The Structure of Research Funding in Germany, the Netherlands and England (UK)
Gender contributes to personal research funding success in The Netherlands
We examined the application and review materials of three calls (n= 2,823) of a prestigious grant for personal research funding in a national full population of early career scientists awarded by the Netherlands Organization for Scientific Research (NWO). Results showed evidence of gender bias in application evaluations and success rates, as well as in language use in instructions and evaluation sheets. Male applicants received significantly more competitive “quality of researcher” evaluations (but not “quality of proposal” evaluations) and had significantly higher application success rates than female applicants. Gender disparities were most prevalent in scientific disciplines with the highest number of applications and with equal gender distribution among the applicants (i.e., life sciences and social sciences). Moreover, content analyses of the instructional and evaluation materials revealed the use of gendered language favoring male applicants. Overall, our data reveal a 4% “loss” of women during the grant review procedure, and illustrate the perpetuation of the funding gap, which contributes to the underrepresentation of women in academia.
In this article convergence in European countries’ legislative rules concerning the use of embryos in research is studied by looking at how such rules have been formulated in France, Germany, the Netherlands and the United Kingdom. An answer will be given as to whether these countries’ rules concerning the use of embryos in research have converged and if so what direction this convergence has taken, either liberalization or an extension of moral regulation by the state. This analysis shows to some extent that liberalization of the legislative rules concerning the use of embryos in research has taken place in these countries but also exposes how eu research funding policy has slowed it down. Subsequently, attention will be paid to the driving forces behind the liberalization as well as the countering forces it evokes.
Abstract Background: Patients’, parents’ and providers’ preferences with regard to medical interventions may have a major impact on the implementation of innovations, often delaying initiation significantly. Illustratively, as early as 1997, Carlsson et al. suggested that a 30% reduction of consumption of clotting factor concentrate in prophylactic treatment could be attained by dosing based on an individual pharmacokinetic (PK) profile, with a concomitant cost reduction. Therefore, we aim to evaluate do’s and don’ts in hemophilia patients, parents and professionals with regard to individualized dosing according to PK-profile of prophylaxis with clotting factor concentrate. This in order to successfully implement this intervention when imperative. Methods: In this study we included patientswith hemophilia currently or previously on prophylactic treatment with clotting factor concentrate (n=114) and parents of patients aged 12-18 years (n=19) from five Dutch Academic Hemophilia Treatment Centers, and hemophilia professionals attending the World Federation of Haemophia congress 2012 from throughout the world (n=91). Data were analysed using a Discrete Choice Experiment. Patients’, parents’ and professionals’ preferences with regard to the intervention, are measured by specific attributes with varying levels: ‘number of blood samples necessary to construct individual PK-profile’, ‘advised frequency of prophylactic infusions’, ‘frequency of repetitive PK-profiling’, ‘risk of bleeding’, ‘estimated cost reduction of treatment with benefit for society’. Results: For patients and parents (response rate 64%), a higher dosing frequency e.g. daily dosing was an important barrier. They were however willing to infuse more frequently, if bleeding was consequently reduced. ‘Reduction of costs for society’ by implementation of individualized dosing according to PK profile was found relevant and motivating to implement PK-guided dosing. For professionals the most important attributes driving implementation were an acceptable ‘advised frequency of prophylactic infusions’ and reduction of ‘risk of bleeding’. Conclusions: When anticipating implementation of a medical intervention, defining of preferences of those involved is of importance. In case of PK-guided prophylactic dosing in hemophilia conclusions are: realise the impact