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Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10−8) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10−7). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.

In clinical practice, the consideration of non-specific symptoms of rare diseases in order to make a correct and timely diagnosis is often challenging. To support physicians, we developed a decision-support scoring system on the basis of retrospective research. Based on the literature and expert knowledge, we identified clinical features typical for Fabry disease (FD). Natural language processing (NLP) was used to evaluate patients’ electronic health records (EHRs) to obtain detailed information about FD-specific patient characteristics. The NLP-determined elements, laboratory test results, and ICD-10 codes were transformed and grouped into pre-defined FD-specific clinical features that were scored in the context of their significance in the FD signs. The sum of clinical feature scores constituted the FD risk score. Then, medical records of patients with the highest FD risk score were reviewed by physicians who decided whether to refer a patient for additional tests or not. One patient who obtained a high-FD risk score was referred for DBS assay and confirmed to have FD. The presented NLP-based, decision-support scoring system achieved AUC of 0.998, which demonstrates that the applied approach enables for accurate identification of FD-suspected patients, with a high discrimination power.

Background: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. Methods: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. Results: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09–1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01–1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. Conclusions: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. Impact: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.

Purpose Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by recurrent genetic aberration in leukemic stem cells, namely Philadelphia chromosome caused by reciprocal translocation t(9;22)(q34;q11). In our study, we analyzed the telomeric complex expression and function in the molecular pathogenesis of CML. Methods We employed CD34+ primary leukemic cells, comprising both leukemic stem and progenitor cell populations, isolated from peripheral blood or bone marrow of CML patients in chronic and blastic phase to analyze the telomere length and telomeric-associated proteins. Results The reduction in telomere length during disease progression was correlated with increased expression of BCR::ABL1 transcript and the dynamic changes were neither associated with the enzymatic activity of telomerase nor with gene copy number and expression of telomerase subunits. Increased expression of BCR::ABL1 was positively correlated with expression of TRF2, RAP1, TPP1, DKC1, TNKS1, and TNKS2 genes. Conclusions The dynamics of telomere length changes in CD34+ CML cells is dependent on the expression level of BCR::ABL, which promotes the expression of certain shelterins including RAP1 and TRF2, as well as TNKS, and TNKS2, and results in telomere shortening regardless of telomerase activity. Our results may allow better understanding of the mechanisms responsible for the genomic instability of leukemic cells and CML progression.

This work was partially supported by intramural funds of the University of Pisa, DKFZ, and University Hospital of Southern Jutland, Denmark, and by a grant of the French National Cancer Institute (INCA). The authors wish to thank Dr. Dominic Edelmann (Division of Biostatistics, DKFZ) for helpful advice about data analysis., There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53-4.69, p = 3.55 x 10(-15) for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34-4.33, p = 1.62 x 10(-13) for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population., University of Pisa, DKFZ, University Hospital of Southern Jutland, Denmark, Institut National du Cancer (INCA) France

Pyoderma gangrenosum (PG) is an uncommon, serious, ulcerating skin disease of uncertain etiology. It manifests as a noninfectious, progressive necrosis of the skin characterized by sterile neutrophilic infiltrates. It seems to be a disorder of the immune system. PG is associated with certain underlying conditions in at least 50% of cases. Therefore, it is important to look carefully for comorbidities in every patient with PG and treat them adequately to improve the prognosis. Here, we demonstrate a 35-year-old man diagnosed with multifocal PG and hemophagocytic lymphohistiocytosis (HLH) with fatal outcome, despite combined, long-term, intensive dermatological and hematological treatment with high doses of steroids, cyclosporin, intravenous immunoglobulins (IVIG), HLH-2004 protocol with intravenously administered etoposide, and anakinra. This case is presented owing to the extremely rare coexistence of PG and HLH and the related diagnostic and therapeutic difficulties. It is also worth underlying that the diagnosis of HLH should perhaps be considered in the presence of a high percentage of double-negative T lymphocytes (DNTs) in flow cytometry, after excluding the diagnosis of lymphoma and leukemia. In this article we have also performed and present the critical literature review of local and systemic options in the management of PG lesions based on a detailed search of the PubMed database.

Indtroduction and methods: In chronic lymphocytic leukemia (CLL), molecular and cytogenetic diagnostics are crucial for the determination of accurate prognosis and treatment choice. Among different genetic aberrations, del(17p13) or TP53 mutations constitute high-risk factors, and early identification of such defects is a high priority for CLL patients. While cytogenetic diagnostics is well-established and accessible for the majority of CLL patients in Poland, molecular diagnostics of TP53 mutations is performed only in a few ERIC-certified centers (eight as of September 2020), and only two of these employ next-generation sequencing (NGS) for routine analysis of TP53 status in CLL patients. Here we report the interim results of a project assessing TP53 mutations with NGS technology in relapsed or refractory CLL patients with confirmed negative del(17p13) status. 249 patients from 32 clinical centers were included in the study. Results: NGS analysis revealed TP53 mutations in 42/249 (17%) patients, half of whom (21/249, 8.5%) had subclonal mutations (VAF ≤10%). These results are in line with published data in relapsed/refractory CLL patients. Conclusions: The results of the project demonstrated the feasibility and accuracy of NGS testing in CLL patients despite several initial logistical and technical obstacles. Our study also proved that, with appropriate funding, CLL patients from any hematological center in Poland can have access to state-of-the-art molecular diagnostics

Background/aim To study the long-term clinical efficacy and tolerability of ibrutinib monotherapy in real-world relapsed and refractory chronic lymphocytic leukemia (RR-CLL) patients outside clinical trials. Patients and methods Clinical data of 171 RR-CLL patients treated with ibrutinib were collected within the observational study of the Polish Adult Leukemia Study Group. Results Median patient age was 64 years. Patients were pretreated with 3 (1-10) median lines of therapy, while 42 (24.6%) had 17p deletion. The median observation time was 40 months (range=1-59 months), while median ibrutinib monotherapy reached 37.5 months (range=0.4-59.2 months). Response was noted in 132 (77.2%) patients. The estimated 5-year progression-free survival (PFS) and overall survival (OS) rates were 61.1% (95%CI=49.3-70.9%) and 56.8% (95%CI=45.6-66.6%), respectively. At the time of analysis 97 (56.7%) remained under ibrutinib monotherapy. Conclusion Ibrutinib is clinically effective and tolerable as a monotherapy in real-world RR-CLL patients.

Contains fulltext : 232394.pdf (Publisher’s version ) (Closed access) We evaluated the association between germline genetic variants located within the 3'-untranlsated region (polymorphic 3'UTR, ie, p3UTR) of candidate genes involved in multiple myeloma (MM). We performed a case-control study within the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 3056 MM patients and 1960 controls recruited from eight countries. We selected p3UTR of six genes known to act in different pathways relevant in MM pathogenesis, namely KRAS (rs12587 and rs7973623), VEGFA (rs10434), SPP1 (rs1126772), IRF4 (rs12211228) and IL10 (rs3024496). We found that IL10-rs3024496 was associated with increased risk of developing MM and with a worse overall survival of MM patients. The variant allele was assayed in a vector expressing eGFP chimerized with the IL10 3'-UTR and it was found functionally active following transfection in human myeloma cells. In this experiment, the A-allele caused a lower expression of the reporter gene and this was also in agreement with the in vivo expression of mRNA measured in whole blood as reported in the GTEx portal. Overall, these data are suggestive of an effect of the IL10-rs3024496 SNP on the regulation of IL10 mRNA expression and it could have clinical implications for better characterization of MM patients in terms of prognosis.

