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1.
Open Forum Infect Dis ; 9(8): ofac350, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-2032082

ABSTRACT

Background: Prison-based hepatitis C treatment is safe and effective; however, many individuals are released untreated due to time or resource constraints. On community re-entry, individuals face a number of immediate competing priorities, and in this context, linkage to hepatitis C care is low. Interventions targeted at improving healthcare continuity after prison release have yielded positive outcomes for other health diagnoses; however, data regarding hepatitis C transitional care are limited. Methods: We conducted a prospective randomized controlled trial comparing a hepatitis C care navigator intervention with standard of care for individuals released from prison with untreated hepatitis C infection. The primary outcome was prescription of hepatitis C direct-acting antivirals (DAA) within 6 months of release. Results: Forty-six participants were randomized. The median age was 36 years and 59% were male. Ninety percent (n = 36 of 40) had injected drugs within 6 months before incarceration. Twenty-two were randomized to care navigation and 24 were randomized to standard of care. Individuals randomized to the intervention were more likely to commence hepatitis C DAAs within 6 months of release (73%, n = 16 of 22 vs 33% n = 8 of 24, P < .01), and the median time between re-entry and DAA prescription was significantly shorter (21 days [interquartile range {IQR}, 11-42] vs 82 days [IQR, 44-99], P = .049). Conclusions: Care navigation increased hepatitis C treatment uptake among untreated individuals released from prison. Public policy should support similar models of care to promote treatment in this high-risk population. Such an approach will help achieve hepatitis C elimination as a public health threat.

2.
N Engl J Med ; 387(6): 514-524, 2022 Aug 11.
Article in English | MEDLINE | ID: covidwho-2031920

ABSTRACT

BACKGROUND: Alpha1-antitrypsin (AAT) deficiency results from carriage of a homozygous SERPINA1 "Z" mutation (proteinase inhibitor [PI] ZZ). The Z allele produces a mutant AAT protein called Z-AAT, which accumulates in hepatocytes and can lead to progressive liver disease and fibrosis. This open-label, phase 2 trial investigated the safety and efficacy of fazirsiran, an RNA interference therapeutic, in patients with liver disease associated with AAT deficiency. METHODS: We assigned adults with the PI ZZ genotype and liver fibrosis to receive fazirsiran at a dose of 200 mg (cohorts 1 [4 patients] and 2 [8 patients]) or 100 mg (cohort 1b [4 patients]) subcutaneously on day 1 and week 4 and then every 12 weeks. The primary end point was the change from baseline to week 24 (cohorts 1 and 1b) or week 48 (cohort 2) in liver Z-AAT concentrations, which were measured by means of liquid chromatography-mass spectrometry. RESULTS: All the patients had reduced accumulation of Z-AAT in the liver (median reduction, 83% at week 24 or 48). The nadir in serum was a reduction of approximately 90%, and treatment was also associated with a reduction in histologic globule burden (from a mean score of 7.4 [scores range from 0 to 9, with higher scores indicating a greater globule burden] at baseline to 2.3 at week 24 or 48). All cohorts had reductions in liver enzyme concentrations. Fibrosis regression was observed in 7 of 15 patients and fibrosis progression in 2 of 15 patients after 24 or 48 weeks. There were no adverse events leading to trial or drug discontinuation. Four serious adverse events (viral myocarditis, diverticulitis, dyspnea, and vestibular neuronitis) resolved. CONCLUSIONS: In this small trial, fazirsiran was associated with a strong reduction of Z-AAT concentrations in the serum and liver and concurrent improvements in liver enzyme concentrations. (Funded by Arrowhead Pharmaceuticals; AROAAT-2002 ClinicalTrials.gov number, NCT03946449.).


Subject(s)
Liver Cirrhosis , RNAi Therapeutics , alpha 1-Antitrypsin Deficiency , alpha 1-Antitrypsin , Adult , Genotype , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Injections, Subcutaneous , Liver/drug effects , Liver/enzymology , Liver/metabolism , Liver Cirrhosis/drug therapy , Liver Cirrhosis/etiology , Liver Cirrhosis/genetics , Mutation , RNAi Therapeutics/adverse effects , RNAi Therapeutics/methods , alpha 1-Antitrypsin/analysis , alpha 1-Antitrypsin/blood , alpha 1-Antitrypsin/genetics , alpha 1-Antitrypsin Deficiency/complications , alpha 1-Antitrypsin Deficiency/drug therapy , alpha 1-Antitrypsin Deficiency/genetics
3.
SSM Popul Health ; 19: 101186, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-2031697

ABSTRACT

Introduction: Excessive optimistic perception about the probability of acquiring coronavirus disease (COVID-19) may hinder people from exercising preventive measures, whereas excessive pessimistic perception can induce psychological problems. Not much focus has been paid to this topic, and prior studies are only online surveys. We determined the characteristics of older adults with optimistic and pessimistic perceptions of the probability of contracting COVID-19. Methods: We used data from the Japan Gerontological Evaluation Study (JAGES), including 18,045 participants aged ≥ 65 years (mean age: 75.7 years) who were physically and cognitively independent. Self-reported questionnaires were sent to 11 municipalities between November 2020 and February 2021. Multinomial logistic regression was used for data analysis. Results: The characteristics of 1,596 (8.8%) participants with optimistic perception and 1,276 (7.1%) with pessimistic perception were compared with that of others (80.4%) with moderate perception. Optimism about infection probability was positively associated with older age; better perceived financial conditions but negatively associated with higher education level; trust in TV news programs, TV information programs, and government-issued newsletters; depressive symptoms; and higher levels of reciprocity. Pessimism was negatively associated with higher levels of social cohesion. In contrast, it was positively associated with engagement in paid work; trust in TV news programs, the Internet, and information from medical staff; and depressive symptoms. Conclusion: Optimistic and pessimistic perceptions about the probability of acquiring infection correlated differently with various characteristics. Thus, risk communication during a pandemic should be tailored based on specific individual characteristics.

4.
Soc Sci Med ; 309: 115237, 2022 Aug 07.
Article in English | MEDLINE | ID: covidwho-2031690

ABSTRACT

The COVID-19 pandemic has disproportionately impacted ethnic minorities in the global north, evidenced by higher rates of transmission, morbidity, and mortality relative to population sizes. Orthodox Jewish neighbourhoods in London had extremely high SARS-CoV-2 seroprevalence rates, reflecting patterns in Israel and the US. The aim of this paper is to examine how responsibilities over health protection are conveyed, and to what extent responsibility is sought by, and shared between, state services, and 'community' stakeholders or representative groups, and families in public health emergencies. The study investigates how public health and statutory services stakeholders, Orthodox Jewish communal custodians and households sought to enact health protection in London during the first year of the pandemic (March 2020-March 2021). Twenty-eight semi-structured interviews were conducted across these cohorts. Findings demonstrate that institutional relations - both their formation and at times fragmentation - were directly shaped by issues surrounding COVID-19 control measures. Exchanges around protective interventions (whether control measures, contact tracing technologies, or vaccines) reveal diverse and diverging attributions of responsibility and authority. The paper develops a framework of public health relations to understand negotiations between statutory services and minority groups over responsiveness and accountability in health protection. Disaggregating public health relations can help social scientists to critique who and what characterises institutional relationships with minority groups, and what ideas of responsibility and responsiveness are projected by differently-positioned stakeholders in health protection.

