Roche 454 Research Articles

Novel Salvage Regimens Lead to Better Response and Survival in Relapsed Refractory Classic Hodgkin Lymphoma after Autologous Stem Cell Transplant

Novel Salvage Regimens Lead to Better Response and Survival in Relapsed Refractory Classic Hodgkin Lymphoma after Autologous Stem Cell Transplant

Cost Effectiveness Analysis of Venetoclax Plus Azacitidine Versus Azacitidine in Newly Diagnosed Adult Patients with Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy from a United States Payer Perspective

Background: The phase 3 VIALE-A trial (NCT02993523) demonstrated that venetoclax plus azacitidine (VEN+AZA) improved overall survival (OS) and led to higher remission rates compared with AZA monotherapy, in patients with newly diagnosed (ND) acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. Based on the results from VIALE-A, VEN+AZA received full United States (US) Food and Drug Administration approval in October 2020 for patients with ND AML aged ≥75 years, or who were ineligible for intensive induction chemotherapy due to comorbidities. This study aims to assess the long-term cost-effectiveness value of the VEN+AZA regimen from the VIALE-A trial from a US third-party payer perspective.Methods: A partitioned survival model with a 28-day cycle was developed to estimate costs and outcomes of treatment with VEN+AZA vs. AZA among patients with ND AML, who are ineligible for intensive chemotherapy, over a lifetime time horizon. The model included three health states: event-free survival (EFS), progressive/relapsed disease, and death. Within the EFS state, patients were further partitioned into time spent in complete remission (CR) or CR with incomplete marrow recovery (CRi), and time spent in non-CR/CRi. Efficacy inputs (OS, EFS, and CR/CRi rate) for both treatment arms were estimated using VIALE-A data. Best-fit parametric models per Akaike information criterion (AIC) were used to extrapolate OS until it reached EFS, and extrapolate EFS for each treatment until Year 5. Patients who remained in EFS after Year 5 were considered cured, and were assumed to have the same mortality as the US general population. Mean time on treatment (ToT) for both regimens was based on the time observed in VIALE-A. The costs for drug acquisition, drug administration for initial and subsequent treatments, subsequent stem cell transplant procedures, adverse events (AEs), and healthcare resource utilization (HRU) associated with each health state were obtained from the literature or publicly available data. All costs were inflated to 2021 US dollars. Utilities for each health state were estimated using EuroQol-5 dimension-5 level (EQ-5D-5L) data from VIALE-A, based on the US crosswalk value set. Information on disutilities due to Grade 3/4 AEs were obtained from the literature. Incremental cost-effectiveness ratios (ICERs) per life year (LY) and quality-adjusted life year (QALY) gained were estimated. Deterministic sensitivity analyses (DSA), scenario analyses and probabilistic sensitivity analyses (PSA) were performed to assess the robustness of the results.Results: Over a lifetime time horizon, compared with AZA, VEN+AZA was associated with an increase of 1.89 LYs (1.10 vs. 2.99, respectively) and 1.45 QALYs (0.84 vs. 2.30, respectively). Patients in the VEN+AZA arm incurred higher total costs ($250,486 vs. $110,034 for patients in the AZA arm). The ICER for VEN+AZA vs. AZA was estimated to be $74,141 per LY gained, and $96,579 per QALY gained. Results from the DSA and scenario analyses supported the base-case findings, with ICERs ranging from $60,922 to $138,554 per QALY gained. The results were most sensitive to alternative approaches for ToT estimation, subsequent treatment HRU costs, cure time point, and the extrapolation approach for EFS. Results from PSA showed that compared with AZA, VEN+AZA was cost-effective in 99.9% of cases at a willingness-to-pay (WTP) threshold of $150,000.Conclusions: Compared with AZA monotherapy, VEN+AZA results in a favorable ICER of $96,579 per QALY gained over a lifetime time horizon. The base-case results suggest that, compared with AZA, VEN+AZA is a cost-effective strategy based on a WTP threshold of $150,000 per QALY gained. Sensitivity analyses support the base-case results. Thus, VEN+AZA offers a cost-effective strategy in the treatment of patients with ND AML who are ineligible for intensive chemotherapy from a US third-party payer perspective. DisclosuresPratz: Agios: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding; University of Pennsylvania: Current Employment; BMS: Consultancy, Honoraria; Novartis: Consultancy; Astellas: Consultancy, Honoraria, Research Funding; Cellgene: Consultancy, Honoraria; Millenium: Research Funding. Chai: Analysis Group, Inc.: Consultancy, Current Employment; Genentech, Inc.: Consultancy. Yin: Analysis Group, Inc.: Consultancy, Current Employment; Genentech, Inc.: Consultancy. Nie: Analysis Group, Inc.: Consultancy, Current Employment; Genentech, Inc.: Consultancy. Montez: Genentech, Inc: Current Employment, Other: May hold equity. Iantuono: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Downs: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Ma: Genentech, Inc.: Current Employment, Other: May hold equity.