This work was partially supported by intramural funds of Univerity of Pisa and DKFZ; by Fondo de Investigaciones Sanitarias (Madrid, Spain) [PI12/02688 to J. S., PI17/02276 to J.S.]; by Instituto de Salud Carlos III, co-funded by FEDER funds —a way to build Europe—[PI14-00613 to V.M.] and by Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (Barcelona, Spain) [2017SGR723 to V.M.]. Open Access funding enabled and organized by Projekt DEAL., Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the "teloscore" in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36-2.11; P = 2.97 x 10(-6) for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86-0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival., Univerity of Pisa, Helmholtz Association, Instituto de Salud Carlos III PI12/02688 PI17/02276, Instituto de Salud Carlos III, European Commission, FEDER funds-a way to build Europe PI14-00613, Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (Barcelona, Spain) 2017SGR723, Projekt DEAL

Canadian Institutes of Health Research, Grant/ Award Number: 81274; Huntsman Cancer Institute Pilot Funds; Leukemia Lymphoma Society, Grant/Award Number: 6067-09; the National Institute of Health/National Cancer Institute, Grant/Award Numbers: P30 CA016672, P30 CA042014, P30 CA13148, P50 CA186781, R01 CA107476, R01 CA134674, R01 CA168762, R01 CA186646, R01 CA235026, R21 CA155951, R25 CA092049, R25 CA47888, U54 CA118948; Utah Population Database, Utah Cancer Registry, Huntsman Cancer Center Support Grant, Utah State Department of Health, University of Utah; VicHealth, Cancer Council Victoria, Australian National Health and Medical Research Council, Grant/Award Numbers: 1074383, 209057, 396414; Victorian Cancer Registry, Australian Institute of Health and Welfare, Australian National Death Index, Australian Cancer Database; Mayo Clinic Cancer Center; University of Pisa and DKFZ, The authors thank all site investigators that contributed to the studies within the Multiple Myeloma Working Group (Interlymph Consortium), staff involved at each site and, most importantly, the study participants for their contributions that made our study possible. This work was partially supported by intramural funds of University of Pisa and DKFZ. This work was supported in part by the National Institute of Health/National Cancer Institute (R25 CA092049, P30 CA016672, R01 CA134674, P30 CA042014, R01 CA186646, R21 CA155951, U54 CA118948, P30 CA13148, R25 CA47888, R01 CA235026, R01 CA107476, R01 CA168762, P50 CA186781 and the NCI Intramural Research Program), Leukemia Lymphoma Society (6067-09), Huntsman Cancer Institute Pilot Funds, Utah PopulationDatabase, Utah Cancer Registry, Huntsman Cancer Center Support Grant, Utah StateDepartment of Health, University of Utah, Canadian Institutes of Health Research (Grant number 81274), VicHealth, Cancer Council Victoria, Australian National Health and Medical Research Council (Grants 209057, 396414, 1074383), Victorian Cancer Registry, Australian Institute of Health and Welfare, Australian National Death Index, Australian Cancer Database and the Mayo Clinic Cancer Center.Open Access funding enabled and organized by ProjektDEAL., The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions., Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10(-7) either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients., Canadian Institutes of Health Research (CIHR) 81274, Huntsman Cancer Institute Pilot Funds, Leukemia and Lymphoma Society 6067-09, United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI) P30 CA016672 P30 CA042014 P30 CA13148 P50 CA186781 R01 CA107476 R01 CA134674 R01 CA168762 R01 CA186646 R01 CA235026 R21 CA155951 R25 CA092049 R25 CA47888 U54 CA118948, Utah Population Database, Utah Cancer Registry, Huntsman Cancer Center Support Grant, Utah State Department of Health, University of Utah, VicHealth, Cancer Council Victoria, Australian National Health and Medical Research Council 1074383 209057 396414, Victorian Cancer Registry, Australian Institute of Health and Welfare, Australian National Death Index, Australian Cancer Database, Mayo Clinic Cancer Center, University of Pisa, Helmholtz Association

Cereblon (CRBN) is crucial for antiproliferative and immunomodulatory properties of immunomodulatory drugs. The objective of this study was to verify whether germline single nucleotide polymorphism...

The paper presents results of measurements conducted during multi-stage studies on injectors of WOLA 72H6 engine. The research was conducted to determine the technical condition of the injectors during their operation. As a result of the injector modeling in the CAD environment, the resonant frequencies of the examined element were obtained. The next stage of the study was a stand-alone tests with the simultaneous recording of vibration parameters. The aim of records was to link the vibration parameters with the technical condition of the tested injectors. The study series was finished with measurements on a real object test stand.

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder of mature B lymphocytes characterized by a heterogenous clinical course. Approximately 60% of cases require treatment initiation due to disease advancement. Immunochemotherapy enables achievement of durable remissions in some of the patients, however despite the observed complete responses relapses occur. These are explained by the persistence of residual leukemic cells in blood, bone marrow and lymph nodes, defined as minimal residual disease (MRD). Use of flow cytometry and molecular methods in assessment of treatment response allows for more detailed response quantification and detection of leukemic cells with ≥ 10-5 sensitivity. Elimination of MRD is an important prognosticator of durable remissions following immunochemotherapy. Furthermore, the significance of MRD assessment increases due to its possible role in CLL treatment individualization and potential surrogate marker of response without the need of long lasting observations. Herein in this publication, the clinical significance of MRD assessment emphasizing flow cytometric methodology is summarized.

Cereblon (CRBN) is crucial for antiproliferative and immunomodulatory properties of immunomodulatory drugs. The objective of this study was to verify whether germline single nucleotide polymorphisms (SNPs) in the

Background The 17p deletion is regarded as the strongest poor prognostic factor in chronic lymphocytic leukemia (CLL). Results of recently performed clinical trials have suggested that ibrutinib significantly improves the outcome in this patient group. Aim The study aimed at analyzing the efficacy and adverse events profile of ibrutinib monotherapy in CLL patients with 17p deletion treated in routine clinical practice outside clinical trials. Materials and Methods Clinical response and adverse events profile of ibrutinib monotherapy were assessed in thirty-five CLL patients with 17p deletion treated within the ibrutinib named patients program in Poland. Results Overall response rate was 80% (28/35 patients) with median observation time of 24.2 months (range 0,1 – 30,9). Complete remission was observed in 5 patients (14.3%), partial remission in 11 (31.4%), partial remission with lymphocytosis in 13 (37.1%), whereas stable disease and progression was noted in 4 (11.4%) and 1 (2.9%) respectively. Response was not assessed in 1 patient. Median progression-free survival was 29.5 months, whereas median overall survival was not reached. Eleven patients died (7 because of infection, 1 of CLL progression, 1 of sudden cardiac death, 1 of disseminated breast cancer and 1 of unknown causes). In 13 patients (37.1%) at least one 3 or 4 grade adverse event occurred. In 11 patients (31.4%) the treatment was temporary withheld or the dose reduced due to adverse events. Conclusion Ibrutinib is characterized by high clinical efficacy and acceptable toxicity in CLL patients with 17p deletion in daily clinical practice.