of daily dosing of clotting factor concentrate, use frequent bleeding as a motivator to initiate PK-guided dosing and actively discuss costs of treatment with those undergoing treatment and the cost reduction that may result from PK-guided dosing. Identification of these preferences will secure successful implementation in the near future. Disclosures Lock: ZonMW: Research Funding; Baxter: Research Funding. Laros-van Gorkum:Sanquin: speakers fee Other; Baxter: Unrestricted educational grant was provided to the Hemophilia Treatment Center of the Radboud university medical center, Unrestricted educational grant was provided to the Hemophilia Treatment Center of the Radboud university medical center Other; CSL Behring: Unrestricted educational grant was provided to the Hemophilia Treatment Center of the Radboud university medical center, Unrestricted educational grant was provided to the Hemophilia Treatment Center of the Radboud university medical center Other. Driessens:Baxter: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other; Bayer Schering Pharma: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work, unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other; CSL Behring: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work, unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other; Eurocept: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work, unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other; Novo Nordisk: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other; Pfizer: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other; Sanquin: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other. Fijnvandraat:Baxter: Member of the European Hemophilia Treatment and Standardisation Board sponsored by Baxter Other; CSL Behring: Research Funding; Pfizer: Has given lectures at educational symposiums organised by Pfizer, Has given lectures at educational symposiums organised by Pfizer Other, Research Funding; Bayer Schering Pharma: Has given lectures at educational symposiums organised by Bayer Schering Pharma, Has given lectures at educational symposiums organised by Bayer Schering Pharma Other, Research Funding. Leebeek:CSL Behring: has served on advisory boards of CSL Behring, outside the submitted work Other, Research Funding; Baxter: has served on advisory boards of Baxter, outside the submitted work, has served on advisory boards of Baxter, outside the submitted work Other. Cnossen:Pfizer: Educational funding Other, Research Funding; Bayer Schering Pharma: Educational funding and travel support, Educational funding and travel support Other, Research Funding; Baxter: Educational funding and travel support, Educational funding and travel support Other, Research Funding; Novo Nordisk: Educational funding, Educational funding Other, Research Funding; Novartis: Educational funding and travel support Other, Research Funding.
Abstract Introduction: FOXO3A is a transcription factor shown to be involved in all-trans retinoic acid (ATRA)-induced granulocytic differentiation and apoptosis in acute promyelocytic leukemia (APL). Its biological activity may be significantly enhanced upon metformin, raising the possibility that ATRA and Metformin may act synergistically; which could be useful to overcome ATRA resistance. Despite progress in APL treatment, approximately 10-15% of patients will relapse after treatment with ATRA and anthracyclines and frequently present with ATRA resistance. Relapsed patients respond well to arsenic trioxide (ATO) treatment, but the cost of ATO is a significant barrier in many countries. Aims: Here, we investigated the effects of in vitro treatment with ATRA plus metformin in APL cell lines and primary blasts, and quantified FOXO3A expression and correlated its levels with treatment outcome in a cohort of patients enrolled in the International Consortium on Acute Leukemia (ICAPL2006) study. Finally, we evaluated the effect of induced overexpression of FOXO3A gene in regards to cell viability and proliferation. Methods: Primary leukemic blasts from hCG-PMLRARα transgenic mice (TM; n=4) and APL patients (age, 25-47y; n=4) were treated with metformin alone (5mM/ 10mM) or in combination with ATRA (1µM) and evaluated for cell viability. In addition, 106 patients (age, 18-82y) with newly diagnosed APL enrolled in the ICAPL2006 study were included. As controls, eight samples of bone marrow mononuclear cells (BMMC) from healthy volunteers (age, 18-60y) were