Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 5.560
Filter
2.
Am J Hematol ; 99(7): 1281-1289, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38700035

ABSTRACT

The Phase 2 portion of this study evaluated safety and efficacy of polatuzumab vedotin 1.8 mg/kg and venetoclax 800 mg, plus fixed-dose obinutuzumab 1000 mg or rituximab 375 mg/m2 in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL), respectively. Patients with complete response (CR) or partial response (PR)/stable disease (FL) or CR/PR (DLBCL) at end of induction (EOI; six 21-day cycles) received post-induction therapy with venetoclax and obinutuzumab or rituximab, respectively. Primary endpoint was CR rate at EOI. Safety-evaluable populations included 74 patients (FL cohort; median age 64 years; progression of disease within 24 months on first-line treatment, 25.7%; FL International Prognostic Index 3-5, 54.1%; ≥2 previous therapies, 74.3%) and 57 patients (DLBCL cohort; median age 65 years; International Prognostic Index 3-5, 54.4%; ≥2 previous therapies, 77.2%). The most common non-hematologic adverse events (mostly Grades 1-2) in the FL and DLBCL cohorts were diarrhea (55.4% and 47.4%, respectively) and nausea (47.3% and 36.8%); neutropenia was the most common Grades 3-4 toxicity (39.2% and 52.6%). Efficacy-evaluable populations included patients treated at the recommended Phase 2 dose (FL, n = 49; DLBCL, n = 48). CR rates at EOI were 59.2% (FL) and 31.3% (DLBCL); median progression-free survival was 22.8 months (95% confidence interval [CI], 14.5-not evaluable) and 4.6 months (95% CI, 3.6-8.1), respectively. Polatuzumab vedotin plus venetoclax and obinutuzumab/rituximab had acceptable safety in patients with R/R FL or DLBCL, with promising response rates in R/R FL, including high-risk patients.


Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Bridged Bicyclo Compounds, Heterocyclic , Lymphoma, Large B-Cell, Diffuse , Rituximab , Sulfonamides , Humans , Middle Aged , Aged , Male , Sulfonamides/administration & dosage , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Female , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Lymphoma, Large B-Cell, Diffuse/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Adult , Aged, 80 and over , Rituximab/administration & dosage , Rituximab/therapeutic use , Rituximab/adverse effects , Lymphoma, Follicular/drug therapy , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Recurrence , Immunoconjugates
3.
Eur J Cancer ; 205: 114119, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38759389

ABSTRACT

BACKGROUND: Sorafenib and pazopanib, two tyrosine kinase inhibitors (TKI), are widely used in patients with progressive symptomatic desmoid tumors (DT). Limited real-word data is available on long-term outcomes of patients who progressed on, stopped, or continued TKIs. METHODS: Patients diagnosed with DTs and treated with sorafenib or pazopanib between 2011 and 2022 at 11 institutions were reviewed. Patient history, response to therapy and toxicity were recorded. Statistical analyses utilized Kaplan-Meier and log-rank tests. RESULTS: 142 patients with DT treated with sorafenib (n = 126, 88.7 %) or pazopanib (n = 16, 11.3 %) were analyzed. The median treatment duration was 10.8 months (range: 0.07- 73.9). The overall response rate and the disease control rate were 26.0 % and 95.1 %, respectively. The median tumor shrinkage was - 8.5 % (range -100.0 %- +72.5 %). Among responders, the median time to an objective response was 15.2 months (range: 1.1 to 33.1). The 1-year and 2-year progression-free survival rates were 82 % and 80 %. Dose reductions were necessary in 34 (23.9 %) patients. Grade 3 or higher adverse events were reported in 36 (25.4 %) patients. On the last follow-up, 55 (38.7 %) patients continued treatment. Treatment discontinuation (n = 85, 59.9 %) was mainly for toxicity (n = 35, 45.9 %) or radiological or clinical progression (n = 30, 35.3 %). For the entire cohort, 36 (25.4 %) patients required subsequent treatment. In the 32 responders, only 1 (3.1 %) patient required a subsequent treatment. In patients who discontinued TKI, 25 (44.6 %) with stable disease received subsequent treatment compared to 0 (0.0 %) of responders. CONCLUSION: This retrospective study represents the largest cohort of DT patients treated with sorafenib or pazopanib to date. Discontinuation of treatment in responders is safe. The optimal treatment duration in patients with stable disease remains to be defined.


Subject(s)
Fibromatosis, Aggressive , Indazoles , Pyrimidines , Sorafenib , Sulfonamides , Humans , Sorafenib/therapeutic use , Sorafenib/adverse effects , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Male , Female , Pyrimidines/therapeutic use , Pyrimidines/adverse effects , Middle Aged , Adult , Aged , Young Adult , Fibromatosis, Aggressive/drug therapy , Fibromatosis, Aggressive/pathology , Adolescent , Retrospective Studies , Aged, 80 and over , Progression-Free Survival , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Treatment Outcome
4.
Sci Rep ; 14(1): 10244, 2024 05 03.
Article in English | MEDLINE | ID: mdl-38702350

ABSTRACT

Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa.