Risk of Hospitalization for Vaso-Occlusive Episode in Patients with Sickle Cell Disease after out-Patient Exposure to Systemic Corticosteroids

▪Introduction : Sickle cell disease (SCD) is an inherited disorder which affects 300,000 newborns per year. Vaso-occlusive episodes (VOEs) cause an important morbi-mortality and a decreased quality of life in patients with SCD. Some risk factors of VOE are well known, like infection, cold exposure, stress, pulmonary diseases and dehydration. Exposure to systemic corticosteroids has been suspected to increase the occurrence of VOEs in few case reports or series. However, no comparative study has been conducted to demonstrate this risk which is still debated, resulting in discrepancies among guidelines on SCD management. This study aimed to assess the risk of hospitalization for VOE associated with out-hospital exposure to systemic corticosteroids in patients with SCD in France.Methods : Data source was the French national health insurance system database, named SNDS (Système National des Données de Santé) between 2010 and 2018. The SNDS links sociodemographic, out- and in-hospital data for the entire French population (>66 million inhabitants). The study population consisted in all patients with SCD with at least one hospitalization for VOE during the study period, identified with a primary discharge diagnosis of VOE (D57.0 code of the international classification of disease, 10 th version; positive predictive value: 98.6%). All genotypes (homozygous SS-SCD and double-heterozygous SCD) were included. Because we assessed out-hospital exposure to corticosteroids, patients hospitalized during the three months before the first VOE were excluded. We performed a case-case-time-control study (Figure 1). This self-controlled design results in self-adjustment for time-independent confounders, including genotype. The outcome was the first hospitalization for VOE. The exposure to oral and injectable corticosteroids, identified using out-hospital reimbursement data, was assessed during a case period (28 days before the outcome) compared to the exposure during a control period (28 days, starting 84 days before the outcome). The same comparison was made among future cases (matched patients hospitalized for VOE the year after the given case), in order to adjust for the trend of exposure to corticosteroids (calendar variations of corticosteroid exposure).Results : Overall, 5,151 cases of VOEs were included in the main analysis. Median age at first VOE was 16.9 years; 317 (6.2%) patients were exposed to corticosteroids during the case period. In the main analysis, corticosteroid exposure was significantly associated with the occurrence of hospitalizations for VOEs: adjusted Odds Ratio (aOR): 3.81, 95% confidence interval (95% CI): 2.44 to 5.61. In patients exposed to hydroxyurea, the aOR was 2.61, 95% CI: 1.07 to 6.39, compared with an aOR of 4.00, 95% CI: 2.53 to 6.30 in unexposed patients. In the subgroup analysis by age, the aOR was 2.81, 95% CI: 1.49 to 5.30 in children, and 4.45, 95% CI: 2.37 to 8.37 in adults. The results were consistent in all sensitivity analyses.Conclusion : This study showed an association between outpatient exposure to systemic corticosteroids with an increased risk of hospitalization for VOE, in both adults and children. Hydroxyurea may reduce this risk in adults. [Display omitted] DisclosuresBartolucci: GBT: Consultancy; Emmaus: Consultancy; Fabre Foundation: Research Funding; AGIOS: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Jazz Pharma: Other: Lecture fees; INNOVHEM: Other: Co-founder; Bluebird: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy; Hemanext: Consultancy; Addmedica: Consultancy, Other: Lecture fees, Research Funding. Moulis: Argenx: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Obinutuzumab Short Duration Infusion Is Preferred By Healthcare Providers and Has Minimal Impact on Patient-Reported Symptoms Among Patients with Untreated, Advanced Follicular Lymphoma