analyzed. To validate our data, FOXO3A transcript levels from an independent cohort was used (31 patients from Amazonia!, Probe n. 204131_s_at, and five normal BMMC samples included in the same databank). NB4/NB4R2 (ATRA-resistant) cell lines were transduced with FOXO3A or empty vector (control). After synchronization using double thymidine block, transduced cells were submitted to proliferation and cell cycle assays. For dose-response curves, cells were treated with graded concentrations of ATRA, ATO and metformin. For the apoptosis analysis, cells were treated with ATRA (1µM), metformin (5mM) and combination for 24, 48 and 72 hours. The granulocytic differentiation in response to ATRA treatment was evaluated based on the CD11b surface levels. Results: In primary cells (from TM/APL patients) a 2-fold reduction in viable cells was observed after metformin and metformin plus ATRA treatment (P<.05), compared to only 0.5-fold reduction rate using ATRA alone. In the clinical setting, APL patients expressed a lower absolute level of FOXO3A than normal BMMC (P<.001). These results were corroborated in an external validation cohort (P=.004). The retrospective analysis of patients enrolled in the ICAPL2006 study revealed that the baseline characteristics were similar between patients with low and high FOXO3A levels. Low FOXO3A expression was associated with lower DFS (84%; 95% CI: 63-94%)(HR: 1.25, 95% CI: 0.64-10.4) and OS (76%; 95% CI: 63-84%) (HR: 1.43, 95% CI: 0.12-1.48). The overexpression of FOXO3A in APL cell lines was associated with reduced basal cell viability (P=.02), clonogenicity (P=.001), and proliferation (P=.001) in both APL cell lines. Subsequent cell cycle analysis showed no significant difference between FOXO3A-cells and controls in normal conditions and when treated with ATRA. Using a nonlinear regression analysis, IC50 for ATO was significantly lower for NB4-FOXO3A cells (0.27μM) than control (2.27µM), with no corresponding response for NB4R2 cell line (2µM for empty vector vs 1.46μM for NB4R2 FOXO3A). NB4 (IC50: 14mM) and NB4R2 (IC50: 4.2mM) FOXO3A cells presented higher sensibility to metformin treatment versus control group (IC50: 23mM for NB4; IC50: 22mM for NB4R2). For ATRA treatment alone, only NB4-FOXO3A presented increased sensitivity to ATRA (P=.001). In accordance, ATRA treatment (alone or in combination with metformin) increased the drug-induced apoptosis in a time-dependent manner (P<.05) in NB4-FOXO3A cells, but had no effect on NB4R2-FOXO3A, which presented increased apoptosis rate only with metformin treatment. The differentiation rate was higher in FOXO3A-expressing cells (P<.05). Conclusion: Based on clinical and functional data, the FOXO3A pathway could be an interesting target to overcome ATRA resistance in APL in offsetting where ATO is unavailable in low- and middle-income countries. Disclosures Tallman: BioSight: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board; ADC Therapeutics: Research Funding; AROG: Research Funding; AbbVie: Research Funding; Cellerant: Research Funding; Orsenix: Other: Advisory board. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Lowenberg:Editorial Board "European Oncology & Haematology": Membership on an entity's Board of Directors or advisory committees; Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherlands: Membership on an entity's Board of Directors or advisory committees; Clear Creek Bio Ltd: Consultancy, Honoraria; international Scientific Advisory Board, Institute Gustave Roussy, Paris: Membership on an entity's Board of Directors or advisory committees; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Editorial Board "The Netherlands Journal of Medicine": Membership on an entity's Board of Directors or advisory committees; Editorial Board "International Journal of Hematology": Membership on an entity's Board of Directors or advisory committees; "Up-to-Date", section editor leukemia: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy; Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands): Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.
