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Introduction: Combination of daratumumab (Dara) and lenalidomide (Len) may enhance the function of teclistamab (Tec), potentially resulting in improved antimyeloma activity in a broader population. We present initial safety and efficacy data of Tec-Dara- Len combination in patients with multiple myeloma (MM) in a phase 1b study (MajesTEC-2;NCT04722146). Method(s): Eligible patients who received 1-3 prior lines of therapy (LOT), including a proteasome inhibitor and immune-modulatory drug, were given weekly doses of Tec (0.72-or- 1.5 mg/kg with step-up dosing) + Dara 1800 mg + Len 25 mg. Responses per International Myeloma Working Group criteria, adverse events (Aes) per CTCAE v5.0, and for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) per ASTCT guidelines, were assessed. Result(s): 32 patients received Tec-Dara- Len (0.72 mg/kg, n = 13;1.5 mg/kg, n = 19). At data cut-off (11 July 2022), median follow-up (range) was 5.78 months (1.0-10.4) and median treatment duration was 4.98 months (0.10-10.35). Median age was 62 years (38-75);87.5% were male. Median prior LOT was 2 (1-3), 18.8% were refractory to Dara and 28.1% refractory to Len. CRS was most frequent AE (81.3% [n = 26], all grade 1/2), 95% occurred during cycle1. Median time to onset was 2 days (1-8), median duration was 2 days (1-22). No ICANS were reported. Frequent Aes (>=25.0% across both dose levels) were neutropenia (75.0% [n = 24];grade 3/4: 68.8% [n = 22]), fatigue (43.8% [n = 14];grade 3/4: 6.3% [n = 2]), diarrhoea (37.5% [n = 12];all grade 1/2), insomnia (31.3% [n = 10];grade 3/4: 3.1% [n = 1]), cough (28.1% [n = 9];all grade 1/2), hypophosphatemia (25.0% [n = 8];all grade 1/2), and pyrexia (25% [n = 8];grade 3/4: 6.3% [n = 2]). Febrile neutropenia frequency was 12.5% (n = 4). Infections occurred in 24 patients (75.0%;grade 3/4: 28.1% [n = 9]). Most common were upper respiratory infection (21.9% [n = 7]), COVID-19 (21.9% [n = 7]), and pneumonia (21.9% [n = 7]). Three (9.4%) had COVID-19 pneumonia. One (3.1%) discontinued due to COVID-19 infection and this patient subsequently died of this infection. Overall response rate (ORR, median follow-up) was 13/13 (8.61 months) at 0.72 mg/kg and 13/16 evaluable patients (less mature at 4.17 months) at 1.5 mg/kg. 12 patients attained very good/better partial response at 0.72 mg/kg dose, and response was not mature for 1.5 mg/kg group. Median time to first response was 1.0 month (0.7-2.0). Preliminary pharmacokinetic concentrations of Tec-Dara- Len were similar as seen with Tec monotherapy. Tec-Dara- Len- treatment led to proinflammatory cytokine production and T-cell activation. Conclusion(s): The combination of Tec-Dara- Len has no new safety signals beyond those seen with Tec or Dara-Len individually. Promising ORR supports the potential for this combination to have enhanced early disease control through the addition of Tec. These data warrant further investigation.
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Introduction: Croatian National Cancer Registry of Croatian Institute for Public Health reported that in year 2020 lung cancer was the second most common cancer site diagnosed in men with 16% and the third most common in women with 10% incidence among all cancer sites. Unfortunatelly lung cancer has the highest mortality in both men and women. Haematological malignancies had 7% share in all malignancies in both male and female cances cases. In 2020 190 newly diagnosed cases of lymphatic leukemia in men and 128 cases in women were reporeted, meaning 1.5 and 1.2% of all malignancies, respectively. Chronic lymphatic leukemia (CLL) is an advanced age disease and incidence increases with age. Impaired immunity, T and B cell dysfunction in CLL, chromosomal aberations, long-term immunosuppressive therapy and genetic factors can all cause secondary malignancies. Co- occurence of solid tumors and CLL is very rare. Although patiens with CLL have an increased risk of developing second primary malignancies including lung carcinoma, the data about their clinical outcomes are lacking. Parekh et al. retrospectively analyzed patients with simultaneous CLL and lung carcinoma over a 20-year period, and they found that ~2% of patients with CLL actually developed lung carcinoma. The authors claimed that up to 38% of patients will also develop a third neoplasm more likely of the skin (melanoma and basal cell carcinoma), larynx (laryngeal carcinoma) or colon. Currently there are no specific guidelines for concurrent CLL and non-small cell lung carcinoma (NSCLC) treatment. Usually, when the tumors are diagnosed simultaneously, treatment is based to target the most aggressive malignancy, as the clinical outcomes depend on the response of the tumor with the poorest prognosis. For this reason, a multidisciplinary approach is mandatory. Case report: A patient with history of coronary heart disease, myocardial infarction and paroxysmal atrial fibrillation was diagnosed in 2019 (at the age of 71) with B chronic lymphocytic leukemia with bulky tumor (inguinal lymph nodes 8x5 cm), stage B according to Binet, intermediate risk. He was treated with 6 cycles of chemoimmunotherapy (rituximab/cyclofosfamid/fludarabine). In 10/2019 remission was confirmed, but MSCT described tumor in the posterior segment of upper right lung lobe measuring 20x17 mm and bilateral metastases up to 11 mm. Bronchoscopy and biopsy were performed, and EGFR neg, ALK neg, ROS 1 neg, PD-L1>50% adenocarcinoma was confirmed. He was referred to Clinical Hospital Center Osijek where monotherapy with pembrolizumab in a standard dose of 200 mg intravenously was started in 01/2020. Partial remission was confirmed in October 2020. Immunotherapy was discontinued due to development of pneumonitis, dysphagia and severe weight loss (20kg), but without radiologically confirmed disease progression. At that time he was referred to our hospital for further treatment. Gastroscopy has shown erosive gastritis with active duodenal ulcus, Forrest III. Supportive therapy and proton pump inhibitor were introduced. After complete regression of pneumonitis, improvement of general condition and resolution of dysphagia, no signs of lung cancer progression were found and pembrolizumab was reintroduced in 12/2021. Hypothyroidism was diagnosed in 01/2021 and levothyroxine replacement ther apy was started. In 03/2021 he underwent surgical removal of basal cell carcinoma of skin on the right temporal region with lobe reconstruction. From 02/2021, when pembrolizumab