The efficacy and safety of imatinib generics were not studied and reported on larger cohort of patients yet. We report on efficacy and safety of imatinib generics in 726 chronic myeloid leukemia patients in chronic phase who completed one-year observation, prospectively assessed within Polish Adult Leukemia Group imatinib generics registry. In 99 previously untreated patients the rate of early molecular response achieved at 3 months and major molecular response achieved at 12 months was 65.7% and 53.4% respectively. Complete cytogenetic response at 6 months was achieved in 55.4% of patients. In 627 patients switched from branded to generic imatinib the molecular response was sustained in 64.8%, worsened in 15% and improved in 19% of them. Complete cytogenetic response, major molecular response and MR4,5 were lost in 0.3%, 1.3% and 10.3%, respectively. Hematologic toxicity (grade 3 or 4) and non-hematologic toxicity (any grade) occurred in 3% and 40% of 99 previously untreated patients and in 0.2% and 14.4% of "switched" patients, respectively. In one-year observation the efficacy and safety of tested imatinib generics are not inferior to branded imatinib. No increased switching rate from first to second generation tyrosine kinase inhibitors was noticed This article is protected by copyright. All rights reserved.

Multiple myeloma (MM) is a malignancy of plasma cells usually infiltrating the bone marrow, associated with the production of a monoclonal immunoglobulin (M protein) which can be detected in the blood and/or urine. Multiple lines of evidence suggest that genetic factors are involved in MM pathogenesis, and several studies have identified single nucleotide polymorphisms (SNPs) associated with the susceptibility to the disease. SNPs within miRNA-binding sites in target genes (miRSNPs) may alter the strength of miRNA-mRNA interactions, thus deregulating protein expression. MiRSNPs are known to be associated with risk of various types of cancer, but they have never been investigated in MM. We performed an in silico genome-wide search for miRSNPs predicted to alter binding of miRNAs to their target sequences. We selected 12 miRSNPs and tested their association with MM risk. Our study population consisted of 1,832 controls and 2,894 MM cases recruited from seven European countries and Israel in the context of the IMMEnSE (International Multiple Myeloma rESEarch) consortium. In this population two SNPs showed an association with p

Genetic variants in genes acting during the maturation process of immature B-cell to differentiated plasma cell could influence the risk of developing multiple myeloma (MM). During B-cell maturation, several programmed genetic rearrangements occur to increase the variation of the immunoglobulin chains. Class switch recombination (CSR) is one of the most important among these mechanisms. Germline polymorphisms altering even subtly this process could play a role in the etiology and outcome of MM. We performed an association study of 30 genetic variants in the key CSR genes, using 2632 MM patients and 2848 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the Heidelberg MM Group and the ESTHER cohort. We found an association between LIG4-rs1555902 and decreased MM risk, which approached statistical significance, as well as significant associations between AICDA-rs3794318 and better outcome. Our results add to our knowledge on the genetic component of MM risk and survival., Partially supported by intramural funds of DKFZ, by grants PI12/02688 and PI17/02276 from Fondo de Investigaciones Sanitarias (Madrid, Spain), Instituto de Salud Carlos III, co-funded by FEDER funds –a way to build Europe– grant PI14-00613 and Agency for Management of University and Research Grants (AGAUR) of the Catalan Government grant 2017SGR723. The ESTHER study was funded by grants from the Baden-Württemberg state Ministry of Science, Research and Arts (Stuttgart, Germany), the Federal Ministry of Education and Research (Berlin, Germany), the Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany) and the Saarland Ministry of Social Affairs, Health, Women and Family (Saarbrücken, Germany)

French National Cancer Institute (INCA) and the Fondation Francaise pour la Recherche contre le Myelome et les Gammapathies (FFMRG), the Intergroupe Francophone du Myelome (IFM), NCI R01 NCI CA167824 and a generous donation from Matthew Bell. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank the Association des Malades du Myelome Multiple (AF3M) for their continued support and participation. Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization

Over the past four decades, remarkable progress has been made in the treatment and prognosis of multiple myeloma (MM), although it remains an incurable disease. Chemotherapy resistance is a major hurdle for treatment efficacy. Drug resistance can be innate and so driven by genes involved in the drug metabolism pathways. We performed an association study of 71 germline variants within the major genes in those pathways (ABCB1, ABCC2, ABCG2, and their regulators NR1I2/PXR and NR1I3/CAR) in the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 1365 MM cases with survival information recruited in 5 European countries. Two of the SNPs showed a significant association with the survival of MM patients, namely rs2235013, located in ABCB1 [Hazard ratio (HR) = 1·52, 95% confidence interval (CI) = 1·18-1·95, P = 0·00087], and rs4148388, located in ABCC2 (HR = 2·15, 95% CI = 1·44-3·22, P = 0·0001). ABCC2 plays an essential role in transporting various anticancer drugs, including several used against MM, out of the cell. In silico analyses predict that the variant alleles of four SNPs in linkage disequilibrium with ABCC2-rs4148388 are associated with increased gene expression. Overexpression of ABCC2 increases drug clearance and therefore may induce drug resistance mechanisms. In conclusion, we found a promising association between ABCC2-rs4148388 and MM outcome that is supported by a plausible biological explanation., This work was partially supported by intramural funds of DKFZ and University of Pisa. This work was also partially supported by grant from FIBAO foundation and from the Instituto de Salud Carlos III (Madrid, Spain; PI17/02276)., info:eu-repo/semantics/publishedVersion

Introduction Fludarabine- or bendamustine‑based upfront immunochemotherapy is the current standard of care in fit patients with chronic lymphocytic leukemia (CLL). These regimens are poorly tolerated by patients with comorbidities, for whom the obinutuzumab-chlorambucil combination became the recommended first‑line treatment. Objectives We aimed to analyze real‑life experience with the obinutuzumab-chlorambucil combination as the frontline treatment in elderly and unfit patients. Patients and methods The retrospective analysis included 86 elderly patients (median age, 74 years) with CLL and a significant burden of comorbidities, treated with obinutuzumab-chlorambucil as the frontline regimen. All patients had a Cumulative Illness Rating Scale score greater than 6 and/or creatinine clearance of 30 to 69 ml/min. Results Overall response rate at 2 months after treatment completion was 95.3%, with complete remission (CR) rate of 43% and partial remission (PR) rate of 52.3%. Stable disease rate was 4.7%. Progressive disease was not observed after treatment completion. The median progression‑free survival (PFS) was not reached after a median follow‑up of 18 months; estimated PFS at 30 months was 62%. We observed 6 relapses (7%), 3 (3.5%) in patients obtaining CR, and 3 (3.5%) in those with PR after immunochemotherapy. The most frequent adverse events were neutropenia and infusion‑related reactions (IRRs). Grade-3 neutropenia occurred in 11.6% of patients, and grade-3 IRRs, in 2.3%. There were no adverse events of grade 4 or 5. Conclusions Our data confirm that the obinutuzumab-chlorambucil combination is an effective and well‑tolerated regimen in untreated CLL patients with comorbidities.

