Real-world treatment outcomes in multiple myeloma: Multicenter registry results from Finland 2009-2013

Outcomes for patients with multiple myeloma (MM) have improved with the advent of novel therapies, however, real-world evidence of outcomes in clinical practice is scarce. We conducted a multi-center registry study to build a reliable picture of treatment and patient outcomes in Finland. The aim of this study was also to understand any methodological challenges in assessing treatment outcomes using disease registry data. Methods: We carried out a retrospective, observational study using data from the national Finnish Hematology Registry (FHR) to provide real-world evidence of outcomes for all adult patients diagnosed with and treated for MM between 2009–2013 at one of the six regional hospitals, with at least six months of recorded follow-up. Patients were identified within the FHR by applying eligibility criteria of a diagnosis of MM and verifiable records of medical treatment and lines of treatment during the study period. Patients receiving allogenic stem cell transplantation were excluded from the cohort, as were individuals who only had monoclonal gammopathy of undetermined significance diagnosis and patients who had not initiated treatment during this period. Kaplan Meier curves were used to calculate overall survival and time to next treatment. Stratification was carried out by drug status (conventional/novel) and by autologous stem cell transplant (ASCT) status. Results: A total of 321 patients met the inclusion criteria and were included in this study. Overall survival (OS) was longest in patients who received first-line novel therapy and ASCT (median not reached during 60-month follow-up) versus 46.2 months for novel first-line therapy without ASCT and 25.6 months for first-line conventional therapy without ASCT. Similarly, median time to next treatment were 33.9 months, 12.6 months and 7.8 months, respectively. Conclusions: The adoption of novel treatments in MM in Finland has had substantial impact on patient outcomes. Given the reality of complex treatment combinations for MM and relatively low patient numbers, assessing individual treatment effectiveness will require substantial cohort sizes and advanced, collaborative analytics on an international scale</p

Studies on 15-lipoxygenase in dendritic cells and leukotriene receptors in Hodkin lymphoma

Classical Hodgkin Lymphoma (cHL) is histologically characterized by a minority of malignant cells, the so-called Hodgkin-Reed Sternberg (H-RS) cells, surrounded by inflammatory cells such as T lymphocytes, eosinophils, macrophages and mast cells. It is generally believed that various molecules released by the H-RS cells are of major importance in the pathophysiology of cHL. In paper I, we report a link between inflammatory cell-derived arachidonic acid metabolites, the cysteinyl leukotrienes (CysLT), to tumor cell growth and function in this disease entity. Two HL cell lines, L 1236 and KMH2, were shown to express functional CysLT, receptors, responding with a robust calcium signal upon challenge with LTD4. Incubation of L1236 cells with LTD4 not only stimulated DNA synthesis but also the transcription and protein release of tumor necrosis factor-á, interleukin-6 and -8. Importantly, all these LTD4-induced effects were blocked by the CysLT1, receptor-specific antagonist zafirlukast. Immunohistochemical studies of classical HL biopsies and microarray analysis of laser captured cells revealed that the CysLT1, receptor is expressed also by the Hodgkin Reed-Stemberg cells ex vivo. Since these cells are surrounded by CysLT-producing eosinophils, macrophages and mast cells, our results suggest the CysLTs as novel mediators in the pathogenesis of classical HL by contributing to the growth and the cytokine features of this tumor. Lipoxygenases are highly regulated enzymes that catalyze the introduction of molecular oxygen in polyunsaturated fatty acids. The lipoxygenases are classified with respect to their positional selectivity of the substrate arachidonic acid. 15-lipoxygenase- 1 (15-LO-1), an enzyme implicated in several pathophysiological conditions, possesses the ability to oxygenate free fatty acids and fatty acids bound to membrane phospholipids. The regulation of the enzymatic activity of membrane associated 15- LO-1 is poorly understood. In paper II we demonstrate that calcium ionophore stimulates the translocation of 15-LO-1 to the plasma membrane in human dendritic cells. Furthermore, as shown in a protein-lipid overlay assay, 15-LO-1 was shown to interact with several phosphoinositides. In the presence of calcium, addition of phosphatidylinositol-4.5-bisphosphate (PI(4.5)P2) or PI(3.4)P2 to the vesicles containing arachidonic acid led to a significantly increased formation of 15- hydroxyeicosa-5Z,8Z,11Z,13E-tetraenoic acid (15-HETE) compared to vesicles without phosphoinositides. Kinetic studies further revealed that vesicles containing PI(4.5)P2) or PI(3.4)P2 lowered the Km value (substrate concentration required for maximum enzymatic velocity) for 15-LO-1, whereas Vmax (the maximum enzymatic velocity) was unaffected. These results suggest that 15-LO-1 activity also might be regulated by the phospholipid constitution of membranes