was reintroduced, regression in tumor size was continously confirmed with complete recovery of general condition. He was hospitalized for COVID 19 infection in 09/2021, and due to complications pembrolizumab was discontinued till 11/2021. Lung cancer immunotherapy proceeded till 11/2022, when Multidisciplinary team decided to finish pembrolizumab because of CLL relapse. CLL was in remission till August 2022 when due to B symptoms, lymphcytosis, anemia and generalized lymphadenopathy, hematological workup including biopsy of cervical lymph node was performed and CLL/SLL relapse was confirmed. Initially chlorambucil was introduced, but disease was refractory. Based on cytogenetic test results (IGHV unmutated, negative TP53) and due to cardiovascular comorbidity (contraindication for BTK inhibitors) venetoclax and rituximab were started in 01/2023. After just 1 cycle of treatment normal blood count as well as regression of B symptoms and peripheral lymphadenopathy occured, indicating the probability of complete disease remission. In our patient with metastatic lung adenocarcinoma excellent disease control is achieved during 41 month of treatment in first line setting. Furthermore, relapsed/refractory CLL/SLL is currently in confirmed remission. Conclusion(s): Successful treatment of patients with multiple primary malignancies is based on multidisciplinarity, early recognition and management of side effects, treatment of comorbidities with the aim of prolonging life, controlling symptoms of disease and preserving quality of life.
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Aims and objectives: The aim of this study was to compare the immediate adverse effects of the coronavirus disease 2019 (COVID-19) vaccine (COVAXIN) in a pregnant woman with that of a nonpregnant woman. Material(s) and Method(s): It is a prospective observational study done at Vanivilas Hospital, Bangalore Medical College & Research Institute (BMCRI) for 2 months. The sample size was 100 pregnant and 100 nonpregnant women. Telephonically, patients were followed-up, and details of the side/adverse effects were collected in a proforma after 2 and 14 days. Data collected from both groups were analyzed using the Chi-square test or Fisher's exact test. Result(s): The majority of women were in the age group of <=25 years (64.0% and 36.0%, respectively) with a mean age of 25.01 +/- 3.71 years among the pregnant and 28.52 +/- 6.00 years among nonpregnant women. About 25.0% of pregnant women and 38.0% of nonpregnant women reported side effects. About 15.0% and 22.0% had taken treatment for side effects among pregnant women and nonpregnant women, respectively. Among the pregnant women, the common side effects reported were injection site pain (17) followed by fever (5), fatigue (4), and myalgia (03). Whereas among the nonpregnant women, the common side effects reported were injection site pain (28) followed by fever (6), myalgia (3), headache (2), and fatigue (1). Conclusion(s): Side effects reported following the administration of Covaxin in pregnant and nonpregnant women are fever, fatigue, injection site pain, myalgia, and headache. The proportion of side effects was not significantly different in the pregnant and nonpregnant women following Covaxin administration. Clinical significance: Covaxin is an inactivated killed vaccine against COVID-19 by Bharat Biotech. The vaccine has been recommended for pregnant women by the Government of India during corona pandemic. Studies are lacking regarding the difference in adverse events in pregnant versus nonpregnant women, after vaccine administration.Copyright © The Author(s).
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Background: The interaction between checkpoint inhibitors (CPI) and Sars-COV-2 vaccines has been understudied. One potential complication in pts receiving CPI is immune-mediated adverse events (irAEs) resulting from overactivation of the immune system. It is unknown whether concurrent CPI and Sars-COV-2 vaccine administration increases the risk of irAEs. This retrospective study examined the incidence of severe irAEs in cancer patients receiving CPI therapy at the time of vaccination against Sars CoV-2. Method(s): Following IRB approval, pts with solid tumors who received any approved CPI since FDA authorization of the COVID-19 vaccine in December 2020 were identified via institutional electronic health record. Pts who received one or more doses of an authorized vaccine within 60 days of CPI treatment were included. The primary endpoint was to evaluate the incidence of severe irAE (one or more of the following: grade 3 AE or above, multi-system involvement, need for hospitalization). Secondary endpoints included time between CPI and vaccination, need for immunosuppressive therapy, and rate of discontinuation of CPI due to irAE. Data was analyzed using descriptive statistics. Result(s): 290 pts with bladder, head/neck, liver, skin (melanoma, SCC), renal, and gynecologic cancer were included in analysis. The median age was 67 years (IQR: 59.0-74.0) and 66% pts were male. At the time of vaccination, 201 pts (69.3%) received CPI monotherapy, 53 pts (18.3%) received combination (combo) CPI therapy, and 36 pts (12.4%) received other therapies (chemo, TKIs, etc.) with CPI. The vaccine manufacturer was Pfizer Bio-N-Tech in 162 pts (55.9%), Moderna in 122 pts (42.1%), and Johnson and Johnson in 6 pts (2.1%). The number of vaccinations received was >/= 3 in 214 pts, 2 in 64 pts, and 1 in 11 pts. 30 pts (11.5%) experienced severe irAEs following vaccination. The rate of severe irAEs was 10.3% (30/290) in the total population [6% (12/201) with CPI monotherapy, 19% (10/53) with combo CPI, and 22% (8/36) in the combo CPI-other group]. Severe irAEs occurred after the first vaccine dose in 5 pts (16.7%), second dose in 16 pts (53.3%), and third dose in 9 pts (30%) pts. The median time between CPI treatment and vaccination in pts who experienced irAE was15.5 days (IQR: 10.2-23.0). Hospitalization was required for 19 patients (63.3%). 24 pts (80.0%) required immunosuppressive therapy with a median therapy duration of 98.5 days (IQR 40.2-173.0). 16 pts (53.5%) discontinued CPI therapy following severe irAEs Conclusion(s): In this retrospective study, we observed a 10.3% rate of severe irAE in cancer pts receiving CPI concurrently with COVID-19 vaccines. Further investigation in pts with additional cancer types is warranted to help determine best practice guidelines for COVID-19 vaccination in cancer patients receiving CPI.