Obinutuzumab Short Duration Infusion Is Preferred By Healthcare Providers and Has Minimal Impact on Patient-Reported Symptoms Among Patients with Untreated, Advanced Follicular Lymphoma

Real-World Experience of Patients with Sickle Cell Disease Treated with Voxelotor: A Multicenter, Retrospective Study

Real-World Experience of Patients with Sickle Cell Disease Treated with Voxelotor: A Multicenter, Retrospective Study

A Comparison of Clinical Outcomes from Updated Zuma-5 (Axicabtagene Ciloleucel) and the International Scholar-5 External Control Cohort in Relapsed/Refractory Follicular Lymphoma (R/R FL)

A Comparison of Clinical Outcomes from Updated Zuma-5 (Axicabtagene Ciloleucel) and the International Scholar-5 External Control Cohort in Relapsed/Refractory Follicular Lymphoma (R/R FL)

Ex Vivo Evaluation of the Effect of Plasma-Derived Factor VIII/Von Willebrand Factor in Patients with Severe Hemophilia_A on Prophylaxis with Emicizumab By Thrombin Generation Assay

Introduction: Hemophilia A (HA) patients under emicizumab prophylaxis treatment may require the concomitant use of procoagulant factors for breakthrough bleedings or immune tolerance induction. Thromboembolic events have been described with the concomitant use of emicizumab and activated prothrombin complex concentrate (aPCC), but not with recombinant activated factor VII (rFVIIa). Previous studies showed that the in vitro combination of emicizumab and plasma-derived Factor VIII/Von Willebrand Factor (pdFVIII/VWF) had a non-additive effect on thrombin generation (TG)(Bravo M-I, et al J Thromb Haemost. 2020;18:1934-39). The aim of this study was to evaluate the TG resulting from ex vivo combination of plasma samples from HA patients treated with emicizumab, with a pdFVIII/VWF concentrate (Fanhdi ®, Grifols).Methods: Twelve adult patients with severe HA without inhibitors on prophylaxis with emicizumab and nine healthy controls were included in the study. Blood samples were drawn in citrate plus corn trypsin inhibitor tubes. Then, platelet poor plasma (PPP) was collected for the TG assay, which measures the whole kinetics of TG. Thrombin peak (TP) and endogenous thrombin potential (ETP) were calculated using calibrated automated thrombogram (Thrombinoscope ™ software, Stago) after in vitro activation of coagulation by trigger solution, PPP Reagent LOW TM (4 μM phospholipids/1 pM tissue factor), fluorogenic substrate and CaCl 2 (FLUKAkit TM) reagents (Diagnostica Stago). Fluorescence was read in a Fluoroskan Ascent reader (Thermo) equipped with a 390/460 filter set. Samples were spiked with increasing concentrations of pdFVIII/VWF (10 to 400 IU/dL), rFVIIa (0.9 µg/mL) or aPCC (0.5 U/mL).Results: TG from healthy control samples was measured to establish TP and ETP normal ranges. TP and ETP results obtained from HA plasma with emicizumab were lower than in healthy controls. The addition of pdFVIII/VWF as of 25 IU/kg (prophylaxis dose in HA w/o inhibitors) to samples from HA patients concomitantly treated with emicizumab restored TP and ETP levels within healthy controls normal range (Table 1). Increasing ex vivo concentrations of pdFVIII/VWF maintained TP and ETP similar to healthy controls. The highest concentration of concomitant treatment with pdFVIII/VWF (200 IU/kg) and emicizumab did not result in excessive TP and, importantly, ETP levels were always within the normal range. The combination with the bypassing agent rFVIIa moderately increased TP and ETP values up to normal range. However, when HA plasma was spiked with aPCC in the presence of emicizumab, TP and ETP dramatically increased above normal range resulting in a synergistic procoagulant profile.Conclusions: The concomitant use of pdFVIII/VWF in patients with prophylaxis with emicizumab did not trigger a multiplying effect on TG. These results were aligned with previous in vitro data and suggested the low risk of overdose and thrombotic events of concomitant treatment emicizumab with the pdFVIII/VWF concentrate in HA patients. [Display omitted] DisclosuresBravo: Grifols: Current Employment, Other: Grifols is a manufacturer of the pdFVIII/VWF concentrate, Fanhdi®. Raventós: Grifols: Current Employment, Other: Grifols is a manufacturer of the pdFVIII/VWF concentrate, Fanhdi®. Pérez: Grifols: Current Employment, Other: Grifols is a manufacturer of the pdFVIII/VWF concentrate, Fanhdi®. Alvarez Román: Grifols: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novo-Nordisk: Consultancy, Honoraria, Research Funding; Sobi: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; CSL-Behring: Consultancy, Honoraria, Research Funding; Biomarin: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Butta: CSL-Behring: Research Funding; Roche: Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Novo-Nordisk: Speakers Bureau. Jiménez-Yuste: Bayer: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; BioMarin: Consultancy; Sobi: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding. Costa: Grifols: Current Employment, Other: Grifols is a manufacturer of the pdFVIII/VWF concentrate, Fanhdi®. Willis: Grifols: Current Employment, Other: Grifols is a manufacturer of the pdFVIII/VWF concentrate, Fanhdi®.

