ALBERT

Description: Biogeography of Rhizobium radiobacter and distribution of associated temperate phages in deep subseafloor sediments The ISME Journal 7, 199 (January 2013). doi:10.1038/ismej.2012.92 Authors: Tim Engelhardt, Monika Sahlberg, Heribert Cypionka & Bert Engelen

Description: Acute lymphoblastic leukemia (ALL) is a heterogeneous disease and treatment guidelines are still evolving. Allogeneic stem cell transplantation (allo-SCT) offers a potentially curative option and is recommended in first relapse and for high-risk patients in first complete remission (CR). Survival after allo-SCT could be substantially improved due to better risk stratification, patient selection and adapted treatment protocols leading to reduced non-relapse mortality (NRM). Prognostic factors for survival after allo-SCT still need to be defined: pheno- and genotype, patients´ age, conditioning regimens and remission status prior to allo-SCT are under discussion. We analyzed the outcome of 180 consecutive ALL patients who received allo-SCT at the Freiburg University Medical Center between 1995 and 2018 with regard to treatment response, survival, adverse reactions, and performed subgroup analyses to identify prognostic factors. The median age in our cohort was 37 years (ys), 19% were older than 55 ys. 27% were diagnosed with Philadelphia (Ph)-positive ALL, 24% with T-ALL. 36% were treated with relapsed/refractory disease. 48% of allo-SCTs were conducted with a HLA-matched, 19% with a HLA-mismatched unrelated and 33% with a related donor. In 61% the conditioning regimen included total body irradiation (TBI). In 48% no minimal residual disease (MRD) was detected prior to allo-SCT, 20% were transplanted in MRD-positive CR. The overall response rate was 86%, with MRD-negativity in 78%. With a median follow up of 10 ys, we observed a median overall survival (OS) of 23 months and a median progression free survival (PFS) of 11 months. The 10ys-OS was 33%, the 10ys-PFS 31%. The cumulative incidence of relapse was 68% at 10 ys, the cumulative incidence of NRM 12%. Acute graft-versus-host disease (GvHD) III-IV° occurred in 17%, severe chronic GvHD in 9%. Survival was significantly better in patients reaching MRD-negative CR before allo-SCT (10ys-OS 48% vs. 19%, p

Description: Introduction: Novel therapies for relapsed/refractory multiple myeloma (RRMM) have demonstrated durable responses that prolong survival, thus assessing health-related quality of life (HRQoL) is becoming increasingly important in patient (pt) care. Long-term RRMM treatment may lead to a higher cumulative symptom burden and negatively affect HRQoL. Indeed, the effect of treatment on HRQoL is reduced in pts with RRMM on later vs initial lines of therapy (LoTs) (Nielsen et al, Eur J Hematol 2017). Consequently, there is a need for treatments that demonstrate durable efficacy while preserving HRQoL. Pomalidomide plus dexamethasone (Pd) has been shown to be an effective treatment for RRMM that does not negatively affect HRQoL in later LoTs (Song et al, Haematologica 2015). In the randomized phase 2 ELOQUENT-3 study (NCT02654132), addition of the SLAMF7-targeted monoclonal antibody elotuzumab (elo) to Pd (EPd) showed a 46% reduction in the risk of progression/death vs Pd, and acceptable safety in pts with refractory or relapsed and refractory MM for whom therapy with lenalidomide and a proteasome inhibitor had failed (Dimopoulos et al, EHA 2018 [LB2606]). We present pt-reported outcome (PRO) data to assess the impact of EPd on HRQoL in pts from ELOQUENT-3. Methods: The M.D. Anderson Symptom Inventory MM module (MDASI-MM) and the 3-level version of the EuroQoL 5 Dimensions Questionnaire (EQ-5D-3L), which included the global health visual analog scale (VAS) measure, were administered at baseline (BL) and at the start of every 28-day treatment cycle until discontinuation and at survival follow-up. All randomized pts with BL and ≥1 post-BL assessment were included in the PRO