5.
Mayo Clin Proc Innov Qual Outcomes ; 2022 Aug 08.
Article in English | MEDLINE | ID: covidwho-2031553

ABSTRACT

Objective: To describe changes in ED psychiatric visits during the pandemic in both rural and non-rural regions in the US. Patients and Methods: This cohort study was performed across 22 EDs in the Midwest and Southern United States from January 01, 2019 to April 22, 2021. Prevalence of psychiatric visits were compared before and after the COVID-19 pandemic, defined as starting on March 01, 2020. Psychiatric and nonpsychiatric visits were defined based on primary clinician-assigned diagnosis. The primary endpoint was average daily visits normalized to the average daily visit count prior to the pandemic, labeled as relative mean daily visits (RMDV). Results: Psychiatric visits decreased by 9% (RMDV: 0.91, 95% CI: 0.89-0.93) during the pandemic period, while nonpsychiatric visits decreased by 17% (RMDV: 0.83, 95% CI: 0.81-0.84). Black patients were the only demographic group with a significant increase in psychiatric visits during the pandemic (RMDV: 1.12, 95% CI: 1.04-1.19). Periods of outbreaks of psychiatric emergencies were identified in most demographic groups including among male and pediatric patients. However, outbreaks detected among Black patients were sustained the longest at 6 months. Unlike older adults who experienced outbreaks in the spring and fall of 2020, outbreaks among pediatric patients were detected later in 2021. Conclusion: In this multisite study, total ED visits declined during the pandemic, but psychiatric visits declined less than non-psychiatric visits. Black patients suffered a greater increase in psychiatric emergencies compared to other demographic groups. There is also concern for increasing outbreaks of pediatric psychiatric visits as the pandemic progresses.

6.
Management Research Review ; 2022.
Article in English | Web of Science | ID: covidwho-2032228

ABSTRACT

Purpose During the COVID-19 pandemic, many organizations adopted remote work policies. Meanwhile, the loss of the collocated work environment made it challenging for the supervisors to have a clear vision of their employees, which may impact the quality of the performance evaluation and developmental decisions. This paper aims to resolve this problem by identifying resources in the remote workplace that can help supervisors restore their capacity for a clear vision of the remote employees. Design/methodology/approach The authors take the perspectives of the job resource-demand model and illustrate the theoretical framework that recognizes resources and resource holders at various levels of the organization. The authors see this as the key for supervisors to meet the demand of "seeing" their employees in the remote workplace. Findings Specifically, the employees should offer their information resources via skillful communication because supervisors have lost opportunities for in-person observation. Further, the administration is urged to deliver competence resources through training and development because supervisors may lack the experience of remote work management. Moreover, the organizations should provide social support resources by creating avenues for virtual networking activities, so as to make up the random social opportunities available in the collocated work environment. Research limitations/implications Improving supervisors' vision is a new challenge coming with the installation of the remote workplace. Further research is called for to empirically test this theoretical framework and identify more ways to increase the resources and reduce the demands for supervisors;thus, helping them ease into the new ways of supervision in the virtual workplace. Practical implications This research informs the organizations to adjust their strategy for management development to adapt to the remote workplace. Originality/value The authors noted that increasing concerns of the low visibility of remote workers was partially due to the impaired vision of supervisors, who lost the context of in-person observation. Supervisors' vision of their employees was taken for granted in the traditional work environment and there was not much research done on this topic. This prompted us to develop a theoretical framework based on the job resource demand model.

7.
Benchmarking: An International Journal ; 2022.
Article in English | Web of Science | ID: covidwho-2032211

ABSTRACT

Purpose This study proposes strategies for vaccine center allocation for coronavirus disease (COVID) vaccine by determining the number of vaccination stations required for the vaccination drive, location of vaccination station, assignment of demand group to vaccination station, allocation of the scarce medical professional teams to station and number of optimal days a vaccination station to be functional in a week. Design/methodology/approach The authors propose a mixed-integer nonlinear programming model. However, to handle nonlinearity, the authors devise a heuristic and then propose a two-stage mixed-integer linear programming (MILP) formulation to optimize the allocation of vaccination centers or stations to demand groups in the first stage and the allocation of vaccination centers to cold storage links in the second stage. The first stage optimizes the cost and average distance traveled by people to reach the vaccination center, whereas the second stage optimizes the vaccine's holding and storage and transportation cost by efficiently allocating cold storage links to the centers. Findings The model is studied for the real-world case of Chandigarh, India. The results obtained validate that the proposed approach can immensely help government agencies and policymaking body for a successful vaccination drive. The model tries to find a tradeoff between loss due to underutilized medical teams and the distance traveled by a demand group to get the vaccination. Originality/value To the best of our knowledge, there are hardly any studies on a vaccination program at such a scale due to sudden outbreaks such as Covid-19.