Studies on Cysteinyl Leukotriene Receptor 1 and 15-lipoxygenase-1 in Lymphomas

Classical Hodgkin lymphoma (cHL) is a malignant disorder with striking inflammatory features. Since cysteinyl leukotrienes (cysLTs) are potent inflammatory mediators it was of interest to study their potential role in the pathogenesis of cHL. We have shown that certain HL cell lines express functional CysLT1 receptors, responding with a robust calcium signal upon leukotriene (LT) D4 challenge. Stimulation of these cells with LTD4 induced a CysLT1 receptor-dependent release of interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-alpha. The malignant Hodgkin Reed-Sternberg (H-RS) cells in the majority of the primary cHL biopsies under study also expressed the CysLT1 receptor. Since these cells are surrounded by cysLT-producing eosinophils, macrophages and mast cells, our results suggest that the cysLTs might be of importance for the pathogenesis of cHL (paper I). The cHL cell line L1236 has high expression of 15-lipoxygenase-1 (15-LO-1) and these cells were able to convert arachidonic acid to eoxin (EX) C4, EXD4 and EXE4, pro-inflammatory metabolites recently discovered in human eosinophils and mast cells. Immunohistochemical studies of cHL tumor tissue demonstrated that 15-LO-1 was expressed in primary H-RS cells in the majority of the investigated biopsies. Thus, the expression of 15-LO-1 and the formation of eoxins by H-RS cells are likely to contribute to the inflammatory features of cHL. These findings may have important diagnostic and therapeutic implications (paper II). The expression of the CysLT1 receptor and 15-LO-1 was also elucidated in non-Hodgkin lymphomas (NHLs). The majority of the primary mediastinal B cell lymphomas under study, in contrast to other NHLs, expressed the CysLT1 receptor. Furthermore, T cell-derived anaplastic large cell lymphoma was the only NHL entity shown to express 15-LO-1. Thus, the CysLT1 receptor and 15-LO-1 are potential targets in lymphoma diagnostics and sub-classification (paper III). Finally, we have studied the post-translational regulation of 15-LO-1 in dendritic cells. In the presence of calcium, addition of phosphatidylinositol-4.5-bisphosphate or phosphatidylinositol-3.4-bisphosphate to vesicles containing arachidonic acid led to a significantly increased formation of 15-hydroxyeicosa-5Z,8Z,11Z,13Etetraenoic acid (15-HETE) compared to vesicles without phosphoinositides. These results suggest that 15-LO-1 activity may also be regulated by the phospholipid constitution of membranes (paper IV)

Real-world study of direct medical and indirect costs and time spent in healthcare in patients with chronic graft versus host disease

Chronic graft versus host disease (cGVHD) is a debilitating and costly complication following haemopoietic stem cell transplantation (HSCT). This study describes the economic burden associated with cGVHD. Direct costs associated with specialised healthcare utilisation (inpatient admissions and outpatient visits), as well as indirect costs associated with sickness absence-associated productivity loss were estimated in patients who underwent allogeneic HSCT in Sweden between 2006 and 2015, linking population-based health and economic registers. To capture the period of chronic GVHD, patients were included who survived &gt; 182 days post-HSCT (start of follow-up), and cGVHD was classified based on patient treatment records to correct for any diagnosis underreporting. Patients were classified as 'non-cGVHD' if they received no immunosuppressive treatment, 'mild cGVHD' if they received only systemic corticosteroid treatment or immunosuppressive treatment, or 'moderate-severe cGVHD' if they received extracorporeal photopheresis (ECP) only, corticosteroid treatment and immunosuppressive treatment, or systemic corticosteroid treatment and ECP treatments. Patients with moderate-severe cGVHD spent more time in healthcare, had higher healthcare resource costs and higher sickness absence-related productivity loss compared to patients with non- or mild cGVHD. The cumulative total costs during the first 3 years of follow-up were EUR 14,887,599, EUR 20,544,056, and EUR 47,811,835 for non-, mild, and moderate-severe groups, respectively. The long-term costs incurred with cGVHD following HSCT continue to be very high and significantly impacted by cGVHD severity. This study adds real-world health resource and economic insight relevant for policy-makers and healthcare providers when considering the clinical challenge of balancing immunosuppression to reduce cGVHD

Population-based real-world registry study to evaluate clinical outcomes of chronic graft-versus-host disease

