ALBERT

Beschreibung: Introduction: The role of autologous stem cell transplantation (ASCT) as first line treatment for newly diagnosed patients with myeloma is currently under evaluation given the high response rates to novel induction treatment. The outcomes for patients that do not proceed to ASCT following induction remain unclear and are likely to be determined by genetic risk and response to therapy. In order to evaluate this further, this single arm phase 2 clinical trial conducted at 13 sites in the UK was designed to determine the 2 year progression free survival for patients that achieved ≥ very good partial response (VGPR) following induction therapy without ASCT. Those achieving partial response (PR) were consolidated with ASCT according to routine practice. In this first analysis we report secondary endpoints: disease response and regimen-related toxicity in patients completing induction, including minimal residual disease (MRD) negativity by multiparameter flow cytometry. Methods: Patients with newly diagnosed myeloma eligible for ASCT received PAD (bortezomib 1.3mg/m2 days 1, 4, 8, 11; doxorubicin 9mg/m2 days 1-4 and dexamethasone 40mg days 1-4 (and days 8-11 and 15-18 for the first cycle only)) for up to 6 cycles (minimum of 4). Bortezomib was initially given intravenously (IV), but once approved this was switched to sub-cutaneous (SC). Those failing to achieve PR were offered salvage therapy off protocol. All others had peripheral blood stem cell (PBSC) mobilisation using cyclophosphamide + GCSF, followed by MRD assessment on bone marrow aspirates using multi-parameter flow cytometry. Depending on disease response, patients were then stratified to ASCT (PR) or no further treatment (≥VGPR). Responses were assessed using International uniform response criteria (Durie 2006) by intent-to-treat and toxicity scored according to CTCAE version 4.0. High risk disease was defined by the presence of one or more adverse FISH lesions (t(4;14), t(14;16), t(14;20), del(17p13), +1q21) as described in the MRC Myeloma IX trial. Results: Between March 2011 and January 2014, 153 patients were enrolled (median age of 55, range 28-71 years). 139 (91%) received between 4-6 cycles of PAD. The majority (135, 88%) received SC only bortezomib and 18 (12%) received at least 1 cycle IV. The overall response rate to PAD was 81% with 46% achieving ≥VGPR (sCR: 6 (4%), CR: 13 (8%), VGPR: 51 (33%), PR: 54 (35%)). FISH data was available for 122 patients, 91 (75%) patients were standard risk and 31 (25%) were adverse. Responses were similar irrespective of ISS or genetic risk (standard, ≥VGPR 44%, PR 34%; adverse, ≥VGPR 55%, PR 29%). MRD results are currently available in 70 of the 124 patients achieving PR post PBSC harvest. Of this group 41 achieved ≥VGPR post-harvest (22 MRD+ and 19 MRD-) and hence did not proceed to ASCT, 13 patients achieved CR of which 8 were MRD negative. Toxicity was as expected for PAD and predominantly haematological. Notably the incidence of neuropathy was lower than that previously reported with IV bortezomib. Grade 3-4 events were: neutropenia: 18%; thrombocytopenia 7%. Grade 2-4 peripheral neuropathy was reported in 27% compared to 40% in the HOVON-65/ GMMG-HD4 Trial using IV bortezomib. Grade 1-2 neuropathy was similar for patients who received IV (55.6%) or SC (60%) bortezomib; however only 7% of patients receiving SC bortezomib developed grade 3 neuropathy compared to 28% with the IV route. Conclusions: SC PAD is a highly effective induction regimen for patients with newly diagnosed myeloma achieving a ≥VGPR of 46%. Of the 41 patients achieving ≥VGPR post-harvest with MRD result available, 46% were MRD negative. Response rates were similar across ISS and with adverse FISH. The use of SC bortezomib improved tolerability and substantially reduced neurotoxicity. ISRCTN no: 03381785. Disclosures Popat: Janssen: Honoraria. Cavenagh:Janssen: Honoraria. Schey:Janssen: Consultancy, Honoraria. Cook:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cook:Janssen: Honoraria, Research Funding. Yong:Janssen: Honoraria.

Beschreibung: Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma.