8.
ASAIO Journal ; 68:140, 2022.
Article in English | EMBASE | ID: covidwho-2032190

ABSTRACT

Background: Timing of tracheostomy in COVID-19 patients supported with extracorporeal oxygenation membrane (ECMO) remains unclear. This study aims to compare the short-term outcomes in early (≤7 days from ECMO insertion) (ET) versus late (LT) tracheostomy. Methods: Charts of COVID-19 patients with tracheostomy from 2020 to 2021 were reviewed, retrospectively. Primary endpoint was in-hospital mortality. Secondary endpoints were analgesics/sedatives doses, length of treatment (LOT), and initiation of physiotherapy (PT). Results: Eight patients with ET were compared to six patients with LT. Mean age was 41.4±12.5 (ET) and 49.5±6.9 (LT) years. In both groups, 50% were male with comparable BMI. Twelve patients received venovenous (VV) and two received veno-arterial (VA) ECMO. Tracheostomy post ECMO cannulation was performed in 12 [ET:6(75%);LT:6(100%)] patients, whereas in the remaining two patients, it was performed immediately after initiation of ECMO support. Average duration of ECMO support was 48.0±21.3 (ET) than 42.2±27.0 (LT) days, P=0.34. Requirement of sedatives before [ET:6.4±4.6;LT:9.3±5.3;P=0.15] and after [ET:21.6±11.9;LT:12.2±14.0;P=0.11] along with analgesics before [ET:6.3±4.9;LT:7.0±6.5;P=0.41] and after [ET:19.0±6.9;LT:14.8±15.5;P=0.28] tracheostomy was comparable. No difference was observed in the LOT during sedatives/ analgesics dosing after tracheostomy. However, the LOT before tracheostomy was significantly longer in sedatives [ET:2.9±3.1;LT:11.8±6.2, P<0.01] and analgesics [ET:2.9±2.8;LT:9.8±3.5, P<0.01], explained by the longer interval between ECMO insertion and tracheostomy in LT group. Compared to LT, number of days from ECMO insertion to first PT session was significantly shorter in ET patients [ET:13.6±5.6;LT:26.5±4.5, P<0.01]. In-hospital mortality rate was 21.4% [ET:1(13%);LT:2(33%), P=0.33] patients with comparable ICU stay [ET:56.9±18.6;LT:50.2±26.4, P=0.30] between groups. Conclusion: Although the advantages of ET to reduce the requirement of analgesics and sedatives amongst COVID19 patients supported with ECMO were like LT group, ET was associated with early initiation of PT and improved survival.

9.
ASAIO Journal ; 68:65, 2022.
Article in English | EMBASE | ID: covidwho-2032184

ABSTRACT

Objectives: The purpose of this study was to compare the outcomes of chest tubes (CT) inserted via three approaches in COVID-19 patients undergoing extracorporeal membrane oxygenation (ECMO): open thoracostomies (OT), percutaneously at bedside (PERC), and percutaneously by interventional radiology (PERC IR). Methods: We conducted an institutional review board - approved retrospective study of all COVID-19 patients who required CT placement while undergoing ECMO in our institution from February 2020 till February 2022. Insertions prior to ECMO cannulation or after decannulation, and those related to post-operative lung transplantation during ECMO were excluded from our analysis. Depending on the insertion approach, eligible CT insertion events were divided in three groups: OT, PERC and PERC IR. Data regarding patients' demographics and CT characteristics, clinical indications and associated complications for each group were collected and analyzed. Bleeding related to CT insertion was diagnosed based on requirement of blood transfusion, cessation of anticoagulation and/or ongoing bloody CT output. Results: Study criteria were met by 43 patients, with 35 (83.7%) of male sex. Mean age was 45 years. Mean BMI was 31.6 kg/m2. Forty patients (93.0%) had COVID-related acute respiratory distress syndrome as primary diagnosis. All patients but one had been receiving therapeutic anticoagulation which was held prior to CT insertion. Eighty-seven CT insertion events were recorded, of which 34 (39.1%) comprised the OT group, 20 (23.0%) the PERC group, and 33 (37.9%) the PERC IR group. Table 1 demonstrates a descriptive comparison of CT and insertion data among the three groups. Table 2 depicts the major outcomes among the three groups. Conclusions: For COVID-19 patients on ECMO, insertion of CTs percutaneously by IR is associated with significantly fewer bleeding episodes, transfusions, thoracic consults and explorations in the operating room compared to bedside OT or percutaneous CTs. One third of the percutaneously placed CTs by IR required tube upsizing in the IR suite, a rate still lower compared to the overall CT manipulations or repeat interventions required for CTs inserted via OT or percutaneously at bedside. (Table Presented).

10.
ASAIO Journal ; 68:61-62, 2022.
Article in English | EMBASE | ID: covidwho-2032179

ABSTRACT

Background: Patients with severe COVID-19 related respiratory failure may require veno-venous extracorporeal membrane oxygenation (VV ECMO). After decannulation, patients on VV ECMO have historically had high percentages of cannula-associated deep vein thrombosis (CaDVT). Due to their hypercoagulable state and prolonged course on VV ECMO, we hypothesized that patients with COVID-19 would experience a higher rate of CaDVT when compared to their non-COVID-19 counterparts. We also described the association between location and size of cannula in the development of CaDVTs. Methods: This was a single center retrospective review of patients ≥ 18 years old who were treated with VV ECMO and decannulated from January 1, 2014, to January 10, 2022. Patients who were placed on VV ECMO due to trauma and patients who were cannulated for veno-arterial ECMO were excluded. Patients were managed in a dedicated Lung Rescue Unit and anticoagulated with a heparin infusion at a goal partial thromboplastin time (aPTT) of 45-55 or 60-80 depending on the presence of clotting complications. Post-decannulation venous duplexes were performed 24 hours after decannulation and if positive for DVT, performed again in 2 weeks. Univariate and multivariate analyses were conducted to analyze our primary outcome of the development of CaDVT. Results: A total of 291 patients met our inclusion criteria: 76 COVID-19 VV ECMO patients and 215 non-COVID-19 VV ECMO patients. Decannulated COVID-19 VV ECMO patients had a significantly higher body mass index (BMI) (35.8, 32.9, p= 0.03) and length of ECMO run (hours) (660, 312, p< 0.001) than their non-COVID-19 counterparts. Most decannulated patients in both groups received post-decannulation duplexes (96%, 99%, p= 0.45). COVID-19 and non-COVID-19 patients decannulated from VV ECMO both experienced high incidences of CaDVT on initial post-decannulation ultrasound (95%, 88%, p= 0.13). COVID-19 patients were more likely to have multiple CaDVTs (32%, 11%, p< 0.001). Patients with COVID- 19 experienced a higher rate of right common femoral CaDVT (47%, 17%, p< 0.001) and a higher percentage of 25 French drainage cannula CaDVT (48%, 18%, p< 0.001). COVID-19 VV ECMO patients had a significantly higher incidence of persistent CaDVT on repeat ultrasound (78%, 56%, p= 0.03). A logistic regression was performed with all decannulated patients. Age, BMI, hours on ECMO, COVID-19 status, and size and location of ECMO cannulas did not predict the presence of DVT. Conclusion: Both COVID-19 and non-COVID-19 VV ECMO patients had high rates of CaDVTs. The utilization of VV ECMO in COVID-19 respiratory failure was associated with a higher incidence of CaDVTs on repeat ultrasound as compared to patients with non-COVID-19 related respiratory failure. Regular post-decannulation screening, treatment, and follow up imaging should be performed. Further investigation into the effect of anticoagulation strategy is needed. (Table Presented).

