Efficacy and safety of melflufen plus daratumumab and dexamethasone in relapsed/refractory multiple myeloma: results from the randomized, open-label, phase III LIGHTHOUSE study.

Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with ≥3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received ≥3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade ≥3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies.

Robotic stereotactic radiosurgery with CyberKnife - brain metastases and fibrinolysis.

OBJECTIVES: Deviations in haemostasis are found in about 50 % of patients with cancer and up to 90% of those with metastatic disease. Many studies investigate the dynamics of the processes of coagulation and fibrinolysis and their role as a predictor of therapeutic response, early relapse, or metastasis risk. BACKGROUND: To investigate the serum levels of urokinase plasminogen activator (uPA) in patients with brain metastases treated with robotic stereotactic radiosurgery (SRS) with CyberKnife. MATERIAL AND METHODS: Serum levels of urokinase plasminogen activator (uPA) were measured in 66 patients with solid tumours, divided into two groups, with oligometastatic disease and brain metastases. In this prospective longitudinal study, the serum levels of uPA were measured before starting the therapy and at the first, third, and sixth months after patients were irradiated with the CyberKnife system. RESULTS: Analysis of serum uPA levels in the post-treatment period showed a statistically significant decrease between the baseline and the 6 months post-treatment time point in both patient groups. The baseline value of serum uPA in the group with lung cancer decreased by 62.7 %, and in the group with other types of cancer - by 60 %. Despite the significant reduction of serum uPA levels 6 months after the treatment, the levels remained significantly higher in both groups than in healthy controls. CONCLUSION: Ongoing research on uPA and cancer will enrich our knowledge and expand the possibilities for clinical utilization of the marker in the oncology setting (Tab. 2, Ref. 18).

Markers of activation of coagulation in cancer patients.

BACKGROUND: Prothrombotic tendency is characteristic of tumors. The aim of the study is to investigate the changes in the laboratory parameters for coagulation and fibrinolysis, namely in fibrinogen, thrombin-antithrombin complex (ТАТ), tissue factor (ТF), prothrombin fragment (F1+2), antithrombin III (AT III), D-dimer and screening coagulation tests in cancer patients before initiation of chemotherapy. MATERIALS AND METHODS: Levels of F1+2, fibrinogen, ТАТ, AT III, TF, D-dimer, PT, aPTT and TT were measured baseline in 80 patients with breast and lung cancer before systemic treatment. The same parameters were investigated in 65 healthy volunteers. TF, ТАТ, F1+2 were measured by ELISA; AT III, D-dimer, fibrinogen and screening coagulation tests were measured by automated coagulation system Sysmex CS 2000i.  RESULTS: Levels of F1+2, fibrinogen, ТАТ, TF, and D-dimer in cancer patients were significantly higher than those in the control group, while the levels of ATIII activity were significantly lower (p < 0.001). The highest area under the ROC curve was for D-dimer, which made it a good marker for the risk of thrombosis. CONCLUSION: Higher levels of TF, ТАТ, F1+2, fibrinogen and D-dimer and lower activity of АТ III in cancer patients support our hypothesis of an association between malignant disease and coagulation disorders. Cancer patients are at an increased risk of thrombosis wherefore antithrombotic prophylaxis may be considered (Tab. 6, Fig. 2, Ref. 34). Text in PDF www.elis.sk Keywords: coagulation, fibrinolysis, cancer.

Autoimmune Phenomena in Patients with Solid Tumors.

INTRODUCTION: Autoimmune disorders have been documented in solid tumors and malignant hematological disorders. They are very common and well studied in lymphomas which are associated with immune imbalance. They are less common in solid tumors and are categorized as paraneoplastic syndromes with unclear pathogenesis. AIM: The aim of the present study was to find the frequency of autoimmune phenomena in solid tumors of various origin, location and status of the tumor. PATIENTS AND METHODS: Between 2000 and 2014 we studied 1083 patients with solid tumors that were diagnosed and treated in St George University Hospital, Plovdiv. RESULTS: We found higher incidence of these phenomena in prostate and ovarian carcinomas (9.01% and 5.6%, respectively) than in other solid tumors. Their distribution by type of autoimmune disease showed that vasculitis, polyneuritis and autoimmune hemolytic anemia have the highest frequency of all. Immune thrombocytopenia, seronegative arthritis, psoriasis, polymyositis are less commonly documented. The autoimmune paraneoplastic phenomena manifest themselves metachronously, less commonly synchronously, with the tumor. In most cases, their clinical manifestation is a progressive disease or metastatic malignant disorder which respond favourably to therapy. CONCLUSION: Paraneoplastic autoimmune phenomena are found very commonly in prostate and ovarian carcinomas. They occur in the course of the evolvement of neoplasm and can regress with medicamentous or surgical treatment of the malignoma.