Subject(s)
Antiviral Agents , Hepacivirus , Sofosbuvir , Adult , Female , Humans , Male , Middle Aged , Africa, Central , Africa, Western , Aminoisobutyric Acids , Antiviral Agents/therapeutic use , Antiviral Agents/adverse effects , Benzimidazoles/therapeutic use , Benzimidazoles/adverse effects , Benzopyrans , Carbamates/therapeutic use , Cyclopropanes/therapeutic use , Cyclopropanes/adverse effects , Drug Therapy, Combination , Feasibility Studies , Fluorenes/therapeutic use , Fluorenes/adverse effects , Genotype , Hepacivirus/genetics , Hepacivirus/drug effects , Hepatitis C/drug therapy , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/virology , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Heterocyclic Compounds, 4 or More Rings/adverse effects , Lactams, Macrocyclic , Leucine/analogs & derivatives , Proline/analogs & derivatives , Proline/therapeutic use , Quinoxalines , Ribavirin/therapeutic use , Ribavirin/adverse effects , Sofosbuvir/therapeutic use , Sofosbuvir/adverse effects , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Sustained Virologic Response , Treatment Outcome
5.
Eur J Cancer ; 204: 114073, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38723373

ABSTRACT

BACKGROUND: Treatment with encorafenib plus binimetinib and encorafenib monotherapy is associated with improved progression-free survival (PFS) and overall survival (OS) compared with vemurafenib in patients with BRAF V600E/K-mutant metastatic melanoma. We report results from the 7-year analysis of COLUMBUS part 1 (NCT01909453) at 99.7 months (median duration between randomization and data cutoff). METHODS: 577 patients with locally advanced unresectable or metastatic BRAF V600E/K-mutant melanoma who were treatment-naive or progressed after first-line immunotherapy were randomized 1:1:1 to encorafenib 450 mg once daily (QD) plus binimetinib 45 mg twice daily (BID) (n = 192), vemurafenib 960 mg BID (n = 191), or encorafenib monotherapy 300 mg QD (n = 194). No prior BRAF/MEK inhibitor was allowed. RESULTS: Seven-year PFS and OS rates (95 % CI) were 21.2 % (14.7-28.4 %) and 27.4 % (21.2-33.9%) in the encorafenib plus binimetinib arm and 6.4 % (2.1-14.0 %) and 18.2 % (12.8-24.3 %) in the vemurafenib arm, respectively. Median melanoma-specific survival (95 % CI) was 36.8 months (27.7-51.5 months) in the encorafenib plus binimetinib arm and 19.3 months (14.8-25.9 months) in the vemurafenib arm. Thirty-four long-term responders (complete/partial response ongoing at 7 years) were identified across arms. CONCLUSIONS: This is the longest follow-up from a phase III trial of BRAF/MEK inhibitor combination in BRAF V600E/K-mutant metastatic melanoma. Safety results were consistent with the known tolerability profile of encorafenib plus binimetinib. Results support the long-term efficacy and known safety of encorafenib plus binimetinib in this population and provide new insights on long-term responders. Interactive data visualization is available at the COLUMBUS dashboard (https://clinical-trials.dimensions.ai/columbus7/).


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Benzimidazoles , Carbamates , Melanoma , Mutation , Proto-Oncogene Proteins B-raf , Sulfonamides , Vemurafenib , Humans , Melanoma/drug therapy , Melanoma/genetics , Melanoma/mortality , Carbamates/administration & dosage , Carbamates/adverse effects , Proto-Oncogene Proteins B-raf/genetics , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Benzimidazoles/administration & dosage , Benzimidazoles/adverse effects , Benzimidazoles/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Male , Female , Vemurafenib/administration & dosage , Vemurafenib/adverse effects , Middle Aged , Aged , Adult , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Skin Neoplasms/mortality , Aged, 80 and over , Progression-Free Survival , Young Adult
6.
Clin Res Hepatol Gastroenterol ; 48(6): 102373, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38719148

ABSTRACT

OBJECTIVE: To evaluate the efficacy and safety of vonoprazan therapy as compared to conventional proton pump inhibitors (PPIs) or no vonoprazan for non-erosive esophagitis. METHODS: A thorough search was conducted across databases. The primary outcome was to determine the mean variance in the gastroesophageal reflux disease (GERD) score after vonoprazan treatment. Secondary outcomes comprised alterations in the scores for epigastric pain and post-prandial distress, the proportion of patients displaying improvement, and the occurrence of adverse events. Pooled mean differences and relative risks were determined utilizing random effects models. RESULTS: A total of 1,944 articles were screened and nine of them were included. As compared to PPI or no vonoprazan therapy, vonoprazan treatment led to a significant reduction in the GERD score [mean difference: -3.88 (95 % CI: -5.48, -2.28), p < 0.01, i2=95 %]. As compared to PPI or no vonoprazan therapy, vonoprazan treatment led to a significant reduction in the epigastric pain score [mean difference: -3.02 (95 % CI: -5.41, -0.63), p = 0.01, i2=75 %] and post-prandial distress score [mean difference: -2.82 (95 % CI: -3.51, -2.12), p < 0.01, i2=0 %] (all moderate GRADE evidence). Vonoprazan therapy was found to be safe. CONCLUSION: Treatment with vonoprazan could significantly improve symptoms in patients with non-erosive esophagitis or non-erosive GERD.