11.
ASAIO Journal ; 68:21, 2022.
Article in English | EMBASE | ID: covidwho-2032178

ABSTRACT

Background: SARS-CoV-2 pandemic brought new attention to blood substitutes as a potential remedy for treatment of COVID-19 associated hypoxemia and more importantly to provide relief for sagging blood banks. In fact the American Red Cross declared a national blood crisis, the worst in decades. Although commercialization attempts of 1st generation blood substitutes have been unsuccessful due to toxicity and/or poor efficacy problems, the artificial oxygen carriers' field is rapidly expanding again creating more innovative products. To attenuate the adverse effects of blood substitutes caused by intrinsic toxicity of Hb we implemented a novel concept of 'pharmacologic cross-linking' and formulated a safe and effective blood substitute - HemoTech. Methods: HemoTech consists of pure bovine Hb cross-linked intramolecularly with o-ATP and intermolecularly with oadenosine and conjugated with reduced glutathione (GSH). HemoTech cGMP manufacturing includes a novel, validated orthogonal technology platform for effective clearance of endotoxin, prions and non-enveloped and enveloped viruses. Regulatory mandated requirements have been met including CMC and GLP non-clinical pharmacology, toxicology, genotoxicity and efficacy studies. HemoTech's clinical 'proof-of-concept' was performed in children with sickle cell anemia. Results: HemoTech is formulated as a 6.5 g/dL modified Hb solution in oxy- or carbon monoxy-form, enriched with electrolytes and mannitol. The 'pharmacologic cross-linking' does not interfere with Hb respiratory function, but eradicates Hb's intrinsic toxicity and provides Hb molecules with new medicinal properties of ATP, adenosine and GSH. The results of preclinical and clinical studies indicate that HemoTech is non-toxic and works as a physiological oxygen carrier with prolonged intravascular persistence, is vasodilatory and can reduce vasoconstriction that follows hemorrhage, has antioxidant and anti-inflammatory activities, and erythropoietic properties. Conclusion: HemoTech promises to be an effective blood substitute for various clinical indications.

12.
HemaSphere ; 6:3982, 2022.
Article in English | EMBASE | ID: covidwho-2032174

ABSTRACT

Background: Rituximab is one of the second-line treatments for ITP. At present, there are few studies on low-dose rituximab, lacking of a large number of prospective and randomized trials to support the efficacy and safety of lowdose rituximab, especially in children's ITP. Influenced by COVID-19, we used two low-dose rituximab regimens before and after March 2020 for second-line treatment of children's ITP. Aims: To compare the efficacy and safety of two different regimens for low-dose rituximab of children patients with chronic /refractory ITP, so as to provide basis for clinical treatment. Methods: 83 children patients were enrolled in this study and non-randomly assigned to receive 100mg/200mg (body weight 30kg) rituximab weekly for 4 weeks (group A, 53 cases) or a single dose of 375mg / m2 rituximab (group B, 30cases). The study was follow-up for at least half a year. Results: The baseline data of group A and B were the same. For group A: Overall and complete response (OR and CR) rates were 35.8% and 15%, respectively;the side effects rate is 3.8%. In responders, the median time to response was 4 (1 -12) weeks, with a median follow-up time of 12 (6 ∼ 36) months, 6 of 19 responders (31.6%) relapsed. For group B: OR and CR rates were 36.7% and 23%, respectively;the side effects rate is 10%. In responders, the median time to response was 1 (1 ∼ 4) weeks, with a median follow-up time of 11.5 (6 ∼ 17) months, 4 of 11 responders (36.4%) relapsed. No significant difference in the OR, NR, relapse free survival and incidence of side effects was observed in patients between the two groups. Image: Summary/Conclusion: The two low-dose rituximab regimens in the treatment of ITP in children both are safe and effective;The single-agent scheme is more recommended because of easier use and not increasing safety events.

13.
HemaSphere ; 6:1350-1351, 2022.
Article in English | EMBASE | ID: covidwho-2032173

ABSTRACT

Background: The efficacy of ravulizumab (intravenous [IV] formulation;administered every 8 weeks) for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) has been demonstrated in several randomized trials (NCT02946463, NCT03056040, NCT03406507). In study 303 (NCT03748823), subcutaneous (SC) ravulizumab, administered weekly via an on-body delivery system, showed pharmacokinetic non-inferiority to IV ravulizumab in adult patients with PNH who were clinically stable on prior IV eculizumab treatment. Here, we report results from the first 1 year of SC treatment, starting at day 15 for patients who continued SC ravulizumab during the extension period (SC/SC) and day 71 for patients who switched from IV ravulizumab to SC ravulizumab (IV/SC). Aims: To evaluate the efficacy, treatment administration satisfaction and safety of SC ravulizumab through the first 1 year (day 351) of treatment in adult patients with PNH previously treated with eculizumab. Methods: Patients (≥ 18 years) with clinically stable PNH (lactate dehydrogenase [LDH] levels ≤ 1.5 × upper limit of normal [246 U/L]) and ≥ 3 months prior eculizumab treatment were enrolled in the study, which consisted of a screening period (day-1 to day-30), a 10-week randomized treatment period and an extension period of up to 172 weeks. During the randomized treatment period, patients were assigned (2:1 ratio) to receive either SC ravulizumab or IV ravulizumab;all patients received SC ravulizumab during the extension period. Efficacy endpoints included: change in LDH from baseline;incidence of breakthrough hemolysis;transfusion avoidance;and stabilized hemoglobin (avoidance of a ≥ 2 g/dL decrease in hemoglobin in the absence of transfusion). Treatment administration satisfaction was assessed via the Treatment Administration Satisfaction Questionnaire (TASQ), which has been validated in a PNH population. Safety, including adverse events (AEs), serious AEs (SAEs) and adverse device effects (ADEs), were also assessed up to the 1-year data cut-off. Results: In total, 128 patients received SC ravulizumab (SC/SC: n = 84;IV/SC: n = 44;mean [range] duration of SC treatment: 486.4 [37-709] days). Efficacy endpoints (SC/SC and IV/SC) remained stable over time through 1 year of SC ravulizumab treatment. Mean (standard deviation [SD]) percentage change in LDH from baseline to SC day 351 was 0.9% (20.5%). Breakthrough hemolysis events were infrequent: 5/128 patients (3.9%);no event was considered free C5-related. Transfusion avoidance was maintained in 83.6% of patients during SC treatment, and 79.7% achieved stabilized hemoglobin. Improvement in total TASQ score with SC ravulizumab (compared with baseline IV eculizumab) was apparent at the first post-SC treatment assessment (SC day 29) and maintained until data cut-off (Figure). The most common AEs (reported by ≥ 10% of patients, excluding ADEs related to device product issues) during SC treatment were headache (14.1%, all grade ≤ 2), COVID-19 (14.1%, one death) and pyrexia (10.9%);injection site reaction (4.7%) was the most common non-device related ADE. Treatment-emergent SAEs were experienced by 21.1% of patients through to data cut-off. Although many patients had ≥ 1 device issue ADE, full SC dose administration was achieved in 99.9% of attempts. ADE incidence decreased over time. Image: Summary/Conclusion: The SC method of administration provides an additional treatment option for patients with PNH receiving ravulizumab therapy. Patients may be switched from IV eculizumab or IV ravulizumab to SC ravulizumab without loss of efficacy.