Studies of stress corrosion in X12Cr13 and X20Cr13 steels used for rotor blades of steam turbines have been conducted for determining the average rate of corrosion cracking development da / dt. Specimens were exposed to the salt mist environment of 1,2 ppm NaCl concentration in temperature of 60° C. The research environment represents the initial condensate of humidity from 3÷4%. Average rate of corrosion cracking development for specimens of the X12Cr13 is by 0,005 µm/h higher from specimens of the X20Cr13 steel. Course of the corrosion cracking initiation depends to a high degree on metal structure, and probably the close value of cracking propagation rate depends on the similar structure of those steels – high-tempered martensite with carbides at grain boundaries.

It is widely understood that outcomes of specific therapy and the burden of adverse events (AEs) found in clinical trials may differ from those seen in routine clinical practice. Several clinical t...

Studies exploring the significance of minimal residual disease (MRD) in plasma cell myeloma (PCM) have proven its prognostic value, regardless of the type of administered treatment. In order to assess the current practice for evaluating MRD in Poland, we conducted a survey on the methods for assessing MRD and on the MRD testing time points at Polish hematological centres. Seven out of 15 institutions surveyed use of the flow cytometry (FC) method for MRD assessment. The FC-MRD assessment is performed uniformly only in those patients achieving complete remission (CR). However, the specific indications and assessment time points differed at the tested centres including: testing MRD only after autologous hematopoietic stem cell transplantation (auto-HSCT), after auto-HSCT and consolidation, after completion of first line chemotherapy or after obtaining CR in any line of treatment. The study also showed considerable heterogeneity in the FC-MRD methodology, which affects test sensitivity (from 10–3 to 10–5). None of the surveyed centres uses molecular techniques for MRD assessment. In 8 of the 15 institutions, patients are monitored by imaging techniques. Our survey may thus be useful for developing guidelines and standardization of MRD assessment in PCM in Poland.

Grant sponsor: Polish Ministry of Science and Higher Education; Grant number: NN402178334; Grant sponsors: Research Fund at Region Sjaelland, DK; Baden-Wurttemberg State Ministry of Science, Research and Arts; CRIS Foundation

The introduction of tyrosine kinase inhibitors (TKI) revolutionized therapy of chronic myeloid leukemia (CML) and gives long-lasting remission in majority of patients. However, a significant proportion of patients develops resistance and are at risk of progression. Genomic instability is one of the key features associated with CML progression and as in majority of human malignancies, reduction in telomere length characterize transition from chronic phase (CML-CP) to the blastic phase (CML-BP). Telomere maintenance depends on telomerase nucleoprotein complex consisting of reverse transcriptase TERT, RNA template TERC and structural proteins, such as dyskerin (DKC1), but also on telomere-associated proteins including but not limited to shelterin complex(TRF1, TRF2, RAP1, TIN2, TPP1, POT1) and other telomeric-associated proteins (such as TEP1 and Tankyrase). The role of shelterin complex and its post-translational non-enzymatic modifications in BCR/ABL1-mediated genomic instability in CML progression and resistance to TKIs is not fully elucidated, thus we decided to examine the possible role of different components of shelterin complex and its glycation and carbonylation in promoting genomic instability and CML progression. We employed CML CD34+ primary cells isolated from peripheral blood leukocytes or bone marrow of CML patients at different stages of disease: CML-CP, CML-BP and CML-TKIres (TKI-resistant cells). Blood samples were taken after informed consent. The length of telomeres was determined by Southern blotting and PNA-FISH technique. Enzymatic activity of telomerase, as well as protein glycation was measured immunoenzymatically, while expression of subunits of telomerase and shelterin complexes was examined by RT-qPCR and by Western Blot. We confirmed that reduction in telomere length was positively correlated with CML progression. However, in samples from CD34+ CML-TKIres patients in comparison to CML-CP patients, an increase in telomere length was observed (Fig 1). In addition, the negative correlation between mean telomere length and expression of BCR-ABL1 in CML samples was observed. This suggests involvement of alternative telomere lengthening mechanisms, since dynamic changes in telomere length were neither associated with enzymatic activity of telomerase nor with gene copy number/expression of TERT/TERC. Therefore we postulate that telomere dynamics in CML may have a bi-phasic scenario. We found that the expression of RAP1, DKC1 and Tankyrase1 was increased in CML-BP as compared to CML-CP. Moreover, RAP1 is involved in increased metabolism, which is associated with elevated glycolytic and oxidative rates leading to post-translational non-enzymatic modification of proteins and damage of cellular proteostasis which may indirectly influence telomere length in CML. We found that telomere shortening was associated with accumulation of post-translational non-enzymatic modification ofselected proteins of shelterin complex, namely glycation and carbonylation. In conclusion, we postulate that aberrant expression of members of the shelterin complex such as RAP1 may be responsible for aberrant telomere maintenance mechanisms in CML cells and may play role in genomic instability associated with CML progression as well as the clonal selection and resistance to TKIs. In addition, the changes in the level of protein glycation may influence telomere length in CML. Disclosures No relevant conflicts of interest to declare.

Until now, there has been no randomized study directly comparing the activity of second-generation BCR-ABL tyrosine kinase inhibitors (TKI-2G) nilotinib and dasatinib in chronic myeloid leukemia (CML). The aim of our study was to retrospectively analyze efficacy of nilotinib and dasatinib in the real life setting of CML with resistance or intolerance of imatinib. Of 108 included patients treated in polish hematology centers, 75 received dasatinib and 33 patients received nilotinib. Rates of complete cytogenetic response (CCyR) did not differ between the two groups of patients. After six months of therapy, CCyR was achieved in 34.7% of patients treated with dasatinib and 38.7% treated with nilotinib (p = 0.86), while after 12 months, the CCyR rates were 60.0% and 77.0% in dasatinib and nilotinib groups, respectively (p = 0.11). Moreover, we have not observed any significant difference in the probability of progression-free survival (p = 0.89) or overall survival (p = 0.99) between patients treated with these two TKI-2G. In conclusion, the results of our analysis indicate that nilotinib and dasatinib have comparable and satisfactory efficacy in the treatment of CML patients refractory or intolerant to imatinib. Our findings support current strategy of choice of IKT-2G according to drug toxicity profile and risk of specific adverse events in an individual patient.

