ALBERT

Description: In patients with multiple myeloma (MM), risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches. In the present study, we analyzed the prognostic value of 12 chromosomal abnormalities in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Because of the 2-arm design of the study, we were able to analyze the effect of a bortezomib-based treatment before and after autologous stem cell transplantation (arm B) compared with standard treatment without bortezomib (arm A). For allanalyzed chromosomal aberrations, progression-free survival (PFS) and overall survival (OS) were at least equal or superior in the bortezomib arm compared with the standard arm. Strikingly, patients with del(17p13) benefited the most from the bortezomib-containing treatment: the median PFS in arm A was 12.0 months and in arm B it was 26.2 months (P = .024); the 3 year-OS for arm A was 17% and for arm B it was 69% (P = .028). After multivariate analysis, del(17p13) was an independent predictor for PFS (P 〈 .0001) and OS (P 〈 .0001) in arm A, whereas no statistically significant effect on PFS (P = .28) or OS (P = .12) was seen in arm B. In conclusion, the adverse impact of del(17p13) on PFS and OS could be significantly reduced by bortezomib-based treatment, suggesting that long-term administration of bortezomib should be recommended for patients carrying del(17p13). This trial is registered at the International Standard Randomised Controlled Trial Number Register as ISRCTN64455289.

Description: Abstract 255 Introduction: Standard treatment of acute myeloid leukemia (AML) comprises one or two cycles of chemotherapy to induce complete remission (CR) followed by postremission treatment in order to prevent relapse of the disease (consolidation therapy). In 2003, we initiated a prospective multicenter randomized trial to investigate the impact of different consolidation strategies on long-term outcome in AML patients ≤ 60 years. Consolidation options comprised upfront allogeneic stem cell transplantation (allo SCT) in aplasia after induction therapy, autologous SCT, and three cycles of standard high-dose-cytarabine-based consolidation. For patients receiving high-dose cytarabine, the main study aim was to evaluate the benefit of adding additional mitoxantrone and amsacrine to cytarabine consolidation. Design: From 2003 to 2009, 1182 patients (median age, 48 years; range 16–60 years) with untreated AML were randomly assigned at diagnosis to different consolidation strategies after classical 7+3 induction. According to the risk-adapted treatment strategy of the trial, cytogenetically or molecular intermediate-risk (IR) and adverse-risk (AR) patients should receive an allo SCT as consolidation treatment if an HLA-identical-sibling donor (IR) or HLA-matched related or unrelated donor (AR) was available. IR and AR patients with no available donor should receive autologous SCT. All favorable risk patients and patients with no available donor were scheduled for high-dose cytarabine based consolidation. Half of the patients were randomized for high dose cytarabine based consolidation. Half of the patients were randomized for high dose cytarabine alone while the other half received high dose cytarabine with the addition of amsacrine and mitoxantrone. Standard chemotherapy consisted of three cycles with high dose cytarabine (2 × 3 g/m2, day 1,3,5) whereas combined consolidation contained two cycles of MAC (cytarabine 2 × 1g/m2, day 1–6, mitoxantrone 10 mg/m2, day 4–6) plus one cycle of MAMAC (cytarabine 2 × 1 g/m2, day 1–5, amsacrine 100 mg/m2, day 1–5). In order to evaluate the effect of the two cytarabine based consolidation strategies, we determined overall survival (OS) and event free survival (EFS) using the method of Kaplan Meyer. Survival distributions were compared using the log rank test. Results: 1182 patients were randomized for further intervention (Arm A+B: n=582, 49.3%; Arm C+D: n=600, 50.7 %). Median follow-up was 41.4 months (95%-CI 39.3–43.6). A total number of 375 patients received allogeneic (n=322) or autologous SCT (n=53) and 807 patients were consolidated with cytarabine. Of these patients, 407 were randomized for cytarabine alone and 400were randomized to receive cytarabine plus mitoxantrone and amsacrine (MAC/MAC/MAMAC). Complete remission rate (CR) after second induction therapy was 59.1% (n=698). Between the four arms, there were no significant differences of the CR rates. Five-year OS of patients receiving high dose cytarabine alone was 47.1% (95%-CI 42.0–52.2%), for patients receiving MAC/MAMAC as consolidation therapy it was 46.8% (95%-CI 42.3–51.3%; p = 0.610). Three-year event free survival (EFS) was also not significant with 30.5% (95%-CI 26.6–34.4%) for patients receiving high dose cytarabine alone and 35.6% (95%-CI 31.7–39.5%; p = 0.059) for patients receiving MAC/MAMAC. Conclusions: According to our data, the addition of mitoxantrone and amsacrine to high dose cytarabine consolidation confers no benefit for treatment outcome in younger AML patients. Disclosures: No relevant conflicts of interest to declare.