14.
HemaSphere ; 6:1647-1648, 2022.
Article in English | EMBASE | ID: covidwho-2032170

ABSTRACT

Background: Lenalidomide (LEN) maintenance and continuous LEN-based induction therapy until disease progression have become standard of care for frontline therapy of multiple myeloma (MM). As such, an increasing number of patients (pts) in need of 2nd line therapy have LEN-refractory disease. Optimal treatment in this setting has not been rigorously assessed in randomized studies. The phase I portion of Alliance A061202 demonstrated the safety of the ixazomib-pomalidomide-dexamethasone (IXA-POM-DEX) combination for the treatment of pts with LEN and proteasome inhibitor (PI)-refractory MM. Aims: In the randomized phase II portion, we evaluated the addition of IXA to POM-DEX for PI naïve / sensitive pts progressing on LEN as part of 1st line therapy. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall response rate (ORR), depth of response, survival and safety. Methods: Pts were randomized 1:1 to IXA-POM-DEX or POM-DEX and stratified by prior bortezomib exposure, International Staging System stage (1 and 2 vs 3) and the presence of high-risk cytogenetics. POM was administered at 4 mg on days 1-21;IXA 4 mg on days 1, 8 and 15;and DEX 20 mg (>75 years (yrs)) or 40 mg (≤75 yrs) on days 1, 8, 15 and 22 of a 28-day cycle. Treatment was continued until disease progression, the emergence of unacceptable side effects or withdrawal of treatment consent. Results: 38 and 39 eligible pts were assigned to IXA-POM-DEX and POM-DEX, respectively. The median age was 66 yrs (range 41-83) and 64 yrs (range 52-85). A planned first interim analysis was conducted after 43 out of 57 required events had occurred. PFS favored the IXA-POM-DEX arm (one-sided log rank test value = 4.6345, p=0.03134 [< p-value boundary of 0.058]), yielding a hazard ratio of 0.528 (upper 90% bound = 0.777). A stratified log-rank test found that PFS was superior for the triplet after adjusting for stratification factors (one-sided stratified log rank test value = 5.8371;p=0.0157), adjusted hazard ratio 0.451 (upper 90% bound = 0.694). The ORR favored IXA-POM-DEX (63.2% vs 43.6%, p=0.0853), and the ≥very good partial response was 26.3% vs 5.1%, respectively (p=0.01). The clinical benefit rate (ORR + minimal response rate) was 73.7% and 56.4%. The most common grade 3/4 adverse events included lymphopenia, neutropenia, anemia, and fatigue in 40%, 37%, 16% and 16% of IXAPOM-DEX-treated pts and 26%, 21%, 13%, and 15% of POM-DEX-treated pts. Therapy was discontinued for disease progression in 47.4% of pts on IXA-POM-DEX and 76.9% of pts on POM-DEX and for adverse events in 7.9% and 7.7% of pts, respectively. Summary/Conclusion: The addition of IXA to the POM-DEX backbone improved the depth of response and PFS for pts relapsing on LEN as part of 1st line therapy. Hematologic toxicity was increased with the addition of IXA, but side effects were manageable. The ease of administration of this all-oral combination allowed for safer, uninterrupted treatment during the COVID pandemic. Our results should be confirmed in phase III trials but lend support for this regimen as part of 2nd line therapy for this patient population.