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Background: B-cell lymphoma-2 (Bcl-2) proteins play an important role in multiple myeloma (MM) cell survival and represent an attractive therapeutic target. In prior trials, a subgroup analysis of patients with t(11;14)-positive relapsed/refractory (R/R) MM showed the combination of a Bcl-2 inhibitor, a proteasome inhibitor, and dexamethasone improved progression-free survival with no increased mortality. BGB-11417, a Bcl-2 inhibitor, is more potent and selective than venetoclax. BGB-11417- 105 (NCT04973605) is a phase 1b/2 study assessing the safety and efficacy of BGB-11417 monotherapy, in combination with dexamethasone, or with dexamethasone+carfilzomib in patients with t(11;14)-positive R/R MM. Preliminary safety results for the combination of BGB-11417 + dexamethasone are presented. Method(s): Eligible patients had t(11;14)-positive R/R MM and had been exposed to a proteasome inhibitor, immunomodulatory agent, and anti-CD38 therapy. Patients received 80-, 160-, 320-, or 640-mg BGB-11417 daily with 40-mg dexamethasone weekly until death, intolerability, or disease progression. Dose escalation was guided by a mTPI-2 design and overall review by a safety monitoring committee. Pharmacokinetics (PK) were also assessed. Result(s): As of 1 July 2022, 10 patients were enrolled in the 80-, 160-, and 320-mg (3 patients each) and 640-mg (1 patient) dose-escalation cohorts of BGB-11417 + dexamethasone. The median age was 69 years (range, 52-81) and median prior lines of therapy was 3 (range, 1-5). The median treatment duration was 3.2 months (range, 0.5-6.5). No patients experienced dose-limiting toxicity at any dose level. Three patients died whilst on study: 1 due to COVID-19 complications 157 days after treatment discontinuation (day 208), 1 due to progressive disease 50 days after treatment discontinuation (day 89), and 1 due to COVID-19 whilst on study treatment (day 78). No deaths were associated with study treatment. Two patients experienced Grade >= 3 treatment-emergent adverse events (TEAEs). One patient in the 160-mg cohort experienced Grade 3 increase in liver enzymes and lymphopenia. One patient in the 320-mg cohort experienced Grade 3 lymphopenia. The most common TEAEs were insomnia (50%), fatigue (30%), arthralgia (20%), back pain (20%), lymphopenia (20%), and nausea (20%). BGB-11417 exposure increased dose-dependently from 80 mg to 320 mg with high interpatient PK variability. BGB-11417 exposures after single and multiple doses appeared similar, indicating limited accumulation. Conclusion(s): BGB-11417 plus dexamethasone was generally well-tolerated in patients with R/R MM harbouring t(11;14) at doses <=640 mg. Efficacy data are forthcoming. Recruitment is ongoing in the US, Australia, and New Zealand;the BGB-11417, dexamethasone, and carfilzomib combination arm will open in the future.
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BACKGROUND: The article reflects the clinical significance of the early diagnosis of toxic hepatitis in patients who have undergone a new coronavirus infection with the determination of clinical and laboratory predictors of the response to therapy. A dynamic analysis of the effectiveness of toxic hepatitis therapy in patients of three experimental groups and a control group is presented. AIM: The aim of the present study is to increase the effectiveness of the treatment of toxic hepatitis in patients who have undergone COVID-19. MATERIALS AND METHODS: On the basis of the newly created infection centers of the Central Clinical Hospital "RZhD-Medicine" and Vishnevsky 3-rd Central Military Clinical Hospital 996 patients with COVID-19, who had clinical and laboratory signs of toxic liver damage (cytolytic and/or cholestatic syndromes) against the background of COVID-19 therapy. RESULTS: On the 14th day from the start of therapy in group 3, there was a significant decrease in the clinical manifestations of jaundice in 163 (72.8%) patients, on the 21st day of treatment, this symptom was stopped in all patients. In groups 1 and 2, the decrease in clinical manifestations of jaundice was significantly lower - 122 (55.2%) and 134 (58.8%); p<0.05. At the end of therapy, no manifestations of jaundice were observed in all experimental groups, while in the control group, symptom reduction was achieved only in 47 (14.5%) patients. CONCLUSION: The use of drugs with hepatoprotective effect in the form of monotherapy in groups 1 (UDCA) and 2 (ademethionine) showed a low therapeutic effect with positive dynamics of clinical and laboratory indicators of toxic hepatitis activity. The use of combined treatment in group 3 (UDCA and ademethionine) demonstrated the maximum therapeutic effect, pronounced positive dynamics in the form of normalization of clinical and laboratory indicators of toxic hepatitis activity.