A Retrospective Multicenter Case Study Evaluating the Characteristics, Management and Outcome of Acquired Amegakaryocytic Thrombocytopenia

A Retrospective Multicenter Case Study Evaluating the Characteristics, Management and Outcome of Acquired Amegakaryocytic Thrombocytopenia

Immune-Depleted Tumor Microenvironment Signature Is Associated with BTK Inhibitor Resistance in Mantle Cell Lymphoma

Immune-Depleted Tumor Microenvironment Signature Is Associated with BTK Inhibitor Resistance in Mantle Cell Lymphoma

Cognitive Profile of Adults with Sickle Cell Disease - Cluster Analysis

Background: Published literature on cognitive functioning in adults with sickle cell disease (SCD) is sparse when compared to children. A few reports describe deficits in processing speed and executive functioning. Some studies suggest that these deficits are more severe in patients with silent cerebral infarcts (SCI). Even in the absence of radiological evidence of ischemic injury, some cognitive deficits have been depicted in adults . We hypothesize that in SCD adults, the cognitive profile varies with the presence of ischemic injury (SCI or overt stroke). The aims of this study were 1) to describe the neuropsychological profiles of SCD adults, and 2) to characterize clusters of patients with similar cognitive profiles.Methods: We conducted a retrospective analysis of all consecutive SCD adults who underwent comprehensive neuropsychological assessment during routine care at the UMGGR clinic at Henri Mondor Hospital, Créteil (France), between January 2017 and April 2021. The Montreal Cognitive Assessment (MoCA) and Hospital Anxiety and Depression Scale (HADS) were used for cognitive disorder, anxiety and depression screening, respectively. The cognitive battery combined standardized neuropsychological tests with established clinical utility and validity. Educational attainment was scored based on the number of years of schooling for the highest completed diploma. Principal component analysis was performed. ANOVA was used to compare patients' characteristics between clusters.Results: 80 patients, median age 36.5 [range 19-63] years were included. 40 (50.0%) were male. Genotype distribution was 62 patients (77.5%) with SS/Sbeta 0, 12 (15.0%) with SC and 6 (7.5%) with Sbeta +. On Principal Component Analysis, a 5-factor model presented the best fit (Bartlett's sphericity test (χ²(171)=1174; p<0.001)), explaining 71.8% of the variance in neuropsychological scores. The first factor encompassed tests specifically assessing visual attention/visual organization (right hemisphere). The second included tests for mental/cognitive control (frontal lobe), the third tests of selective inhibition/attention (fronto-parietal), the fourth tests for language/memory (left temporal lobe) and the last referred to shifting skill (sub-cortical loop). On hierarchical classification, 3 different clusters emerged: 32 patients