Months Of Combination Therapy Research Articles

Durable Response After Combination Of Concurrent Chemoradiotherapy And Anti-PD-1 Therapy In HER2-Negative Advanced Gastric Adenocarcinoma: A Case Report.

Advanced gastric cancer (AGC) is difficult to treat with poor prognosis. Despite various possible treatments, the median survival time of such patients remains unsatisfactory. Therefore, new therapeutic approaches or combinations need to be further explored. We herein reported a case of a 54-year-old male patient who was initially diagnosed with HER2-negative advanced gastric cancer. Based on previous studies and patient’s desire, we made a therapeutic plan: the combination of concurrent radiochemotherapy and immune checkpoint blockade therapy. After about 4 months of combined therapy, the patient showed satisfactory complete response to tumor lesions even metastatic lesions (CR, disappearance of all target lesions). In summary, the combination of concurrent SOX regimen chemotherapy, stomach radiotherapy and PD-1 antibody immunotherapy is effective in the treatment of advanced gastric cancer.

Adding hydroxyurea in combination with ruxolitinib improves clinical responses in hyperproliferative forms of myelofibrosis.

Ruxolitinib, an orally bioavailable and selective inhibitor of Janus kinase 1 (JAK1) and JAK2, significantly reduces splenomegaly and disease‐related symptoms in patients with myelofibrosis (MF). However, no clear survival benefit has been demonstrated, which may in part reflect suboptimal drug exposure related to lower dosages needed to minimize hematological toxicity, specifically cytopenias. Furthermore, the optimal management of specific conditions such as leukocytosis or thrombocytosis in patients under ruxolitinib therapy is still undefined. In these cases, combining ruxolitinib with a cytoreductive agent like hydroxyurea might improve hematological response. This observational multi‐center study enrolled 20 adult patients with intermediate‐ or high‐risk primary MF, post‐ polycythemia vera MF, or postessential thrombocythemia MF with hyperproliferative manifestations of the disease and WBC and/or platelet counts not controlled by ruxolitinib therapy. The patients received treatment with a combination of ruxolitinib and hydroxyurea. A clinical response of any type was obtained in 8 patients (40%) during ruxolitinib monotherapy and in 17 patients (85%) during ruxolitinib‐hydroxyurea combination (P = 0.003). After a median duration of 12.4 months of combination therapy, 16/20 patients had a hematological response; 14/17 patients who had started combination therapy to control WBC count and 2/3 who started in order to reduce platelets count. The number of patients requiring ruxolitinib dosage reduction or discontinuations was lower during combination therapy and, at the end of follow‐up the median ruxolitinib dose was increased in 50% of patients. In conclusion, the combination of hydroxyurea with ruxolitinib yielded a high clinical response rate and increased ruxolitinib exposure in patients with hyperproliferative forms of MF.

Ibrutinib Plus Venetoclax in Relapsed/Refractory CLL: Results of the Bloodwise TAP Clarity Study

Ibrutinib Plus Venetoclax in Relapsed/Refractory CLL: Results of the Bloodwise TAP Clarity Study

Synergistic Effect of Imatinib and Ruxolitinib in a Patient with JAK2V617F positive Myelofibrosis and Concomitant BCR-ABL1 positive Chronic Myeloid Leukemia

