Introduction. Efficacy and safety of daratumumab monotherapy (DARA mono) in relapsed/refractory multiple myeloma (rrMM) has been shown in the single-arm phase I/II trial GEN501 and the single-arm ...phase II trial SIRIUS (1, 2). Since then, several indirect treatment comparisons of DARA mono versus comparator therapies have been published showing consistent results with an overall survival benefit for DARA mono (3, 4, 5, 6). This analysis compares efficacy and for the first time also safety of DARA mono data versus an international historic control group, adjusting for differences in patient populations based on individual patient level data (IPD).
Methods. IPD from the SIRIUS trial and from the International Myeloma Foundation (IMF)-cohort (7), a retrospective, multicenter cohort, were compared using a multivariate Cox proportional hazards model, on the endpoints of efficacy (overall survival (OS)) and safety (discontinuation due to adverse events (DISCONAE)). The IMF-cohort included patients with rrMM who received at least three prior lines of therapy, were refractory to both an immunomodulator (IMiD) and a proteasome inhibitor (PI), and were exposed to an alkylating agent. An inclusion criterion for the historic control group in this analysis was treatment with EU approved regimens. Baseline covariates adjusted for in the regression model included age, gender, prior lines of therapy, albumin, beta-2 microglobulin, prior exposure to pomalidomide and carfilzomib, and PI/IMiD refractory status. Several sensitivity analyses were run, including multiple imputation of missing values.
Results. Data from 106 patients treated with DARA mono (16 mg/kg) were available from SIRIUS; 258 patients from the IMF chart review fulfilled the inclusion criteria; most frequent treatment regimens contained pomalidomide plus dexamethasone (PomDex) (n=172), bortezomib (n=31), carfilzomib (n=21), cyclophosphamide (n=14) and lenalidomide (n=9). The adjusted HR for OS was 0.41 0.25, 0.69, p<0.001, and 0.23 0.05, 1.00, p=0.050 for DISCONAE, in favor of daratumumab. Results were consistent across a range of sensitivity analyses and were similar when restricting the comparison to DARA vs. PomDex, with HR=0.35 0.19, 0.64, p<0.001 for OS and 0.20 0.03, 1.54, p=0.123 for DISCONAE.
Conclusions. This comparison using real-world data of rrMM patients suggests improved efficacy and safety for DARA mono compared to approved therapy regimens used in clinical practice, including PomDex.
References.Lokhorst, H. M., Plesner, T., Laubach, J. P., Nahi, H., Gimsing, P., Hansson, M., et al. Targeting CD38 With Daratumumab Monotherapy in Multiple Myeloma. The New England Journal of Medicine. 2015.Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab Monotherapy in Patients with Treatment-Refractory Multiple Myeloma (SIRIUS): An Open-Label, Randomised, Phase 2 Trial. The Lancet. 2016.Usmani S, Ahmadi T, Ng Y, Lam A, Desai A, Potluri R, Mehra M. Analysis of Real-World Data on Overall Survival in Multiple Myeloma Patients With ≥3 Prior Lines of Therapy Including a Proteasome Inhibitor (PI) and an Immunomodulatory Drug (IMiD), or Double Refractory to a PI and an IMiD. The Oncologist. 2016.Van Sanden S, Ito T, Diels J, Vogel M, Belch A, Oriol A. Comparative Efficacy of Daratumumab Monotherapy and Pomalidomide Plus Low-Dose Dexamethasone in the Treatment of Multiple Myeloma: A Matching Adjusted Indirect Comparison. The Oncologist. 2017.Usmani SZ, Diels J, Ito T, Mehra M, Khan I, Lam A. Daratumumab monotherapy compared with real-world historical control data in heavily pretreated patients with highly refractory multiple myeloma: An adjusted treatment comparison. American Journal of Heamtology. 2017.Jelínek T, Maisnar V, Pour L, Špička I, Minařík J, Gregora E, et al. Adjusted comparison of daratumumab monotherapy versus real-world historical control data from the Czech Republic in heavily pretreated and highly refractory multiple myeloma patients. Current Medical Research an Opinion. 2017.Kumar SK, Dimopoulos MA, Kastritis E, Terpos E, Nahi H, Goldschmidt H, et al. Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia. 2017.