Description: Key Points The results of this retrospective analysis do not support intrathecal prophylaxis or radiotherapy to ECFI patients in complete remission/unconfirmed complete remission.

Description: Introduction: Gene expression profiling (GEP) has significantly contributed to the elucidation of the molecular heterogeneity of multiple myeloma plasma cells (MMPC) and only recently it has been recommended for risk stratification. Prior to GEP MMPC need to be enriched resulting in an inability to immediately freeze bone marrow aspirates or use RNA stabilization reagents. As a result in multi-center MM trials sample processing delay due to shipping may be an important confounder of molecular analyses and risk stratification based on GEP data. In order to determine the impact of "shipping delay" on MMPC gene expression we analyzed a set of 573 newly diagnosed German MM patients including 230 in-house and 343 shipped samples. Materials and Methods: We included publicly available GEP data of newly diagnosed MM patients treated in the GMMG HD4 and MM5 trials. All samples had been processed in a central laboratory in Heidelberg and include 85 HD4 and 145 MM5 in-house and 97 HD4 and 246 MM5 shipped samples. Prediction of sample status was done on publicly available GEP, including data from the UK, UAMS and MMRC. Differential gene expression was assessed using empirical Bayes statistics in linear models for microarray data. Predictor for shipment status was generated on the MM5 cohort using prediction analysis for microarrays. Pathway enrichment analysis was done using WebGestalt. Risk signatures and molecular subgroups were obtained as previously described. Fisher's exact test was used to compare the subgroup distribution between cohorts. If applicable, results were corrected for multiple testing using the Benjamini-Hochberg method. In all statistical tests, an effect was considered statistically significant if the P-value of its corresponding statistical test was not greater than 5%. Results: Applying the Goeman's global teston the MM5 set showed that "shipping delay" significantly impacted global gene expression (P 1.5-fold and 826 a 〉2-fold difference in expression level. Differentially expressed genes were enriched in processes like ribosome biogenesis, cell cycle, and apoptosis. We observed significantly lower proliferation rates in shipped samples (P

Description: Introduction In multiple myeloma, initially, there are increased numbers of osteoclasts showing increased activity, but bone formation by osteoblasts is keeping step. In later stages, parts of the bone remodeling compartments are disrupted by the interaction with myeloma cells leading to increased bone resorption which can no longer be compensated (myeloma bone disease, uncoupling of bone formation and bone resorption). Lenalidomide and bortezomib have been shown to target both, myeloma cells and the microenvironment: lenalidomide inhibits osteoclastogenesis, bortezomib is also able to stimulate osteoblast differentiation leading to increased bone formation. Aim of this study is to evaluate the impact of bortezomib-based induction treatment, high-dose therapy, and lenalidomide consolidation on alterations of bone turnover, i.e. surrogates of osteoblast- (osteocalcin, OC) and osteoclast- (collagen type I fragments, CTX-I) function, and their induction by myeloma cells (DKK1-level). Methods Serum was collected during routine sampling within the GMMG-MM5 trial (EudraCT 2010-019173-16), and levels of CTX-I, OC, and DKK1 were assessed by ELISA in triplicates using commercially available assays according to the manufacturer’s instructions (RnD Systems and Immunodiagnostic Systems). The following time points were assessed: at inclusion (n=365), after induction therapy with either PAd (n=88) or VCD (n=84), stem cell mobilization using CAD (n=69), high-dose melphalan (n=92), and 2 months lenalidomide consolidation (n=92). Up to now, serum samples of 69 patients were measured sequentially at five time points in line with the GMMG-MM5 trial. DKK1 levels were correlated with the expression in CD138-purified myeloma cells (Affymetrix microarrays, n=365). Results Prior to treatment, CTX-I levels are increased, those of OC decreased compared to healthy donors (uncoupled bone turnover). DKK1 protein levels are increased and correlate with DKK1-expression in myeloma cells. After induction therapy, osteoclast activity (CTX-I) is decreased below normal values. PAd unlike VCD further decreases osteoblast activity (OC-levels); DKK1-levels are normalized. Subsequent treatment further decreases DKK1-levels below normal values and blocks osteoclast function. After 2 months lenalidomide consolidation, no normalization of osteoblast activity is found. Conclusion The main impact on bone turnover by bortezomib-based induction treatment is a reduction of osteoclast activity alongside a decrease in DKK1-levels. During the reported period, no normalization of decreased osteoblast function was observed. Disclosures: Seckinger: Novartis Pharma: Research Funding. Goldschmidt:Novartis Pharma: Research Funding. Hose:Novartis Pharma: Research Funding.