Subject(s)
COVID-19 , Chemical and Drug Induced Liver Injury , Jaundice , Humans , Drug Therapy, Combination , Chemical and Drug Induced Liver Injury/diagnosis , Chemical and Drug Induced Liver Injury/epidemiology , Chemical and Drug Induced Liver Injury/etiology , Treatment OutcomeABSTRACT
Background/Aims It is recognised that immunosuppressive medications, often relied upon in the management of autoimmune rheumatic disease, inhibit vaccine-induced immunity against the SARS-CoV-2 virus. A key challenge for rheumatologists is maximising immunity provided by the vaccine in their patients. Recent data has implicated methotrexate (MXT), a commonly used disease modifying anti-rheumatic drug (DMARD), in reducing patients' vaccine-induced immunity against the virus and studies have demonstrated the effectiveness of pausing MXT medication for 2-weeks after receiving the vaccine in boosting patients' immunity. There is a lack of data exploring the impact of concurrent biologic-DMARD (b-DMARD) use with MXT on COVID-19 infection rates in vaccinated individuals. This analysis forms part of a larger programme of research (clinicaltrials.gov NCT04542031) exploring COVID-19 in patients with rheumatic disease. Here we provide a comparative analysis of COVID-19 infection rates between patients taking MXT either with or without b-DMARD therapy and those on no immunosuppression. Methods We distributed two web-based questionnaires via SMS-messaging in April 2020 and December 2021 and two interim monitoring questionnaires in December 2020 and June 2021. All rheumatology patients with a valid mobile telephone number under follow up at the Royal Wolverhampton Trust were invited to participate in the study;those that consented received follow up questionnaires. We collected information on demographics, rheumatology diagnosis and treatment, vaccination status, and COVID-19 infection rates. Data were collected 7-days following questionnaire distribution. Results Initial questionnaires were sent to 7911 active follow up patients, 1636/ 7911 (21%) responded and consented to further follow up;906/1636 (55.4%) provided a complete response to the final survey which was subsequently linked to survey one enabling analysis. Responders were female (622/906, 68.7%), white (865, 95.5%), 60 years or above (519, 57.3%), and vaccinated (898/906;99.1%). Of those vaccinated significantly more patients that were on any immunosuppressive therapy compared to those on no immunosuppression (92/530 (17.4%) vs. 26/368 (7.1%);p<0.001), and more in the MXT monotherapy group compared to no immunosuppression (33/222 (14.9%) vs. 26/368 (7.1%);p=0.001) contracted COVID-19. Similar numbers in the MTX and b-DMARD and b-DMARD without MXT groups (23/140 (16.4%) vs. 36/168 (21.4%);p=0.23) contracted COVID-19. Conclusion Recent trial data from the VROOM study has demonstrated that omitting a patients MXT therapy for a 2-week period following administration of the COVID-19 vaccine doubles their antibody response. This data highlights that the risk of COVID-19 infection in vaccinated rheumatology patients is doubled in patients on any immunosuppressive medication compared to those on no immunosuppression, while there is no significant difference in infection rates between patients on MXT and a b-DMARD and b-DMARD therapy without MXT. Further work exploring the impact of different types of immunosuppression on COVID-19 vaccine-induced immunity and simple interventions to maximise this immunity in immunosuppressed individuals is required.
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Introduction: Liver injury is frequently seen in coronavirus disease 2019 (COVID-19), and it has been reported to be associated with the severity of COVID-19. The direct action of the virus, cytokine storm, coagulation abnormalities, drug-induced, etc. are considered to be the causes of liver injury, and antiviral agents against COVID-19 and steroids used as anti-inflammatory agents have also been reported to contribute to the appearance of liver injury. In Japan, remdesivir, dexamethasone (Dex), baricitinib, etc. are used as therapeutic agents for COVID-19, but there is still not enough evidence about the frequency of liver injury as an adverse event. Aims & Methods: This study aimed to clarify the influence of Dex monotherapy for liver injury in COVID-19 with respiratory failure. We examined 171 patients with COVID-19 with liver injury in the respiratory failure groups and the nonrespiratory failure groups and investigated 41 patients with moderate COVID-19 with respiratory failure who received Dex monotherapy in the liver injury group and the nonliver injury group at the time before treatment. Result(s): The respiratory failure group had 64% more liver damage than the non-respiratory failure group, was older, had more men, and had significantly more complications of lifestyle-related diseases such as hypertension and diabetes. Obesity was more common in the liver injury group prior to Dex monotherapy, and the liver CT value was significantly lower than in the non-liver injury group. Liver injury worsened in 41% of patients after Dex monotherapy, but there was no significant difference in the frequency before Dex monotherapy between the liver injury group and the non-liver injury group, and the degree of liver injury was mild in all cases, improving in 38% of the liver injury group. Conclusion(s): Dex monotherapy was a safe treatment for moderate COVID-19 with respiratory failure, which frequently resulted in liver injury.