Demmer:Janssen: Employment. Huschens:Janssen: Employment. Potthoff:Janssen: Employment. Tomeczkowski:Janssen: Employment. Englisch:Janssen: Employment. Thilakarathne:Janssen: Employment. Diels:Janssen: Employment. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Durie:Celgene: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Eisele:Janssen: Employment.
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The importance of the conservation of all three fundamental levels of biodiversity (ecosystems, species and genes) has been widely acknowledged, but only in recent years it has become technically ...feasible to consider intraspecific diversity, i.e. the genetic component to biodiversity. In order to facilitate the assessment of biodiversity, considerable efforts have been made towards identifying surrogates because the efficient evaluation of regional biodiversity would help in designating important areas for nature conservation at larger spatial scales. However, we know little about the fundamental relationships among the three levels of biodiversity, which impedes the formulation of a general, widely applicable concept of biodiversity conservation through surrogates. Here, we present the set-up of an international, interdisciplinary project, I
ntraB
ioD
iv (
http://www.intrabiodiv.eu), which studied vascular plant biodiversity at a large scale, i.e. across the European Alps and the Carpathians. Our assessment comprises species richness (high-mountain flora), genetic variation (amplified fragment length polymorphisms, AFLPs) and environmental diversity (modelled potential habitat diversity). Our primary aims were to test for correlations between intra- and interspecific diversity and to identify possible environmental surrogates to describe biodiversity in the two study regions. To the best of our knowledge, I
ntraB
ioD
iv represents the first multispecies study on intraspecific, molecular-genetic variation in relation with species and habitat diversity. Here, we outline the theoretical background, our sampling scheme, the technical approaches and the feasibility of a concentrated and standardized sampling effort. We further show exemplary results. Our three data sets will be made freely available and will provide a playground for further hypothesis testing in conservation, ecology or evolution open to the scientific community.
Patients with cancer have an increased risk of developing venous thromboembolism. Neutrophils and neutrophil extracellular traps (NETs) reportedly influence the risk of cancer-associated thrombosis. ...Subpopulations of high and low-density neutrophils (HDN/LDN) are of specific interest, as they might have different functions in cancer patients.
We aimed to investigate differences between HDNs and LDNs of patients with lung cancer and healthy controls, and their ability of activation and NET formation.
Within the framework of the Vienna Cancer and Thrombosis Study, a prospective observational cohort study, HDNs and LDNs from 20 patients with lung cancer and 20 controls were isolated by density gradient centrifugation. The ability of neutrophil subpopulations for activation and NET formation was investigated by flow cytometry.
Compared to controls, patients with cancer had higher numbers of total leukocytes, HDNs, and LDNs. LDNs of patients were more frequently in an activated state (CD62L↓/CD16↑) at baseline (median IQR 5.9% 3.4-8.8 vs 2.5% 1.6-6.7). HDNs and LDNs from patients showed a significantly increased response to stimulation with ionomycin (CD11b HDN: 98.5 95.4-99.4 vs 41.7 13.4-91.6; LDN: 82.9 63-94 vs 39.6 17.3-72.1). In addition, HDNs from patients showed a higher capability of NET formation after ionomycin stimulation compared to HDNs from healthy controls (18509.5 12242.5-29470.3 vs 10001 6618.8-18384.3).
Protumorigenic LDNs were elevated, and neutrophil subpopulations showed an increased activation profile and ability for NET formation in patients with cancer. These mechanisms might be involved in tumor promotion and contribute to the prothrombotic phenotype of neutrophils in cancer.