The original article was published on 22 July 2015: https://doi.org/10.1038/ncomms8539. The article is also available at: http://hdl.handle.net/1822/62280, [Excerpt] In this Article, members of the UCSF cohort who had been alive for longer than two years were inadvertently included in the data presented in Table 3. USCF/old treatments should have 109 patients with a hazard ratio of 3.35 and a P value of 0.00028 instead of the 124 patients with a hazard ratio of 3.37 and a P value of 0.00026. The USCF/new patients should have 187 patients with a hazard ratio of 3.57 and a P value of 0.0007 instead of the 208 patients with a hazard ratio of 3.62 and a P value of 0.0006. [...]

The idiopathic hypereosinophilic syndrome (HES) comprises a heterogenous group of disorders characterized by marked blood eosinophilia with eosinophilia-associated organ damage. Eight patients with a median age at diagnosis of 42 years (range 19-67) received imatinib mesylate (IM) for FIP1L1-PDGFRα-negative HES resistant to previous conventional treatment. Median number of prior therapies was 3 (range 2-4). Median time from diagnosis to IM initiation was 112 months (range 2-293). Four patients were treated daily with 100 mg IM, whereas the remaining four patients were treated daily with 400 mg IM. Four male patients (50%) achieved complete haematologic response (CHR) after median of 7 days (range 3-150) using 100 mg daily IM (n = 2) and 400 mg (n = 2). Median duration of IM treatment for IM responders was 18 months (range 2-88). No adverse events were reported throughout the treatment duration. Two patients maintained CHR while on 100 mg weekly IM. Four patients (2 men and 2 women) failed IM treatment. Median duration of IM for non-responding patients was 3 weeks (range 3-12). Non-responding HES patients were significantly older and had lower percentage of blood eosinophilia when compared with IM responders. Our results suggest that IM, even at lower than conventional doses, may induce and maintain long-term remission for FIP1L1-PDGFRα-negative HES.

A corrigendum to this article was published on 09 December 2015: https://doi.org/10.1038/ncomms10203. The corrigendum is also available at: http://hdl.handle.net/1822/62281 This work was supported by the Steve and Nancy Grand Multiple Myeloma Translational Initiative and a grant from Expression Analysis and a grant from the National Cancer Institute (R21CA191896). E.Z. is supported in part by a mid-career award in patient research from the National Cancer Institute (K24169004). Collection of blood samples from Polish patients and controls from Łodz area, and DNA extraction was supported by a grant from Polish Ministry of Science and Higher Education (No. NN402178334).DNA extraction from Danish healthy controls was supported by The Research Fund at Region Sjælland, Denmark. The Utah study was supported by LLS 6067–09, CA152336and CA134674, with data collection made possible, in part, by the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR). Partial support for all data sets within the UPDB is provided by the Huntsman Cancer Institute (HCI) and the HCICancer Center Support grant, P30 CA42014. The UCR is supported in part by NIH contract HHSN261201000026C from the NCI SEER Program with additional support from the Utah State Department of Health and the University of Utah. In Utah, we thank Jathine Wong for support in formatting files and advice on R programming. Several authors (E.Z., N.C., F.C., C.V.) are members of the International Multiple Myeloma Consortium. We are grateful to the leadership and other members of the International Multiple Myeloma Consortium for facilitating this collaborative study.

BACKGROUND: Genetic background plays a role in multiple myeloma susceptibility. Several single-nucleotide polymorphisms (SNP) associated with genetic susceptibility to multiple myeloma were identified in the last years, but only a few of them were validated in independent studies. METHODS: With the aim to conclusively validate the strongest associations so far reported, we selected the polymorphisms rs2227667 (SERPINE1), rs17501108 (HGF), rs3136685 (CCR7), rs16944 (IL1B), rs12147254 (TRAF3), rs1805087 (MTR), rs1800629 (TNF-a), rs7516435 (CASP9), rs1042265 (BAX), rs2234922 (mEH), and rs1801133 (MTHFR). We genotyped them in 1,498 multiple myeloma cases and 1,934 controls ascertained in the context of the International Multiple Myeloma rESEarch (IMMEnSE) consortium, and meta-analyzed our results with previously published ones. RESULTS: None of the selected SNPs were significantly associated with multiple myeloma risk (P value range, 0.055-0.981), possibly with the exception of the SNP rs2227667 (SERPINE1) in women. CONCLUSIONS: We can exclude that the selected polymorphisms are major multiple myeloma risk factors. IMPACT: Independent validation studies are crucial to identify true genetic risk factors. Our large-scale study clarifies the role of previously published polymorphisms in multiple myeloma risk., Collection of blood samples from Polish patients and controls from Lodz area and DNA extraction was supported by a grant from Polish Ministry of Science and Higher Education (No. NN402178334). DNA extraction from Danish healthy controls was supported by The Research Fund at Region Sj ae lland, DK.

Background: Generic imatinib is already available in several countries. The use of generic imatinib is expected to lower the cost of CML therapy, however the data regarding their efficacy and tolerability in larger populations of CML patients are lacking. Aim: The aim of the study was to evaluate the efficacy and tolerability of imatinib generics in patients suffering from chronic phase CML previously untreated, and in the group of patients switched from branded imatinib to imatinib generics during a one-year of observation. Methods: We report on 726 patients prospectively observed for one year within Polish Adult Leukemia Group (PALG) Imatinib Generics Registry. In 99 previously untreated patients (group A) the rate of BCR/ABL1 reduction to < 10% at 3 months and to < 1% at 6 months of therapy, the rate of optimal response, and failure according to current ELN guidelines, the rate of CCyR,MMR,MR4, and MR4,5 achieved at 12 months of therapy, and the rate of patients switched to second generation TKI have been assessed. In 627 patients switched to generic from branded imatinib (group B) the rate of sustained, improved and worsened molecular response, the rate of CCyR, MMR, MR4, and MR4,5 loss have been evaluated. To assess the tolerability of imatinib generics in both groups the rate of hematologic (3rd or 4th grade), and of non-hematologic adverse events (all grades according to CTCAE criteria) have been recorded. The one-year, "real-life" observation started on 03.APR.2014 in CML-CP patients treated in 12 Polish Hematology Centers. The registry records approximately 900 patients, in the current report we analyzed only patients who completed 12-month observation (all patients with available RQ-PCR result at 12 month), with MMR achieved before start of therapy with imatinib generics, and treated with generics for more than 12 months (group B). Results: Ninety nine patients started de novo treatment with generics: 62 with Nibix (62.6%) , 24 with Meaxin (24.2%), other generics were used to treat 13 (13.1%) patients, and 627 patients were switched from Glivec to imatinib generics: 445 to Nibix (70.9%), 146 to Meaxin (23.3%), 31 to Teva (4.3%), and to other generics in remaining 5 patients (0.8%). Early molecular response (BCR/ABL1 < 10% at 3 months) was achieved in 65.2% , the reduction of BCR/ABL1 to < 1% at 6 months in 53.3%, and an optimal response (MMR at 12 months) in 53.3% of patients in the group A. The hematologic toxicity (grade 3 or 4 according to CTCAE criteria) occurred in 3 patients (3%) (1 neutropenia, 2 thrombocytopenia). One patient (1%) was switched to 2GTKI due to recurrent thrombocytopenia. The non - hematologic toxicity was recorded in 40 patients (40.4%) . In the group A 26 patients (26.3%) have been switched from imatinib generics to 2GTKI, 12 patients (46.2%) due to intolerance (11 due to a non-hematologic toxicity), 13 patients (50%) due to resistance, and 1 patient (3.8%) due to progression to acceleration phase. In the group B the molecular response under therapy with generics was sustained, improved and worsened in 406 (64.8%) , 119 (19%), and in 94 (15%) of patients, respectively. Complete cytogenetic response, MMR and MR4,5 was lost in 2 (0.3%), 8 (1.3%) and 65 (10.3%) patients, respectively. During a one-year observation 22 patients (3.5%) were switched to 2GTKI: 15 (2.4%) due to intolerance, 4 (0.6%) due to resistance, and 2 (0.3%) patients due to progression to acceleration phase. Conclusion: This is the first report from prospective observation on imatinib generics effectiveness and tolerability in a large cohort of CML patients. Tested generics of imatinib (Meaxin, Nibix, Imatinib Teva, Imatinib Polfa, Imakrebin, and Telux ) seem to be not inferior to branded imatinib in terms of clinical efficacy and tolerability in patients with CML CP. We did not observe an increased switching rate between imatinib generics and 2GTKI during the observation period. Disclosures Sacha: Incyte: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Gora-Tybor:Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria. Szarejko:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Bober:BMS: Honoraria; Novartis: Honoraria. Grzybowska-Izydorczyk:Novartis: Honoraria; BMS: Honoraria. Niesiobędzka-Krężel:BMS: Honoraria; Novartis: Honoraria. Dudziński:BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Wasilewska:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Myśliwiec:Novartis: Honoraria. Gil:BMS: Honoraria; Novartis: Honoraria. Gniot:BMS: Speakers Bureau. Mędraś:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau.