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Introduction: Pancreatitis is a very common gastrointestinal disease that results in hospital admission. Early detection and treatment leads to better outcomes. This is the first reported case of pancreatitis secondary to elevated tacrolimus in a patient with prior renal transplantation after receiving Paxlovid for a COVID-19 infection. Case Description/Methods: A 57-year-old male with past medical history of 4 renal transplants secondary to posterior urethral valves who presented to the emergency room with acute onset epigastric pain for 24 hours. He was on tacrolimus 5 mg every 48 hours monotherapy for his immunosuppression. 10 days prior to his presentation he had developed chills and anxiety. He tested positive for COVID-19 at that time on a home rapid test. His symptoms had not significantly improved and given his immunosuppressed state he was given Paxlovid (Nirmatrelvir/ritonavir). He took 2 days of Paxlovid, however after his second day of treatment he developed severe epigastric pain requiring him to go to the emergency room. On admission his labs were notable for a lipase of 150 U/L (ULN 63 U/L). He underwent a CT scan was notable for an enlarged pancreatic head and neck with peripancreatic fat stranding (Figure). He also had a right upper quadrant ultrasound without any cholelithiasis and only trace sludge noted. His creatinine was noted to be 1.81 mg/dl which was above his baseline of 1.2 mg/dl. His tacrolimus trough level resulted at a level 45.6 ng/ml and later peaked at 82.2 ng/ml. His liver enzymes were normal. He was treated as acute pancreatitis with hydration and his tacrolimus was held with overall clinical improvement. Discussion(s): Tacrolimus is one of the most common medications used in solid organ transplantation. It is a calcineurin inhibitor that inhibits both T-lymphocyte signal transduction and IL-2 transcription. It is metabolized by the protein CYP3A and levels are monitored closely. Paxlovid is currently prescribed as an antiviral therapy for COVID-19 infection. The ritonavir compound in Paxlovid is potent inhibitor of CYP3A. Currently the guidelines do not recommend Paxlvoid as a therapeutic in patients taking tacrolimus as there is concern about increased drug levels. There have been several case reports of pancreatitis in setting of tacrolimus. This case report helps to demonstrate the need for close monitoring of therapeutics levels, especially in medications with high risk of drug to drug interaction to help prevent serious side effects such as tacrolimus induced pancreatitis.
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Introduction: Advanced MZL is generally incurable, with periods of remission and relapse. Zanubrutinib (BGB-3111), a potent and highly specific next-generation Bruton tyrosine kinase (BTK) inhibitor, was approved in the US and Canada for R/R MZL based on the MAGNOLIA primary analysis (BGB- 3111-214;NCT03846427);here, the final MAGNOLIA analysis is presented. Method(s): This was a phase 2, multicenter, single-arm study of adult patients (pts) with R/R MZL (>=1 prior CD20-directed therapy). Zanubrutinib (160 mg twice daily) was given until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) by independent review committee (IRC) per Lugano classification. Secondary endpoints were investigator-assessed ORR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Efficacy was assessed by positron emission tomography (PET)-based Lugano criteria for IRC-confirmed fluorodeoxyglucose (FDG)-avid disease at baseline;non-avid disease was assessed by computed tomography (CT)-based criteria. Result(s): As of May 4, 2022, 68 pts were treated (median age=70 y [range 37-95];>=75 y=27.9%). MZL subtypes included extranodal (38.2%), nodal (38.2%), splenic (17.6%), and unknown (5.9%). The median number of prior therapies was 2 (range 1-6);32.4% of pts had disease refractory to last therapy, most (89.7%) had prior chemoimmunotherapy, and 7 (10.3%) had rituximab monotherapy as their only prior treatment. Sixty-one pts (89.7%) had FDG-avid disease. After a median follow-up of 28.0 mos (range 1.6-32.9) and a median treatment duration of 24.2 mos (range 0.9-32.9), 66 pts were efficacy- evaluable. IRC-assessed ORR (complete response [CR]+partial response [PR]) was 68.2% (CR=25.8%). By subtype, (Figure Presented)(Figure Presented)ORR/CR rates were 64.0%/40.0% (extranodal), 76.0%/20.0% (nodal), 66.7%/8.3% (splenic), and 50.0%/25.0% (unknown). Median DOR, PFS, and OS were not reached. Over 70.0% of pts were alive or progression-free after 2 years (Figure). Sensitivity analysis using only CT-based criteria (n=66) showed an ORR of 66.7% and CR of 24.2%. The most common treatment-emergent AEs were bruising (23.5%), diarrhea (22.1%), and constipation (17.6%). Neutropenia (8.8%) and COVID-19 pneumonia (5.9%) were the most common Grade >=3 AEs. Five pts (7.4%) died due to unrelated AEs: COVID-19 pneumonia=2, acute myeloid leukemia=1, myocardial infarction=1, septic encephalopathy=1. Hypertension occurred in 3 pts (4.4%), atrial fibrillation and atrial flutter in 1 pt (1.5%) each;none led to treatment withdrawal. One pt (1.5%) had a Grade 3 gastrointestinal hemorrhage while receiving rivaroxaban. None of the pts required dose reduction. Conclusion(s): In this final analysis with over 2 years of median follow-up, zanubrutinib continues to demonstrate durable disease control and was generally well tolerated, with no new safety signals observedCopyright © 2023 American Society for Transplantation and Cellular Therapy
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RNA viruses are the major class of human pathogens responsible for many global health crises, including the COVID-19 pandemic. However, the current repertoire of U.S. Food and Drug Administration (FDA)-approved antivirals is limited to only nine out of the known 214 human-infecting RNAviruses, and almost all these antivirals target viral proteins. Traditional antiviral development generally proceeds in a virus-centric fashion, and successful therapies tend to be only marginally effective as monotherapies, due to dose-limiting toxicity and the rapid emergence of drug resistance. Host-based antivirals have potential to alleviate these shortcomings, but do not typically discriminate between infected and uninfected cells, thus eliciting unintended effects. In infected cells where host proteins are repurposed by a virus, normal host protein functions are compromised;a situation analogous to a loss-of-function mutation, and cells harboring the hypomorph have unique vulnerabilities. As well-established in model systems and in cancer therapeutics, these uniquely vulnerable cells can be selectively killed by a drug that inhibits a functionally redundant protein. This is the foundation of synthetic lethality (SL). To test if viral induced vulnerabilities can be exploited for viral therapeutics, we selectively targeted synthetic lethal partners of GBF1, a Golgi membrane protein and a critical host factor for many RNA viruses including poliovirus, Coxsackievirus, Dengue, Hepatitis C and E virus, and Ebola virus. GBF1 becomes a hypomorph upon interaction with the poliovirus protein 3A. A genome-wide chemogenomic CRISPR screen identified synthetic lethal partners of GBF1 and revealed ARF1 as the top hit. Disruption of ARF1, selectively killed cells that synthesize poliovirus 3A alone or in the context of a poliovirus replicon. Combining 3A expression with sub-lethal amounts of GCA - a specific inhibitor of GBF1 further exacerbated the GBF1-ARF1 SL effect. Together our data demonstrate proof of concept for host-based SL targeting of viral infection. We are currently testing all druggable synthetic lethal partners of GBF1 from our chemogenomic CRISPR-screen, in the context of dengue virus infection for their abilities to selectively kill infected cells and inhibit viral replication and infection. Importantly, these SL gene partners of viral-induced hypomorphs only become essential in infected cells and in principle, targeting them will have minimal effects on uninfected cells. Our strategy to target SL interactions of the viral-induced hypomorph has the potential to change the current paradigm for host-based therapeutics that can lead to broad-spectrum antivirals and can be applied to other intracellular pathogens. This work is supported by National Institutes of Health grants R01 GM112108 and P41 GM109824, R21 AI151344 and foundation grant FDN-167277 from the Canadian Institutes of Health Research.Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.