Beschreibung: Abstract 2361 Introduction: Reduced intensity allogeneic transplants represent a potentially curative therapy in older patients with haematological malignancies. However the upper age limit for transplantation using a sibling or unrelated donor is unclear and few studies have addressed this important issue. In the UK in vivo T cell depletion utilising alemtuzumab is commonly used as a strategy to reduce the risk of acute and chronic graft-versus-host disease (GVHD) but this manoeuvre impairs immune reconstitution and may pose a particular problem in older patients. Aim: We analysed the outcome of patients over the age of 60 after an alemtuzumab based reduced intensity allograft from five UK Transplant Centres with the aim of identifying factors determining long term outcome and also factors affecting the duration of inpatient admission during the first 100 days post transplant. A modified Charlson's comorbidity index score (Sorror modified HCT comorbidity index) was applied to analyse the transplant outcomes of these patients according to the presence of transplant co-morbidities. Patients and Methods: We have studied the outcome of 161 patients (89 male, 72 female) after an alemtuzumab conditioned reduced allograft allograft for a haematological malignancy. The median age of the patients was 62 years(range 60–72). 115 patients had a transplant for myeloid malignancies (87 acute myeloid leukaemia, 21 myelodysplastic syndrome, 2 chronic myeloid leukaemia, 5 myelofibrosis) and 46 for lymphoid malignancies (18 Non_Hodgkin's lymphoma, 14 chronic lymphocytic leukaemia, 4 T-prolymphocytic leukaemia, 7 multiple myeloma and 3 acute lymphoblastic leukaemia). 93 patients received an unrelated donor transplant and 68 had a sibling transplant. The great majority of patients were transplanted using a Fludarabine/Melphalan conditioning regimen(n=118) whilst 13 received a combination of fludarabine and busulphan, 21 BEAM (BCNU, cytarabine, etoposide, melphalan) and 9 a combination of BEAM and fludarabine. The median follow up was 19.1 months (range 2–94 months). Results: The one year overall survival for the whole group was 52% and the predicted two year OS 46%. The transplant related mortality (TRM) was 19% in the first 100 days post transplant and 23% in the first year post transplant. 40 patients (25%) relapsed. 25 patients (21%) developed Grade III-IV acute GvHD and 16 (10%) patients developed chronic extensive GvHD. There was a weakly negative correlation between Age and Bed Days(p:0.05843) but the correlation between high comorbidity index (3 or greater than 3) and increased bed days is significant(P:0.0013). Transplant outcomes were affected by Sorror modified comorbidity index for HCT.A score of 3 and above was significantly associated with decreased overall survival (P:0.001) and interestingly with decreased disease free survival (P:0.02). CMV status and stem cell dose did not have any impact on overall survival and disease free survival and CR1 at transplantation was showed a trend towards increased overall survival(P:0.05). Conclusions: Reduced intensity alemtuzumab based stem cell transplant can be delivered safely in patients above the age of 60. It appears that a Sorror comorbidity score of 3 and above has a negative impact on overall survival and disease free survival of these patients and significantly increases inpatient days.These observations require confirmation in a larger cohort of patients but suggest that the selection of patients above the age of 60 for a reduced intensity transplants will be facilitated by incorporation of the Sorror HCI comorbidity index into a transplant algorithm. Disclosures: No relevant conflicts of interest to declare.