Subject(s)
Gastroesophageal Reflux , Proton Pump Inhibitors , Pyrroles , Sulfonamides , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Humans , Gastroesophageal Reflux/drug therapy , Pyrroles/therapeutic use , Pyrroles/adverse effects , Proton Pump Inhibitors/therapeutic use , Treatment Outcome
7.
Helicobacter ; 29(3): e13094, 2024.
Article in English | MEDLINE | ID: mdl-38790090

ABSTRACT

BACKGROUND: This study aims to evaluate the efficacy and safety of vonoprazan-amoxicillin (VA), vonoprazan-amoxicillin-clarithromycin (VAC), vonoprazan-based bismuth-containing quadruple therapy (VBQT), and PPI-based triple (PAC) or quadruple therapy (PBQT) for H. pylori infection with the consideration of duration of therapy and amoxicillin dose (H: high; L: low). MATERIALS AND METHODS: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched for eligible randomized controlled trials (RCTs) up to December 15, 2023. The efficacy outcome was eradication rate, and safety outcomes included the rates of adverse events and treatment discontinuation. RESULTS: Twenty-seven RCTs were included. The pooled eradication rates were 82.8% for VA, 89.1% for VAC, and 91.8% for VBQT, which increased with the higher amoxicillin frequency of administration and extended duration of therapy within each regimen. There were no significant differences in eradication rate when comparing 7-VA versus 7-VAC and 14-VA versus 14-VAC. VA was at least comparable to PAC. The eradication rate did not differ significantly between 10-H-VA or 14-H-VA versus 14-PBQT. 7-L-VAC demonstrated higher eradication rate versus 7-PAC and comparable rate to 14-PAC. 14-VBQT showed higher eradication rates versus 14-PBQT. The adverse events rate was 19.3% for VA, 30.6% for VAC, and 38.4% for VBQT. VA had similar risk of adverse events versus VAC and significantly fewer adverse events compared to PBQT. The treatment discontinuation rate did not differ significantly between treatments. CONCLUSIONS: The eradication rate of VBQT was the highest at above 90% followed by VAC and VA. VA was as effective as VAC and superior to PPI-based therapies with favorable safety, highlighting the potential of VA therapy as a promising alternative to traditional PPI-based therapies. VPZ-based triple or quadruple therapies was more effective than PPI-based therapies. Further studies are needed to establish the optimal treatment regimen especially in the western countries.


Subject(s)
Amoxicillin , Anti-Bacterial Agents , Drug Therapy, Combination , Helicobacter Infections , Helicobacter pylori , Proton Pump Inhibitors , Pyrroles , Randomized Controlled Trials as Topic , Sulfonamides , Humans , Helicobacter Infections/drug therapy , Proton Pump Inhibitors/therapeutic use , Proton Pump Inhibitors/adverse effects , Proton Pump Inhibitors/administration & dosage , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Sulfonamides/administration & dosage , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/administration & dosage , Helicobacter pylori/drug effects , Amoxicillin/therapeutic use , Amoxicillin/administration & dosage , Amoxicillin/adverse effects , Pyrroles/therapeutic use , Pyrroles/administration & dosage , Pyrroles/adverse effects , Treatment Outcome , Clarithromycin/therapeutic use , Clarithromycin/adverse effects
8.
Hematol Oncol ; 42(3): e3274, 2024 May.
Article in English | MEDLINE | ID: mdl-38711253

ABSTRACT

Venetoclax, a highly selective BCL-2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine or decitabine, is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated venetoclax plus HMA in an inpatient setting owing to concerns of tumor lysis syndrome (TLS). This study (NCT03941964) evaluated the efficacy and safety of venetoclax plus HMA in a United States community-based outpatient setting in patients with ND AML (N = 60) who were treatment naïve for AML, ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed as appropriate candidates for outpatient initiation of venetoclax plus HMA by the investigator. Patients received venetoclax in combination with azacitidine (75 mg/m2) or decitabine (20 mg/m2) for up to 6 cycles during the study. With a median time on study of 18.3 weeks, the best response rate of composite complete remission was 66.7%, and the overall post-baseline red blood cell (RBC) and platelet transfusion independence rate was 55.0%, consistent with results of studies in which treatment was initiated in an inpatient setting. Key adverse events included nausea, anemia, thrombocytopenia, neutropenia, and white blood cell count decrease of any grade (≥50% of patients). The observed safety profile was generally consistent with that of venetoclax plus HMA observed in inpatient AML studies. With close monitoring, 2 cases of TLS were identified, appropriately managed, and the patients were able to continue study treatment. CLINICAL TRIALS REGISTRATION: This study is registered at ClinicalTrials.gov. The registration identification number is NCT03941964.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Azacitidine , Bridged Bicyclo Compounds, Heterocyclic , Decitabine , Leukemia, Myeloid, Acute , Sulfonamides , Humans , Sulfonamides/administration & dosage , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Azacitidine/administration & dosage , Azacitidine/therapeutic use , Azacitidine/adverse effects , Leukemia, Myeloid, Acute/drug therapy , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Decitabine/administration & dosage , Decitabine/therapeutic use , Decitabine/adverse effects , Female , Male , Aged , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Aged, 80 and over , Adult , Outpatients
9.
Arthritis Res Ther ; 26(1): 98, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38730460