Description: Abstract 305 Chromosomal aberrations are important prognostic parameters in multiple myeloma (MM). By using interphase fluorescent in situ hybridization (FISH) on CD138-enriched plasma cells, specific changes in interphase cells can be detected, overcoming the lack of dividing cells required for conventional cytogenetics. We evaluated the association of FISH results and outcome of a subgroup of patients (pts) within the HOVON-65/GMMG-HD4 trial, a prospective, randomized phase III trial for pts with newly diagnosed MM stage II or III according to Salmon & Durie up to 65 years. Pts were randomized to receive three cycles of VAD (arm A; vincristine, adriamycin, dexamethasone) or PAD (arm B; bortezomib, adriamycin, dexamethasone). Hematopoietic stem cells were mobilized using the CAD regimen and G-CSF. All pts received one or two cycles of high dose melphalan (200 mg/m2) with autologous stem cell transplantation followed by maintenance therapy with thalidomide 50 mg daily (arm A) or bortezomib 1.3 mg/m2 once every 2 weeks (arm B), respectively, for a maximum of 2 years. Sites in Germany, the Netherlands and Belgium participated in this trial (n=833 pts). For the German pts (GMMG, n=399) FISH was performed in a single laboratory prior to start of treatment. Cytospins of CD138 purified plasma cells were subjected to FISH with two-color probe sets for the detection of numerical changes for the following chromosome regions: 1q21/8p21, 6q21/15q22, 9q34/22q11, 11q23/13q14, and 17p13/19q13, as well as for the translocations t(4;14)(p16;q32), t(11;14)(q13;q32), and t(14;16) (q32;q23). As of July 2010 data from the first consecutively enrolled 626 patients of the trial have been analyzed, including 284 GMMG pts. For this analysis, FISH results from 258 (91%) GMMG pts were available (n=131 in arm A; n=127 in arm B). Patient characteristics in the GMMG subgroup are comparable to the analyzed trial population of 626 pts. For all pts the median follow-up time from randomization was 40.3 months (mo.). The most pronounced impact on prognosis was seen for t(4;14), del17p13, and gain1q21, each significantly associated with poor prognosis with respect to progression free survival (PFS) and overall survival (OS). The strongest prognostic impact was found for del17p13. FISH analysis detected del17p13 in 9.4% of pts (A: 12.3% vs. B: 6.4%), t(4;14) in 14.8 % (16.3% vs. 13.4%), and gain 1q21 in 33.7% of pts (33.1% vs. 34.4%). When comparing pts in the two arms for PFS, we found a borderline significance for the interaction between t(4;14) and treatment arm (p=0.06), indicating that the effect of t(4;14) depends on the treatment. Pts with t(4;14) in arm A show a very poor prognosis with a median PFS time only half as long compared to patients without translocation (18 vs. 36 mo.; p=0.003). No such negative effect was observed for patients in arm B with t(4;14) (36 vs. 40 mo.; p=0.97). PAD resulted in improved 3yr-OS rates for pts with t(4;14) (A:39% vs B:76%), while 3yr-OS was 79% and 87% in pts without t(4;14). Median PFS for pts with gain 1q21 was 22 mo. (arm A) vs. 30 mo. (arm B) compared to 41 mo. in both arms for patients without gain 1q21. Pts with gain 1q21 showed a significantly better OS when treated with bortezomib (3yr-OS rates: A: 59%, B: 83%, p=0.016). Del17p13 was significantly associated with poor prognosis in both arms for OS (A: p