Evaluation of the Effect of Radiosurgery for Target and Non-Target Lesions in Patients with Brain Metastases Using RANO-BM Criteria.

OBJECTIVES: The current therapeutic indications of radiosurgery are constantly expanding. Magnetic resonance imaging (MRI) has an important role in the diagnostic and post-therapeutic period of primary and secondary brain tumor formations. METHODS: A total of 66 patients with verified cancer disease and brain metastases were separated into two groups. The first group includes 34 patients with primary non-small cell lung cancer and the second one 32 patients with other types of primary cancer. All of them received high-dose radiotherapy in 1-5 fractions. The number, size, and location of the treated lesions responded to robotic stereotactic radiosurgery criteria. The Response Assessment Criteria for Brain Metastases (RANO-BM) is an international multidisciplinary group of experts who developed acceptable criteria for assessing brain metastases. Before treatment and on the first, third, sixth month after radiosurgery, a MRI and blood tests were performed. RESULTS: Treated lesions were separated into four groups depending on the results - complete response, partial response, progressive disease, and stable disease. In both groups of patients, the percentage of complete or partial response had increased in the third and sixth months. CONCLUSION: The results give us a reason not to recommend an MRI 1 month after treatment if the patient doesn't have any new neurological symptoms, because there may be a pseudo-progression. MRI results valued by RANO-BM criteria give us a good option to evaluate brain metastases on the third and sixth month after after stereotactic radiosurgery.

A single-center study of bone mineral density in adult patients with severe hemophilia A in correlation with markers of bone metabolism.

INTRODUCTION: Osteopenia and osteoporosis are well-known hemophilia A comorbidities. The pathogenesis of bone turnover alteration resulting in reduced bone mass includes impaired osteoblastic differentiation and disinhibition of RANKL-induced osteoclastogenesis as a result of a low FVIII level. AIM: To evaluate the bone mineral density (BMD) in adult patients with severe hemophilia A and assess a possible correlation with the bone remodeling biomarkers OPG/RANKL, CTX-1, osteocalcin, and Vit D. MATERIALS AND METHODS: 28 male subjects with severe hemophilia A and 33 age-matched controls were recruited. The biomarkers were tested with the ELISA assay and BMD with DEXA of the lumbar spine (LS) and total hip (TH). RESULTS: The patients had lower LS-BMD (-0.955±0.145 vs. 1.118±0.079, p=0.05) and TH-BMD (-0.840±0.147 vs. 0.951±0.075, p=0.05) than those of the controls. The TH T-scores were -1.41±0.91 vs. 0.4±0.49 (p=0.05) and the LS T-scores -1.16±1.046 vs. 0.14±0.72 (p=0.05). 66.6% of patients under 50 years had osteopenia and 8.3% had osteoporosis. Fifty percent of those over 50 years old had osteopenia and 20% had osteoporosis. We found significantly higher OPG levels (123.69±107.05 vs. 41.98±18.95, p=0.05) than that in controls and lower sRANKL levels (23.49±29.39 vs. 131.32±201.27, p=0.05) and sRANKL/OPG ratio (0.27±0.35 vs. 5.28±10.01, p=0.05) than those in controls. A positive correlation was found between sRANKL and the BMD T-score of lumbar spine (p=0.001) in the patient group. CONCLUSIONS: sRANKL level and ratio can be used as predictors of low BMD.

Assessment of clinical utility and predictive potential of pre-chemotherapy soluble urokinase plasminogen activator receptor: Observational single center study.