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Aim. To assess the clinical outcomes and tolerability of antihypertensive therapy with single pill combinations (SPC) amlodipine + telmisartan and hydrochlorothiazide + telmisartan in clinical practice.Material and methods. Patients with hypertension of grade 1-3 (n=13647;57.6% women;age 59.3 +/- 11.4 years) who received therapy with SPCamlodipine + telmisartan or hydrochlorothiazide + telmisartan were included in an observational multicenter study. Information on complaints, history,previous therapy, history of novel coronavirus infection (COVID-19) during the previous year was obtained. Also, measurement of height, bodyweight, waist circumference (WC) and hips (HC), office blood pressure (BP) three times with an interval of 4 weeks, completion of questionnaires ofsatisfaction with therapy using the Likert scale, and assessement of adherence to therapy according to the patient's opinion was performed.Results. A statistically significant decrease in systolic (SBP) and diastolic blood pressure (DBP) was found both in all patients and in the analysis of sub-groups according to the grade of hypertension (p<0.001 between visits in all cases). The degree of BP reduction depended on baseline BP levels. Theaverage decrease in SBP/DBP at the 3rd visit for the grade 1 hypertension was 24.5/14.6 mm Hg, for the grade 2 hypertension - 34.4/16.8 mmHg,for the grade 3 hypertension - 49.6/22.1 mmHg (p<0.001 between groups). Target levels of SBP (<= 140 mmHg) and DBP (<= 90 mmHg) wereachieved in 95.3% and 98.1% of patients, respectively. Target levels of SBP (<= 130 mmHg) and DBP (<= 80 mmHg) were achieved in 74.9% and78.2% of patients, respectively. WC decreased by 0.5%;HC - by 1.5%;body weight - by 0.42% (p<0.001 in all cases). Scores in patients with ahistory of COVID-19 did not differ from those in individuals without a history of COVID-19. There were no violations of the therapy regimen during theobservation period in 94% of patients. Most doctors and patients were "satisfied" or "completely satisfied" with the clinical effect, convenience and tol-erability of therapy. Adverse events occurred in 1.35% of patients.Conclusion. Therapy with SPC amlodipine + telmisartan or hydrochlorothiazide + telmisartan in clinical practice had a high antihypertensive efficacyand had an optimal safety profile. The efficacy of therapy did not depend on the initial grade of hypertension, as well as the past infection with COVID-19. The results of the ON TIME study confirm the feasibility of using the SPC amlodipine + telmisartan and hydrochlorothiazide + telmisartan for a wide range of hypertensive patients.
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Background: Pulmonary Arterial Hypertension (PAH) is a form of pulmonary hypertension, where the narrowing of arteries in the lungs restricts blood flow and so increases pressure in the vessels. Studies have demonstrated that initial combination therapies are optimal for PAH management. However, prescription of monotherapy treatment is still prevalent as a first line therapy. Purpose(s): The purpose of this research was to investigate prescribing trends of physicians for first line patients with PAH in the UK, Germany, Italy and Spain. We investigated the proportions of newly diagnosed patients and the prescription trends for monotherapy and combination therapy prior to and during the COVID-19 pandemic. Method(s): A multi-country, multi-centre online medical chart review study of patients with PAH was conducted between April - June of 2019, 2020 and 2021 respectively. Recruited from a large access panel, 178 treating cardiologists, pulmonologists & rheumatologists in the UK (n=16), Germany (n=55), Italy (n=55) and Spain (n=52) were screened for duration of practice in their speciality and caseload (>=5 PAH patients in the last 3 months), and provided data on 694 PAH patients (UK = 71, Germany = 206, Italy = 208, Spain = 209). Reported patient data pertained to medical chart information reflecting the prior year, i.e., Q2 2021 data reflected the 2020 period (advent of the COVID-19 pandemic). Result(s): In this dataset, there has been a consistent decrease in the proportion of newly diagnosed (i.e. diagnosed within 12 months of being reported) patients reported from 2019 to 2020 and 2021. In 2019, 49% of the reported patients were diagnosed within the last 12 months. However, the newly diagnosed patient population dropped to 37% in 2020 and continued to drop to 27% in 2021. Despite this, there has been an increase in reported first line patients within the newly diagnosed segment from 74% in 2019, to 75% in 2020, then at 87% in 2021. This increase can be seen to coincide with the ongoing COVID-19 pandemic. In 2019, 58% of reported newly diagnosed patients were recorded as receiving monotherapy. This did drop to 33% in 2020;however, in 2021 monotherapy uptake increased to 47%. Of note, the usage of the endothelin receptor antagonist (ERA) drug class increased from 67% in 2019 to 83% in 2020 but dropped to 69% in 2021. Conclusion(s): This data set suggests a decreasing trend in newly diagnosed patients and a gradual shift in treatment type to first line monotherapy prescription, which coincided with the height of the COVID-19 pandemic. More newly diagnosed patients (those diagnosed within 12 months of being reported) are receiving monotherapy treatment at the expense of combination therapy, and this has also coincided with the pandemic. Further investigation using comparator cohort is warranted to assess whether the challenges physicians faced during the pandemic has had a causal effect on the prescribing habits for PAH therapies.