ABSTRACT

BACKGROUND: Targeted small-molecule drugs in the treatment of systemic lupus erythematosus (SLE) have attracted increasing attention from clinical investigators. However, there is still a lack of evidence on the difference in the efficacy and safety of different targeted small-molecule drugs. Therefore, this study was conducted to assess the efficacy and safety of different targeted small-molecule drugs for SLE. METHODS: Randomized controlled trials (RCTs) on targeted small-molecule drugs in the treatment of SLE in PubMed, Web of Science, Embase, and Cochrane Library were systematically searched as of April 25, 2023. Risk of bias assessment was performed for included studies using the Cochrane's tool for evaluating the risk of bias. The primary outcome indicators were SRI-4 response, BICLA response, and adverse reaction. Because different doses and courses of treatment were used in the included studies, Bayesian network meta-regression was used to investigate the effect of different doses and courses of treatment on efficacy and safety. RESULTS: A total of 13 studies were included, involving 3,622 patients and 9 targeted small-molecule drugs. The results of network meta-analysis showed that, in terms of improving SRI-4, Deucravacitinib was significantly superior to that of Baricitinib (RR = 1.32, 95% CI (1.04, 1.68), P < 0.05). Deucravacitinib significantly outperformed the placebo in improving BICLA response (RR = 1.55, 95% CI (1.20, 2.02), P < 0.05). In terms of adverse reactions, targeted small-molecule drugs did not significantly increase the risk of adverse events as compared to placebo (P > 0.05). CONCLUSION: Based on the evidence obtained in this study, the differences in the efficacy of targeted small-molecule drugs were statistically significant as compared to placebo, but the difference in the safety was not statistically significant. The dose and the course of treatment had little impact on the effect of targeted small-molecule drugs. Deucravacitinib could significantly improve BICLA response and SRI-4 response without significantly increasing the risk of AEs. Therefore, Deucravacitinib is very likely to be the best intervention measure. Due to the small number of included studies, more high-quality clinical evidence is needed to further verify the efficacy and safety of targeted small-molecule drugs for SLE.


Subject(s)
Lupus Erythematosus, Systemic , Randomized Controlled Trials as Topic , Humans , Lupus Erythematosus, Systemic/drug therapy , Randomized Controlled Trials as Topic/methods , Treatment Outcome , Azetidines/therapeutic use , Azetidines/adverse effects , Purines/therapeutic use , Purines/adverse effects , Molecular Targeted Therapy/methods , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Pyrazoles
10.
Hematology ; 29(1): 2343604, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38703055

ABSTRACT

PURPOSE: To explore the efficacy and safety of venetoclax-based combination therapy for older patients with newly diagnosed acute myeloid leukemia (AML). METHODS: We performed a systematic review and meta-analysis of clinical trials comparing venetoclax plus hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) with mono-HMAs or LDAC. The random or fixed effects model was applied to the studies based on heterogeneity. Dichotomous data were summarized using the risk ratio (RR) and 95% confidence interval (CI). Continuous variable data were reported as weighted mean differences (WMDs). RESULTS: Nine studies, including a total of 1232 patients, were included in this meta-analysis. Thec complete remission (CR)/complete remission with incomplete hematological recovery (CRi) rate of the venetoclax (Ven) + azacytidine (Aza) group was significantly greater than that of the Aza monotherapy group (RR: 2.42; 95% CI: 1.85-3.15; P < 0.001). Similarly, the CR/CRi rate of the Ven + LDAC group was also significantly greater than that of the LDAC monotherapy group (RR: 2.57; 95% CI: 1.58-4.17; P = 0.00). The same results were observed for OS among these groups. However, the incidence of febrile neutropenia was greater in the Ven + Aza group than in the Ven + Decitabine (Dec) or monotherapy Aza group (RR: 0.69; 95% CI: 0.53-0.90; P = 0.006 and RR: 2.19; 95% CI: 1.58-3.03; P < 0.001, respectively). In addition, the Ven + LDAC group had significantly greater rates of constipation, diarrhea, nausea, and vomiting than the LDAC monotherapy group, with RRs and CIs of 0.61 (95% CI 0.44-0.83, P = 0.002), 1.81 (95% CI 1.22-2.67, P = 0.003), 1.39 (95% CI 1.06-1.82, P = 0.016), and 1.80 (95% CI 1.19-2.72, P = 0.005), respectively. CONCLUSION: Venetoclax combined with azacitidine, decitabine, or LDAC significantly improved the CR/CRi and OS of patients with previously untreated AML. However, venetoclax plus azacitidine or LDAC was more likely to lead to increased febrile neutropenia and gastrointestinal toxicity.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Bridged Bicyclo Compounds, Heterocyclic , Leukemia, Myeloid, Acute , Sulfonamides , Humans , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Sulfonamides/therapeutic use , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Leukemia, Myeloid, Acute/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Azacitidine/administration & dosage , Azacitidine/adverse effects , Azacitidine/therapeutic use , Treatment Outcome , Aged , Cytarabine/administration & dosage , Cytarabine/therapeutic use , Cytarabine/adverse effects
11.
Clin Rheumatol ; 43(6): 2133-2138, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38703283