Abstract Introduction: Peripheral T-cell lymphomas (PTCL) comprise a heterogenous group of mature T-cell neoplasms with generally an unfavorable prognosis. Presentation of PTCL with stage I(E) disease, according to the Ann Arbor classification, is uncommon. Clinical trials in diffuse large B-cell lymphoma (DLBCL) support the use of an abbreviated treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone combined with radiotherapy (combined modality therapy (CMT)) in case of stage I(E) disease. CMT in stage I(E) PTCL has been adapted in daily practice, but clinical trials are lacking. A recent population-based study conducted in Scandinavia indicated that the outcome in patients with limited stage PTCL is as poor as in patients with extensive disease. However, the outcomes of different treatment modalities were not analyzed. Aim: The aim of this nationwide population-based cohort study is to describe first-line treatment and outcome of patients with stage I(E) PTCL in comparison to advanced stage PTCL. Methods: All newly diagnosed patients ≥ 18 years with stage I(E) PTCL who were diagnosed in 1989-2018 were identified in the Netherlands Cancer Registry (NCR). Survival follow-up was available through February 1, 2021. The PTCL subgroups analyzed included anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), enteropathy associated T-cell lymphoma (EATL) and peripheral T-cell lymphoma NOS (PTCL NOS). Patients were categorized according to treatment regimen, i.e. chemotherapy, chemotherapy followed by autologous stem cell transplantation (ASCT), radiotherapy, CMT, and no/other therapy. Calendar period analyses (1989-1999 and 2000-2018) were conducted to assess trends in primary therapy and overall survival (OS) over time. The calendar periods were defined according to the implementation of CMT in patients with limited stage DLBCL from approximately 2000 onward in the Netherlands. The primary endpoint was OS, defined as all-cause-death post-diagnosis. Results: From 1989 to 2018, 854 patients with a median age of 62 years were diagnosed with stage I(E) PTCL, accounting for 19% of all PTCL diagnoses. In stage I(E), the predominant PTCL subtype was PTCL NOS (40%, n=343). Furthermore, 26% (n=222) of patients were diagnosed with ALCL, 3% (n=28) with AITL, 11% (n=93) with EATL and 20% (n=168) with other histological subtypes. In contrast, for patients with advanced stage disease, 42% was diagnosed with PTCL NOS, 23% with ALCL, 24% with AITL, 6% with EATL and 5% with other histological subtypes . To evaluate treatment and survival outcome in patients with stage I(E) PTCL, patients with ALCL, AITL, PTCL NOS and EATL were included for further analyses (n=686). Patients with ALCL, AITL and PTCL NOS were most commonly treated with CMT (n=164; 28%) or chemotherapy only (n=154; 26%). Only 10 patients (1%) received chemotherapy followed by ASCT. The remaining patients were treated with either radiotherapy only (n=116; 20%) or received other/no therapy (n=149; 25%). More patients were treated with CMT in 2000-2018 as compared to 1989-1999 (36% versus 17%, p<0.01). Patients with EATL were most commonly treated with either chemotherapy only or other/no treatment (both n=45; 48%), while 3 patients (4%) received chemotherapy in combination with ASCT (n=2) or CMT (n=1). In EATL, no differences in treatment strategy were observed over time. Overall, 5-year OS for all stage I(E) PTCL was 52%. There was no significant difference in outcome between the two time periods (53% vs. 52%, p=0.92). EATL had a worse prognosis when compared to ALCL, AITL and PTCL NOS (5-year OS 15% vs. 58%, respectively; p<0.01). Five-year OS was significantly higher for patients with ALCL, AITL and PTCL NOS treated with CMT (71%) as compared to patients treated with either chemotherapy alone or with radiotherapy alone (52%, and 53%, respectively; p<0.01). Independent predictors for poor prognosis were higher age, male gender and EATL subtype whereas CMT was associated with a lower risk of mortality when evaluated for in multivariable analysis. Conclusions: For stage I(E) ALCL, AITL and PTCL NOS, 5-year OS is 58%. This compares favorably to the reported outcomes in advanced stage disease. EATL, even when presenting with limited stage disease, is associated with a very poor prognosis. CMT is associated with superior OS when compared to either chemotherapy or radiotherapy alone. Disclosures Van Der Poel: Roche, Janssen, Abbvie: Honoraria. Kersten: Kite/Gilead: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy; Miltenyi Biotech: Consultancy; Novartis: Consultancy, Honoraria; Roche: Honoraria; Takeda: Consultancy. Mutsaers: BMS: Consultancy; AstraZeneca: Research Funding. Woei-a-Jin: University Hospitals Leuven, Belgium: Current Employment; Recordati: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Kyowa Kirin: Research Funding.
