas or MCL were randomized to receive B-R or CHOP-R for a maximum of 6 cycles. The primary endpoint was PFS; secondary endpoints included OS, TTNT, and sNPL. Results: 514 randomized pts were evaluable (261 B-R; 253 CHOP-R). Patient characteristics were well balanced between arms; median age was 64 years. Fewer pts treated initially with B-R needed second-line treatments due to disease progression compared to CHOP-R treated pts: 93 pts (36%) in the B-R group received salvage treatment compared with 140 pts (55%) in the CHOP-R group. Of those in the CHOP-R group, 69 pts (49%) received B-R as salvage. TTNT was significantly prolonged with B-R compared with CHOP-R (HR 0.53, 95% CI 0.40-0.68; p The difference in complete response (CR) rates (independent of treatment arms) between male (n=272, median age 63 years) and female (n=242, median age 64 years) pts was statistically significant: 28.6% for male pts versus 42.1% for female pts (p=0.0016). Female pts had a longer median TTNT compared to male pts (not yet reached vs. 52.2 months, respectively; HR 0.70, 95% CI 0.54-0.90; p=0.006). The achievement of a CR was associated with significantly prolonged OS, with an estimated 10-year survival rate of 72.6% for pts with a CR and 63.6% for pts with a partial response (p=0.006). The difference in OS between the treatment arms was not statistically significant, with 65 and 76 deaths in the B-R and CHOP-R arms, respectively. The estimated 10-year survival rates were 67.4% for B-R and 60.1% for CHOP-R (p=0.262). In pts with indolent lymphomas (total group without MCL), there was a trend toward longer survival for the B-R group compared with the CHOP-R group, with 43 deaths out of 215 pts (20.0%) in B-R and 58 deaths out of 205 pts (28.3%) in CHOP-R. The estimated 10-year survival rates for pts with indolent lymphomas were 71.9% for B-R and 61.5% for CHOP-R (HR 0.70, 95% CI 0.48-1.04; p=0.076). No difference in OS was found in the subgroup of pts with MCL (n=95) (HR 1.28, 95% CI 0.69-2.39; p=0.429). Twenty sNPL were observed in the B-R group compared with 23 in the CHOP-R group, with 1 hematological malignancy in each group (1 MDS in B-R, 1 AML in CHOP-R) to date. Updated sNPL results will be presented at the ASH meeting. Conclusions: In pts with previously untreated indolent lymphomas, and in elderly pts with MCL, B-R demonstrates a PFS and TTNT benefit over CHOP-R. OS for the entire group of patients was not significantly different while treatment with B-R resulted in a trend toward survival benefit in the group of pts with indolent lymphomas. Disclosures Off Label Use: Indication and dosage of bendamustine.