15.
HemaSphere ; 6:373-375, 2022.
Article in English | EMBASE | ID: covidwho-2032169

ABSTRACT

Background: Patients with red blood cell disorders (RBCD), are likely to be at increased risk of complications from SARS-Co-2 (Coid-19), but eidence in this population is scarce due to its low frequency and heterogeneous distribution. Aims: ERN-EuroBloodNet, the European Reference Network in rare hematological disorders, established a European registry to determine the impact of COVID-19 on RBCD patients and identify risk factors predicting seere outcomes. Methods: The ERN-EuroBloodNet registry was established in March 2020 by VHIR based on Redcap software in accordance with the Regulation (EU) 2016/679 on personal data. The local Research Ethics Committee confirmed that the exceptional case of the pandemic justifies the waier of informed consent. Eligible patients had confirmed RBCD and COVID-19. Data collected included demographics, diagnosis, comorbidities, treatments, and COVID-19 symptoms and management. For analysis of COVID-19 seerity, two groups were established 1) Mild: asymptomatic or mild symptoms without clinical pneumonia and 2) Seere: pneumonia requiring oxygen/respiratory support and/or admission to intensie care unit. Continuous ariables were compared using the Wilcoxon rank-sum test or Kruskall Wallis test, while categorical ariables were analyzed using the Chi-square test or Fisher's Exact test. Releant factors influencing disease or seerity were examined by the logistic regression adjusted for age. Results: As of February 25, 2022, 42 medical centers from 10 EU countries had registered 428 patients: 212 Sickle cell disease (SCD), 186 Thalassemia major and intermedia (THAL). The mean age of SCD was lower (22y) than of THAL (39.4y). Splenectomy and comorbidities were higher in THAL (51.4% and 61,3%) than in SCD (16,3% and 46,8%) (p<0.001, p=0.004). Age and BMI correlated with COVID-19 seerity, as described in the general population (p=0.003, p<0.001). Fig 1 shows age distribution and COVID-19 seerity by disease seerity groups. The mean age for seere COVID-19 was lower in patients with seere SCD (SS/SB0 s SC/SB+: 23y s 67.5y) and THAL (major s intermedia: 43.5 s 51.3y) (p<0.001). Potential risk factors such as eleated ferritin, current chelation or history of splenectomy did not confer additional risk for deeloping seere COVID-19 in any patient group. Only diabetes as a comorbidity correlated with seerity grade in SCD (p=0.01) and hypertension in THAL (p=0.009). While seere COVID-19 infection in SCD was associated with both ACS (p<0.001) and kidney failure requiring treatment (p<0.001), this was not predicted by a history of preious ACS or kidney disease in steady state. Oerall, 14,6% RBC patients needed oxygen/respiratory support, 4% were admitted to ICU with an oerall mortality rate of 1%, much lower than reported in other similar cohorts. Hospital Son Espases, Palma de Mallorca, Spain;54 Clinical Pharmacology Serice, Hospital Uniersitari Vall d'Hebron, Barcelona, Spain;55 Vall d'Hebron Institut de Recerca, Barcelona, Spain;56 Diision of Hematology and Oncology, Department of Internal Medicine, American Uniersity of Beirut Medical Center, Beirut, Lebanon;57 UOC Pediatric Hematology Oncology, Uniersity of Padoa, Padoa, Italy;58 Department of Haematology, Oxford Uniersity Hospitals NHS Foundation Trust, Oxford, United Kingdom;59 Translational Research in Child and Adolescent Cancer, Vall d'Hebron Institut de Recerca, Barcelona, Spain Background: Patients with red blood cell disorders (RBCD), are likely to be at increased risk of complications from SARS-Co-2 (Coid-19), but eidence in this population is scarce due to its low frequency and heterogeneous distribution. Aims: ERN-EuroBloodNet, the European Reference Network in rare hematological disorders, established a European registry to determine the impact of COVID-19 on RBCD patients and identify risk factors predicting seere outcomes. Methods: The ERN-EuroBloodNet registry was established in March 2020 by VHIR based on Redcap software in accordance with the Regulation (EU) 2016/679 on personal data. The local Research Ethics Committee confirm d that the exceptional case of the pandemic justifies the waier of informed consent. Eligible patients had confirmed RBCD and COVID-19. Data collected included demographics, diagnosis, comorbidities, treatments, and COVID-19 symptoms and management. For analysis of COVID-19 seerity, two groups were established 1) Mild: asymptomatic or mild symptoms without clinical pneumonia and 2) Seere: pneumonia requiring oxygen/respiratory support and/or admission to intensie care unit. Continuous ariables were compared using the Wilcoxon rank-sum test or Kruskall Wallis test, while categorical ariables were analyzed using the Chi-square test or Fisher's Exact test. Releant factors influencing disease or seerity were examined by the logistic regression adjusted for age. Results: As of February 25, 2022, 42 medical centers from 10 EU countries had registered 428 patients: 212 Sickle cell disease (SCD), 186 Thalassemia major and intermedia (THAL). The mean age of SCD was lower (22y) than of THAL (39.4y). Splenectomy and comorbidities were higher in THAL (51.4% and 61,3%) than in SCD (16,3% and 46,8%) (p<0.001, p=0.004). Age and BMI correlated with COVID-19 seerity, as described in the general population (p=0.003, p<0.001). Fig 1 shows age distribution and COVID-19 seerity by disease seerity groups. The mean age for seere COVID-19 was lower in patients with seere SCD (SS/SB0 s SC/SB+: 23y s 67.5y) and THAL (major s intermedia: 43.5 s 51.3y) (p<0.001). Potential risk factors such as eleated ferritin, current chelation or history of splenectomy did not confer additional risk for deeloping seere COVID-19 in any patient group. Only diabetes as a comorbidity correlated with seerity grade in SCD (p=0.01) and hypertension in THAL (p=0.009). While seere COVID-19 infection in SCD was associated with both ACS (p<0.001) and kidney failure requiring treatment (p<0.001), this was not predicted by a history of preious ACS or kidney disease in steady state. Oerall, 14,6% RBC patients needed oxygen/respiratory support, 4% were admitted to ICU with an oerall mortality rate of 1%, much lower than reported in other similar cohorts. Summary/Conclusion: Results obtained so far show that seere COVID-19 occurs at younger ages in more aggressie forms of SCD and THAL. Current preentie approaches focus on age oer disease seerity. Our data highlights the risk of seere COVID-19 infection in some young patients, particularly those with SS/SB0 SCD, suggesting that immunization should be considered in this pediatric group as well. Results between similar sized cohorts of RBCD patients ary between each other and those presented here, highlighting the importance of collecting all of these small cohorts together to ensure adequate statistical power so that definitie risk factors can be reliably identified and used to guide management of patients with these rare disorders in the light of the ongoing pandemic. (Figure Presented).

16.
HemaSphere ; 6:1395-1396, 2022.
Article in English | EMBASE | ID: covidwho-2032168

ABSTRACT

Background: Persistent cytopenia due to poor graft function (PGF) is a life-threatening complication in patients undergoing allogeneic HSCT (allo-HSCT). Several therapeutic approaches have been tested in this subset of patients with poor clinical results. Aims: The objective of this multicenter open-label interventional prospective phase II Novartis study (ELTION, ClinicalTrials.gov id: NCT03718533), was to analyze efficacy and safety of EPAG in patients with post-allo-HSCT poor graft function. Methods: Adult patients diagnosed with PGF (defined as severe cytopenia after day +30 post-transplant, with two or more of the following: platelets <20000/μL-mandatory-, ANC <1000/μL, hemoglobin< 10 g/dL), and full donor chimerism, were eligible to enter the trial. Study treatment consisted of EPAG. at 150 mg/day administered up to 36 weeks;dose adjustments were contemplated as per protocol on an individual basis. The primary efficacy endpoint was the overall hematologic response (partial and complete), as determined by platelet, hemoglobin and neutrophil counts by 16 weeks after the initiation of EPAG. Results: Although the aim of the study was to include 33 patients, recruitment stopped prematurely due to the difficulties for hospital visits posed during COVID-19 pandemic, and eventually only 10 patients were included. The decision for this premature termination is not related to any safety concern related to the drug. Patient characteristics are shown in the table 1 attached below. At EPAG. initiation, all 10 patients showed thrombocytopenia (<20000/μcL), 5 presented with anemia (Hgb <10 g/dL), and 4 had neutropenia (ANC <1000/μcL). Four patients discontinued EPAG before week 12 due to: disease progression/relapse (2 patients), protocol deviation (1 patient), and CMV infection (1 patient). In none of the cases, the event was related to study drug. At week 16, 4 patients (4/10, 40%) and at week 24, 5 patients, showed improvement in at least one of the 3 hematologic cell lines (partial response), respectively. Counts pre-and post-EPAG and global response in patients who stayed on treatment > 12 weeks are displayed below: Image: Summary/Conclusion: In our experience, EPAG worked well in subjects with PGF, an otherwise life-threatening condition for patients, and its use at 150 mg/day is safe and well tolerated in this setting. Our data suggest that eltrombopag might improve hematologic cell counts in patients with PGF, especially in those patients who remained on treatment at week 24, however further research is warranted to extend its applicability for larger cohorts.