analysis. Changes from BL scores were evaluated descriptively: high scores indicate better health for EQ-5D-3L, but more severe symptoms for MDASI-MM. Time to first deterioration was evaluated, with a deterioration event defined as the absolute value of the change from BL ≥ the responder definition threshold (MDASI-MM symptom item assessing pain, fatigue, and bone aches: 2; EQ-5D-3L VAS: 7). Results: This analysis included 117 randomized pts (EPd, n=60; Pd, n=57) who had received a median of 3 prior LoTs. PRO completion rates at BL were 79% for MDASI-MM (EPd, 85%; Pd, 72%) and 84% for EQ-5D-3L (EPd, 88%; Pd, 79%). Although completion rates between treatment groups were similar throughout the study, analysis of QoL was not feasible after Cycles 13 for EPd and 10 for Pd as the number of pts with questionnaires dropped below 20%. Mean BL QoL scores were similar for EPd vs Pd (EQ-5D-3L utility, 0.676 vs 0.682; EQ-5D-3L VAS global health status, 61.9 vs 62.9). A clinically meaningful deterioration from BL in EQ-5D-3L VAS health status (mean change -9.0) was observed with Pd at Cycle 2. In contrast, there were no clinically relevant deteriorations in EQ-5D-3L VAS health status with EPd, and a sustained improvement from BL was observed between Cycles 9 and 12 (mean change 8.2, 11.7, 9.7, and 10.4, respectively; Figure). MDASI-MM symptom scores for pain and bone aches showed no clinically relevant change from BL levels in both groups, but fatigue worsened (mean change 2.5) in the Pd group at Cycle 9. Pts who discontinued treatment early tended to have lower HRQoL in both treatment arms. There were no differences in time to first deterioration for EPd vs Pd for MDASI-MM symptoms pain, fatigue, or bone aches, or EQ-5D-3L and VAS domains. Although the risk of deterioration in the severity of MDASI-MM core symptoms (symptoms common across cancer types and treatments) was reduced by 17% (hazard ratio 0.83; 95% CI 0.49-1.42) for those receiving EPd vs Pd, this was not statistically significant (p=0.618); the median time to deterioration was 3.8 mo with EPd and 1.2 mo with Pd. Conclusions: In ELOQUENT-3, pt-reported health status was maintained in pts who remained on EPd per EQ-5D-3L VAS, with no worsening of pain, fatigue, or bone aches per MDASI-MM. There were minimal differences in QoL between pts who received EPd and Pd, suggesting that the addition of elo to Pd does not impair HRQoL, although HRQoL may have been overestimated due to the small sample and treatment discontinuation. These pt-reported findings complement strong clinical data that demonstrated clinically relevant improvements in efficacy and a favorable safety profile for EPd, further supporting the use of this regimen in RRMM. Study support: BMS. Writing support: Simon Wigfield, Caudex, funded by BMS. Figure. Figure. Disclosures Weisel: Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene, Janssen, and Sanofi: Research Funding. Paner:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. Taylor:Adelphi Values: Employment; Bristol-Myers Squibb: Consultancy. Cocks:Adelphi Values: Employment; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Endomag Ltd.: Consultancy. Espensen:Adelphi Values: Employment; Bristol-Myers Squibb: Consultancy, Other: I am an employee of Adelphi Values, a consulting firm that has received payment from BMS for statistical data analysis in BMS trials. Popa-McKiver:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Cavo:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Introduction: Tumor boards have become a crucial institution in oncology practice to provide paramount interdisciplinary cancer treatment, stream-line patient (pt) entries and to ensure treatment according to clinical pathways (CP). We initiated a weekly MM-TB at our institution in 6/2012. Participating experts are hematologist-oncologists, pathologists/cytogenetic specialists, orthopedists, radiotherapists, immunologists/rheumatologists and, if