Alteration of urokinase plasminogen activator receptor (uPAR) in neoplasms is a prerequisite for invasiveness and metastatic ability. In the present study, we aimed to evaluate the relationship of pre-chemotherapy soluble uPAR (suPAR) with the odds for metastasis, lack of disease control, and its predictive ability for progression-free survival (PFS). Baseline plasma suPAR levels were measured by ELISA in 89 patients with various cancers prior to initiation of systemic treatment. Patients were followed prospectively until metastatic progression or death. TCGA Pan-Cancer dataset was mined for available RNAseq expression data of the PLAUR gene in patients with breast, colon, and lung cancer, and therelevant genomic and clinical data were extracted for further analysis. Pre-chemotherapy suPAR levels were significantly associated with white blood cell counts and fibrinogen and were significantly elevated both in patients with metastatic disease and in patients with progression. Increasing suPAR was significantly associated with odds for progression in the prespecified multivariate analysis (odds ratio 2.47, 95% confidence interval 1.3 - 5.11). In univariate Cox regression, suPAR was predictive of shortened progression-free survival (PFS) (hazard ratio 1.065, 95% confidence interval 1.002 - 1.13; p = 0.041). There was a trend towards shortened PFS in patients with higher baseline suPAR levels (cutoff 8.1 ng/mL). In the TCGA lung cancer cohort, PLAUR mRNA expression was significantly associated with shortened PFS in both univariate and multivariate analyses. High PLAUR gene expression conferred significant survival disadvantage only in patients with colon and lung cancer. SuPAR may bear predictive potential for adverse outcomes in cancer, but its utility as a biomarker seems to be more pronounced in cancers with associated inflammatory state.

Liquid Biopsy - Possibilities for Monitoring the Therapeutic Response in Non-Small Cell Lung Cancer.

Lung cancer is the leading cause of death from malignancy worldwide. Its heterogeneity and tumour biology make treatment considerably more difficult. The introduction of target molecules heralded the beginning of the personalized medicine which tailors medical treatments to the molecular and genetic profile of a patient. Liquid biopsy is an innovative, non-invasive method which is used both for diagnostic purposes and for therapeutic monitoring. Liquid biopsy has the potential to help manage non-small cell lung cancer throughout all stages of this cancer: screening, detection of minimal residual disease to guide adjuvant treatment, early detection of relapse, systemic treatment initiation, monitoring of response to targeted or immune therapy, and the emergence of resistance to applied treatment. At present, the study of circulating tumour DNA is used in clinical practice, but circulating tumour cells, miRNAs, exosomes, and platelets formed in the tumour also show promising results.

Longitudinal Dynamics of Coagulation and Angiogenesis Markers in Cancer Patients During and After Chemotherapy.

Hemostatic parameters have been investigated as molecular determinants of tumor progression. To analyze the dynamics of microparticle-associated tissue factor activity (MPTF), tissue factor antigen (TF-Ag), and angiopоietin-2 (ANG-2) in cancer patients before, during, and after active treatment and to explore their potential as biomarkers for metastatic occurrence and death. Blood for the analysis of MPTF, TF-Ag, ANG-2, and conventional hemostatic tests was sampled in 111 patients with various cancers at 4 consecutive visits: before first chemotherapy cycle, after 3 courses, at the sixth course, and 3 months after chemotherapy cessation. Patients were followed up until metastatic progression/death or the end of the study. MPTF did not change during chemotherapy, but increased significantly after treatment cessation. Total TF-Ag and ANG-2 decreased throughout active treatment. Significant drop of their levels was observed 3 months post therapy cessation. Progressive disease was significantly associated with higher pre-chemotherapy TF-Ag and fibrinogen. Elevated baseline levels of fibrinogen were associated with increased risk of shortened progression free survival. Cessation of chemotherapy is associated with significant change of hemostatic parameters. Pre-chemotherapy levels of TF-Ag and fibrinogen may be informative of disease state and prognosis.

Clinical characteristics, disease evolution and survival in patients with chronic myeloid leukemia, BCR-ABL1 (+) and T315I mutation.

INTRODUCTION: The T315I mutation in patients with chronic myeloid leukemia (CML) has been associated with therapeutic resistance and an unfavourable prognosis. AIM: To study the frequency of T315I mutation in patients with CML, BCR-ABL (+), their clinical characteristics, disease evolution, and median survival. PATIENTS AND METHODS: We studied 75 patients with CML and BCR-ABL1 (+). T315I mutation was detected by digital droplet PCR and BCR-ABL1 was analyzed by RT-PCR. A comparative analysis was performed by sex, age, disease phase, risk group, treatment, molecular response (MR), and median survival in T315I (+) and T315I (-) patients. RESULTS: T315I mutation was detected in 11 patients (14.7%). No significant difference was found in the phase, risk group, and first-line therapy. A significantly higher proportion of T315I (+) did not achieve MR >3.5 log: 8 (72.7%) vs. 22 (34.4%) (p=0.023). The lowest mean BCR-ABL1 levels were significantly higher in the CML T315I (+) group compared to the CML T315I (-) group: 12.1±6.0 vs. 3.77±1.28 (p=0.009). The median survival of T315I (+) patients was significantly shorter: 73 months vs. 175 months (p<0.0001, CI 95%). CONCLUSIONS: Our data confirm the world experience on the frequency of T315I mutation, including the unfavourable evolution, resistance to TKI treatment and short survival. ddPCR is a highly sensitive method for early detection of genetic mutations which gives the chance for effective treatment.