17.
HemaSphere ; 6:1596-1597, 2022.
Article in English | EMBASE | ID: covidwho-2032166

ABSTRACT

Background: The bortezomib, lenalidomide, and dexamethasone (VRd) regimen is a standard of care for newly diagnosed multiple myeloma (NDMM). Belantamab mafodotin (belamaf) is a B-cell maturation antigen-binding antibody-drug conjugate that eliminates myeloma cells by a multimodal mechanism: direct cell kill and anti-myeloma tumor immune response. Belamaf has demonstrated deep and durable responses as a monotherapy in the DREAMM-2 study of patients (pts) with relapsed/refractory multiple myeloma (RRMM). Preclinical evidence of belamaf in combination with bortezomib or lenalidomide suggests enhanced anti-myeloma activity, providing rationale for this treatment combination. Aims: To evaluate the safety and tolerability of this combination in adult pts with transplant-ineligible (TI) NDMM and establish the recommended Phase III dose. Methods: DREAMM-9 (NCT04091126) is an ongoing Phase I, open-label, randomized study of belamaf + VRd. The belamaf dose cohorts currently being evaluated are Cohort 1 (1.9 mg/kg Q3/4W), Cohort 2 (1.4 mg/kg Q6/8W), Cohort 3 (1.9 mg/kg Q6/8W), Cohort 4 (1.0 mg/kg Q3/4W), and Cohort 5 (1.4 mg/kg Q3/4W). Belamaf is given with VRd Q3W until Cycle 8, and with Rd Q4W thereafter. After evaluation of safety data for Cohort 1, Cohorts 2-5 were opened in parallel and enrolled pts were randomized 1:1:1:1. Primary endpoint is safety. Secondary endpoints include efficacy, tolerability, and pharmacokinetics (PK). Results: As of data cutoff (07 Dec 2021), 64 pts were analyzed across all cohorts. Median age (range) was 73.0 (51- 88) years, 55% were male, 80% were white, 8% had extramedullary disease, 59% were International Staging System stage II or III, 20% had amp1q, and 17% had high-risk cytogenetics (≥1 of: t(4;14), t(14;16), del17p). The median duration of follow-up varied: Cohort 1 (17.4 months [mo]), Cohort 2 (5.9 mo), Cohort 3 (6.1 mo), Cohort 4 (4.7 mo), Cohort 5 (5.8 mo). Median number of belamaf cycles were: Cohort 1 (6), Cohort 2 (3), Cohort 3 (3.5), Cohort 4 (4.5), and Cohort 5 (5). Most common adverse events (AEs) across cohorts included thrombocytopenia (49%), constipation (43%), diarrhea (32%), and peripheral sensory neuropathy (30%). AEs related to study treatment were experienced by 61 (97%) pts. Belamaf-related grade 3/4 AEs occurred in 24 (38%) pts. Belamaf dose reductions occurred in 11 (18%) pts, with dose delays in 10 (16%) pts. Three pts experienced a fatal severe AE (unrelated to study treatment);2 due to COVID-19 infection, 1 due to pancreatic adenocarcinoma. Early deep responses were observed;67-92% pts achieved ≥very good partial response (VGPR) (Table), with median time to VGPR of 2.1-2.9 months across cohorts. Of pts with ≥VGPR, 17 were minimal residual disease (MRD) negative, 10 in Cohort 1. As of data cutoff, 8-75% of pts achieved best response of complete response (CR) or stringent CR (sCR). Grade 3 corneal exam findings were reported in 25-58% of pts;grade 3 visual acuity changes were reported in 21-75% of pts. No grade 4 corneal exam findings or visual acuity changes were reported in pts receiving belamaf Q6/8W, compared with 0-17% and 0-8%, respectively, in the Q3/4W cohorts. Belamaf PK profile was similar to that in pts with RRMM, accounting for baseline characteristics. Image: Summary/Conclusion: Belamaf + VRd demonstrated high response rates in pts with TI NDMM, with a high rate of MRD negativity indicating deep responses. No new safety signals were observed relative to DREAMM-2. Study is ongoing to evaluate the safety and efficacy of variable dose intensities of belamaf in combination with VRd.

18.
HemaSphere ; 6:161, 2022.
Article in English | EMBASE | ID: covidwho-2032164

ABSTRACT

Background: High-risk (HR) cytogenetic is associated with poor outcome in transplant eligible (TE) newly diagnosed myeloma multiple myeloma (NDMM). The triplet combination carfilzomib lenalidomide and dexamethasone (KRD) plus transplantation demonstrated high efficacy with faorable safety profile in TE-NDMM patients (FORTE). The addition of daratumumab (Dara) to frontline therapy also improed response rate and progression free-surial in TE-NDMM patients (CASSIOPEIA, GRIFFIN). Double transplant also improed outcome of HR TE NDMM patients (EMN02, STAMINA). Aims: The phase 2 trial 2018-04 from the Intergroupe Francophone du Myelome (IFM) is ealuating an intensie strategy with Dara-KRD induction and consolidation plus double transplant in HR TE NDMM (NCT03606577). Methods: HR MM was defined by the presence of del17p, t(4;14) and/or t(14;16). Stategy includes Dara-KRD induction (6 cycles), autologous stem cell transplantation (ASCT), Dara-KRD consolidation (4 cycles), second ASCT, Dara-lenalidomide maintenance. The primary endpoint was the feasibility of this intensie strategy. Here, we report efficacy and safety analysis of Dara-KRD induction. Results: Fifty patients with preiously untreated NDMM were included from july 2019 to march 2021 in 11 IFM centers Median age was 57 (range 38 -65). ISS stage 3 was present in 12 (24%) patients. Based on inclusion criteria, all patients had HR cytogenetic, including 17p deletion (n=20, 40%), t(4;14) (n=26, 52%) or t(14;16) (n=10,20%). Forty-six patients completed Dara-KRD induction. Two patients discontinued treatment due to seere aderse eent (COVID-19 infection, n=1 ;drug-induced hepatitis, n=1) and 2 patients discontinued treatment due to disease progression. Grade 3-4 treatment related aderse eent (>5% of patients) were neutropenia (38%), anemia (14%), thrombocytopenia (8%), infection (6%), renal insufficiency (6%) and deep-ein thrombosis (6%). Two patients (6%) experienced stem-cell collection failure. Oerall response rate was 96%, including 92 % > ery good partial response. Among 37/46 ealuable patients post induction, Minimal Residual Disease negatiity rate (NGS, 10-5) was 62%. Summary/Conclusion: Dara-KRD as induction prior ASCT is safe and allows deep responses in TE NDMM patients with high-risk cytogenetic profile. IFM 2018-04 study is ongoing and longer follow-up is needed to ealuate safety and efficacy of the oerall strategy with Dara-KRD induction and consolidation plus double transplant in this subset of HR patients.