Beschreibung: Introduction Polyneuropathy, organomegaly, endocrinopathy, dermopathy associated with a paraproteinaemia (POEMS syndrome) is a rare paraneoplastic syndrome secondary to a plasma cell dyscrasia. Effective treatment of the underlying plasma cell dyscrasia, including ASCT, can control the disease and often dramatically control symptoms though limited data is available for ASCT in POEMS. Specific Aim The aim of this study was to describe the clinical outcome of ASCT for patients with POEMS syndrome. We wish to determine the impact of patient and disease-specific factors on prognosis and effectively measure the extent of systemic disease involvement and organ-specific responsiveness of ASCT. Methodology Patient-, disease-, and transplant-related variables were collected according to the data entries in the EBMT database, including tracking incomplete data entries from participating centers. Systemic involvement and organ-specific response to ASCT was detailed utilizing an organ involvement tool pre- and post-ASCT. Results 127 patients underwent an ASCT between 1997-2010 and satisfied the entry criteria. The median age was 50 years (range 26-69) with 51.2% ≤50 years of age. The extent of systematic disease involvement was: peripheral neuropathy in 58.6%, volume overload in 66.2%, organomegaly in 48.3%, papilledema in 19.8%, dermopathy in 46.6% and 34.5% had sclerotic bone lesions at presentation. The median time from diagnosis to ASCT was 7.5 months (range 1-346) with 31.5% of patients receiving an ASCT 〉12 months from diagnosis. The graft source was PBSC in 100% of patients. Disease status at ASCT was: 47.5% CR/PR, 34% SD/MR/untreated and 18.4% in PD (missing information in 19% of patients). The conditioning regimen was Melphalan ≥200mg/m2 in 52.5%, Melphalan

Beschreibung: Background: Immune reconstitution after AlloSCT is a highly complex process influenced by both graft & recipient-related factors including post-graft therapies. Delayed T-cell reconstitution remains a source of morbidity & mortality and may contribute to limited anti-tumour effect. We sought to evaluate the immune reconstitution kinetics in the setting of post-graft Lenalidomide (Revlimid®) to augment the graft-versus-myeloma effect, by defining key immune biomarkers, in the NCRI LenaRIC phase II trial. Material & Methods: All patients recruited into the study underwent a reduced intensity conditioned (RIC) AlloSCT using Fludarabine & 2Gy TBI with ATG (Fresenius) as in vivo T-cell depletion, following a high dose melphalan ASCT (planned tandem SCT programme). Patients were scheduled to receive Lenalidomide (5mg-10mg/day) on day+35 if stable donor engraftment in the absence of GvHD. Lenalidomide discontinuation was planned at 12 months post-transplant, with donor lymphocyte infusions (DLI) given to patients with evidence of residual disease, relapse or mixed chimerism. Sequential peripheral blood samples were drawn at predetermined time frames before (baseline) and after graft infusion (D+30,+60,+90,+180,+270 & D+360) in all trial registrants. Using multi-parameter flow cytometry (MFC), a comprehensive panel of immune subset & functional/activation markers were used to define characteristics of T-cell, B-cell, regulatory T-cell & NK cells. The inflammatory proteome (IL-1b, IL-4, IL-5, IL-6, IL-10, IFNg, TNFa, CXCL8 & GM-CSF) and soluble immune checkpoints (PD-1 & ICOS) were analyzed using LUMINEX assays on serial serum samples at parallel points. PB cell subset-specific Complete Donor Chimerism (CDC) was analysed by single tandem repeat PCR at day (D)+100,+180,+270 and D+365. Results: From January 2011 to May 2015, 40 patients with myeloma ≥VGPR after 1st or 2nd ASCT, were recruited into the LenaRIC protocol. The median age was 49 years (range 35-65) with PB as the graft source (Matched Related Donor n=16, 10/10 Matched Unrelated Donor n=23; 1 patient not transplanted). Viable samples were received from 37/40 patients (92.5%), with no cycles of Lenalidomide received by 3/37 (8.1%) patients, 1-6 cycles received by 13/37 (35.1%) patients & 〉6 cycles received by 21/37 (56.8%) patients. 