needed, nephrologists, cardiologists and others. Pt applications to be discussed are centrally organized through our CCCF, with the TB advice being centrally stored within our electronic pt information system. Recommended TB advice is made according to best current literature/knowledge and international CP. The development of mandatory CCCF-CP and transparency of decision making are key quality criteria. Methods: This first analysis focused on a) discussed TB questions, b) given recommendations, c) pt characteristics, d) pts’, referring- and participating-physicians' satisfaction with the TB, e) inclusion of these challenging-to-treat pts in clinical trials (CT) and f) PFS/OS of TB pts as compared to the literature (Kumar SK. Leukemia 2012). Grades of recommendations were assigned using the GRADE criteria (Engelhardt M. Haematologica 2014) and meticulously assessed, as well as whether TB recommendations were pursued. Pts’, referring- and participating-physicians' satisfaction with the TB was evaluated via standardized questionnaires, the aimed sample size being n=100 for consecutive pts and ~n=30 each for participating and referring physicians. Results: From 6/2012-5/2014, 483 pts have been discussed within 90 MM-TB sessions, substantially increasing these from 2011 to 2012, 2013 and 2014 by 12-fold. Of the entire MM cohort seen at our institution, 60% of these challenging-to-treat pts were discussed within the TB in 2012, increasing to 71% in 2013. We have currently assessed 200 TB-protocols for pt characteristics, clinical outcome and adherence to TB decisions. Of those, 2% were presented for explicit diagnosis-finding, 17% had newly diagnosed MM, 41% relapsed/refractory MM and 40% had attained stable disease or better with their last-line therapy and were discussed to resolve their ongoing treatment. Expectedly, most pts (89%) were discussed for their next-line treatment, 43% due to strains with comorbidities, symptom control, side effects, diagnosis finding and MM-staging, and 11% due to various other reasons (multiple entries possible). Mean treatment lines of pts discussed in the TB was 2 (range 0-10), deciding on their 3rd-line-treatment. Within the TB cohort, 70% were presented once, but 30% several times (mean 2, range 2-4). Of these multiple presentations, most pts had relapsed or refractory MM, this rate further increasing towards the 3rd and 4th TB-presentation. The adherence to TB-recommendations was excellent with 93% of decisions being pursued. Reasons for adapted approaches were practicable issues or disagreement of the pt, family or referring physician. Of currently 80/100 interviewed pts, 95% were entirely satisfied with their care, treating oncologists/MM-expert team and very supportively perceived the MM-TB. Of note, 94% considered their cancer care ideally achieved by the TB, 92% that their local physician profited greatly and 88% that their personal preferences were also accounted for. Of 30 interviewed participating physicians, 97% considered themselves well-educated and their time well-spent. Of currently 18 referring physicians, 73% were unconditionally satisfied with all TB-diagnostics and -therapies, with the university centers' cooperation and 65% acknowledged no information loss. Of 288 pts assessed for their CT suitability, 28% were suggested by the TB to be included, with 53% actually being able to enter therein. Thus, 15% of our MM-TB cohort could be included in a CT, which is considerable since these were challenging-to-treat pts who had received extensive prior therapies and showed several comorbidities. This also confirms current CT accrual rates for cancer pts of 5-15%, which can be increased with well-structured TB. Conclusions: Our preliminary results suggest that this MM-TB is a highly relevant exchange platform and allows physicians from different disciplines to intensely and rewardingly collaborate for state-of-the-art cancer care. Disclosures No relevant conflicts of interest to declare.