In patients with lymphoid malignancies, the involvement of the central nervous system (CNS) adversely affects outcome. Standard treatment protocols for acute lymphoblastic leukemia (ALL) and aggres...

Background: Cereblon (CRBN), a subunit of cullin 4-based E3 ubiquitine ligase complex, has been characterized as the main immunomodulatory drugs (IMiDs), thalidomide, lenalidomide and pomalidomide, binding protein that is crucial for their antiproliferative and immunomodulatory properties. Several recent reports have suggested that CRBN gene and protein expression or alternative splicing affect sensitivity to IMiDs in multiple myeloma (MM). It can be speculated that CRBN expression level, alternative splicing or CRBN-E3 ubiquitine ligase substrate specificity in MM and microenvironment cells may be partially determined by inherited genetic background including functional single nucleotide polymorphisms (SNPs). Aim: The objective of this study was to verify whether naturally occurring SNPs in CRBN encoding CRBNgene (locus chromosome 3p26.2) may influence outcome of lenalidomide-based therapy in patients with MM. Methods: We genotyped 14 tagging SNPs in CRBN gene in 169 Polish Caucasian patients with refractory/relapsed MM treated with lenalidomide-based therapy. Among these patients 151 (89%) received lenalidomide/dexamethasone (Len-Dex) regimen while the remaining patients were treated with lenalidomide-based three drug combinations. Genomic DNA samples were collected and genotyped in the context of the IMMEnSE consortium. The influence of CRBNallelic variants on probability to achieve clinical response (at least partial response, PR) to lenalidomide-based therapy, achievement of complete response (CR), duration of progression-free survival (PFS) and overall survival (OS) were tested in regard to established clinical and laboratory predictive factors using logistic regression and proportional-hazards regression models. For all genotyped SNPs co-dominant, dominant and recessive inheritance modes were tested. Results: We found that carriers of minor alleles of two studied SNPs, namely CRBN rs1714327G>C and CRBN rs1705814T>C significantly associated with lower probability of achievement of clinical response (≥PR) to lenalidomide-based therapy using dominant inheritance model (OR=0.25, 95%CI 0.10-0.63; p=0.0033, Bonferroni corrected p=0.019 and OR=0.21, 95%CI 0.07-0.61; p=0.0041, Bonferroni corrected p=0.024, respectively). Moreover, in concordance with these findings one of these two SNPs, namely CRBN rs1705814T>C, was also significantly associated with shorter PFS in the analyzed group of lenalidomide treated MM patients (OR=2.49; 95%CI 1.31-4.74; P=0.0054, Bonferroni corrected p=0.032). In contrast, none of the tested allelic variants of CRBN showed significant influence on OS. Conclusions: Taken together, our observations suggest that selected germline CRBN SNPs (rs1714327G>C and rs1705814T>C) affect lenalidomide efficacy in relapsed/refractory MM. Further studies are needed to explain functional mechanisms underlying these associations as well as to establish whether CRBN genetic variants may be useful as potential biomarkers for IMiDs-based therapy. Acknowledgments: This work was supported by the grants of Polish Young Heamatologists Club and Polish Myeloma Consortium. The work of Pawe³ Gaj was supported by a grant from the European Commission 7th Framework Programme: FP7-REGPOT-2012-CT2012-316254-BASTION Disclosures No relevant conflicts of interest to declare.

Background: Inherited background in mechanisms regulating cellular uptake, elimination and metabolism of imatinib and other BCR-ABL tyrosine kinase inhibitors may influence treatment outcome in chronic myeloid leukemia (CML). Despite good efficacy of imatinib in CML therapy, a proportion of patients show suboptimal responses or even primary resistance. Imatinib is a well-established substrate of ABC-superfamily xenobiotic transporters ABCB1 (MDR1, Pg-P) and ABCG2 (BCRP). However, the results of published studies regarding impact of ABCB1 and ABCG2 single nucleotide polymorphisms (SNPs) on imatinib treatment outcome have shown discrepant results. Moreover, little is known on the potential role of polymorphisms of regulators of xenobiotic transport and metabolism, pregnane X receptor (PXR, NR1|2) and constitutive androstane receptor (CAR, NR1|3) in imatinib efficacy. Aim: In this study we verified whether 61 tagging SNPs in drug transporters genes (ABCB1 and ABCG2) and regulators of xenobiotic transport and metabolism gene (PXR and CAR) genes affect imatinib therapy outcomes in CML. Methods: Genotyping was performed in 256 patients of Polish Caucasian origin (141 men and 117 women) treated with imatinib as first line treatment (229; 89.5%) or after second-line after interferon therapy (27; 10.5%). Tagging SNP approach was used to select the genetic variants and resulted in a selection of 61 tagging SNPs including 26 SNPs for ABCB1, 17 SNPs for ABCG2, 11 SNPs for PXR and 7 SNPs for CAR gene. Complete clinical data on imatinib treatment outcome were assessable for analyses of associations with tested SNPs. The influence of SNPs on imatinib outcomes including achievement of complete cytogenetic response (CCyR) at 12 months, achievement of major molecular response (MMR) at 18 months, progression-free survival (PFS), time to treatment failure (TTF) and overall survival (OS) were tested in regard to established clinical and laboratory predictive factors using logistic regression and proportional-hazards regression models. Three inheritance models (co-dominant, dominant and recessive) were tested for all allelic variants. Results: In this study we found that carriers of minor allele of CAR rs4073054A>C SNP significantly associated with shorter TTF on imatinib therapy (OR=2.42, 95%CI 1.41 - 4.17; p=0.0014; Bonferroni corrected p=0.048). In contrast, no impact of other tested allelic variants in ABCB1, ABCG2, PXR and CAR genes on proportion of patients who achieved CCyR at 12 months, MMR at 18 months as well as on probability of PFS, TTF and OS was observed. Conclusion: Our data suggest that inherited variants in the regulator of xenobiotic transport and metabolism CAR gene may modify results of imatinib therapy in CML patients. In contrast, the results of this relatively large study indicate that polymorphic variants in ABCB1, ABCG2 and PXR genes do not seem to play major role as determinants of response to imatinib in CML. Disclosures Robak: MorphoSys AG: Research Funding.