Description: Background: While 6 to 8 cycles of CHOP in combination with rituximab are widely accepted as standard regimen of care for aggressive lymphomas, the optimal dose and number of rituximab application have not been determined to date. In a previous pharmacokinetic study we had shown that the concomitant application of CHOP and rituximab does not achieve a plateau of rituximab trough levels until cycle 5 (Reiser, Blood 108, 778a, 2006). In order to achieve high rituximab levels early, we increased the number of rituximab applications. Methods: 100 elderly patients with aggressive CD20+ B-cell lymphoma received 6 cycles of biweekly CHOP-14 combined with 12x rituximab (375 mg/m2) on days 0, 1, 4, 8, 15, 22, 29, 43, 57, 71, 85, and 99. Radiotherapy was planned to sites of initial bulk and/or extranodal involvement. The primary endpoint was event-free survival (EFS). 306 patients treated within the RICOVER-60 trial (Pfreundschuh et al., Blood 64a, 2006) with 6xCHOP-14 and 8 applications of rituximab served as control. Results: 97/100 patients are evaluable for response. Dose-dense rituximab resulted in plateau trough serum levels of rituximab as early as day 1 of the first chemotherapy cycle and higher rituximab levels were maintained throughout the treatment compared to 8 bi-weekly applications. Because 3 therapy-associated deaths were observed among the first 20 patients treated, prophylaxis with levofloxacin, acyclovir and cotrimoxazol became mandatory for the following patients. Despite a less favorable study population DENSE-R-CHOP-14 resulted in a somewhat higher complete remission (83% vs. 78%) and lower progression under therapy rate (5% vs. 7%) rate, but event free and overall survival were not different compared to 8 biweekly applications of rituximab. However, a subgroup analysis of patients according to IPI risk group showed that DENSER-R-CHOP-14 resulted in a higher complete response rate of patients with poor-prognosis (IPI:3–5) disease (81% vs. 68%). This advantage translated into a better 1-year event-free survival rate (74% vs. 65%) of these patients. Conclusion: In combination with 6 cycles of CHOP-14 densification of rituximab achieves higher rituximab serum levels and results in higher complete remission and event-free survival rates in elderly patients with poor-prognosis DLBCL. These observations from a phase-II trial must be confirmed in a randomized study.

Description: Clinical trials on different cytarabine doses for treatment of AML provide evidence of a dose response effect, but also for increase toxicity after high dose AraC (HDAC). Pharmacokinetic measurements of cytarabine-triphosphate (AraC-CTP), which is the most relevant cytotoxic metabolite of AraC, have revealed its formation in leukemic cells to be saturated with infusion rates above 250 mg/m2/h, this being significantly lower than used in HDAC schedules. Methods: Based on a pharmacological model and encouraging results of a phase II study we conducted a prospective randomized multicenter clinical trial comparing the effects of two different application modes of AraC in patients up to 60 years with untreated newly diagnosed AML. Patients were randomized to receive AraC at two different infusion rates (IR) during induction and consolidation treatment: arm A/experimental: 1 × 2 g/m2/d AraC over 8 hours (IR 250 mg/m2/h) arm B/standard: 2 × 1 g/m2/d AraC over 3 hours (IR 333 mg/m2/h). Induction and first consolidation consisted of AraC (days 1, 3, 5, 7) in combination with an anthracycline (Idarubicine 12 mg/m2 or Mitoxantrone 10 mg/m2, days 1–3). The final dosage points (AraC day 7 and anthracycline day 3) were excluded from the second consolidation. The third consolidation consisted of either allogeneic or autologous stem cell transplantation or of chemotherapy identical to second consolidation. Results: From 02/97 to 04/02 419 patients were enrolled in the study. The present analysis is based on 361 eligible and evaluable patients with a median follow up of 7 years. CR was reached in 249/361 (69%; 95%CI: 65%–74%) patients. No statistically significant differences were detected between arms A and B with regard to CR-rate (69% vs 69%) or early death rate (11% vs 8%). Hematological recovery of median white blood cell count (WBC) 〉 109/l and median platelets (plt) 〉 50 × 109/l revealed no difference between arms A and B after induction (WBC day 22 vs 22, p=0,68; plt day 25 vs 26, p=0,41) and consolidation (WBC day 28 vs 27, p=0,07; plt day 42 vs 40, p= 0,58). The event free survival (EFS) after 5 years is 0,25 ± 0,03 % for all patients with an overall survival of 0,31 ± 0,03 % after 5 years. For the purposes of analysis, the 83 transplant patients (23 allogeneic MRD, 14 allogeneic MUD and 46 autologous) were censored at time of transplant. No statistically significant difference between arms A and B in regard to EFS (0,25 ± 0,04 vs 0,25 ± 0,04, p=0,99), relapse incidence (0,63 ± 0,06 vs 0,60 ± 0,06, p=0,89), overall survival (0,32 ± 0,04 vs 0,30 ± 0,04, p=0,44) and therapy associated mortality (0,18 ± 0,04 vs 0,17 ± 0,03, p=0,95) were detectable after adjustment of prognostic factors. An analysis of risk factors by multivariate cox regression model confirmed cytogenetics at diagnosis to be the most important risk factor for CR rate (p