5 patients completed 12 cycles as per protocol treatment; of those completing 〉= 10 cycles, 5/16 received DLI. Only 10/37 (27%) of patients achieved a CD4+ cell count 〉200/µl in a median of 180 days compared with 30/37 (81%) of patients who achieved a CD8+ cell count 〉200/µl in a median of 60 days. In patients who did not receive any doses of Lenalidomide, higher levels of CD8+ cells (p=0.013) but lower NK cell levels (p=0.071) were evident at D+30 compared with those eligible to proceed with Lenalidomide. No difference was noted between Lenalidomide exposure subgroups in relation to CD8+ or CD4+ cell recovery. Treg cells were increased at D=270 & D+365 in those who received 〉6 cycles of Lenalidomide, though this corresponded with a higher level of HLA-DR expression on CD8+ T cells representing global immune activation. Significant differences between Lenalidomide exposure subgroups were evident in the inflammatory proteome readout at D+90. CXCL8 levels peaked at D+270, especially in those who received 〉6 cycles of Lenalidomide. Of 30 evaluable patients, T-cell CDC was seen in 63.3% at D100, with 84% of evaluable patients having CDC at D365. No difference between subgroups was evident in relation to rapidity of CDC and stability of CDC. Conclusions: The sequential monitoring of immune biomarkers in the setting of post-graft Lenalidomide following a T-deplete RIC-AlloSCT highlights the rapid and sustained quantitative and functional reconstitution of donor immune homeostasis. The clinical significance of these findings requires correlation with both the anti-tumour immune effect and theimmunopathy ofAlloSCT (GvHD). Unrestricted educational grants were provided by Cancer Research UK and byCelgene.Lenalidomideprovided free of charge byCelgene. The support and time of participating patients and their families is gratefully acknowledged Figure 1 a) Changes in circulating CD8+ T-cells according to Lenalidomide exposure following RIC-Allo SCT for myeloma b) Changes in circulating CD4+CD25+FoxP3+ T-Reg cells according to Lenalidomide exposure following RIC-Allo SCT for Myeloma Figure 1. a) Changes in circulating CD8+ T-cells according to Lenalidomide exposure following RIC-Allo SCT for myeloma. / b) Changes in circulating CD4+CD25+FoxP3+ T-Reg cells according to Lenalidomide exposure following RIC-Allo SCT for Myeloma Disclosures Cook: Glycomimetics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Brock:AstraZeneca: Equity Ownership; GlaxoSmithKline: Equity Ownership. Cavenagh:Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Cook:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria; Cancer Research UK: Research Funding; Takeda: Honoraria.

Beschreibung: Background Bendamustine has efficacy as first-line treatment in multiple myeloma (MM) (in combination with prednisone), and in refractory patients who have been heavily pre-treated. Dose finding studies have not been performed for bendamustine in heavily pre-treated relapsed/refractory patients. MUK one is a randomised phase II selection trial assessing the activity & tolerability of two doses of bendamustine (B), 60mg/m2 vs 100mg/m2, in combination with thalidomide (T) & dexamethasone (D) in patients with relapsed/refractory MM. Methods Patients were randomised to receive B(60)TD or B(100)TD (B days 1 & 8 ; T 100mg od; D 20mg d1, 8, 15 & 22; 28 day cycle). Eligibility was based on confirmed MM with measurable disease, ECOG 0-3, platelets 〉75x109/L & neutrophils 〉1.5x109/L at 1st or later relapse. In the initial protocol, patients with lower platelets/neutrophils attributable to myeloma were eligible. Activity and tolerability were joint primary endpoints. The primary activity endpoint was ≥PR within 6 cycles. Tolerability was defined as the ability to receive at least 2 cycles of treatment at full dose with no delays of 〉2 weeks, without primary growth-factor support. Response rates 75x109/L, regardless of marrow infiltration. Consequently, two analysis populations are defined. (i) Primary analysis population: patients fulfilling amended eligibility criteria without PD after 1 cycle, having ≥1 dose of study drug, (B60TD evaluable n=45; B100TD evaluable n=14). (ii) Combined population: as for (i) but including patients with PD after cycle 1, (B60TD combined n=54; B100TD combined n=20). This group represents an intention to treat population with the amended criteria. 46% (80% CI [37-56]) of patients in the B60TD combined population achieved ≥PR, with a median PFS of 7.5 months (95% CI [5.3-8.7]). In the B100TD combined population 25% (80% CI [13-42]) of patients achieved ≥PR, with a median PFS of 2.6 months (95% CI [1.7-5.6]). In the assessment of tolerability, 70% (80% CI [59-79]) of B60TD primary patients assessable for tolerability received ≥2 cycles of full-dose treatment with no delay 〉2 weeks. Median number of B60TD cycles was 6 (range 1-9), with 64% patients receiving ≥6 cycles. 