Introduction:JAK2V617Fmutation is present in majority of polycythemia vera (PV) and in 50-60% of patients with primary myelofibrosis (MF). JAK1/2 inhibitor ruxolitinib (RUX) is approved for treatment of both PV and intermediate/high risk MF. Two independent randomized studies showed the benefit of RUX in MF with significant reduction in spleen volume and improvement in constitutional symptoms compared to best supportive care. Clonal evolution may occur in PV and MF upon acquisition of new mutations and transformation to acute myeloid leukemia. Rarely, patients with JAK2V617Fpositive PV or MF have also concomitant BCR-ABL1 fusion gene with phenotype of chronic myelogenous leukemia (CML). Imatinib, a BCR-ABL1 inhibitor, induces long-term cytogenetic and molecular remissions in CML. Single agent imatinib has shown no clinical benefit in MF patients despite in vitro efficacy (Gaikwad et al Exp. Hematol. 2007). We describe here a patient with JAK2V617F positive post-PV MF who later developed concomitant BCR-ABL+ CML. Splenomegaly was initially resolved by RUX but returned coincidently with the diagnosis of CML and was again normalized by imatinib alone. Massive splenomegaly reappeared along with elevated hematocrit on imatinib and was resolved by the addition of low dose RUX.Case report: A 71-year old woman initially presented in September 2011 with isolated erythrocytosis and splenomegaly. A diagnosis of PV was established based on the presence of the JAK2V617Fmutation and hypercellular marrow. Bone marrow karyotype was normal (Table 1). The patient was randomized to pegylated interferon arm in the MPD Consortium study. A complete hematologic response was achieved after nearly 2 years on maximal dose 180 mcg weekly. In early 2015, she developed constitutional symptoms, and progressive splenomegaly. Progression to post-PV MF was confirmed on bone marrow evaluation. The patient was taken off study and started on RUX 20 mg BID. She developed severe anemia 4 months later requiring dose reduction to 10 mg BID. The anemia markedly improved, while JAK2V617F allele burden remained high at 88% with normal cytogenetics. In December 2017, the patient developed anemia, fatigue and rapid regrowth of spleen. Marrow karyotype showed Philadelphia (Ph) chromosome in 25% of the cells analyzed, PCR was positive for BCR-ABL1 p210, and JAK2V617F allele burden was reduced to 56.4%. In January 2018, she started imatinib 400 mg daily and RUX was discontinued due to toxicity concerns. In April 2018, her hematocrit increased and massive splenomegaly returned. Restart of initial RUX 20 mg BID was followed by severe pancytopenia which normalized when RUX was reduced to 5 mg BID with continuing imatinib regimen. After 8 weeks, splenomegaly completely resolved (Figure 1). A complete cytogenetic response and major molecular response were achieved after 3 months and 6 months of combination therapy respectively.Methods: Mononuclear cells from peripheral blood collected in June 2018 were plated in methylcellulose without erythropoietin or other cytokines. After 14 days, colonies were plucked, with ½ of each colony used for JAK2V617F allele-specific PCR and ½ prepared as cytospins for BCR-ABL fluorescent in situ hybridization (FISH) with the Vysis LSI BCR/ABL Dual Color, Dual Fusion Translocation Probe from Abbott Laboratories.Results: Analysis of 3-6 EPO-independent colonies of each CFU-E, G, M, GM, GEMM, BFU-E showed no BCR-ABL1 positive cells, while a single CFU-GEMM colony was positive and also homozygous for JAK2V617F. Frozen marrow cells from the time of the original diagnosis are being analyzed.Conclusion: The recurrence of splenomegaly in this patient following single agent RUX indicates emergence of novel BCR-ABL1+ clone. While single agent imatinib temporarily normalized the splenomegaly and leukocytosis for several months, MF phenotype reoccurred. Splenomegaly resolved completely in 8 weeks with the addition of very low dose RUX to standard dose imatinib, providing the first clinical observation of in vivo synergism of RUX and imatinib. We are investigating serial samples during her course, which will be presented at the meeting. The analysis of a single clone demonstrate that BCR-ABL1 mutation did not occur in previously normal dormant stem cell but in JAK2V617F positive progenitors and represent in this pts a novel subclone of previous PV/MF stem cell. DisclosuresDeininger:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy.

A Phase Ib/II Study of Ibrutinib in Combination with Obinutuzumab-Gazyva As First-Line Treatment for Patients with Chronic Lymphocytic Leukemia > 65 Years Old or with Coexisting Conditions

A Phase Ib/II Study of Ibrutinib in Combination with Obinutuzumab-Gazyva As First-Line Treatment for Patients with Chronic Lymphocytic Leukemia > 65 Years Old or with Coexisting Conditions

Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patients

Resminostat is an oral inhibitor of class I, IIB, and IV histone deacetylases. This phase I/II study compared the safety and efficacy of resminostat plus sorafenib versus sorafenib monotherapy as first-line therapy for advanced hepatocellular carcinoma (HCC). In phase I, resminostat (400mg or 600mg/day on days 1 to 5 every 14days) was administered with sorafenib (800mg/day for 14days) to determine the recommended dose for phase II. In phase II, patients were randomized (1:1) to sorafenib monotherapy or resminostat plus sorafenib. The primary endpoint was time-to-progression (TTP). Nine patients (3: 400mg, 6: 600mg) were enrolled in phase I, and the recommended dose of resminostat was determined to be 400mg/day. Then 170 patients were enrolled in phase II. Median TTP/overall survival (OS) were 2.8/14.1months with monotherapy versus 2.8/11.8months with combination therapy (Hazard Ratio [HR]: 0.984, p = 0.925/HR: 1.046, p = 0.824). The overall incidence of adverse events was similar in both groups (98.8% versus 100.0%). However, thrombocytopenia ≥ Grade 3 was significantly more frequent in the combination therapy group (34.5% versus 2.4%, p < 0.001). Subgroup analysis revealed that median TTP/OS was 1.5/6.9months for monotherapy versus 2.8/13.1months for combination therapy (HR: 0.795, p = 0.392/HR: 0.567, p = 0.065) among patients with a normal-to-high baseline platelet count (≥ 150 × 103/mm3). In patients with advanced HCC, first-line therapy with resminostat at the recommended dose plus sorafenib showed no significant efficacy advantage over sorafenib monotherapy.