Description: Introduction: The development of the escalated BEACOPP regimen let to an improved outcome in patients with advanced Hodgkin Lymphoma (HD9 study of the GHSG). However, the application of high dose etoposide (cumulative 4,8 g/m2 per 8 cycles) seems to be associated with an increased incidence of secondary MDS and AML, respectively. Therefore, the aim of our multicenter pilot study was to evaluate the efficacy and toxicity of the etoposide free as well as dose intensified BACOPP-D protocol. Methods: Since May 2000 a total of 115 patients with Hodgkin Lymphoma (HL) stage IIB, III, and IV were treated with BACOPP-D which included cyclophosphamide 1250 mg/m2 (d1), adriamycin 25 mg/m2 (d1+2), dacarbazine 250 mg/m2 (d1-3), procarbazine 100 mg/m2 (d1-7), prednisolone 40 mg/m2 (d1-14), bleomycin 10 mg/m2 (d8) and vincristine 1,4 mg/m2 (maximum 2 mg, d8) at three-weekly intervals with granulocyte colony-stimulating factor (G-CSF). A consolidating involved field radiation (30 Gy) was performed only in patients who achieved less than CR following chemotherapy. Post-treatment follow-up included PET imaging. Results: Until now 97 patients (median age 35 years, range 17-65; 61 male, 36 female) are assessable for toxicity and treatment outcome. We analyzed the acute toxicity for 728 cycles of BACOPP-D. CTC/WHO grade III/IV haematological toxicities per patient were observed as follows: leukopenia 93%, anemia 39%, and thrombocytopenia 33%. CTC grade III/IV non-haematological side effects included documented infection (4%) and lung toxicity (one patient). A total of 85 patients (88%) achieved complete remission, 9 patients (9%) achieved partial remission, three patients (3%) had progressive disease. At a median observation time of 39 months (0,9-77 months), five patients have relapsed, and nine deaths were documented (4 HL-specific and 3 treatment related deaths, 1 death due to ruptured Meckel diverticulum with peritonitis, one 65 year-old woman died in CR following myocardial infarction). One patient developed a second neoplasia (hypopharyngeal carcinoma in an alcoholic). The overall survival and freedom from treatment failure rates at 39 months were 91% and 85%, respectively. FDG-PET scans after BACOPP-D chemotherapy were performed in 68 of 97 patients. PET scans revealed no increased FDG uptake in 48/68 patients (71%), in 20 patients (29%) increased FDG uptake was detected. In the group of patients with increased FDG uptake, one patient developed progressive disease and four patients relapsed. In the group with PET-negative findings no patient relapsed. Diskussion: BACOPP-D regimen appears as a feasible and effective treatment which induced a complete morphologic and metabolic remission in a high proportion of patients with advanced HL. The treatment was associated with moderate acute toxicity. No secondary AML or MDS occurred until now.

Description: Introduction: With many treatment options for chronic myeloid leukemia (CML), endpoints like health-related quality of life (HRQoL) move into focus and might be essential for deciding on treatment strategies. We sought to evaluate HRQoL in CML patients who had been registered in four consecutive studies of the German CML study group. Methods: The EORTC QLQ-C30 questionnaire was used to assess HRQoL of CML patients. Functional scales and global health status were calculated in accordance with Aaronson (1993) and Fayers (2001). With scales ranging from 0 to 100, 8 points are regarded as a minimally important difference (Efficace et al., 2013). Baseline data of responders (R) and non-responders (NR) were compared. Associations between two variables were assessed by the Fisher or Mann-Whitney tests, as appropriate. The global health status and the functioning scores were compared between groups with the van Elteren test, if the groups were stratified for another variable. Furthermore, results of the global health status and the functioning scores in our sample were standardized in accordance with the age (18-29, 30-39, 40-49, 50-59, 60-69, ≥70 years) and sex distribution of the 2448 participants of the German HRQoL outcome study reported by Hinz et al. 2014. The outcome of our sample was then compared with the outcome of these 2448 patients representing QoL of the German population in general. Comparison was performed using a t test. Results: A questionnaire was sent to 1634 patients. During January to April 2011, 858 questionnaires (53%) were sent back. Compared to NR, R were older (median age: 55 vs. 58, p=0.0426); years since diagnosis (median 6.5 vs. 7.4) and the percentage that had been transplanted were lower (24%vs.18%). No differences were observed regarding sex, Euro score, or time after allogeneic hematopoietic stem cell transplantation (HSCT). When answering the questionnaire, 517 (60%) patients received imatinib 400mg (IM400) and 102 (12%) were off therapy after HSCT. Less than 10% of patients received imatinib 800mg, imatinib+AraC or interferon alpha, nilotinib, or dasatinib. Time since diagnosis was ≤3 years in 156 (18%), 〉3 and ≤7 years in 309 (36%), and 〉7 years in 393 (46%) of the patients. Women (352, 41%) perceived a significant reduction in global health status (mean: 62.7, p