in cluster 1, 32 in cluster 2 and 16 in cluster 3. Cluster 1 had a lower mean educational level (F(2,77) = 15,65; p<0,001). Cluster 1 showed the lowest mean MoCA score (20.0/30.0), relative to cluster 2 and 3 (24.6 and 26.4; p<0.001 and p<0.001, respectively). Cluster 1 patients presented deficits on all five factors. Cluster 2 patients compared to cluster 3 were altered in 4 factors (factors 1-4), but to a lesser extent than cluster 1. Processing speed was slower and some frontal-executive deficits were present in cluster 2 compared to cluster 3. There was no statistical difference between clusters in terms of ethnic origins. There was a trend for the presence of more cerebral vasculopathy in cluster 1 (chi2; p=0.06). Regarding stroke, 70% occurred during childhood in cluster 1, whereas 70% during adulthood in cluster 2, and 100% during adulthood in cluster 3.Conclusions: Overall, these results suggest at least three different cognitive profiles in adults with SCD: 1) few or no cognitive deficits (cluster 3), 2) some cognitive impairment with a sub-cortical cognitive profile (cluster 2) and 3) more global cognitive impairment with cortical/sub-cortical profile and specific deficits of memory, language and constructional praxis, depending on the location of prior overt neurological events (cluster 1). To reduce the long-term cognitive morbidity of SCD, patients can be identified by their distinct cognitive profiles and neurorehabilitation tailored to their unique profile should be applied. The large proportion of childhood stroke in patients with global cognitive impairment in contrast with majority of those with milder to no cognitive impairment having had their stroke in adulthood emphasize the crucial importance of preventing early childhood stroke and implementing early neurorehabilitation. DisclosuresForté: Canadian Hematology Society: Research Funding; Pfizer: Research Funding; Novartis: Honoraria. Kuo: Pfizer: Consultancy, Research Funding; Bluebird Bio: Consultancy; Novartis: Consultancy, Honoraria; Apellis: Consultancy; Alexion: Consultancy, Honoraria; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Bioverativ: Membership on an entity's Board of Directors or advisory committees. Bartolucci: Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; Emmaus: Consultancy; GBT: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; Hemanext: Consultancy; INNOVHEM: Other: Co-founder; Bluebird: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Fabre Foundation: Research Funding; Addmedica: Consultancy, Other: Lecture fees, Research Funding.

Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Follicular Lymphoma: Primary Analysis from a Phase 2 Study (CITADEL-203)

Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Follicular Lymphoma: Primary Analysis from a Phase 2 Study (CITADEL-203)

Age-Associated Decline in Blood Parameters in Individuals with Sickle Cell Disease