Combination therapy with clomiphene citrate and anastrozole is a safe and effective alternative for hypoandrogenic subfertile men.

To assess the efficacy and safety of combination therapy with clomiphene citrate (CC) and anastrozole (AZ) for male hypoandrogenism. We identified patients treated with a combination of CC + AZ in the period 2014 to 2017. Data were gathered on patient characteristics and laboratory values at baseline. Total testosterone, bioavailable testosterone, oestradiol and testosterone:oestradiol ratio were measured before combination therapy (treatment with CC only) and at CC + AZ combination therapy follow-ups. Treatment side effects were recorded; prostatic-specific antigen and haematocrit levels were measured to assess safety after 6 months. As a secondary outcome, semen characteristics were compared at baseline and after at least 3 months of combination therapy when these data were available. Data were analysed using a paired t-test and Wilcoxon's signed-rank test. A total of 51 men were included, with a mean age of 35.4 ± 7.4 years and a mean body mass index of 35.0 ± 8.0 kg/m2 . After CC treatment, total testosterone, bioavailable testosterone, and oestradiol levels all significantly increased. AZ was added in all patients with hyperoestrogenaemia (oestradiol >50 pg/mL) or a testosterone:oestradiol ratio <10. CC + AZ therapy maintained therapeutic total testosterone and bioavailable testosterone levels while also normalizing oestradiol levels and testosterone:oestradiol ratio. Eleven patients experienced side effects: anxiety/irritability, n = 5; decreased libido, n = 4; elevated (>54%) haematocrit, n = 2. Combination therapy with CC + AZ is an effective and safe alternative for patients with elevated oestradiol level or low testosterone:oestradiol ratio.

ENDOTHELIAL PROTECTIVE EFFECT OF LIRAGLUTIDE IN TYPE 2 DIABETES MELLITUS

Background . Endothelial dysfunction underlies the development of chronic complications in type 2 diabetes mellitus. Glucose-lowering drugs with additional protective effects on endothelium are required. Objective . To study endothelial protective action of liraglutide in patients with type 2 diabetes mellitus and to detect its relation with glycemic control. Design and methods . The study was held in patients with type 2 diabetes mellitus with glycated hemoglobin 7,5–9,0 % who received metformin monotherapy. Metformin dose had been titrated for 3 months. Patients who reached glycated hemoglobin level less than 7,5 % were included in the group 1 — they had received metformin monotherapy for next 6 months. Patients with glycated hemoglobin over 7,5 % after 3 months formed the group 2, and they received liraglutide in addition to metformin for the following 6 months. At baseline, at 3, 6 and 9 months, endothelium-dependent vasodilation was evaluated by forearm microcirculation dopplerography with 0,3 % acetylcholine solution ionophoresis. Results. At baseline, patients of groups 1 and 2 showed impaired endothelium-dependent vasodilation (decrease of the reaction to acetylcholine, curve form change). There was no significant change in the linear blood flow parameters in the group 1 when euglycemia was reached by metformin monotherapy. Additional administration of liraglutide in the group 2 led to the increase in the amplitude and favourable change of the curve form. These changes were more prominent after 6 months of combined therapy. Endothelium-dependent vasodilation amplitude reached values observed in healthy subjects after 9 months from the study beginning. Conclusions. The improvement of glycemia control (euglycemia) does not have endothelial protective properties on its own. Liraglutide has its own endothelial protective action independent of glycemia control.

Sustained benefit from combined plasmapheresis and allogeneic mesenchymal stem cells transplantation therapy in systemic sclerosis

BackgroundSystemic sclerosis (SSc) is an autoimmune disease involving the skin and several internal organs. Most therapies available for this disease are symptomatic. Given the difficulty in treating SSc, we conducted this study to investigate the effect of combined plasmapheresis (PE) and allogeneic mesenchymal stem cells transplantation (MSCT) therapy on SSc.MethodsFourteen patients underwent three repeated PE treatments with subsequent pulse cyclophosphamide on days 1, 3 and 5. Patients received a single MSCT (1 × 106 cells/kg of body weight) on day 8. During follow up, evaluations performed included complete physical examination, serologic testing, and organ function.ResultsThe mean modified Rodnan skin score (MRSS) improved from 20.1 ± 3.1 to 13.8 ± 10.2 (P < 0.001) at 12 months of follow up. Three patients had interstitial lung disease, all had improvement of lung function and improved computed tomography (CT) images after 12 months of combined therapy. This combined treatment also significantly decreased the anti-Scl70 autoantibody titer and serum transforming growth factor-β and vascular endothelial growth factor levels during follow up.ConclusionThe results indicate that PE combined with MSCT is a feasible treatment associated with possible clinical benefit for SSc patients.Trial registrationClinicalTrials.gov, NCT00962923. Registered on 19 August 2009.