ABSTRACT

INTRODUCTION: Rheumatoid arthritis (RA) is usually treated with disease modifying antirheumatic drugs (DMARDs), including biological DMARDs (bDMARDs) and more recently, Janus kinase inhibitors (JAKi). Randomized trials suggest similar infection risks for JAKi and bDMARDs, but real-world data are scarce. METHODS: From a nationally representative prescription database, adult RA patients starting a new JAKi or bDMARD between August 1st, 2018, and January 31st, 2021, were included. Prescriptions of antibiotic, antiviral or antifungal medication were used as proxy for infections. Infection incidence rates (IR) were compared between JAKi and bDMARDs and infection risks were estimated using multilevel Poisson regression adjusted for follow-up time and potential confounders and stratified for age < 65 and ≥ 65 years. RESULTS: In 14,989 patients, we identified 20,050 treatment episodes with either JAKi or bDMARDs. The infection IR was significantly higher in JAKi (48/100 patient years) compared bDMARDs (35/100 patient years, adjusted incidence rate ratio (IRR) 1.22, 95% CI 1.12-1.33). More herpes zoster infections were seen in JAKi compared to bDMARDs (adjusted IRR 2.65, 95% CI 1.94-3.60). No significant differences in infection IRs were found comparing JAKi baricitinib and tofacitinib. In older patients, infection IRs were higher, but IRRs were similar between age groups. CONCLUSION: In comparison to bDMARDs, JAKi are associated with a slightly higher infection risk and a higher risk of herpes zoster specifically. In older patients, infection IRs are higher but similar infection risks for JAKi and bDMARDs are observed. No differences in infection risk between tofacitinib and baricitinib were found. Key Points • Compared to bDMARDs, JAKi are associated with a slightly higher infection risk for all ages • An increased risk of herpes zoster in patients who use JAK inhibitors was confirmed • No significant differences in infection incidence were found between tofacitinib and baricitinib.


Subject(s)
Antirheumatic Agents , Arthritis, Rheumatoid , Azetidines , Janus Kinase Inhibitors , Piperidines , Purines , Pyrazoles , Pyrimidines , Sulfonamides , Humans , Male , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/adverse effects , Female , Middle Aged , Arthritis, Rheumatoid/drug therapy , Purines/therapeutic use , Purines/adverse effects , Antirheumatic Agents/adverse effects , Antirheumatic Agents/therapeutic use , Piperidines/therapeutic use , Piperidines/adverse effects , Aged , Pyrimidines/therapeutic use , Pyrimidines/adverse effects , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Azetidines/therapeutic use , Azetidines/adverse effects , Pyrazoles/adverse effects , Pyrazoles/therapeutic use , Incidence , Herpes Zoster/epidemiology , Herpes Zoster/chemically induced , Adult , Infections/epidemiology , Infections/chemically induced
13.
J Viral Hepat ; 31(7): 409-415, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38654438

ABSTRACT

Glecaprevir/pibrentasvir (GLE/PIB) is an approved guideline-recommended chronic hepatitis C virus infection treatment. GLE/PIB coadministration with ethinyl oestradiol (EE) is not recommended in current labels owing to a Phase 1 study observing Grade ≥2 alanine aminotransferase (ALT) elevation in 2 out of 12 healthy women cotreated for 11 days with GLE/PIB and oral contraceptive (OC) containing 35 µg/250 µg EE/norgestimate. No Grade ≥2 elevation was observed with low-dose (20 µg) EE (n = 14). This Phase 1 study examined safety/tolerability of GLE/PIB coadministered with an OC containing low-dose EE using a larger sample size and longer treatment duration. Healthy premenopausal women were treated with EE/levonorgestrel alone (20/100 µg, Cycles 1-2), followed by coadministration with GLE/PIB (300/120 mg; Cycles 3-4). A safety criterion of special interest was a confirmed Grade ≥2 ALT elevation (>3× upper normal limit). Adverse events (AEs) and study drugs concentrations were examined. Of 85 enrolled women, 72 initiated combined GLE/PIB + EE/levonorgestrel treatment, 66 completed the study and 19 discontinued prematurely (non-safety reason, n = 16; AE [deemed unelated to GLE/PIB], n = 3). No participant met the safety criterion of special interest of confirmed Grade ≥2 ALT elevation. No serious/Grade ≥3 AEs were reported. Study drug concentrations were within the expected ranges. GLE/PIB in combination with an OC containing low-dose EE was generally well tolerated with no confirmed Grade ≥2 ALT elevation and no evidence of drug-induced liver injury. No pattern to the reported AEs and no new safety issues were identified. This was a Phase 1 study of healthy volunteers, not a registered clinical trial.