131 Introduction. Autologous stem cell transplantation (ASCT) after cytoreductive induction is considered standard of care for younger patients (pts) with multiple myeloma (MM). The previous standard of induction, the Vincristin-Adriamycin-Dexamethasone (VAD) combination, achieves inferior results compared with induction regimens which combine the proteasome inhibitor Velcade (V = Bortezomib) with Dexamethasone (D)(=VD) and a cytostatic drug such as Doxorubicin (PAD = VD plus Doxorubicin). Velcade-based induction therapy was shown to translate into better myeloma control after high dose melphalan and to lead to prolonged progression-free survival. In order to find a more efficacious and safer drug combination for induction therapy in MM, we tested the combination of Velcade with Cyclophosphamide and Dexamethasone (VCD). Methods. This trial was designed as an open, prospective, multi-center, uncontrolled, combined phase II/III study. As previously reported (Kropff M et al., Ann Hematol 2009), in the first 30 pts the optimal dose of iv Cyclophosphamide in combination with V and D was defined as 900 mg/m2 on d1. Between 03/2006 and 03/2009 we enrolled an additional 370 pts up to 60 years of age with untreated MM to receive three 3-week cycles of induction treatment with V 1.3 mg/m2 iv d1,4,8,11; D 40 mg/d orally d1,2,4,5,8,9,11,12; and C 900mg/m2 iv d1 before scheduled high dose melphalan and ASCT. The primary endpoint of the study is response rate on day 63 after 3 cycles of VCD according to EBMT and IMWG criteria. Results. Final data from 400 pts from 39 German centers will be presented at the meeting. In the currently evaluable 300 pts (mean age 52.3 years; 1.7% stage I, 21.3% stage II, 77.0% stage III) molecular cytogenetic analysis showed a prevalence of 13q- in 38%, of t[4;14] in 13% and of 17p- in 12% of pts (no changes in 35%). All 300 pts (88.3% of whom completed three cycles) were included in the intent-to-treat analysis. Overall response rate (ORR = CR+PR) was 84%, with 10% CR and 74% PR, 5.7% MR, 7.3% NC and 2.3% PD. The negative prognostic impact of 13q- or t[4;14] was abrogated (ORR normal 87.3%, 13q- 83.7%, t[4;14] 90.0%), the unfavorable influence of p53 loss in the 17p- subgroup was still detectable (ORR 69.2%) but this did not reach statistical significance. VGPR rates will be reported at the meeting. Serious adverse events were documented in 78/300 (26.0%) patients. Death rate was remarkably low (1.3%, of which one was not related to the trial medication). 155/300 (52%) of pts experienced grade 3/4 non-serious AEs and of these leucopenia (93/300 pts= 31%), thrombocytopenia (7%), neutropenia (6%), anaemia (5%) were the most frequent events. 80 AEs grade 3 or 4 and 45 SAEs were of infectious origin and occurred in 47/300 pts. 80/130 SAEs (61.5%) were at least possibly related to Velcade. 101/300 pts (34%) developed episodes of peripheral neuropathy. PNP was grade 1 in 62/300 pt (20.7%), grade 2 in 31/300 pt (10.3%) and grade 3 in 7/300 pts (2.3%). Conclusion. This analysis demonstrates that proteasome inhibition by Velcade in combination with Dexamethasone and iv Cyclophosphamide (VCD) is an induction regimen for newly diagnosed MM which is highly effective in a short period of time, has a rather low toxicity profile and is feasible for administration in an outpatient setting. Based on these characteristics, VCD qualifies to become a new standard for MM induction therapy. | Response to VCD | % | |:---------------:| --- | | ORR | 84 | | CR | 10 | | PR | 74 | | MR | 5.7 | | SD | 7.3 | | PD | 2.3 | Table 1: Response to study therapy (intent-to-treat set, according to investigator, n=300) | | Responding patients (≥ PR) | |:-------------------:| -------------------------- | ---- | | n | % | | No FISH abnormality | 69/79 | 87.3 | | 13q- | 72/86 | 83.7 | | t(4;14) | 27/30 | 90 | | 17p- | 18/26 | 69.2 | | Other | 68/77 | 88.3 | Table 2: Response by result of cytogenetic analysis (intent-to-treat set, according to investigator, n=300) Disclosures: Einsele: OrthioBiotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Bortezomib is licensed as monotherapy for use in relapsed/refractory MM and in combination with melphalan/Prednisone in the first-line treatment of MM pts ineligible for HD-MEL and ASCT. . Liebisch: OrthoBiotech: Consultancy, Honoraria. Langer: OrthoBiotech: Consultancy. Kropff: OrthoBiotech: Consultancy, Honoraria. Kroger: OrthoBiotech: Honoraria. Ostermann: OrthoBiotech: Honoraria. Mugge: OrthoBiotech: Honoraria. Wolf: OrthoBiotech: Honoraria. Gramatzki: OrthoBiotech: Consultancy, Honoraria. Maschmeyer: OrthoBiotech: Travel Grant. Sezer: OrthoBiotech: Consultancy, Honoraria. Heidemann: OrthoBiotech: Honoraria. Jager: OrthoBiotech: Honoraria. Dechow: Celgene: Research Funding. Simon: OrthoBiotech: Honoraria. Straka: OrthoBiotech: Consultancy, Honoraria, Research Funding. Fingerle-Rowson: orthoBiotech: Employment. Knop: OrthoBiotech: Honoraria.