Safety and Efficacy of Combination ACTHar Gel and Tacrolimus in Treatment-Resistant Focal Segmental Glomerulosclerosis and Membranous Glomerulopathy

IntroductionH.P. ACTHar gel is a preparation of melanocortin peptides that has been used to treat resistant forms of nephrotic syndrome. To determine whether combination therapy with ACTHar gel and tacrolimus reduces proteinuria and stabilizes renal function, we conducted a prospective, open-label trial in patients with treatment-resistant membranous glomerulopathy (MGN) and focal segmental glomerulosclerosis (FSGS).MethodsNine patients with treatment-resistant MGN and 13 with treatment-resistant FSGS received subcutaneous ACTHar gel for 6 months. Patients with no response or a partial response to ACTHar gel alone received an additional 6 months of therapy with combination ACTHar gel and oral tacrolimus. The study endpoint was the percentage of patients achieving a complete or partial remission after 6 months of combination therapy.ResultsAmong patients with MGN, treatment with ACTHar gel alone achieved a partial remission in 44% and no response in 56% of patients. No patient achieved a complete response with ACTHar gel therapy alone. An additional 6 months of combination therapy with ACTHar gel and tacrolimus resulted in partial and complete response rates of 25% and 75%, respectively. Among patients with FSGS, ACTHar gel therapy alone resulted in complete and partial response rate of 7.7% and 62.0%. Combination therapy increased complete response rates to 17% and partial responses to 66%. Proteinuria (urinary protein-to-creatinine ratio) was significantly reduced in both patients with MGN and those with FSGS after 6 months of ACTHar gel alone and was further reduced among the patients with MGN with the addition of tacrolimus. There were no significant changes in estimated glomerular filtration rate during the treatment phase or long-term follow-up.DiscussionCombination therapy with ACTHar gel and tacrolimus was well tolerated by patients with treatment-resistant MGN and FSGS and significantly reduced proteinuria and improved clinical response rates compared with ACTHar gel alone.

Determination and significance of serum MPO and amylin in adult patients with OSAHS after short-range noninvasive positive pressure ventilation

Objective:The aim of this study to investigate the determination and significance of serum MPO and amylin in adult patients with OSAHS after short-range noninvasive positive pressure ventilation. Method:Eighty-seven OSAHS patients were divided into severe group (30 cases), moderate group (30 cases) and mild group (27 cases) according to the AHI range. Twenty-seven outpatient health persons were selected as the control group. Serum amylin and myeloperoxidase were measured by ELISA; Amyloid and myeloperoxidase were reassessed in 30 patients with severe OSAHS after 6 months of combined therapy, and the relationship between amylin, myeloperoxidase and PSG was analyzed. Result:①With the severity of OSAHS patients increased, the serum amylin and myeloperoxidase levels gradually increased (F=22.486, 19.755;P<0.01); There was no significant difference in MPO and amylin concentration between the mild group and the control group (P>0.05), and the other groups were significantly different from each other (P<0.01). ②There was no correlation among serum amylin and myeloperoxidase level and BMI and age in OSAHS patients (P>0.05); and a negative correlation with SaO₂, and AHI was positively correlated (P<0.01). ③After 3 months of CPAP treatment, LSaO₂ increased which the AHI and peripheral blood MPO, amylin levels lower than before in 30 patients (P<0.05); The amylin and myeloperoxidase concentrations of blood after 6 months of treatment were significantly lower than those of 3 months after treatment (P<0.05), which still increased compared with the control group. Conclusion:The determination of serum amylin and MPO in patients with OSAHS has a certain reference value in predicting the condition and curative effect of diabetes mellitus and insulin resistance. CPAP treatment can significantly reduce the degree of hypoxiapatients and cardiovascular damage in OSAHS patients, which was significantly correlated with the treatment time.

Treatment of patients with high cardiovascular risk: a modern view on combined therapy

Introduction. Lack of efficacy of treatment with several medications in patients with arterial hypertension (AH) and high cardiovascular disease (CVD) risk is often explained by low compliance to treatment. Using combined therapy (CT) is one of the ways to increase compliance. Objective. To evaluate the influence of CT consisting of amlodipine, lisinopril and rosuvastatin on arterial elastance and serum fibrosis marker levels in patients with high CVD risk. Materials and methods. The study included 66 patients (mean age 66.5 years, 5% male, 95% female) with atherosclerosis of the brachiocephalic arteries. Serum levels of cholesterol and low density lipoprotein (LDL); brachial and central blood pressure (BP); brachial-ankle and carotid-femoral pulse wave velocity (baPWV and cfPWV, respectively); and augmentation index (AI) were determined initially and after 6 months of CT. Results. Against the background of CT statistically significant reduction of levels of LDL from 4.1 (3.6; 4.7) to 2.2 (1.8; 2.5) mmol/L (p