Introduction Chronic graft-versus-host disease (cGVHD) is a serious immune-mediated complication after allogeneic haematopoietic stem cell transplantation (HSCT), but in patients with malignancy, cGVHD development is associated with superior survival. Lack of reliable biomarkers and clinical underreporting means there is insufficient understanding of cGVHD clinical outcomes and balance between cGVHD treatment and maintaining beneficial graft-versus-tumour effects. Methods We performed a Swedish population-wide registry study following patients who underwent allogeneic HSCT 2006–2015. cGVHD status was retrospectively classified using a real-world method based on the timing and extent of systemic immunosuppressive treatment. Results cGVHD incidence among patients surviving ≥6 months post-HSCT (n = 1246) was 71.9%, significantly higher than previously reported. 5-year overall survival in patients surviving ≥6 months post-HSCT was 67.7%, 63.3%, and 65.3%, in non-, mild, and moderate-severe cGVHD, respectively. Non-cGVHD patients had a mortality risk almost five-fold higher compared to moderate-severe cGVHD patients 12-months post-HSCT. Moderate-severe cGVHD patients had greater healthcare utilization compared with mild and non cGVHD patients. Conclusion cGVHD incidence was high among HSCT survivors. Non-cGVHD patients had higher mortality during the first 6 months of follow-up; however, moderate-severe cGVHD patients had more comorbidities and healthcare utilization. This study highlights the urgent need for new treatments and real-time methods to monitor effective immunosuppression after HSCT

Population-based real-world registry study to evaluate clinical outcomes of chronic graft-versus-host disease.

IntroductionChronic graft-versus-host disease (cGVHD) is a serious immune-mediated complication after allogeneic haematopoietic stem cell transplantation (HSCT), but in patients with malignancy, cGVHD development is associated with superior survival. Lack of reliable biomarkers and clinical underreporting means there is insufficient understanding of cGVHD clinical outcomes and balance between cGVHD treatment and maintaining beneficial graft-versus-tumour effects.MethodsWe performed a Swedish population-wide registry study following patients who underwent allogeneic HSCT 2006-2015. cGVHD status was retrospectively classified using a real-world method based on the timing and extent of systemic immunosuppressive treatment.ResultscGVHD incidence among patients surviving ≥6 months post-HSCT (n = 1246) was 71.9%, significantly higher than previously reported. 5-year overall survival in patients surviving ≥6 months post-HSCT was 67.7%, 63.3%, and 65.3%, in non-, mild, and moderate-severe cGVHD, respectively. Non-cGVHD patients had a mortality risk almost five-fold higher compared to moderate-severe cGVHD patients 12-months post-HSCT. Moderate-severe cGVHD patients had greater healthcare utilization compared with mild and non cGVHD patients.ConclusioncGVHD incidence was high among HSCT survivors. Non-cGVHD patients had higher mortality during the first 6 months of follow-up; however, moderate-severe cGVHD patients had more comorbidities and healthcare utilization. This study highlights the urgent need for new treatments and real-time methods to monitor effective immunosuppression after HSCT

Transcriptional regulation of 15-lipoxygenase expression by histone h3 lysine 4 methylation/demethylation.

15-Lipoxygenase-1 (15-LOX-1) oxidizes polyunsaturated fatty acids to a rich spectrum of biologically active metabolites and is implicated in physiological membrane remodelling, inflammation and apoptosis. Its deregulation is involved in the pathogenesis of diverse cancer and immune diseases. Recent experimental evidence reveals that dynamic histone methylation/demethylation mediated by histone methyltransferases and demethylases plays a critical role in regulation of chromatin remodelling and gene expression. In the present study, we compared the histone 3 lysine 4 (H3-K4) methylation status of the 15-LOX-1 promoter region of the two Hodgkin lymphoma (HL) cell lines L1236 and L428 with abundant and undetectable 15-LOX-1 expression, respectively. We identified a potential role of H3-K4 methylation in positive regulation of 15-LOX-1 transcription. Furthermore, we found that histone methyltransferase SMYD3 inhibition reduced 15-LOX-1 expression by decreasing promoter activity in L1236 cells. SMYD3 knock down in these cells abolished di-/trimethylation of H3-K4, attenuated the occupancy by the transactivator STAT6, and led to diminished histone H3 acetylation at the 15-LOX-1 promoter. In contrast, inhibition of SMCX, a JmjC-domain-containing H3-K4 tri-demethylase, upregulated 15-LOX-1 expression through induction of H3-K4 trimethylation, histone acetylation and STAT6 recruitment at the 15-LOX-1 promoter in L428 cells. In addition, we observed strong SMYD3 expression in the prostate cancer cell line LNCaP and its inhibition led to decreased 15-LOX-1 expression. Taken together, our data suggest that regulation of histone methylation/demethylation at the 15-LOX-1 promoter is important in 15-LOX-1 expression