19.
HemaSphere ; 6:1985-1987, 2022.
Article in English | EMBASE | ID: covidwho-2032163

ABSTRACT

Background: Ibrutinib (IBR) is an oral covalent Bruton tyrosine kinase inhibitor (BTKi), licensed for treatment of relapsed or refractory mantle cell lymphoma (MCL). Under NHS interim Covid-19 agreements in England, IBR with or without rituximab (R) was approved for the frontline treatment for MCL patients (pts) as a safer alternative to conventional immunochemotherapy. Although recent phase 2 studies have reported high response rates in low-risk patients for this combination in the frontline setting, randomised phase 3 and real-world data are currently lacking. Aims: To describe the real-world response rates (overall response rate (ORR), complete response (CR) rate) and toxicity profile of IBR +/-R in adult patients with previously untreated MCL. Methods: Following institutional approval, adults commencing IBR +/-R for untreated MCL under interim Covid-19 arrangements were prospectively identified by contributing centres. Hospital records were interrogated for demographic, pathology, response, toxicity and survival data. ORR/CR were assessed per local investigator according to the Lugano criteria using CT and/or PET-CT. Results: Data were available for 66 pts (72.7% male, median age 71 years, range 41-89). Baseline demographic and clinical features are summarised in Table 1. 23/66 pts (34.8%) had high-risk disease (defined as presence of TP53 mutation/deletion, blastoid or pleomorphic variant MCL, or Ki67%/MiB-1 ≥30%). IBR starting dose was 560mg in 56/62 pts (90%) and was given with R in 22/64 pts (34%). At a median follow up of 8.7 months (m) (range 0-18.6), pts had received a median of 7 cycles of IBR. 19/60 pts (32%) required a dose reduction or delay in IBR treatment. New atrial fibrillation and grade ≥3 any-cause toxicity occurred in 3/59 pts (5.8%) and 8/57 (14.0%) respectively. For the whole population and high-risk pts only, ORR was 74.4% and 64.7% respectively (p=0.2379), with a median time to response of 3.8m, coinciding with the first response assessment scan. Seven pts (16.7%), of whom 2 had highrisk disease, attained CR at a median of 6.0m. ORR for pts receiving vs not receiving R were 84.2% and 66.7% respectively (p=0.1904). IBR was discontinued in 20/61 pts (32.8%) at a median time to discontinuation of 4.1m, due to progressive disease (PD, 19.7%), toxicity (4.9%), death (3.3%;1 pt each of Covid-19 and E. coli infection), pt choice (3.3%) and other unspecified reasons (1.6%). 15/66 pts (22.7%) overall and 7/23 (30.4%) with high-risk disease progressed on IBR at a median time to PD of 4.0m. No pts underwent autologous stem cell transplantation consolidation during the study period. 12/57 pts (21.1%) received second line treatment (R-chemotherapy n=7, Nordic MCL protocol n=2, VR-CAP n=2, pirtobrutinib n=1). Response to second line treatment was CR in 4/11 pts, PD in 7/11. Of the 2 Nordic-treated patients, 1 had CR after cycle 2 and 1 PD. Fourteen pts (21.2%) died during the follow up period, due to MCL (n=11), Covid-19 (n=2) and congestive cardiac failure (n=1). Overall survival was lower for patients with high-risk disease (HR 0.55, p=0.038). Image: Summary/Conclusion: In this real-world UK cohort of pts receiving first-line IBR +/-R for MCL, including older and high-risk pts, we report high ORR rates in a similar range to the phase II Geltamo IMCL-2015 study of combination IBR-R in an exclusively low-risk population. Documented CR rates were lower, possibly reflecting a low usage of rituximab in the Covid-19 pandemic as well as CT assessment of response. Treatment was generally well tolerated, with low rates of toxicityrelated treatment discontinuation. The study is ongoing.

20.
HemaSphere ; 6:1104-1105, 2022.
Article in English | EMBASE | ID: covidwho-2032162

ABSTRACT

Background: The introduction of venetoclax into clinical practice has improved the outcome of patients with relapsed/refractory chronic lymphocytic leukemia (RR-CLL). The results of the MURANO trial published in March 2018 showed significantly longer progression-free survival (PFS) and overall survival (OS) in RR-CLL patients treated with venetoclax and rituximab (VEN-R) comparing to bendamustine and rituximab (BR) and resulted in the approval of VEN-R in the therapy of RR-CLL in the European Union and the United States. It should be noted that the results of registration studies often do not correspond with the data from real-life observations. Aims: To study the clinical efficacy and safety profile of VEN-R treatment in RR-CLL patients outside clinical trials. Methods: We performed retrospective analysis of RR-CLL patients treated with VEN-R in hematology centers of the Polish Adult Leukemia Study Group (PALG) from 2019 to 2021. Results: Clinical data of 117 RR-CLL patients treated with VEN-R were collected. Median patient age upon initiation of VEN-R therapy was 67 years (range 33 - 84 years). Seventy-two patients (61.5%) were men. Median Cumulative Illness Rating Scale (CIRS) was 6 (range 2 -16). Patients were treated with a median of 2 (range 1-9) previous lines of therapy, whereas 32 patients (27.4%) had relapsed following the first line of treatment. Overall, 25 patients (21.4%) had 17p deletion, whereas TP53 mutation was identified in 13 patients (11.1%). The median follow-up was 9.96 months (range 0.27 -29.13). The overall response rate (ORR) was 95.2%. Seventeen patients (14.5%) achieved complete remission (CR), 83 (70.9%) partial remission (PR), while in 5 patients (4.3%) disease progression was noted. In the patients with 17p deletion (n=22) or TP53 mutation (n=11), CR and PR were observed in 4 (12.1%) and 29 (87.9%) patients, respectively. The median PFS in the whole cohort was 20.8 (95% CI 18.43 -not reached) months and the median OS was not reached. In our study none of the analyzed clinico-pathological factors had significant impact on ORR, PFS and OS. During the follow-up time four (3.4%) cases of Richter transformation were diagnosed. There were 18 deaths recorded during the course of observation;3 (16.7%) due to disease progression and 7 (38.9%) due to COVID-19 infection. The others were due to infections other than SARS-CoV-2 (n=3, 16.7%) and the cause of death could not be specified in five cases (27.8%). Eighty-three patients (70.9%) remain on treatment, while treatment was discontinued in thirty-four cases (29.1%). Reasons for therapy discontinuation included patient's death (52.9%), treatment-related cytopenias (17.6%), disease progression (14.7%), Richter's transformation (11.8%), autoimmune hemolytic anemia (5.9%), diarrhea (2.9%) and infections (8.8%). In one case treatment discontinuation was due to consent withdrawal and one patient was lost to follow-up. The following adverse events of VEN-R treatment were reported during the study: all grade neutropenia (71.8% with grade 3/4 in 55.6%), anemia (51.3%), thrombocytopenia (47%), pneumonia (9.4%), neutropenic fever (6.8%), autoimmune hemolytic anemia (4.3%), immune thrombocytopenic purpura (1.7%), diarrhea (4.3%) and in one case exacerbation of heart failure was observed. Summary/Conclusion: In this retrospective analysis the outcomes of treatment with the VEN-R regimen in real-life setting were worse than those reported in the MURANO trial.

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