P386 A target 6-thioguanine nucleotide ≥125 is associated with a higher rate and longer durability of response in infliximab–thiopurine combination therapy: a retrospective study in Crohn's disease patients

Background: Recent data suggest that lower doses of thiopurines are as effective as higher doses in combination with infliximab (IFX) in Crohn's disease (CD), and that 6-thioguanine nucleotide (TGN) levels ≥125 pmol/8×108 RBC positively influence IFX pharmacokinetics. We aim to assess clinical outcomes after induction and during maintenance in CD patients treated with IFX and a thiopurine with respect to TGN and IFX levels. Methods: CD patients commenced on IFX between 2010–15 with or without concomitant thiopurines were retrospectively identified. “Response” to induction (CRP <5mg/L and absence of activity on physician global assessment) or “non response” (lack of clinical improvement during induction or flare requiring CD therapy adjustment or surgery during first 6 months) were assessed at week 14. Maintenance outcomes were assessed in 6-month semesters and classed as “response”, “flare” or “failure” (IFX cessation due to active disease or intolerance). TGN and IFX trough levels were recorded during induction and maintenance. Results: Of 89 patients (49 male, mean age 35y, range 18–61), combination therapy (n=73) had a higher response than IFX monotherapy (n=16) on induction (78% vs 50%, p=0.02). Median TGN was similar between responders and non-responders (314 vs 254, p=0.12), with TGN ≥125 patients more likely to respond (76% vs 47%, p=0.018). On multivariable analysis, TGN ≥125 was associated with response (OR 5.7; 95% CI: 1.6–20.1; p=0.006). Mean time to IFX failure was 26 months for monotherapy vs 53 months for combination therapy (p=0.55); a significant difference was observed when re-stratified by TGN ≥125, p=0.043 (Fig. 1). Figure 1. Kaplan-Meier survival analysis of time to failure, TGN ≥125 vs <125. Of 395 maintenance semesters, 323 (82%) were classified remission, 61 (15%) flare, and 11 (3%) fail. There was no difference in number of remission semesters between combination and monotherapy (79% vs 79%). Median TGN was similar in remission and non-remission semesters (p=0.44), with no difference observed when stratified by TGN ≥125. Median IFX levels were higher in remission vs non-remission semesters (4.5 vs 3 μg/mL; p=0.01), and higher IFX levels were independent predictors of response to maintenance therapy on multivariable analysis (OR 1.3 [1.05–1.5], p=0.014). Conclusions: Combination therapy was superior to monotherapy for induction, with a target TGN ≥125 associated with a higher response rate and longer durability of response. Continuing combination therapy during maintenance was not associated with better clinical outcomes, suggesting a role for thiopurine withdrawal.

Современный подход к лечению больных высокого сердечно-сосудистого риска: возможности комбинированной терапии

Introduction. Lack of efficacy of treatment with several medications in patients with arterial hypertension (AH) and high cardiovascular disease (CVD) risk is often explained by low compliance to treatment. Using combined therapy (CT) is one of the ways to increase compliance. Objective. To evaluate the influence of CT consisting of amlodipine, lisinopril and rosuvastatin on arterial elastance and serum fibrosis marker levels in patients with high CVD risk. Materials and methods. The study included 66 patients (mean age 66.5 years, 5% male, 95% female) with atherosclerosis of the brachiocephalic arteries. Serum levels of cholesterol and low density lipoprotein (LDL); brachial and central blood pressure (BP); brachial-ankle and carotid-femoral pulse wave velocity (baPWV and cfPWV, respectively); and augmentation index (AI) were determined initially and after 6 months of CT. Results. Against the background of CT statistically significant reduction of levels of LDL from 4.1 (3.6; 4.7) to 2.2 (1.8; 2.5) mmol/L (p<0.01); systolic and diastolic brachial BP from 127 (116; 144) to 122 (115; 132) mm Hg (p<0.01) and from 79 (72; 89) to 75 (70; 83) mm Hg (p<0.01), respectively; systolic and diastolic central BP from 125 (112; 139) to 120 (110; 124) mm Hg (p<0.01) and from 80 (75; 87) to 76 (70; 81) mm Hg (p<0.01), respectively; baPWV from 13.6 (12.5; 15.9) to 12.9 (11.8; 14.2) m/s (p<0.01); cfPWV from 11 (9; 12.2) to 9,4 (8.4; 10.2) m/s (p<0.01); and AI from 31 (25; 35) to 26 (21; 32) (p<0,05) was observed. Conclusion. CT consisting of amlodipine, lisinopril and rosuvastatin resulted in BP and LDL target level achievement and arterial stiffness reduction in patients with AH and high CVD risk. Further research is also necessary to more thoroughly assess efficacy of CT.

Fighting tuberculosis by drugs targeting nonreplicating Mycobacterium tuberculosis bacilli.