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Background: Coronavirus disease 2019 (COVID-19) has been a pandemic that is still very prevalent. Patients with Inflammatory Bowel Disease (IBD) represent a special population considering their already altered immune system and their exposure to several immunosuppressive therapies. We pretend to study the impact of COVID-19 on IBD patients in our community, Castilla-La Mancha (a region in central Spain). Method(s): Retrospective observational study using an artificial intelligence with natural language processing capability, the SAVANA manager, we analyzed data from 1 808 010 patients with Electronic Medical Records (EMR) within the public health system of Castilla-La Mancha from March 1st 2020 to January 1st 2021. Data on demographic characteristics, hospitalization, ICU admission and mortality were collected. We compared COVID outcomes between IBD and non-IBD patients. We compared COVID outcomes in IBD patients according to their treatment (comparing each treatment group to those IBD patients with no treatment);we considered: Immunomodulators (azathioprine, mercaptopurine, methotrexate), antiTNF alone or combined with immunomodulator, vedolizumab, ustekinumab and tofacitinib;mesalazine and corticosteroids were not analyzed. Result(s): 2 243 patients with IBD suffered COVID-19, compared to COVID-19 cases without IBD there were less females, they suffered more arterial hypertension, diabetes mellitus, dyslipidemia, obesity, or tabacco use (TABLE 1). And yet, despite these being proven risk factors for worse outcomes for COVID-19, no differences were appreciated in hospitalization rate, ICU admission, or mortality between those with or without IBD (TABLE 2). COVID-19 was more frequent in IBD patients (32.59 vs 13.28%). Comparing IBD patients with COVID-19 according to their treatments (TABLE 3), vedolizumab is the only treatment with a higher risk for COVID-19 infection, however the hospitalization risk for vedolizumab is lower than for those without it. Immunomodulators do also have a lower hospitalization risk both alone or in combination with antiTNF, no differences were found for antiTNF monotherapy, ustekinumab or tofacitinib. ICU rate and mortality are no different between treatments, except for tofacitinib (0.00% ICU rate, 10.00% mortality), however the small number of patients using this treatment may bias this result. Conclusion(s): COVID-19 in IBD patients is no different in hospitalization, ICU admission or mortality compared to non-IBD population. IBD patients exposed to immunomodulators and vedolizumab have less hospitalization risk than those not exposed, no differences were found for antiTNF alone or ustekinumab. The impact of tofacitinib in COVID outcomes requires further investigation.
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Passive immunization with mAbs has been employed in COVID-19. We performed a systematic review of the literature assessing the endogenous humoral immune response against SARS-CoV-2 in patients treated with mAbs. Administration of mAbs in seronegative patients led to a reduction in both antibody titres and neutralizing activity against the virus.Copyright © 2022
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Background: Patients with Inflammatory bowel disease (IBD) receiving anti-TNF or JAK-inhibitor therapy have attenuated responses to COVID-19 vaccination. We aimed to determine how IBD treatments affect neutralising antibody responses against the currently dominant Omicron BA.4/5 variants. Method(s): We prospectively recruited 329 adults (68 healthy controls (HC) and 261 IBD) who had received three doses of COVID-19 vaccine at nine UK centres. The IBD population was established (>12 weeks therapy) on either thiopurine (n=60), infliximab (IFX) (n=43), thiopurine and IFX combination (n=46), ustekinumab (n=43), vedolizumab (n=46) or tofacitinib (n=23). Pseudoneutralisation assays were performed and the half maximal inhibitory concentration (NT50) of participant sera was calculated. The primary outcome was anti-SARSCoV-2 neutralising response against wild-type (WT) virus and the BA.4/5 variant after the second and third doses of anti-SARS-CoV-2 vaccine, stratified by immunosuppressive therapy, adjusting for prior infection, ethnicity, vaccine type and age. Result(s): Heterologous (two doses adenovirus vaccine, third dose mRNA vaccine) and homologous (three doses mRNA vaccine) vaccination strategies significantly increased neutralising titres against both WT SARS-CoV-2 virus and the BA.4/5 variants in HCs and IBD (fig 1). Antibody titres against BA.4/5 were significantly lower than antibodies against WT virus in both groups (Geometric Mean Ratio (GMR) [95% CI], 0.11 [0.09, 0.15], P<0.0001 in healthy participants;GMR 0.07 [0.06, 0.08], P<0.0001 in IBD patients). Multivariable models showed that neutralising antibodies against BA.4/5 after three doses of vaccine were significantly lower in IBD patients on IFX (GMR 0.44 [0.20, 0.97], P=0.042), IFX and thiopurine combination (GMR 0.34 [0.15, 0.77], P=0.0098) or tofacitinib (GMR 0.37 [0.15, 0.92], P=0.032), but not in patients on thiopurine monotherapy, ustekinumab or vedolizumab. Breakthrough infection was associated with lower neutralising antibodies against WT and BA.4/5 (P<0.05). Conclusion(s): A third dose of COVID-19 vaccine based on the WT spike glycoprotein boosts neutralising antibody titres in patients with IBD. However, responses are lower against the currently dominant variant BA.4/5, particularly in patients taking anti-TNF or JAK-inhibitor therapy. Breakthrough infections are associated with lower neutralising antibodies and immunosuppressed IBD patients may receive additional benefit from bivalent vaccine boosters which target Omicron variants. .