32% patients experienced ≥ grade 3 neutropenia, 25% ≥ grade 3 thrombocytopenia, & 14% ≥ grade 3 anaemia. There was 1 grade 3 neurotoxicity, & no grade 3 nausea or GI disturbance. Of the B100TD primary patients 71% (80% CI [51-87]) met tolerability criteria. Median number of cycles was 4 (range 1-9), 29% patients receiving ≥6 cycles. 64% patients experienced ≥ grade 3 neutropenia, 21% ≥ grade 3 thrombocytopenia, & 21% ≥ grade 3 anaemia. There were 3 grade 3 neurotoxicities, no grade 3 nausea & 1 grade 3 diarrhoea. Thromboembolism rates with prophylactic anticoagulation was 4% overall. 84% of patients had ≥3 prior therapies, PS 0/1 (85%) & relapsed MM (78%); 37% were ISS 3 at entry, mean b2M=5.6. Most had prior T (90%), Lenalidomide (74%) & Bortezomib (84%); 74% had ≥1 prior autograft. Discussion The combination of BTD shows promising response rates at the 60mg/m2 dose, despite only 70% of evaluable patients receiving at least 2 full cycles of bendamustine with ≤2 week delay, in this challenging multi-treated group of patients. The B100TD arm closed to recruitment at interim analysis due to lack of tolerability on the basis of pre-defined stopping rules. Responses were also lower in this arm compared to B60TD arm, which may reflect the ability of patients to receive more cycles of treatment to schedule at 60mg/m2 than at 100mg/m2. Although not passing the strict pre-specified tolerability boundaries, B60TD appears deliverable beyond 2 cycles in multiply-pretreated MM, with PR in excess of 45%, comparing favourably other novel agent combinations in this heavily pre-treated population. Disclosures: Schey: Napp: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Cook:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Cavet:Celgene: Consultancy, Research Funding.

Beschreibung: Abstract 4115 Introduction: Polyneuropathy, organomegaly, endocrinopathy, skin changes associated with a paraproteinaemia (POEMS syndrome) is a rare paraneoplastic syndrome secondary to a plasma cell dyscrasia. Effective treatment, including ASCT, of the underlying plasma cell dyscrasia can control the disease and often dramatically control symptoms. Limited data is available for ASCT in POEMS. Specific Aim: The aim of this study was to describe the clinical outcome of ASCT for patients with POEMS syndrome, determining the impact of patient and disease-specific factors on prognosis. The incidence of engraftment syndrome and the presentation of relapse were examined. Methodology: Patient-, disease-, and transplant-related variables were collected according to the data entries in the EBMT database, including tracking incomplete data entries from participating centers. Results: 116 patients underwent an ASCT between 1997–2009 and satisfied the entry criteria. The median age was 50 yrs (range 26–69) with 56.8% of patients '50 year of age. 58.6% had peripheral neuropathy, 66.2% volume overload, 48.3% had organomegaly, 19.8% had papiloedema, 46.6% had dermopathies and 34.5% had sclerotic bone lesions at presentation. The median time from diagnosis to ASCT was 7.8 mns (range 1–346) with 34.5% of patients receiving an ASCT 〉12 months from diagnosis. The graft source was PBSC in 100% of patients. Disease status at ASCT was: 32% CR/PR, 30% SD/MR/untreated and 5 in PD. Missing information on stage in 33% of the cases. The conditioning regimen was Melphalan ≥200mg/m2 in 52.5%, Melphalan

Beschreibung: A major challenge in modern myeloma management is the selection of the best initial treatment from a plethora of available therapies. PAD (bortezomib, doxorubicin, and dexamethasone) is a highly effective regimen which may obviate the need for an upfront high-dose melphalan stem cell transplant (HDSCT). However, it is not clear a priori which patients will benefit from this treatment. In the phase 2 PADIMAC trial, patients with newly diagnosed myeloma were treated with six cycles of PAD and stratified to receive HDSCT in partial remission (PR) or watch and wait in very good partial remission (VGPR) or better. To identify predictive biomarkers, we extracted somatic RNA prior to treatment and performed massively parallel RNA sequencing (RNAseq). Basic quality control metrics suggested a high-quality RNAseq dataset. Furthermore, spiked expression of IgH fusion partners was consistent with fluorescent in situ hybridization (FISH) data for each sample. All t(4;14) and t(4;16) cases were correctly identified by RNAseq on the basis of the relevant fusion transcript. As a final quality control measure, recurrent variants (e.g. NRAS, KRAS, TP53, FAM46C, DIS3) were identified in the expected proportions. We performed a pre-planned analysis of differential gene expression between those patients achieving a VGPR or better, sustained for at least 12 months without HDSCT (excellent responders), and those patients who achieved less than a PR (poor responders). 