Current tuberculosis (TB) treatment requires 6 months of combination therapy with isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol for active TB and 9 months of INH or 3 months of rifapentine (RFP) + INH for latent TB. The lungs of patients with active and latent TB contain heterogeneous mixtures of cellular and caseous granulomas harboring Mycobacterium tuberculosis bacilli ranging from actively replicating (AR) to nonreplicating (NR), phenotypically drug-resistant stages. Several in vitro models to obtain NR cells were reported, including exposure to hypoxia, nutrient starvation, acid + nitric oxide, and stationary phase. Overall, these models showed that RIF, RFP, PA-824 (PA), metronidazole (MZ), bedaquiline (BQ), and fluoroquinolones were the most active drugs against NR M. tuberculosis. In hypoxia at pH 5.8, some combinations killed AR plus NR cells, as shown by lack of regrowth in liquid media, whereas in hypoxia at pH 7.3 (the pH of the caseum), only RIF and RFP efficiently killed NR bacilli while several other drugs showed little effect. In conventional mouse models, combinations containing RFP, BQ, PA, PZA, moxifloxacin, sutezolid, linezolid, and clofazimine sterilized animals in ≤2 months, as shown by lack of viable bacilli in lung homogenates after 3 months without therapy. Drugs were less effective in C3HeB/FeJ mice forming caseous granulomas. Overall, in vitro observations and in vivo studies suggest that the search for new TB drugs could be addressed to low lipophilic molecules (e.g., new rpoB inhibitors with clogP < 3) killing NR M. tuberculosis in hypoxia at neutral pH and reaching high rates of unbound drug in the caseum.

Short-Term Impact of a Combined Nutraceutical on Cognitive Function, Perceived Stress and Depression in Young Elderly with Cognitive Impairment: A Pilot, Double-Blind, Randomized Clinical Trial.

The prevalence of senile dementia is increasing worldwide, especially in the developed countries. Nevertheless, drug therapy isn't often enough to treat this condition. Researchers are evaluating the possible impact of a preventive approach, based on an improvement of lifestyle and the intake of micronutrients. Moreover, there is an increasing interest for combined nutraceuticals that can act as memory and learning enhancers, with a significant and beneficial potential on the cognitive disorders. To evaluate the effects of a rational assemblage of nutraceuticals on cognitive functions in a sample of 30 elderly subjects. Double bind, cross-over designed trial versus placebo Setting: outpatient clinical practice. 30 elderly subjects with basal Mini-Mental State Examination score between 20 and 27 and self-perceived cognitive decline. Treatment with a combination of nutraceuticals based on Bacopa monnieri, L-theanine, Crocus sativus, copper, folate and vitamins of B and D group. After2 months of treatment or placebo. Patients were evaluated with Mini-Mental State Examination (MMSE), Perceived Stress Questionnaire (PSQ) and Index and Self-Rating Depression Scale (SRDS). MMSE and PSQ Index significantly improved in the active treatment arm, both versus baseline and versus the parallel arm. Both groups experienced a significant improving in the SRDS scores. We obtained a good and significant improvement of the cognitive functions tested with the MMSE, PSQ-Index and SRDS score, after 2 months of combined therapy of nutraceuticals. Further confirmation will be needed to verify these observations on the middle and long term in a larger number of subjects.

Ocular hypotensive effect of systemic beta-blockers in patients with primary glaucoma and arterial hypertension

to evaluate the ocular hypotensive efficacy of systemic beta-blockers in primary glaucoma patients suffering from arterial hypertension (AH). The study included 29 patients with POAG (58 eyes) aged from 47 to 83 years. Patients with stage I-III POAG received instillations of prostaglandin analogs and carbonic anhydrase inhibitors. All POAG patients also suffered from arterial hypertension and were prescribed selective beta-blockers (metoprolol, bisoprolol, or nebivalol) as monotherapy or as part of combination therapy (if the target arterial pressure had not been achieved under the initial treatment). After the start of oral beta-blockers therapy, the patients were re-examined at 2 and 4 weeks, 3 months, 6 months, and 1 year. A clinically significant reduction of IOP in the most seriously affected eye - by 3.3 mmHg (p<0.05), or 14% - occurred four weeks after the start of selective beta-blockers. Over three months of combination therapy, IOP in the 'worst' eye decreased by 4.4 mmHg (18.5%). At 1 year, IOP in the 'worst' eye was 6.2 mmHg (26%) lower than at baseline (p<0.05). Aged and senile patients with primary glaucoma usually suffer from polypathy (on average, they have 6.3±0.6 concurrent somatic diseases). To reduce the risk of polypharmacy and the frequency of side effects in the treatment of POAG and AH patients, it is advised that the treatment includes oral selective beta-blockers able to provide target levels of arterial pressure and IOP. In this study, oral beta-blockers in POAG and AH patients enabled IOP reduction as great as 18.5%-26% of baseline values over a 1-year follow-up period.