Type 2-diabetes (T2D) is thought to be a relevant risk factor for multiple myeloma (MM), but the relationship between both traits is still not well understood. Thus, we decided to conduct a population-based case-control study in a population of 1420 MM patients (705 women and 715 men) and 1858 controls (916 women and 942 men) to evaluate whether 58 genome-wide association studies (GWAS)-identified common variants for T2D influence the risk of developing MM. Logistic regression analyses showed that carriers of the KCNQ1rs2237892T allele or CDKN2A-2Brs2383208G/G, IGF-1rs35767T/T and MADDrs7944584T/T genotypes had an increased risk of MM (OR=1.32, 95%CI 1.01-1.71, P=0.039; OR=1.86, 95%CI 1.12-3.11, P=0.016; OR=2.13, 95%CI 1.35-3.37, P=0.001 and OR=1.33, 95%CI 1.06-1.67, P=0.014, respectively) whereas those carrying the KCNJ11rs5215C, KCNJ11rs5219T and THADArs7578597C alleles or the FTOrs8050136A/A and LTArs1041981C/C genotypes showed a decreased risk for the disease (OR=0.85, 95%CI 0.73-0.99, P=0.38; OR=0.84, 95%CI 0.72-0.99, P=0.034; OR=0.81, 95%CI 0.68-0.98, P=0.032; OR=0.78, 95%CI 0.64-0.95, P=0.013; and OR=0.76, 95%CI 0.58-0.99, P=0.042, respectively). The associations of these T2D-related variants with an increased or decreased risk of MM were due to non-diabetogenic alleles, which suggests a non-diabetogenic mechanism underlying the effect of these variants to determine the risk of the disease. A gender-stratified analysis also revealed a significant gender effect modification for ADAM30rs2641348, and NOTCH2rs10923931 SNPs (Pinteraction=0.001 and 0.0004 and Phet=0.19 and 0.60, respectively), which also underlies the importance of considering gender as a factor modifying the risk for MM. Men harbouring the ADAM30rs2641348C and NOTCH2rs10923931T alleles had a decreased risk of MM (OR=0.71, 95%CI 0.54-0.94, P=0.015 and OR=0.66, 95%CI 0.50-0.86, P=0.0019) whereas an opposite but not significant effect was observed in women. Finally, SNP-SNP interaction analysis revealed overall significant two- and three-locus interaction models to increase the risk of MM (FAM148Brs11071657-KCNJ11rs5219, and SLC30A8rs13266634-KCNJ11rs5219-FTOrs8050136; P=0.01 and 0.001, respectively) whereas a significant four-locus model was also found to increase the risk of MM in men (FADS1rs174550-TSPAN8rs7961581-PROX1rs340874-KCNJ11rs5219, P=0.001). Although further studies in independent populations are warranted to replicate these findings, these results suggest that TD2-related variants may influence the risk of developing MM, likely through non-diabetogenic mechanisms. Abstract 2044. Table 1. Demographical characteristics of IMMEnSE cases and controls. CASES CONTROLS Region* Gender M/F (Total) Mean Age (± STD) Gender M/F (Total) Mean Age (± STD) Control type Italy 117/107 (224) 62.60±9.90 127/105 (232) 58.75±10.92 General population Poland 173/198 (371) 62.35±10.39 124/226 (350) 50.68±19.43 Blood donors Spain 139/133 (272) 63.06±11.04 218/192 (410) 63.12±11.94 Hospitalized subjects France 42/33 (75) 55.80±9.04 95/89 (184) 44.07±15.22 Blood donors Portugal 32/35 (67) 65.79±11.16 52/42 (94) 60.88±07.88 Blood donors Hungary 49/87 (136) 65.83±11.19 50/51 (101) 73.18±10.10 Hospitalized subjects Denmark 163/112 (275) 55.20±07.32 276/211 (487) 43.26±11.84 General population Total 715/705 (1420) 61.06±10.57 942/916 (1858) 53.56±16.45 Table 2. Selected type-2 diabetes-related polymorphisms Gene name dbSNP rs# Gene name dbSNP rs# ADAM30 rs2641348 JAZF1 rs864745 ADAMTS9 rs4607103 KCNJ11 rs5215 ADCY5 rs11708067 rs5219 ADRA2A rs10885122 KCNQ1 rs2237897 ARAPI, CENTD2 rs1552224 rs2074196 BCL11A rs10490072 rs2237892 CDC123 rs12779790 rs2237895 CDKAL1 rs7754840 KCNQ1OT1 rs231362 CDKN2A-2B rs564398 LTA rs1041981 rs10811661 MADD rs7944584 rs2383208 MCR4 rs12970134 COL5A1 rs4240702 MTNR1B rs1387153 CRY2 rs11605924 NOTCH2 rs10923931 DCD rs1153188 PKN2 rs6698181 EXT2 rs1113132 PPARG rs1801282 FADS1 rs174550 PRC1 rs8042680 FAM148B rs11071657 PROX1 rs340874 FLJ39370 rs17044137 RBMS1 rs7593730 FTO rs8050136 SLC2A2 rs11920090 G6PC2 rs560887 SLC30A8 rs13266634 GCK rs1799884 TCF2 rs7501939 GCKR rs1260326 TCF7L2 rs7903146 HHEX rs1111875 TCF7L2 rs12255372 HMGA2 rs1531343 THADA rs7578597 HNF1A, TCF1 rs7957197 TP53INP1 rs896854 IGF1 rs35767 TSPAN8 rs7961581 IGF2BP2 rs4402960 VEGFA rs9472138 IL13 rs20541 WFS1 rs734312 IRS1 rs2943641 rs10010131 Disclosures No relevant conflicts of interest to declare.