Introduction Sickle cell disease (SCD) is a hereditary red blood cell disorder characterized by severe anemia, acute and painful vaso-occlusive crises and progressive organ failure. Success of health management of children with SCD is highly contingent on caregivers' capabilities. Caregivers of SCD affected children must perform a variety of tasks including communication with healthcare providers, reading and understanding of health information, interpretation of acute symptoms and administration of medication and complex decision making with regard to treatment options. A construct which describes the knowledge and competences of persons to meet the complex demands of health is 'health literacy' (HL) (1, 2). The measurement and assessment of HL is of growing importance due to expected and reported relationships between inadequate HL and health outcomes (3-5). In addition, caregivers with higher HL levels feel more confident in their ability to perform caregiving tasks, e.g. have a higher self-efficacy, often associated with higher quality of life (6, 7). Information on literacy levels and the relationship between HL, disease knowledge and self-efficacy may guide interventions in comprehensive SCD care. The aims of this study were to: (a) gain insight into levels of HL in caregivers of children with SCD using objective and subjective measures and to (b) assess the relationship between HL, caregivers self-efficacy' in communication with healthcare professionals and knowledge of SCD on different topics related to the illness. This abstract reports preliminary results. Methods In this cross-sectional, observational study, we included caregivers of children with SCD who attended the outpatient clinic of the Sickle Cell Comprehensive Care Center in the Erasmus Medical Center for a routine follow-up visit. Caregivers included in the study had to be able to communicate verbally in Dutch with professionals. HL was measured using the Short Assessment of Health Literacy in Dutch (SAHL-D) (8, 9); self-reported HL was evaluated by the Set of Brief Screening Questions (SBSQ) (10, 11). Self-efficacy was measured using the Perceived Self-Efficacy in Caregiver-Patient Interactions (PECPI) scale (12). Knowledge of SCD was assessed using a structured 13-item questionnaire (SCD-K) based on information and education provided in our clinic. Since data were not-normally distributed, they were analyzed using non-parametric statistics. Results To date, a total of 42 caregivers were included. Study inclusion will continue until at least 75 caregivers have been included. Demographics are presented in Table 1. Caregivers were mainly the child's mother (81.0%) often the single head of household (66.7%). The mean age of caregivers was 34.4 years. Educational level ranged from never attended school to post college Almost a quarter (23.8%) of caregivers was born in the Netherlands, others the rest were non-western migrants (76.2%). 78.6% of caregivers had low HL according to the SAHL-D. Caregivers with lower HL were more likely to have lower education (p=0.012) and to have been born outside the Netherlands (p=0.002). Only four caregivers (9.5%) reported having difficulties in understanding and applying health information (measured by SBSQ). The correlation between the SAHL-D and the SBSQ scores was weak (r=0.39). Mean scores on the SBSQ and PECPI were high, indicating that caregivers perceived their abilities for self-efficacy and their ability to read and understand medical information as quite high. Responses to individual SCD-K items however suggest large knowledge deficits: only 64.3% of caregivers knew which temperature is considered as fever [>38.0 °C or >38.5 °C] and only 14.3% was aware which risk factors are able to provoke sickle cell crises. The relationship between literacy status and item responses on SCD-K assessment scale was also examined. Caregivers with low literacy scored significantly lower on almost every individual item. Discussion Inadequate HL is highly prevalent in caregivers of children with SCD. Not being born in the Netherlands and lower education levels are strong predictors of low HL. Our study suggests that healthcare professionals should be attentive to possible low HL. In addition, these results underline that health information should be tailored to the HL skills and specific context of patients and their families. Disclosures Cnossen: NWO: Other: Governmental grants , ZonMW, Innovation fund and Nationale Wetenschapsagenda 2018; Roche: Other: Travel Grants; Takeda: Other: Travel Grants, Research Funding; Shire: Other: Travel Grants, Research Funding; Baxter: Other: Travel Grants, Research Funding; Sobi: Research Funding; CSL Behring: Other: Travel Grants, Research Funding; Nordic Pharma: Research Funding; Novo Nordisk: Research Funding; Pfizer: Other: Travel Grants, Research Funding; Bayer: Other: Travel Grants, Research Funding.