Subject(s)
Antiviral Agents , Benzimidazoles , Ethinyl Estradiol , Healthy Volunteers , Premenopause , Pyrrolidines , Quinoxalines , Sulfonamides , Humans , Female , Adult , Benzimidazoles/adverse effects , Benzimidazoles/administration & dosage , Quinoxalines/adverse effects , Quinoxalines/administration & dosage , Ethinyl Estradiol/adverse effects , Ethinyl Estradiol/administration & dosage , Sulfonamides/adverse effects , Sulfonamides/administration & dosage , Antiviral Agents/adverse effects , Antiviral Agents/administration & dosage , Antiviral Agents/therapeutic use , Young Adult , Pyrrolidines/adverse effects , Pyrrolidines/administration & dosage , Middle Aged , Contraceptives, Oral/adverse effects , Contraceptives, Oral/administration & dosage , Alanine Transaminase/blood , Aminoisobutyric Acids , Leucine/analogs & derivatives , Leucine/adverse effects , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug Combinations
14.
Rinsho Ketsueki ; 65(3): 135-141, 2024.
Article in Japanese | MEDLINE | ID: mdl-38569855

ABSTRACT

Acute myelogenous leukemia (AML) has a poor prognosis in patients who are ineligible for intensive chemotherapy. The combination of azacitidine and venetoclax has been shown to have high overall efficiency and remission rates, even in patients ineligible for aggressive chemotherapy. However, myelosuppression is often prolonged after treatment, and infection can also occur. Severe myelosuppression is often addressed by dose titration, but specific dose titration methods have not been clarified. We used the standard induction therapy with azacitidine plus venetoclax, and if blasts decreased to 20% or less, switched to 7+7 therapy to shorten venetoclax to 7 days starting from the next cycle. In the 19 patients we treated (median age 80 years), response rate above MLFS was 100%, CR 57.9%, CRc (CR+CRi) 78.8%, median OS 693 days, median PFS 458 days, and median OS was not reached in previously untreated patients. This indicates that 7+7 is a highly effective and well-tolerated treatment.


Subject(s)
Azacitidine , Leukemia, Myeloid, Acute , Humans , Aged, 80 and over , Azacitidine/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Sulfonamides/adverse effects , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/etiology
15.
Anticancer Res ; 44(5): 2003-2007, 2024 May.
Article in English | MEDLINE | ID: mdl-38677735

ABSTRACT

BACKGROUND/AIM: The combination of venetoclax (VEN) and azacitidine (AZA) (VEN+AZA) leads to higher complete remission rates and longer overall survival (OS) in patients with untreated acute myeloid leukemia (AML) who are ineligible for intensive combination chemotherapy. In practice, the doses of VEN and AZA are reduced at the attending physician's discretion to avoid adverse events; however, the impact of dose and duration reductions has not been fully clarified. We analyzed whether the efficacy was maintained with reduced VEN+AZA compared to AZA monotherapy in the real world. PATIENTS AND METHODS: A total of 33 patients were included; 17 (10 newly diagnosed, 7 primary refractory or relapsed) received VEN+AZA, and 16 (7 newly diagnosed, 9 primary refractory or relapsed) received AZA. We analyzed complete remission (CR) and CR with incomplete hematologic recovery (CRi) rates, OS, and the incidence of adverse events. RESULTS: CR/CRi were achieved in 7/17 (41.2%) and 11/17 (64.7%) patients in the VEN+AZA group and 0/15 (0%) and 2/15 (6.7%) patients in the AZA group, respectively. The CR/CRi rate was higher in the VEN+AZA group than in the AZA group (p=0.001). OS was longer in the VEN+AZA group than in the AZA group (p=0.03), with a median of 506 days [95% confidence interval (CI)=234-585 days] and 208 days (95% CI=52-343 days), respectively. CONCLUSION: The doses of the VEN+AZA combination were reduced at the attending physician's discretion, resulting in a higher CR/CRi rate and longer OS than AZA monotherapy and is considered useful for AML in the real world.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Azacitidine , Bridged Bicyclo Compounds, Heterocyclic , Leukemia, Myeloid, Acute , Sulfonamides , Humans , Azacitidine/therapeutic use , Azacitidine/adverse effects , Azacitidine/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/mortality , Male , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Female , Aged , Sulfonamides/therapeutic use , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Aged, 80 and over , Treatment Outcome , Remission Induction , Adult
16.
Diagn Microbiol Infect Dis ; 109(3): 116266, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38643677

ABSTRACT

The aim of this study was to describe a case of a patient with ocular toxoplasmosis, which has resulted in Kyrieleis plaques formation (segmental periarteritis associated with severe inflammation) and later follow-up and alternative treatment due to documented allergy to sulfonamide. A 33-year-old Brazilian woman diagnosed with acute toxoplasmosis, initially treated with sulfonamide, developed a critical cutaneous rash. Cotrimoxazole was changed to clindamycin and pyrimethamine, and prednisone was started. The medication was maintained for 45 days. Four months later, she developed retinal lesions suggestive of toxoplasmosis with Kyrieleis plaques in the upper temporal vessels. Pyrimethamine, clindamycin, and prednisone were initiated until healing. She presented reactivation months later, and a suppressive treatment with pyrimethamine was instituted for one year. This is the first report to use the combination of clindamycin with pyrimethamine in the treatment and recurrence prophylaxis for OT in a documented allergy to sulfonamide.