Addition of Obinutuzumab to Ibrutinib Enhances Depletion of CLL Cells in the Peripheral Blood and Bone Marrow after 1 Month of Combination Therapy: Initial Results from the Bloodwise TAP Iciclle Extension Study

Background: A major aim of treatment in CLL is to eradicate detectable minimal residual disease (MRD). Ibrutinib is a major step forward in the treatment of CLL but results in an immediate lymphocytosis that persists in most patients for at least several months. Obinutuzumab is a second generation anti-CD20 monoclonal antibody which appears to be highly effective in CLL resulting in a rapid eradication of peripheral blood lymphocytosis and the eradication of MRD in a proportion of patients. The IcICLLe Extension Study expands on the IcICLLe trial (ISRCTN 12695354) to examine the efficacy and safety of the combination treatment of obinutuzumab and ibrutinib.Patients: The IcICLLetrial recruited 40 participants with CLL requiring treatment (20 treatment-naïve, 20 relapsed/refractory disease) receive continuous ibrutinib therapy until achievement of <0.01% residual disease in bone marrow or disease progression. The IcICLLe Extension Study involves 40 participants with relapsed/refractory CLL requiring treatment who will all receive continuous oral therapy with ibrutinib and 6 cycles of obinutuzumab. Of the 40 participants, >20 will have had no prior Ibrutinib treatment (ibrutinib naive), and ≤20 will have received at least 12 months of Ibrutinib monotherapy as part of the IcICLLe trial before enrolling in the Extension Study . Adverse Events (AEs) are collected from registration until 30 days after treatment cessation and reported at 1, 3 and 6 months, and 6-monthly thereafter using the Common Terminology Criteria for Adverse Events v4.0.Results: 17 participants (12 ibrutinib naïve and 5 IcICLLe monotherapy patients) are evaluable for response assessment after one month of combination treatment. In the 12 Ibrutinib-naïve cases, the peripheral CLL counts remained at or below baseline levels in most (9/12) cases from week 1 onwards. After one month of combination therapy the peripheral B-cell count was a median 35% of baseline levels (range <1% to 174%) compared to a median 215% (range 29% to 3570%) for relapsed/refractory patients on Ibrutinib monotherapy. The percentage of CLL cells in the bone marrow aspirate for patients after 1 month of combination therapy showed a median 20% reduction (range 1% increase to 55% decrease, paired t-test P<0.001, baseline median 74% CLL cells, range 23-94%) while there was no change for relapsed/refractory patients on ibrutinib monotherapy (median 1% increase, range 39% increase to 24% decrease, paired t-test P=0.35, baseline median 85% CLL cells, range 11-96%). The reduction in bone marrow aspirate CLL percentage was also evident by morphological assessment of the trephine biopsy with all 10 evaluable patients showing improvements in the cellularity and/or extent of infiltration.Bone marrow assessment was not mandated for the 5 patients previously on ≥12 months (range 14-20 months) continuous ibrutinib monotherapy because they had already undergone 4 biopsies in the prior year, however all five patients showed a reduction in peripheral CLL counts (median 1.3 log reduction, range 0.3 to 2.4 log) which was significantly greater than the reduction seen in the prior 6 months of ibrutinib monotherapy (median 0.5 log reduction, range -1.0 to 0.8, paired t-test P=0.043)Of the 17 participants recruited to the IcICLLe Extension Study there have been no reports of Tumour Lysis Syndrome within the first month of combination treatment. There was a single report of a grade 2 Infusion Related Reaction (IRR) for one participant following the first infusion (100mg) of obinutuzumab. No further IRRs have been reported.Conclusions: The data indicate that the addition of obinutuzumab to ibrutinib results in a substantial improvement in the depletion of CLL cells from the peripheral blood and bone marrow after only one month of combination therapy.Date of Data Freeze: 19-Jul-2016 DisclosuresRawstron:Gilead: Consultancy, Honoraria, Research Funding; BD Biosciences: Other: Remuneration; Celegene: Honoraria; Roche: Honoraria; Janssen: Research Funding; GlaxoSmithKline: Honoraria; AbbVie: Honoraria; Genzyme: Honoraria. Munir:Alexion pharmaceuticals: Honoraria. Brock:AstraZeneca: Equity Ownership; GlaxoSmithKline: Equity Ownership. Bloor:Janssen: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Gilead: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees. Pettitt:Roche: Research Funding, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Infinity: Research Funding. Fox:Roche: Consultancy; Janssen: Honoraria, Other: Travel support. Fegan:Gilead Sciences: Honoraria; Roche: Honoraria; AbbVie: Honoraria. Devereux:Roche: Consultancy, Other: Travel, Accommodations, Expenses ; GSK: Consultancy; Gilead: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding.