Background: Genome wide association studies (GWAS) have recently identified 8 loci identified with multiple myeloma (MM) susceptibility. We hypothesized that germ line genetic variants may also affect MM progression. We performed the first GWAS of MM survival, by conducting a meta-analysis of two existing studies at University of California San Francisco (UCSF) and the Mayo Clinic, and replicating findings in the International Multiple Myeloma rESEarch (IMMEnSE) consortium. Methods: The UCSF study included 353 MM patients genotyped on an Illumina Omni5 and Illumina 660 array. The Mayo clinic study included 239 MM patients genotyped on an Affymetrix 6.0 array. We imputed missing genotypes using the 1000 Genomes dataset and performed a GWAS for survival using proportional hazards models adjusting for age and gender and genetic ancestry using principal components analysis. We conducted a meta-analysis of the results from the two GWAS. We replicated the top SNPs in the IMMEnSE cohort which included 772 patients with survival data from 7 European countries and one North American site. We used the dataset from Grundberg et al (Nat Genetics 2012) to test for an association between SNPs associated with survival and gene expression in immortalized lymphocytes. We used gene expression data from Zhan et al (Blood 2006) to analyze the association between expression and survival. Results: In meta-analysis, we found a genome wide significant association between SNPs on a region at 16p13 and survival (rs72773978; p=2.9x10e-10). Patients with the minor allele were at increased risk for mortality (HR 2.73; 95% CI: 1.99 - 3.73). The top associated SNPs were all in strong linkage disequilibrium and were centered over the gene FOPNL. We replicated the association in the IMMEnSE cohort and found a significant association between the top SNP from the discovery dataset (rs72773978 p=0.037). We used previously published data to determine the association between gene expression and the top associated SNPs from the GWAS. The top SNP (rs72773978) was not in previously published eQTL databases, so we used rs7201759 which was also associated with survival in our data (p=3.8x10e-10) as a proxy. The minor allele for this SNP was associated with increased levels of expression of FOPNL (p=9x10e-5), but not with expression of any other genes within a 1 megabase region. Finally, we also observed an association between increased expression of FOPNL and shorter survival (HR: 2.62 per standard deviation.; 95% CI: 1.08 - 6.32). Conclusion: Germ line variants at 16p13 near the FOPNL gene are associated with survival among MM patients. FOPNL is thought to be involved in centrosomal function, and centrosomal activity has previously been associated with survival in MM patients. Our results support this previous observation. Furthermore, they suggest that germ line variants could also be useful in assessing prognosis for patients with MM. Citation Format: Elad Ziv, Eric Dean, Donglei Hu, Alessandro Martino, Daniel Serie, Daniele Campa, Blake Aftab, Paige Bracci, Gabriele Buda, Jennifer Caswell, Charles Dumontet, Marek Dudziński, Laura Fejerman, Alexandra Greenberg, Scott Hunstman, Artur Jurczyszyn, Krzysztof Jamroziak, Shaji Kumar, Herlander Marques, Thomas Martin, Joaquin Martinez-Lopez, Vincent Rajkumar, Juan Sainz, Annette Juul Vangsted, Marzena Watek, Jeffrey Wolf, Susan Slager, Federico Canzian, Celine Vachon. Genome wide association study identifies variants at 16p13 associated with survival in multiple myeloma patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5078. doi:10.1158/1538-7445.AM2014-5078

We established the IMMEnSE (International Multiple Myeloma rESEarch) consortium, to increase our understanding of the genetic determinants of multiple myeloma (MM) risk, response to therapy and survival. At present we have DNA samples of over 3200 MM cases and 3000 healthy controls from 10 countries, mainly in Europe. For the majority of the cases clinical data on known prognostic factors, therapy outcome and survival have been also collected. We already performed several association studies in the context of the IMMEnSE consortium. In particular, associations were found between MM risk and SNPs in the ABCB1 gene, which encodes for an efflux pump that has a key role in protecting cells from chemical damage (rs10264990: odds ratio (OR) =0.79, 95% confidence interval (CI) 0.68-0.91; p=0.001, and rs17327442: OR=1.99; 95%CI 1.32-3.02; p=0.001). We also investigated the 8q24 region, which has been shown to harbor multiple loci of susceptibility to various cancers, and found an association between a SNP mapping in this region and MM risk (rs2456449: OR=1.37; 95%CI 1.12-1.68; p=0.0022). In addition, IMMEnSE cases and controls were also genotyped for three MM risk SNPs from the first genome-wide association study (GWAS), and the association of two of them (rs4487645 on chromosome 7p15.3 and rs6746082 on chromosome 2p23.3) was confirmed. Finally, SNPs of key telomere-related genes were genotyped and telomere length was measured in MM cases and controls, and a pleiotropic and functional variant of the TERT gene was found to be associated with reduced MM risk (rs2242652: OR=0.81; 95%CI 0.72-0.92; p=0.001). A suggestive association between longer telomeres and increased MM risk was also found (ptrend=0.01). We will study new SNPs emerging as promising candidates from ongoing GWAS on MM risk and survival, as well as SNPs of key genes involved in the pathogenesis of MM. Finally, we plan to study methylation status of key genes involved in MM etiology, and mitochondrial copy number. The role of all these factors will be investigated in relation to MM risk and prognosis. Collection of samples and data of MM cases and controls is ongoing, as well as of subjects with monoclonal gammopathy of undetermined significance (MGUS). Table 1. MM cases and healthy controls collected in the IMMEnSE consortium Country Cases Median age(5th-95th percentile) Controls Median age(5th-95th percentile) Control type Italy 232 63 (46-78) 237 59 (42-76) General population Poland 1,286 63 (42-82) 200 68 (43-79) Blood donors Spain 322 64 (46-82) 1,131 66 (43-84) Hospitalized subjects France 642 57 (37-68) 191 48 (18-63) Blood donors Portugal 70 68 (45-82) 100 58 (53-79) Blood donors Hungary 148 68 (34-90) 105 74 (55-87) Hospitalized subjects Denmark 348 56 (43-65) 1,000 63 (52-73) Blood donors Israel 109 60 (41-77) 95 - Blood donors Canada 62 58 (42-70) - - - Japan 51 66 (47-84) - - - Total 3,270 63 (37-84) 3,059 63 (18-92) Figure 1 Centers involved in IMMEnSE Figure 1. Centers involved in IMMEnSE Disclosures No relevant conflicts of interest to declare.

Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia in Western countries. Venetoclax, a BCL-2 inhibitor, in combination with rituximab is an effective therapeutic option approved for the treatment of refractory and relapsed CLL. Neutropenia diagnosed before or during the above-mentioned therapy is a significant clinical problem, which often involves the need to reduce the dose or temporarily discontinue venetoclax in the initial period of therapy. In Experts’ opinion, the use of granulocyte colony-stimulating factor (G-CSF) during venetoclaxrituximab combined therapy is reasonable in patients with baseline neutrocyte count < 1000–500/mm 3 and with high-risk neutropenia. The second important group for the use of G-CSF are patients developing grade 3 asymptomatic neutropenia during venetoclax dose escalation. Using G-CSF can prevent episodes that affect the maintenance of the venetoclax dose intensity and treatment continuity.