Abstract Abstract 5071 Background: Multiple myeloma (MM) is de second most common haematological malignancy in adults worldwide. MM is common in the elderly. While the general life expectancy is increasing an ever increasing number of patients has to be expected. In the last decade treatment strategies are changed continuously because of the introduction of novel agents and allogeneic and autologous stem cell transplantation. In randomized controlled trials, overall survival in patients up to 65 years is improving convincing. In contrast with results in older patients. We studied data of patients treated outside clinical trials derived from the population based registry in the Netherlands to recognize trends in incidence en survival during 1989–2009. Patients and methods: We included all patients with newly diagnosed MM in the period 1989 – 2009 who were recorded in the Netherlands Cancer Registry (n =16.822 ). Follow-up was until January, 2010. We calculated the yearly age-standardised incidence rates for males and females and age-specific incidence rates in 10 year age groups for both sexes separately and combined. Changes in incidence were evaluated by calculating the estimated annual percentage change (EAPC). We then calculated relative survival, which may be interpreted as disease-specific survival within a cancer patient population. Traditional cohort-based, relative survival analysis was applied for patients diagnosed during 1989–2009. Since follow-up was available until 2010, 5 year relative survival for patients diagnosed in 2004–2009 was estimated using period-based relative survival analysis. Results: The number of newly diagnosed MM cases rose between 1989 and 2009 from 631 to 968 cases respectively. Significantly more males were diagnosed than females over time (p=0.01). Furthermore the proportion of male patients increased slightly over these time periods. However, the overall age standardised incidence rate for males and females remained stable over time but was higher among males than females. The median age at diagnosis was 71 years (p10-P90 range 53–84) and stable over time (p=0.07). Incidence was highest in the 70–79 age group for both sexes. However, because of the aging population the age-specific incidence rates (ASIR) were highest for patients aged 80+ years for both sexes. Within specific age groups significant changes were seen. In the population 50–59 years, the ASIR increased from 5.0 per 100,000 in 1989 to 6.9 in 2009 (EAPC 1989–2009 = + 0.7%; 95% CI: 0.0 –1.3). A decrease was seen in females aged 80+ years from 25.1 per 100,000 in 1989 to 22.4 in 2009 (EAPC 1989–2009 = −1,0; 95% CI: −1.8; −0.2). In the overall patient population the 1-year relative survival increased only slightly from 72% to 77% between 1989 and 2009. 5-year relative survival increased from 28% to 37%. Small improvements in survival were observed for all age groups in the past two decades except for patients aged 80+ years. Relative survival decreased with increasing age. In contrast, in the group aged 40–64 years improvements are already detectable from 1994 on. In 2004–2009 the highest 5-year relative survival, 62%, was seen in patients 40–49 year of age. However the strongest improvement over time was observed among the group 50–59 years. Conclusion: Although the average annual age-adjusted incidence rate remained stable from 1989–2009, the number of newly diagnosed MM patients increased because of the aging population. Relative survival increased slowly but continuously in time for patients until 80 years of age with strongest increase seen in patients up to 64 years of age. Improvement for these younger patients is most likely caused by the introduction of novel agents based regiments as well as by the introduction of high dose chemotherapy followed by stem cell transplantation. Our findings in trends of incidence and survival of MM are similar to those reported in other western populations. Disclosures: Sonneveld: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees.
Abstract Background: The Slit-Robo pathway has been shown to participate in the pathogenesis of several malignant diseases in addition to its physiologic role during the development of the central nervous system (CNS). However, the relevance of the Slit-Robo pathway in acute promyelocytic leukemia (APL) is presently unknown. We investigated the status of the Slit-Robo pathway in APL following the recent demonstration by Amodeo et al (CellRep. 