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Background: COVID-19 vaccination recommendations for cancer patients (pts) are similar to the general population. The interaction between checkpoint inhibitors (CPI) and Sars-COV-2 vaccines has been understudied. One potential complication in pts receiving CPI is the occurrence of immune-mediated adverse events (irAEs) resulting from overactivation of the immune system. This retrospective study examined the incidence of severe irAEs in pts with bladder urothelial cancer (UC) treated with CPI therapy who received concurrent vaccinations against Sars-CoV-2. Method(s): Following IRB approval, UC pts who received any approved CPI treatment since FDA authorization of the first COVID-19 vaccine in December 2020 were identified via institutional electronic health record. Pts who received 1 or more doses of an authorized vaccine within 60 days of CPI treatment were included. The primary endpoint was to evaluate the incidence of severe irAE (defined as one or more of the following: grade 3 AE or above, multi-system involvement, need for hospitalization). Secondary endpoints included time between CPI and vaccination, need for immunosuppressive therapy, and rate of discontinuation. Data was analyzed using descriptive statistics. Result(s): Forty pts were included in our analysis with a median age of 72.5 years (IQR: 66.0-79.2);82% pts were male. At the time of vaccination, 37 pts (92.5%) received CPI monotherapy, 2 pts (5.0%) received combination (combo) CPI therapy, and 1 pt (2.5%) received combo platinum-based chemotherapy and CPI. The vaccine manufacturer was Pfizer Bio-NTech in 22 pts (55.0%), Moderna in 17 pts (42.5%), and Johnson and Johnson in 1 pt (2.5%). Number of vaccinations received was>/= 3 in 27 pts, 2 in 11 pts, and 1 in 2 pts. Six pts (15.0%) experienced severe irAEs following vaccination, including nephritis, colitis, pneumonitis, DKA, and infusion-related reaction. Rates of severe irAEs were 16.2% (6/37) with CPI monotherapy, no severe irAEs occurred in the combo CPI and combo CPI-chemo groups. Severe irAEs occurred after the first vaccine dose in 1 pt (16.7%), second dose in 3 pts (50.0%), and third dose in 2 pts (33.3%) pts. The median time between CPI treatment and vaccination in this group was 22.0 days (IQR: 15.8-36.5. Hospitalization was required for all 6 patients (100%). Three pts (50.0%) required immunosuppressive therapy with a median therapy duration of 64.0 days (IQR 47.0-83.5). Five pts (83.3%) discontinued CPI therapy following severe irAEs. Conclusion(s): In this retrospective study, we observed a 15% rate severe irAE in UC pts receiving CPI concurrently with COVID-19 vaccines. Further investigation in pts with additional cancer types is warranted to help determine best practice guidelines for COVID-19 vaccination in cancer patients receiving CPI.
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Background: Targeted Immune-Modulating Therapies (TIMT) and immunomodulators (IMM) for Immune Mediated Inflammatory diseases (IMID) theoretically interfere with humoral responses against COVID19. However, IMID patients and particularly patients receiving immunosuppressive treatment were excluded from phase-3 COVID19 vaccination efficacy trials. Real-world observational data is therefore required to provide more insight into the efficacy of COVID19 vaccination in IMID patients. Method(s): The BELCOMID study is a multidisciplinary, prospective observational cohort study performed at two university hospitals and set up with the intention to explore the interaction between IMIDs, immune-modulating treatment modalities and SARS-CoV-2 infection and vaccination in a real-life patient cohort. Consecutive patients seen between 17/12/2020 and 28/02/2021 during routine follow-up for IMIDs of the gut, joints and skin were invited to participate. Both patient data and serological samples were collected at 3 predefined periods (Figure 1: Before vaccination, after start of the national vaccination campaign before booster vaccination, after booster vaccination). Spike (S) protein antibodies were analysed with the Abbott ArchitectTM assay. R version 4.0.2 was used to perform analyses. Result(s): At inclusion period 2, 2065 patients (Table 1) participated of whom 1547 had received complete baseline vaccination (2 doses mRNA-1273, BNT162b2, ChadOx1 nCoV-19 or 1 dose JN78436735). S-antibody seroconversion rate was 91.2%. At inclusion period 3, data was available for 1566 patients of whom 74.7% had received 1 booster (BNT162b2 or mRNA-1273) vaccination leading to a S-antibody seroconversion rate of 98.3%. In 130 patients who had received 2 boosters, S-antibody seroconversion rate was 100%. At period 3, 37 patients had refused all vaccinations. Although 23 of these had experienced confirmed COVID19 since previous inquiry, no S-antibody seroconversion was found in 15 of them. Logistic regression analyses revealed that the odds of no S-antibody seroconversion were significantly higher in IMID patients treated with IMM, combination of IMM+TIMT, systemic steroids and smoking patients at both inclusion periods (Table 2). TIMT monotherapy did not influence seroconversion rates at inclusion period 3 but was associated with higher odds of the lowest S-antibody titre quartile (OR2.32, P<0.001). Among TIMT options, rituximab had higher odds of S-seronegativity. Conclusion(s): S-antibody seroconversion rate in this real-life IMID population was high after baseline vaccination and increased further proportionally with booster vaccination, highlighting the value of repeated vaccination. However, the serologic response may be blunted due to different IMID treatment modalities and smoking.