Abstract 2687 Poster Board II-663 Background: The addition of Rituximab to standard chemotherapy has substantially improved the prognosis of NHL. Over the last years, a trend towards intensified protocols with multiple applications of Rituximab has been observed. We are able to report a unique cohort that has also been treated with only 1 or 3 courses of Rituximab within a prospective randomized phase II trial, contrasting current standard procedures. Patients and Methods: Between 2000 and 2005, 126 patients (pts) with stage III/ IV CD20+ follicular lymphoma (FL) were randomized in a prospective multicenter trial to receive 1, 3 or 6 courses Rituximab with 6 courses standard CHOP chemotherapy. The primary endpoint was to compare the three treatment arms with regards to molecular remission rates (mRR) among pts with positive PCR at diagnosis. Secondary endpoints were clinical remission rates, progression-free (PFS) and overall-survival (OS) and toxicity. After screening failure (n = 21) or protocol violation (n = 6) had occurred, 99 pts form the base for this analysis. Among those, only 28 pts were PCR positive at start of treatment and met the criteria for inclusion into the primary endpoint analysis. Results: Due to a limited number of evaluable pts, mRR and duration of molecular remission could not be analyzed. Among 99 pts eligible for the secondary endpoint analysis, 31 received 1 course of Rituximab (arm A), 36 received 3 courses (arm B) and 32 received 6 (arm C). 42% were male. The median age at diagnosis was 56 years (range 23–79). Histological grade was 1 in 49%, 2 in 35% and 3 in 12%. Stage according to Ann Arbor was 3 in 30% and 4 in 70% of pts. B symptoms were present in 36%. According to FLIPI, 21% were classified as low risk (0–1), 39% as intermediate risk (2), and 39% as high risk (3–5). At least one extranodal manifestation was detected in 81 pts, with over 60% of extranodal manifestations being located in the bone marrow. Bulky disease was detected in 57 pts. Following immunochemotherapy, 37% received consolidating involved-field radiotherapy. There was no difference between the three treatment arms with regards to presenting or demographic characteristics (p>.05). Treatment was terminated prematurely in 19 pts due to protocol violation (n = 10), stable disease/ disease progression (n=5), pts′ preference (n = 3) or death (n = 1). After completion of immunochemotherapy, 29 of 99 pts had achieved CR and 58 PR; no or minimal response or progression was observed in 6 pts, and 6 pts were not evaluable. There was no statistically significant difference of clinical remission status between pts in arm A and B compared to those in arm C (p = .66), and between pts in arm B and C compared to arm A (p = .07). There was no trend in clinical remission rates through different courses of Rituximab (p = .09). However, 3 courses were not inferior to 6 courses with regards to clinical remission rate. After a median follow-up of 60 months (range 4–90) 94% of pts in each arm had achieved at least PR. Relapse occurred in 36 pts, with no significant difference in remission duration between the three arms (p = .28). In comparison to 1 course, multiple courses did not significantly prolong the duration of remission (p = .12). 6-year PFS was 45% in arm A, 60% in arm B and 65% in arm C, with no difference between the three arms (p = .35). Neither 3 (p = .29) nor 6 courses (p = .18) did significantly alter PFS compared to 1 course. The difference in PFS between 1 course vs. 3 or 6 courses was not significant (p =.16). 6-year OS was 72% in arm A, 82% in arm B and 80% in arm C, with no significant difference between the three arms (p = .46). Neither 3 (p = .26) nor 6 courses (p = .36) significantly altered OS when compared to 1 course. The difference in OS between 1 course vs. 3 or 6 courses was also not significant (p = .22). Toxicities most frequently observed were grade 3/4 leucopenia. There was no difference with regards to infections (p = .67) and allergic reactions (p = .70). Death occurred in 18 pts. Conclusion: There was no difference in remission rates, remission duration, PFS and OS between pts treated with different courses of Rituximab, with more frequent applications not differing from less frequent applications. In this study, a non-inferiority of fewer applications of Rituximab could not be detected. Therefore, the advantage of multiple courses of Rituximab remains uncertain. To our knowledge, this is the first study that randomized pts to receive fewer doses of Rituximab than currently applied in standard protocols. Disclosures: No relevant conflicts of interest to declare.

Metabolism of carbon tetrachloride in rats at atmospheric and reduced oxygen pressure has been determined indirectly by its disappearance from the inhaled air; it is inversely related to oxygen concentration and increases with decreasing partial pressure, as expected for reductive dehalogenation; oxygen partial pressure has been reduced to about a third of normobaric conditions. Concurrently exhalation of ethane and pentane as indication of lipid peroxidation has been monitored, showing a drastic increase when the oxygen partial pressure is reduced in the presence of carbon tetrachloride. Time course and duration of these processes indicate that the total metabolism of carbon tetrachloride is limited by the concomitant destruction of cytochrome P-450; also, oxidative destruction of polyunsaturated fatty acids apparently does not proceed beyond the end of metabolic activation of carbon tetrachloride. The molar ratios of the amount of metabolized carbon tetrachloride to the amounts of exhaled hydrocarbons lead to the same conclusion, namely that "lipid peroxidation" in this case does not proceed as an autocatalytic, self-propagating chain reaction.

Determination of alkanes in breath of laboratory animals and humans has become a standard-method for monitoring lipid peroxidation in vivo. Isothermal gas chromatography on Porasil C enables sensitive, rapid and repetitive determination of all C2-C5-hydrocarbons in breath. Volatile toxicants and metabolites, which would coelute with the alkanes of later injected samples, are deviated by using a precolumn. An automatic switching unit controls withdrawal and injection of samples and backflush of the precolumn in a repetitive manner at fixed intervals. This increases accuracy and sensitivity of analysis and enables virtually unattended operation. The system has been applied for a study on the oxygen-dependance of CCl4-metabolism in the rat.

Arachidonic and docosahexaenoic acid in hepatic microsomal lipids from male Sprague-Dawley rats are greatly lowered when the animals have been exposed to tetrachsoromethane; at the same time, palmitic, oleic and linoleic acid are significantly increased. Hypoxia alone causes similar derangements, but to a lesser extent. These are largely corrected 18 h after exposure; the effects induced by tetrachloromethane are persistent. The increases in 16:0,18:1 and 18:2 suggest that in both cases microsomal enzymes involved in fatty acid metabolism are inhibited, either reversibly or irreversibly. Reduction of oxygen partial pressure during tetrachloromethane exposure has little effect upon hepatotoxicity as judged by hepatic enzymes in serum; only the onset of their release into the bloodstream is earlier.