Associations of serum sclerostin with bone mineral density, markers of bone metabolism and thalassaemia characteristics in adult patients with transfusion-dependent beta-thalassaemia.

Aim of the study: To assess serum sclerostin in transfusion-dependent beta-thalassaemia patients versus healthy controls and to examine its associations with bone mineral density, bone metabolism markers and beta thalassaemia alterations.Material and methods: Sixty-two transfusion-dependent beta-thalassaemia (TDßT) patients and 30 healthy controls were evaluated for serum sclerostin, osteocalcin, beta-cross laps, osteoprotegerin and serum level of receptor activator of nuclear factor kappa-Β ligand (sRANKL). Bone mineral density was measured at the lumbar spine and femoral neck. Thalassaemia characteristics were collected from the patients' medical records.Results: A significantly higher sclerostin level (median 565.50 pmol/L) was observed in the transfusion-dependent beta-thalassaemia patients vs. the healthy controls (median 48.65 pmol/L, p < .001). Sclerostin showed significant associations with the Z-scores at the lumbar spine and femoral neck, osteocalcin, beta-cross laps, osteoprotegerin, sRANKL, pretransfusion haemoglobin, liver iron concentration and female gonadal state. Significantly higher levels of sclerostin were observed in splenectomized TDßT patients and in those with fragility fractures. Age, sex, body mass index, disease severity, serum ferritin, cardiac T2* and male gonadal state did not show significant associations with sclerostin.Conclusion: Sclerostin may play a role in the bone pathophysiology of beta-thalassaemia patients and could serve as a marker of severe osteoporosis.KEY MЕSSAGESSerum sclerostin is more than 10-fold higher in adult patients with transfusion-dependent beta-thalassaemia compared to healthy controls.Serum sclerostin is negatively associated with bone mineral density and the bone synthesis markers and positively with the bone resorption indices.Serum sclerostin is significantly associated with pre-transfusion haemoglobin, liver iron concentration, splenectomy status and fragility fracture events in adult patients with transfusion-dependent beta-thalassaemia.Serum sclerostin could serve as a marker of severe osteoporosis in beta-thalassaemia patients.

Changes in the Contractile Activity and Reactivity to 5-HT of Smooth Muscles of Rats Following Total Body Irradiation with Accelerated Electrons.

BACKGROUND: Besides its "classical" neurotransmitter function in the central and peripheral nervous systems, serotonin, or 5-hydroxytryptamine (5-HT) is also a local hormone in a number of tissues, including those of the GI tract. Radiation is known to be able to disrupt certain functions of the tract, modulated by 5-HT-signaling pathways, or the serotonin receptors themselves. AIM: The present investigation focused on clarifying the nature and extent of influence of an accelerated electron beam with energy of 9 MeV on the serotonergic mediation of healthy smooth muscle gastric tissue of rats following total body irradiation of the animals. MATERIALS AND METHODS: The study involved a control group and two experimental groups of animals exposed to 1 and 5 Gy, respectively, using Siemens Primus S/N 3561. Circular smooth muscle tissues were isolated from rats 1 hour and 18 hours after they were exposed to 1 and 5 Gy and also 5 days after irradiation from the rats that received a dose of 5 Gy in order to investigate the action of exogenous serotonin at increasing concentrations from 10-8 to 10-4 mol/l. The contractile reactivity of each group SM preparations was registered isometrically. RESULTS: Electron beams with energy of 9 MeV did not damage the contractile apparatus of gastric SM of rats and had a stimulating effect on contractility resulting from rapidly developing processes (1 hour) or later occurring once (5 days). CONCLUSIONS: Difference was observed in the importance of the factors of received dose, lapse of time from irradiation to investigation of SM tissues, and exogenous 5-HT concentration for the changes in SM reactivity in serotonin-induced tonic and phasic responses.