Phase Ib Study (GO28440) of Venetoclax with Bendamustine/Rituximab or Bendamustine/Obinutuzumab in Patients with Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia

Phase Ib Study (GO28440) of Venetoclax with Bendamustine/Rituximab or Bendamustine/Obinutuzumab in Patients with Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia

A Randomized Phase II Trial of Interferon (IFN)/GM-CSF Versus K562/GM-CSF Vaccination in Chronic Phase CML Patients on Frontline Tyrosine Kinase Inhibitor (TKI) Therapy: Potential of IFN to Enhance Molecular Remissions

Background: Tyrosine kinase inhibitors (TKIs) have dramatically improved outcomes in chronic myeloid leukemia (CML), but most patients either never achieve a complete molecular remission (CMR) or recur upon TKI discontinuation due to the persistence of leukemic stem cells. The kinetics of the initial TKI response appear predictive of long term outcomes as front-line imatinib patients who achieve a major molecular response (MMR) at 12 months have a 72% chance of attaining a CMR versus just 5% for those who do not (median time on Imatinib (IM) prior to CMR 66 months) (Branford. Clin Cancer Res. 2007). Interestingly, patients who achieve and maintain a CMR for ≥2 years on single agent IM have been the subject of several TKI discontinuation trials demonstrating that 38-47% of such patients maintain treatment-free remissions (TFR) at 2 years (median time on IM prior to discontinuation of 50-70 months) (Mahon. Lancet Oncol. 2010 and Ross. Blood. 2013). Interferon-alpha (IFN) and K562/GM-CSF vaccines have been shown to enhance the frequency of deep molecular responses to TKIs (Preudhomme. N Engl J Med. 2010 and Smith. Clin Cancer Res. 2010). We have shown that IFN targets LSCs, which may be the mechanism of improved IM responses (Angstreich. Br J Haematol. 2005). We now report initial outcomes for patients randomized between these treatments as a means of achieving TFR.Methods: Patients with Ph+ CML in complete cytogenetic remission on first-line TKI treatment for ≥1 year were randomized to receive either K562/GM-CSF vaccination at 3 week intervals (vaccine) or daily interferon/GM-CSF (IFN/GM) in combination with their TKI. If CMR was achieved after a minimum of 6 months of adjuvant treatment, then all therapy was stopped, and monthly BCR-ABL PCR testing was performed to monitor for relapse. Based on the limits of detection of our assay, CMR is defined as at least MR4.3, which is IS <0.01. At disease recurrence, or if CMR was not achieved at 12 months of combination therapy, patients were allowed to cross-over. The treatment arms were defined as IFN alone (A), vaccine alone (B), IFN followed by vaccine (C), or vaccine followed by IFN (D).Results: 34 patients were enrolled with final treatment allocation shown in Table 1. Most patients were on IM (n=31), nilotinib (n=2) and dasatinib (n=1) with a median duration of TKI use at enrollment of 19 (range 12-80) months. Both arms of the trial were well-tolerated. The vaccine arm was notable for grade 1 and 2 injection site reactions in all patients. Predictably, the IFN arm produced grade 1 and 2 myalgias and flu-like symptoms in the majority of patients. Three patients had to discontinue treatment on the IFN arm due to grade 3 adverse events including a neurological event of unknown causality (1) and ALT elevation (2). Table 1 shows the responses by treatment arm with 62% of patients achieving CMR at a median of 28.6 (range 11-100) months of TKI therapy (compared to 66 months in IRIS). 15 patients (44%) discontinued TKI treatment per study plan after a median of 27.5 (range 19-56) months of TKI treatment (compared to median of 50-70 months of TKI in STIM/TWISTER), and 4 patients (27%) remain off therapy with TFRs of 64, 64, 85, and 92 months. Those with recurrence were off TKI for a median of 3 (range 1-5) months. Importantly, the long term responders who achieved CMR with adjuvant therapy all received IFN adjuvant, and all had relatively little prior TKI treatment (21, 27, 28, and 44 months) compared to published discontinuation studies. As expected in this group, all 4 had achieved a MMR at 12 months on TKI alone (p=0.05). What was unexpected was that 50% of patients treated with one of the IFN arms who had not achieved a MMR at 12 months on TKI alone went on to CMR after treatment on study compared to previous reports and just 15% of historical controls in our institutional database who achieved CMR on TKI alone (p=0.02)Conclusions: Adjuvant therapies may improve the likelihood of achieving CMR and allow for discontinuation of TKI in CML patients with minimal TKI exposure. Even patients predicted to not achieve CMR based on a lack of MMR at 12 months did so at a higher rate than expected following IFN treatment. IFN likely played a role in long term TFR in 4 exceptional responders who successfully discontinued IM sooner than in previously reported discontinuation trials, possibly owing to IFNs effect on primitive CML progenitors. [Display omitted] DisclosuresSmith:Actinium Pharmaceuticals, Inc.: Research Funding.