Subject(s)
Clindamycin , Pyrimethamine , Sulfonamides , Toxoplasmosis, Ocular , Humans , Female , Adult , Pyrimethamine/therapeutic use , Pyrimethamine/adverse effects , Toxoplasmosis, Ocular/drug therapy , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Clindamycin/therapeutic use , Recurrence , Trimethoprim, Sulfamethoxazole Drug Combination/therapeutic use , Trimethoprim, Sulfamethoxazole Drug Combination/adverse effects , Drug Hypersensitivity/etiology , Brazil , Antiprotozoal Agents/therapeutic use , Antiprotozoal Agents/adverse effects , Treatment Outcome , Prednisone/therapeutic use
17.
J Ocul Pharmacol Ther ; 40(4): 240-245, 2024 May.
Article in English | MEDLINE | ID: mdl-38598266

ABSTRACT

Purpose: To compare the efficacy of Brinzolamide-Brimonidine (BB) (1%+0.2%) with the gold standard Latanoprost-Timolol (LT) (0.005%+0.5%) in treating primary open-angle glaucoma (POAG) and ocular hypertension (OHT). Methods: A 1-year prospective study, spanning from May 2022 to May 2023, conducted at a tertiary eye-care hospital. Participants, aged 40-60, with a baseline intraocular pressure (IOP) >21 mm Hg, requiring a >30% reduction, were enrolled. Group A (n = 100) received BB, and Group B (n = 100) received LT. Outcomes were assessed at 1 month (IOP difference from baseline), 3 and 6 months (mean diurnal variations). Results: The mean age at presentation was 55.5 ± 4.5 years in Group A and 54.7 ± 4.2 years in Group B. At 1 month, Group A exhibited a mean IOP of 18.7 mm Hg, while Group B had 17.6 mm Hg, with no statistically significant difference (P = 0.53). No significant diurnal variation was observed in either group (P = 0.07). Target pressure was achieved in 88% of patients in Group A and slightly higher at 92% in Group B. Moreover, no serious side effects were reported, and compliance was higher in Group B (98%) compared to Group A (96%). Conclusion: Although LT showed slightly better and sustained IOP reduction, the difference was not statistically significant. Both BB and LT demonstrated comparable outcomes for managing POAG and OHT.


Subject(s)
Antihypertensive Agents , Brimonidine Tartrate , Glaucoma, Open-Angle , Intraocular Pressure , Latanoprost , Ocular Hypertension , Sulfonamides , Timolol , Humans , Glaucoma, Open-Angle/drug therapy , Middle Aged , Intraocular Pressure/drug effects , Ocular Hypertension/drug therapy , Latanoprost/administration & dosage , Latanoprost/therapeutic use , Latanoprost/pharmacology , Brimonidine Tartrate/administration & dosage , Brimonidine Tartrate/therapeutic use , Brimonidine Tartrate/pharmacology , Brimonidine Tartrate/adverse effects , Male , Female , Prospective Studies , Timolol/administration & dosage , Timolol/therapeutic use , Timolol/adverse effects , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/therapeutic use , Antihypertensive Agents/adverse effects , Antihypertensive Agents/pharmacology , Adult , Sulfonamides/administration & dosage , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Sulfonamides/pharmacology , Thiazines/administration & dosage , Thiazines/therapeutic use , Thiazines/adverse effects , Drug Combinations , Treatment Outcome , Ophthalmic Solutions/administration & dosage
18.
J Dermatol ; 51(6): 849-853, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38433352

ABSTRACT

Atopic dermatitis (AD) is a common chronic inflammatory skin disease characterized by recurrent, pruritic, and localized eczema. Various types of new drugs have been recently investigated for treating AD. The efficacy and safety of abrocitinib in treating AD has been reported in clinical trials, but the real-world data from Japan has not been reported. Herein, we analyzed 12 Japanese patients with AD treated with 100 mg of abrocitinib using our real-world data. We also performed transcriptome analysis with peripheral blood to investigate the effects of abrocitinib on cytokine expressions and inflammatory pathways in AD from three patients. This study included patients with moderate to severe AD treated with abrocitinib at Gunma University Hospital, Japan. All patients were systemic treatment-naïve. All patients received a 100-mg dose of abrocitinib daily, and used strong or very strong topical steroids and moisturizers. The Eczema Area and Severity Index (EASI) response analysis revealed that after 4 weeks, 25% (three of 12) of the cases reached a 75% reduction in the EASI score (EASI-75) and a 90% reduction in the EASI score (EASI-90). After 12 weeks, 83.3.% (10 of 12), 41.6% (five of 12), and 16.7% (two of 12) of the patients reached EASI-50, a 75% reduction in the EASI score (EASI-75), and EASI-90. Peak Pruritus Numerical Rating Scale was achieved in nine patients (75%) at week 12. The most frequent adverse reaction was acne (six cases [50%]). Gene Ontology pathway analysis using Differentially expressed genes from RNA sequencing analysis revealed attenuation of defense responses to biotic stimulus, virus, and cytokines. Th2 cytokine expression was not suppressed, but several chemokines, especially CXCL1, were suppressed by abrocitinib treatment. Our results indicate abrocitinib as a fast-acting and highly antipruritic agent that is effective for moderate skin eruptions.