IntroductionIndividuals with sickle cell disease (SCD) in resource-rich countries are now living longer due to the implementation of newborn screening, use of prophylactic penicillin, and introduction of hydroxyurea. The impact of SCD on the bone marrow and peripheral blood counts as individuals with SCD age is not well described in the hydroxyurea era. As a result of increased red blood cell (RBC) turnover due to hemolysis in SCD, potential ineffective erythropoiesis, and well-described systemic inflammatory processes, the increased stress in the bone marrow may manifest as decreased peripheral blood cell counts over time in a during an aging process unique to those with SCD.ObjectiveThe objective was to model routine clinical blood measurements (n=5,328) with a longitudinal cohort of 447 patients, resulting in models of circulating blood counts as a potential marker of bone marrow function across the lifespan in adults with SCD. Our working hypothesis was that increasing age would be associated with decreases in certain blood counts, with trends modified by SCD genotype severity.MethodsIn this large, single institution retrospective cohort study, we analyzed blood count measurements from adults with SCD. We used an accelerated longitudinal cohort design to examine changes in white blood cell count (WBC), hemoglobin (HGB), absolute reticulocyte count (ARC), and platelet count over time. Genotypes were grouped as severe (HbSS or HbSβ 0-thalassemia; n=301), non-severe (HbSC or HbSβ +-thalassemia; n=136), or other (n=10). For HGB and ARC, we adjusted for estimated glomerular filtration rate (eGFR) and serum creatinine.ResultsPatients ranged in age at enrollment from 18 to 84 (M = 31.9, SD=12.9), with median follow-up time of 3.6 years and a median of 6 measurements per patient. Overall, HGB and ARC decreased across the lifespan; however, trends were moderated by genotype. Compared to individuals with non-severe genotypes, those with the severe genotypes had consistently lower HGB levels that did not differ by age. For ARC, the severe genotypes had higher levels in young adulthood, which slowly decreased with age. WBC also decreased with age for this group. In contrast, individuals with the non-severe genotype showed an increase in WBC by age. Platelet counts decreased with increasing age for those with the severe genotype while those with non-severe genotypes showed an increase with age.ConclusionSevere SCD genotypes are associated with decreases in HGB, ARC, WBC, and platelet count by age. For HGB and ARC, these declines are significantly attenuated by renal function, suggesting that such declines are largely related to worsening renal function with age. However, an intrinsic bone marrow contribution to this aging process should also be explored in future studies. Decreases in WBC and platelet count with time, observed in the severe genotypes, support the presence of pathological processes of bone marrow dysfunction that may worsen with age. A possible etiology of the increasing bone marrow dysfunction in SCD may be a result of bone marrow exhaustion or cellular senescence. Prospective studies to explore contributors to reduced blood counts during the aging process in individuals with SCD are needed. We are actively exploring potential biomarkers associated with this process. [Display omitted] DisclosuresCarden: Forma Therapeutics: Current Employment. Derebail: Novartis: Consultancy; UpToDate: Patents & Royalties; Travere Therapeutics: Consultancy; Bayer: Consultancy. Ataga: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy; Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Real World Treatment Patterns and Outcomes of Venetoclax (Ven) and Hypomethylating Agents (HMA) in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) in the United States

Real World Treatment Patterns and Outcomes of Venetoclax (Ven) and Hypomethylating Agents (HMA) in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) in the United States