2017) that the PML protein induces neural stem/progenitor cells migration by inhibiting the SLIT2 gene, which was associated with an increased presence of H3K27me3 in the SLIT2 promotor region. Moreover, sensitivity towards the PML-targeting drug arsenic trioxide in primary glioblastoma cells was shown to be regulated by the PML/SLIT axis. Aims: Here, we quantified SLIT2 transcript levels in bone marrow (BM) samples from APL patients and healthy subjects and determined whether they are associated with clinical and laboratory features at diagnosis and treatment outcomes. In addition, we evaluated the effect of increased SLIT2 protein on leukemic cell survival, proliferation and clonogenecity. Methods: Cell cycle distribution, proliferation index (Ki-67/proliferation curve), colony formation and rate of apoptotic cells (annexin V/PI) were evaluated in both APL cell lines NB4 (ATRA-sensitive), NB4R2 (ATRA- resistant) and four primary APL samples following the treatment with the human recombinant SLIT2 protein (50 ng/ml) for 24 to 72 hours. In addition, 88 patients (age, 18-73y) with newly diagnosed APL enrolled in the International Consortium on Acute Leukemia (ICAL) study - ICAPL2006 were included. For comparison, BM mononuclear cells from five healthy volunteers (age, 18-60y) were also included. SLIT2 transcripts was determined by qPCR and expressed as comparative Ct method. Patients were dichotomized into "low" and "high" SLIT2 expression groups using a cut off value of 1.53 based on survival receiver operating characteristic (ROC) curve and the C index analyses. The following parameters were used to evaluate treatment outcome: complete hematological remission (CHR); 5-year Disease-Free Survival (DFS) and 5-year Overall Survival (OS) rates. Results: At the end of the sixth day, in vitro treatment with SLIT2 significantly reduced the proliferation rate (P=.01) and clonogenicity (P=.01) in primary APL samples, while significantly increasing the apoptotic rate after 72 hours treatment with SLIT2 (P=.03). In accordance, SLIT2 treatment decreased cell proliferation and clonogenicity (all P<.01) and increased the drug-induced apoptosis in a time-dependent manner in NB4 and NB4R2 cells (P<.01). Cell cycle analysis revealed that the cell cycle was arrested in the S-phase (P=.001) with a reduction of the G2/M phase (P=.001) in NB4 after 72 hours of treatment but no such impact was observed on NB4R2. In the clinical setting, patients with APL had a higher-than-normal expression of SLIT2 (6.7-fold higher than BMMC; P=.01). Baseline characteristics were similar between patients with low and high SLIT2 levels, except for a higher white blood cell count in patients with low SLIT2 expression (P=.024). Overall, 80/94 (85%) patients achieved complete hematological remission (CR). SLIT2 transcript levels had no impact on CR rate (P=.099). The estimated 5y DFS and the CIR rates were 87% (95% CI: 80-92%) and 12% (95% CI: 7-17%), respectively. Patients with low SLIT2 expression presented a lower 5y DFS rate (79%, 95% CI: 48-92%) than those with high SLIT2 expression (96%, 95% CI: 64-97%) (P=.026). In addition, patients with low SLIT2 expression exhibited an enhanced CIR rate compared to high SLIT2 expression (21% vs 11%) (P=.03). With a median follow up of 32 months (1-101 months), the estimated 5y OS rate was 79% (95% CI: 72-84%). Patients with lower SLIT2 expression had a lower 5y OS rate (68%, 95% CI: 45-83%) compared to those with higher SLIT2 expression (84%, 95% CI: 73-91%) (P=.008). This result was consistent with the multivariable proportional hazards analysis (HR: 1.02; 95% CI: 1.01-1.03; P=.001). Conclusion: Our results suggest that SLIT2 transcript levels may predict outcomes in APL patients treated with ATRA and anthracycline-based chemotherapy. Our data show that SLIT2 treatment represses APL cell growth, colony formation and induces apoptosis in vitro and we are currently assessing the role of the Slit-Robo pathway in the hCG-PML/RARA transgenic mouse model. Disclosures Pagnano: EMS: Other: Financial support for participation in congress; Novartis: Consultancy; Shire: Other: Lecture; Abbvie: Consultancy. Tallman:Daiichi-Sankyo: Other: Advisory board; Cellerant: Research Funding; ADC Therapeutics: Research Funding; AROG: Research Funding; AbbVie: Research Funding; Orsenix: Other: Advisory board; BioSight: Other: Advisory board. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Lowenberg:Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy; Editorial Board "European Oncology & Haematology": Membership on an entity's Board of Directors or advisory committees; international Scientific Advisory Board, Institute Gustave Roussy, Paris: Membership on an entity's Board of Directors or advisory committees; Clear Creek Bio Ltd: Consultancy, Honoraria; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Editorial Board "The Netherlands Journal of Medicine": Membership on an entity's Board of Directors or advisory committees; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Editorial Board "International Journal of Hematology": Membership on an entity's Board of Directors or advisory committees; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherlands: Membership on an entity's Board of Directors or advisory committees; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands): Membership on an entity's Board of Directors or advisory committees; "Up-to-Date", section editor leukemia: Membership on an entity's Board of Directors or advisory committees.