Subject(s)
Dermatitis, Atopic , Gene Expression Profiling , Severity of Illness Index , Adult , Female , Humans , Male , Middle Aged , Young Adult , Boron Compounds/adverse effects , Boron Compounds/therapeutic use , Cytokines/blood , Cytokines/metabolism , Dermatitis, Atopic/blood , Dermatitis, Atopic/diagnosis , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/genetics , East Asian People , Japan , Pyrimidines/adverse effects , Pyrimidines/therapeutic use , Sulfonamides/adverse effects , Sulfonamides/therapeutic use , Transcriptome , Treatment Outcome
19.
Clin Colorectal Cancer ; 23(2): 174-182.e6, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38553360

ABSTRACT

BACKGROUND: The phase 3 BEACON CRC study demonstrated the survival benefits of encorafenib and cetuximab, with or without binimetinib (the BEACON triplet or doublet regimen), for BRAFV600E-mutant metastatic colorectal cancer (mCRC). This expanded access program (EAP) and subsequent follow-up study assessed the efficacy and safety of the BEACON triplet regimen in Japanese patients with BRAFV600E-mutant mCRC. MATERIALS AND METHODS: The EAP was an open-label, single-arm study including Japanese patients with BRAFV600E-mutant mCRC whose disease progressed after 1 to 2 prior regimens. The patients received the BEACON triplet regimen with 28-day cycles. The subsequent follow-up study assessed the survival outcomes following EAP completion. Safety was assessed only during the EAP. RESULTS: Among the 86 enrolled patients, 81 received the BEACON triplet regimen. The objective response rate and median progression-free survival were 27.6% (95% confidence interval [CI], 18.0%-39.1%) and 5.26 (95% CI, 4.14-5.52) months, respectively. Grade 3 to 4 adverse events and treatment-related adverse events occurred in 43.2% and 28.4% of patients, respectively. No new safety signals were observed during the EAP. Among 58 patients with confirmed survival at EAP completion, 57 were included in the follow-up study. With a median observation period of 9.17 months through the EAP and follow-up study, the median overall survival was 10.38 (95% CI, 9.00-16.16) months. CONCLUSION: The efficacy and safety of the BEACON triplet regimen in Japanese patients with BRAFV600E-mutant mCRC were consistent with those reported in the BEACON CRC trial, supporting its use as a standard treatment for pretreated patients with BRAFV600E-mutant mCRC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Benzimidazoles , Carbamates , Cetuximab , Colorectal Neoplasms , Sulfonamides , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Benzimidazoles/adverse effects , Benzimidazoles/therapeutic use , Carbamates/adverse effects , Carbamates/therapeutic use , Cetuximab/adverse effects , Cetuximab/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/mortality , East Asian People , Follow-Up Studies , Japan , Mutation , Progression-Free Survival , Proto-Oncogene Proteins B-raf/genetics , Sulfonamides/adverse effects , Sulfonamides/therapeutic use
20.
Clin Cancer Res ; 30(10): 2048-2056, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38446982

ABSTRACT

PURPOSE: Although fewer than 5% of high-grade gliomas (HGG) are BRAF-V600E mutated, these tumors are notable as BRAF-targeted therapy shows efficacy for some populations. The purpose of this study was to evaluate response to the combination of encorafenib with binimetinib in adults with recurrent BRAF-V600-mutated HGG. PATIENTS AND METHODS: In this phase 2, open-label, Adult Brain Tumor Consortium (ABTC) trial (NCT03973918), encorafenib and binimetinib were administered at their FDA-approved doses continuously in 28-day cycles. Eligible patients were required to have HGG or glioblastoma with a BRAF-V600E alteration that was recurrent following at least one line of therapy, including radiotherapy. RESULTS: Five patients enrolled between January 2020 and administrative termination in November 2021 (due to closure of the ABTC). Enrolled patients received treatment for 2 to 40 months; currently one patient remains on treatment. Centrally determined radiographic response rate was 60%, with one complete response and two partial responses. Methylation profiling revealed that all tumors cluster most closely with anaplastic pleomorphic xanthoastrocytoma (PXA). Transcriptional profile for MAPK-response signature was similar across all tumors at baseline and did not correlate with response in this small population. Circulating tumor DNA measured in plasma samples before treatment, during response, and upon progression showed feasibility of detection for the BRAF-V600E alteration. No new safety signal was detected. CONCLUSIONS: Encorafenib and binimetinib exhibit positive tumor responses in patients with recurrent BRAF-V600E mutant HGG in this small series, warranting therapeutic consideration. Although toxicity remains a concern for BRAF-targeted therapies, no new safety signal was observed in these patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Benzimidazoles , Brain Neoplasms , Carbamates , Glioma , Mutation , Proto-Oncogene Proteins B-raf , Sulfonamides , Humans , Proto-Oncogene Proteins B-raf/genetics , Carbamates/administration & dosage , Carbamates/therapeutic use , Benzimidazoles/administration & dosage , Benzimidazoles/adverse effects , Benzimidazoles/therapeutic use , Sulfonamides/administration & dosage , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Female , Male , Middle Aged , Glioma/drug therapy , Glioma/genetics , Glioma/pathology , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Aged , Treatment Outcome , Neoplasm Grading
SELECTION OF CITATIONS
SEARCH DETAIL
...