Causes and Circumstances of Death: Analysis in 266 Sickle Cell Adult Patients

IntroductionSickle cell disease is a genetic disease with acute and chronic complications. Pediatric mortality has decreased in recent decades with the introduction of systematic antibiotic therapy, preventive management of cerebral vasculopathy and therapeutic education of families. However, in the absence of cohort follow-up at birth, life expectancy, which is a different concept from age at death, cannot be assessed.In this retrospective, monocentric study, we describe causes and circumstances of death, acute chronic complications, long-term treatments and baseline biology of these patients. It seems important to analyze the risks of morbidity and mortality in order to decide on the necessary preventive measures.Material and method:Records of patients deceased between 2000 and 2020, from the national referral center (Henri Mondor Hospital), were retrospectively reviewed. The referral center follows 3500 patients. All deaths reported to the hospital, by families, other hospitals and health professionals were retrieved from computerized records. Deaths published by the INSEE (National Institute of Statistical and Economical study) from 2000 to December 2020 were accessible and compared with our databases to identify all our deceased patients. All patients with a medical record in our center were included for the study. Patients who had never visited our center were excluded.Results:During this period 226 patients including 128 women and 138 men are recorded. Genotypes for these patients were 204(76%) SS, 41 (15%) SC, 14(5%) Sβ°thalassemia and 7 (2%) Sβ+thalassemia. The median age at death was 41 years with an IQR [32-51]. 186 (70%) patients were hospitalized, 129 (70%) of whom were admitted to intensive care. 36 (13%) patients died at home, including 15 with opioid addiction and 5 patients with psychiatric pathology, and 4 patients on dialysis. This information was not available for 44 (16%) patients.The causes of death were vaso-occlusive complications with multivisceral failure in 44 cases, 42 sepsis, among which there were 11 renal failures, 9 of which were dialyzed. 5 patients died of COVID 19. Cerebral hemorrhage and neurological accident occurred in 22 cases, 4 of which were known to have macrovasculopathy. 25 patients died of a direct complication of renal failure, of which 17 were dialysed, 8 pre-dialysed and 3 transplanted. Acute liver failure in 16 cases, 10 precapillary pulmonary hypertension, 14 DHTR, 10 end-stage heart failure were noted. Two road accidents, 2 suicides, 1 dementia are repoted. For 51 cases, there was no information on the cause or circumstance of death. The causes of death according to genotype is on Table 1.Concerning the chronic complications, 94/266 (35%) patients had significant chronic organ damage. Sixteen patients had required renal or liver transplantation in their history. End-stage organ damage was frequent, 42 had end-stage renal failure, 21 had major liver failure, of which five were transplanted and 16 were awaiting transplantation. Twenty-one patients had known heart failure, 10 of which were associated with end-stage renal disease. Ten patients were followed for significant precapillary pulmonary hypertension.Transfusion difficulties due to a history of DHTR were found for 33 patients. Fourteen patients had an opioid addiction. Nine patients were pregnant and nine had received corticosteroids.Discussion:Causes of death have changed and chronic organ failure is the leading cause of death, especially in patients with kidney, liver and heart disease. This study does not calculate life expectancy, but there was an increase in age at death of about 1/4 of the patients who were between 51 and 81 years old.The management of sickle cell disease has progressed in recent years and new therapies are being proposed. Prevention of the development of these complications is one of the new challenges, especially for renal disease, which is associated with premature mortality. DHTR and cerebral hemorrhage, Covid-19 are new entities and DHTR was probably underdiagnosed in previous publications. Pregnancy remains a period at risk, for which surveillance should be reinforced. The analysis is ongoing and correlations are currently being investigated between different parameters to find risk factors for mortality. [Display omitted] DisclosuresHabibi: Novartis: Consultancy, Honoraria; bluebird bio: Consultancy, Honoraria, Research Funding. Audard: Addmedica: Consultancy. Michel: Novartis: Consultancy; Amgen: Consultancy; Rigel: Honoraria; Alexion: Honoraria; UCB: Honoraria; Argenx: Honoraria. Galactéros: Addmedica: Membership on an entity's Board of Directors or advisory committees. Bartolucci: INNOVHEM: Other: Co-founder; Bluebird: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy; GBT: Consultancy; Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; Hemanext: Consultancy; Emmaus: Consultancy; Fabre Foundation: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Addmedica: Consultancy, Other: Lecture fees, Research Funding.