Abstract Introduction Clinical trials have shown improved response rates, progression-free survival and overall survival (OS) in patients with multiple myeloma (MM) when using the novel agents thalidomide, lenalidomide and bortezomib. However, outcome data provided by population-based registries, reflecting real-life, report predominantly improved OS in younger MM patients and only minimal improvement in OS in unselected MM patients older than 65 years. Population-based studies in unselected MM patients in the era of novel agents are relatively limited. Explanations for the marked variation in prognosis across patients may in part be explained by the heterogeneity in the initial clinical presentation, the pre-existing comorbidities, disease biology and response to the therapy. Specific end-organ damage caused by the disease, such as hypercalcemia, renal failure, anemia and bone lesions known as the CRAB symptoms may be associated with worse prognosis in the elderly MM patients. This descriptive prospective population-based cohort study was designed to determine the OS in patients with MM in Friesland, The Netherlands in the era of novel agents, and to analyze the influence of the CRAB symptoms and comorbidities at initial presentation on survival. Methods Since 2005 all patients diagnosed with hematological malignancies in Friesland, a province of the Netherlands, are prospectively registered and followed by their clinicians in a population-based registry, the HemoBase. For this analysis, data on clinical characteristics, comorbidities, treatment and outcome of all patients with newly diagnosed MM in Friesland during the period of January 2005 to January 2013 with a follow-up until January 2014 were retrieved from HemoBase. Supplementary information was obtained from the individual patient hospital records. Both symptomatic and asymptomatic patients were included in the study with subgroup analysis on the symptomatic patients. According to the guidelines from IMWG, each CRAB symptom was divided into two categories (11 mg/dL < serum calcium ≤ 11 mg/dL; 2 mg < creatinine ≤ 2 mg/dL; 10.2 g/d ≤ hemoglobin < 10.2 g/dL and the presence or absence of bone lesions). The patients were divided by age groups (<65, 65 – 75 and ≥75 years old) to illustrate differences in survival in the three age categories. Results From 2005 till 2013 a total of 270 patients were diagnosed with MM in Friesland. The median observation period was 29 months (range 0.26 - 104; IQR 33). Median age was 70 years (range 32 - 92; IQR 15) with a male predominance (60% male). 34, 34 and 32% of patients were < 65 years, 65 - 75 years and ≥ 75 years, respectively. The Charlson Comorbidity Index (CCI) was 0,1 or ≥2 in 60, 22, 18% of patients, respectively. Sixteen percent of patients were asymptomatic. Of symptomatic patients 63% and 27% had CRAB scores of 1-2 and 3-4, respectively. Ten percent of patients had a CRAB score of 0, but were regarded symptomatic by their treating hematologist. Among the symptomatic MM patients 80% received novel agents, 15% other chemotherapy 6% only radiotherapy. The median OS of all patients is 49.5 months, with median OS for symptomatic and asymptomatic patients of 40 and >100 months respectively. Divided into age categories < 65, 65 – 75 and ≥75 years old, the 50% OS is respectively 92, 40 and 29 months (figure 1). For all patients, implementing novel therapies improved OS compared to other therapies (43.5 vs. 21.1 months, hazard ratio (HR) = 1.8, P = 0.017. Patients with a CCI score of 0 have a higher median OS than patients with a score ≥ 2 (HR = 0.6, P = 0.036). Patients with two or more CRAB symptoms have a lower median OS than patients without any CRAB symptoms (HRadjusted = 2.2, P = 0.028). In multivariate analysis, differences in median OS were significant better for patients without hypercalcemia compared to patients with hypercalcemia (HRadj. = 0.6, P = 0.011) and for patients with a serum creatinine ≤ 2 mg/dL vs. ≥ 2 mg/dL (HRadj. = 0.4, P < 0.0001). Conclusion In this population-based study of a complete Dutch cohort of unselected MM patients over the last decade a median OS of 49.5 months was observed. Despite extensive introduction of novel agents increasing age remains an adverse prognostic factor. High comorbidity scores (CCI ≥ 2) and CRAB symptoms, such as hypercalcemia and impaired renal function at initial presentation were significantly correlated with worse median OS. Disclosures Hovenga: Jansen Cilag: Research Funding. Woolthuis:Jansen Cilag: Research Funding. Hoogendoorn:Jansen Cilag: Research Funding.