•Patients with lung cancer have increased numbers of high and low-density neutrophils•Neutrophils from lung cancer patients and healthy controls were characterized•Neutrophil subpopulations in lung cancer bear an increased activation potential upon stimulation•High-density neutrophils from lung cancer patients have an increased ability to form NETs
Patients with schizophrenia often experience comorbid obsessive-compulsive syndromes (OCSs). Within these patients, a significant subgroup developed secondary OCS during treatment with ...antiserotonergic, atypical antipsychotic agents such as clozapine. Although cognitive behavioral therapy and antiobsessive antidepressants brought up inconsistent results, in some cases, dose reductions of clozapine in combination approaches were able to alleviate OCS. One suggestive agent for antiobsessive add-on treatment is aripiprazole, a partial agonist at dopamine and serotonin receptors.Here, we summarize the courses of 7 patients (6 men; mean age, 37 years; mean duration of psychotic illness, 17 years). They had been treated with clozapine for 9 years. The distressing and treatment-resistant comorbidity with OCS emerged approximately 4 years after the start of clozapine therapy. During combined treatment with mean doses of 22.9 mg of aripiprazole for 9.7 weeks, we assessed a small yet statistically not significant improvement of the psychotic disorder, whereas a marked reduction of obsessions and significant improvements of compulsions could be observed. The mean total Yale Brown Obsessive Compulsive Rating Scale decreased from 18.7 to 12.4 (P = 0.003).These data support the findings of 2 previous case reports and point toward an antiobsessive potency of aripiprazole. The relevant disabling comorbidities of psychosis and OCS need further investigation with multimodal neurobiological approaches. The proposed strategy should be further evaluated in prospective controlled trials with severity of comorbid OCS as a primary end point.
Many schizophrenic patients have comorbid obsessive-compulsive syndromes (OCS) frequently associated with antiserotonergic second-generation antipsychotics such as clozapine and olanzapine. Whereas ...cognitive behavioral therapy and antiobsessive antidepressants brought up inconsistent results, pharmacological add-on strategies were able to alleviate OCS. One suggestive agent for antiobsessive add-on treatment is aripiprazole, a partial agonist at dopamine and serotonin receptors. Here, we summarize the course of a patient with paranoid schizophrenia. She developed OCS during long-term treatment with olanzapine at 20 mg/d over a period of 10 years. Baseline assessment showed severe obsessions (Yale Brown Obsessive Compulsive Scale (YBOCS) subscale score : 13) and compulsions (YBOCS subscale score : 10), whereas the psychotic syndrome was compensated (Positive and Negative Syndrome Scale, 11/17/28). The combination with aripiprazole (15 mg/) over a period of 12 weeks resulted in a marked improvement of OCS (YBOCS, 8/3) and some further improvement of the psychotic symptoms (Positive and Negative Syndrome Scale, 9/13/27). This observation points toward an antiobsessive potency of aripiprazole in combination with olanzapine, quite similar to approaches involving clozapine. Hence, the proposed strategy should be further evaluated in prospective controlled trials.
Patients with psychotic disorders often suffer from intercurrent major depressive episodes (MDE). Case reports suggested successful antidepressive treatment with duloxetine, a selective dual reuptake ...inhibitor of serotonin and norepinephrine. We initiated this open prospective clinical trial to evaluate efficacy, safety and tolerability of this approach. Patients with a psychotic lifetime diagnosis suffering from mildly severe MDE were treated with duloxetine over a period of 6 weeks. We evaluated effects on mood, monitored the psychotic psychopathology and assessed side effects, basal clinical and pharmacological parameters. Twenty patients were included and experienced a significant improvement of their MDE during the observation period (Calgary Depression Scale for Schizophrenia and Hamilton Depression Scale). Psychotic positive symptoms remained stably absent, while negative syndrome and global psychopathology considerably improved (Positive and Negative Syndrome Scale). In general, the treatment was well tolerated, serum prolactin levels stayed unchanged, but pharmacokinetic interactions with a number of antipsychotic agents were observed. This open prospective evaluation showed antidepressive efficacy of duloxetine in patients with co-morbid psychotic disorders. With regard to the psychotic disorder, the treatment appears to be safe and well tolerable. Further investigations should involve a randomized control group.
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