Description: Introduction:Multiple myeloma (MM) disease progression is dependent on the ability of the MM plasma cells (PC) to leave the bone marrow (BM), re-enter the peripheral blood (PB) and disseminate to other BM sites. Previous studies show that expression of CXCL12 by BM stromal cells is crucial for MM PC retention within the BM. However, the mechanisms which overcome this retention signal enabling MM PC egress and dissemination via the PB are poorly understood. Previous studies in haematopoietic progenitor cells have demonstrated that CCL3 overcomes the CXCL12 retention signal to drive mobilisation to the PB (Lord et al. Blood 1995). Here, we examined the role of the CCL3 chemokine receptor CCR1 in driving MM PC dissemination. Methods and results: Initially, we assessed the expression of CCR1 protein on CD138+CD38++CD45loCD19- PC from 28 MM, 8 MGUS and 2 SMM patients by flow cytometry. Results show CCR1 expression is significantly increased in newly diagnosed MM compared with premalignant MGUS and SMM patients (p=0.03; CCR1 MFI mean±SEM, MGUS: 53.0±33.6; SMM: 37.6±8.9 MM: 250.9±71.6). Furthermore, CCR1 expression on PB MM PC positively correlated with PB MM PC numbers (p=0.03; n=11 patients). To identify mechanistically how CCR1 may promote dissemination, the effect of CCL3 on the response to CXCL12 in human myeloma cell lines (HMCL) was assessed in vitro. The migration of RPMI-8226 and OPM2 cells was induced by CCL3 or CXCL12 chemoattractant in a transwell assay. Notably, pre-treatment of RPMI-8226 or OPM2 with CCL3 abrogated migration towards CXCL12 and blocked F-actin remodelling in response to CXCL12 in vitro. These findings suggest that CCL3 can desensitise cells to exogenous CXCL12, providing a potential mechanism facilitating loss of the CXCL12 retention signal. To confirm whether CCR1 is required for driving MM PC dissemination, homozygous CCR1 knockout (KO) cells were generated using a lentiviral CRISPR/Cas9 system in OPM2 cells. CCR1-KO OPM2 cells were confirmed to have no detectable CCR1 expression by flow cytometry and could no longer migrate towards CCL3 in vitro. Empty vector (EV) or CCR1-KO OPM2 MM PC were injected into the tibia of immune-compromised NOD-scidgamma (NSG) mice. After 4 weeks, primary tumour within the injected tibia and disseminated tumour in the PB and the contralateral tibia and femur was assessed by flow cytometry. We found that mice bearing CCR1-KO cells have a 45.5% decrease in primary tumour growth (p=0.008; % GFP+ of total mononuclear cells, EV: 77.2±17.2; CCR1-KO: 42.1±24.4), a 97.8% reduction in PB MM PC (p

Description: 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 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

Description: Patients (pts) with mature (peripheral) T-cell lymphoma are known to have a poor prognosis when receiving standard conventional chemotherapy. This leads many physicians to regard high dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) as standard therapy for these pts. We here present a retrospective analysis on 424 pts with mature T-cell lymphoma who have received HDT and ASCT in EBMT centres between 2000 and 2005. Patients with primary cutaneous or immature (lymphoblastic) lymphoma were not included. Histological subtypes were anaplastic large cell lymphoma (ALCL, n=98, 23.1%; 19 anaplastic large cell kinase (ALK) positive, 42 ALK negative and for 37 pts the ALK status was unknown), peripheral T-cell lymphoma (PTCLu, n=176, 41.5%), angioimmunoblastic T-cell lymphoma (n=120, 28.3%) and aggressive T-cell lymphoma unspecified (n=30, 7.1%). Median age at ASCT was 51 years (17.2–73.5), median time from diagnosis to ASCT was 9 months (4–99), and median follow up for surviving pts was 36 months (0.4–99). 268 pts (63%) were male. 1/3 received HDT and ASCT after only one previous treatment line. 35% of the pts were treated in CR1, and 52% in chemosensitive disease worse than CR1. At the time point of ASCT only 12 pts (2.8%) had a poor performance status. 9% of the pts received total body irradiation as part of the conditioning regimen. At 3 years after ASCT non relapse mortality (NRM) was 7.4% and the relapse rate (RR) was 43.1%. In multivariate COX analysis for NRM refractory disease (p