85 genes were upregulated in poor responders and 225 in excellent responders. Interestingly, there was no significant overlap between our PAD-predictive signature and the Arkansas 70 gene poor prognosis signature, the Arkansas 17 gene poor prognosis signature, or the EMC92 prognostic signature. This is likely to reflect in part, the greater sensitivity of RNAseq for gene expression compared to microarrays. However, it also implies that there is a selective signature for PAD responsiveness. We employed the Gage and Pathview packages to identify non-redundant pathways associated with PAD responsiveness. Significantly upregulated genes in poor responders were those involved in: DNA replication, base excision repair, and the Fanconi anaemia pathway. Genes upregulated in excellent responders included those involved in: several signalling pathways (including RAS, NF-Kappa B, FOXO and JAK-STAT pathways); chemokine and cell adhesion; protein processing in the endoplasmic reticulum; and immune activation pathways such as T-cell receptor signalling and natural killer cell-mediated cytotoxicity. Finally, we investigated the ability of expression signatures to stratify patients on the basis of PAD responsiveness. Our analysis suggests that RNASeq-defined transcriptional profiles could aid in the selection of patients for PAD therapy (leading to an increase in overall response rate from 70% to 86%), as well as the stratification of patients in CR to a non-HDSCT protocol. We anticipate that our current analysis could easily incorporate specific response signatures for other regimens and could make personalized therapy for myeloma a reality in the foreseeable future. Disclosures Yong: Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding. Streetly:Guys and St. Thomas' NHS Trust: Honoraria. Schey:Celgene, Takeda: Honoraria; Celgene: Consultancy; Celgene, Johnson & Johnson: Speakers Bureau. Cook:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria. Cook:Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Myeloma UK: Membership on an entity's Board of Directors or advisory committees.

Beschreibung: Introduction Immune dysfunction in multiple myeloma (MM) is now a well accepted, if not yet completely understood, phenomenon contributing to both an increased incidence of infection and suboptimal responses to immunotherapies. The recently described Th17 subset of T helper cells is expanded in a range of cancers, and may contribute either to the evolution or control of tumours, but its role in myeloma pathogenesis remains unclear. We therefore investigated the presence, phenotype and function of this novel immune subset in a cohort of MM patients and healthy donors. Methods Peripheral blood (PB) samples were taken from healthy donors (HC, n=27) and MM patients (n=31); mononuclear cells (PBMC) were isolated by density centrifugation. Bone marrow aspirate (BM) samples were taken from MM patients (n=7) and HC (n=3); mononuclear cells were isolated by red cell lysis (BioLegend). For phenotyping, cells were treated with phorbol 12-myristate 13-acetate, ionomycin and brefeldin A and assessed by flow cytometry. Where stated, cells were stimulated with candidal wall mannoprotein MP65 (Peptivator, Miltenyi Biotec). For coculture experiments, CD4+T cells were isolated from PBMC using magnetic bead separation (MACS, Miltenyi Biotec) and cultured with human myeloma cell lines (HMCLs: U266B, JIM3, KMS11) with or without human bone marrow stromal cell lines (BMSC: HS-5, HS-27). Statistical analysis was performed using GraphPad Prism v6. Results As noted in previous studies, patients with myeloma have a marked CD4+ T-cell lymphopenia. Within the CD4+ population, MM patients also had a reduced frequency of IL-17+ cells (Th17) compared to HC: 0.41% (95% CI 0.27-0.56) vs. 0.81% (95% CI 0.47-1.15), p=0.0241 (student’s t-test). Using the mean fluorescence intensity for IL-17 as a surrogate indicator of cytokine production, IL-17 production in Th17 from MM patients was significantly reduced compared to HC (p=0.0195). Advancing disease stage correlated significantly with a reduction in PB Th17 frequency (p

Beschreibung: Background. Aprotinin, an antifibrinolytic medication, reduces the requirement for allogeneic red blood cell (RBC) transfusion following elective cardiac surgery in adults. The effect of aprotinin for this indication in children is unclear. Objective. To determine if intravenous aprotinin, administered perioperatively to patients