Potential Utility of Circulating Tumor DNA Monitoring in Primary Mediastinal B-Cell Lymphoma Treated with R-DA-EPOCH

Potential Utility of Circulating Tumor DNA Monitoring in Primary Mediastinal B-Cell Lymphoma Treated with R-DA-EPOCH

Recombinant Porcine Factor VIII in Patients with Congenital Hemophilia a with Inhibitors Undergoing Surgery: Phase 3, Multicenter, Single Arm, Open-Label Study

Recombinant Porcine Factor VIII in Patients with Congenital Hemophilia a with Inhibitors Undergoing Surgery: Phase 3, Multicenter, Single Arm, Open-Label Study

Development of Novel CAR Therapies for Diffuse Large B-Cell Lymphoma Using Genome-Wide Overexpression Screens

Despite recent therapeutic advances in the management of non-Hodgkin lymphoma (NHL), up to 50% of patients with diffuse large B-cell lymphoma (DLBCL) relapse after first line therapy, and for DLBCL patients who relapse within 12 months after subsequent stem cell transplant (SCT), the median overall survival (OS) is 6.3 months. Recently, chimeric antigen receptor (CAR) T-cell therapy has shown remarkable activity in relapsed DLBCL with complete response (CR) rate of 40% and 54% for the two of the FDA-approved CAR T-cell products, tisagenlecleucel and axicabtagene ciloleucel, respectively. However, at a median follow-up of 18 months, only 36% of patients treated with tisagenlecleucel remained in CR; with longer follow-up for axicabtagene ciloleucel the median progression free survival (PFS) was 5.9 months. Immune escape and immune evasion are primary mechanisms of CAR-T resistance; clearly improvements are needed to increase response rate and cure.While CRISPR-based loss-of-function screens have shown promise for high-throughput identification of genes that modulate T-cell response, these methods have been limited thus far to negative regulators of T-cell functions, and raise safety concerns due to the permanent nature of genome modification. Here we identify positive T-cell regulators via overexpression of ~12,000 barcoded human open reading frames (ORFs). Using this genome-scale ORF screen, we found modulator genes which increased primary human CD4+ and CD8+ T-cell proliferation, including activation markers like CD25 and CD40L, and secretion of key cytokines like interleukin-2 and interferon-gamma. In addition, we developed a single-cell genomics method (OverCITE-seq) for high-throughput quantification of the transcriptome and surface proteome in ORF-engineered T-cells.The top-ranked ORF, lymphotoxin beta receptor (LTBR), is typically expressed in a subset of myeloid cells but absent in lymphocytes. When expressed in T-cells, LTBR induces a profound transcriptional remodelling, resulting in increased resistance to exhaustion and activation-induced apoptosis, as well as upregulation of a plethora of proinflammatory cytokines, co-stimulatory molecules and antigen presentation machinery. In order to investigate the mechanism of action of LTBR, we developed an epistasis assay which allows for simultaneous gene knockout and LTBR overexpression in primary T cells. Thus, LTBR appears to induce both canonical and non-canonical NFkB pathways - but the phenotype observed in T cells is dependent only on the former.Finally, we co-expressed several top-ranked genes, including LTBR, with FDA approved CD19-targeting CARs utilizing either 4-1BB or CD28 co-stimulatory domains. In line with previous results, co-expression of top-ranked ORFs increased proinflammatory cytokine secretion and cytotoxicity against CD19+ positive cancer cell lines. This functional improvement was also observed when top-ranked ORFs and CARs were delivered to T cells isolated from DLBCL patients as shown in Figure 1. Our results provide several strategies for improving next generation CAR T-cell therapies via induction of new synthetic cell programs which may optimize immune activation and enhance the efficacy of these important therapies, a high priority for patients with relapsed and refractory DLBCL and other lymphomas. [Display omitted] DisclosuresMimitou: Immunai: Current Employment. Smibert: Immunai: Current Employment. Diefenbach: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; IMab: Research Funding; Gilead: Current equity holder in publicly-traded company; Celgene: Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; MEI: Consultancy, Research Funding; Perlmutter Cancer Center at NYU Langone Health: Current Employment; Incyte: Research Funding; Trillium: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding. Sanjana: Qiagen: Consultancy; Vertex: Consultancy.

Eptacog Beta Efficacy in Children and Adolescents with Hemophilia A or B and Inhibitors: Subset Analysis Suggests Improved Caregiver Capacity to Assess Bleeding Episode Resolution with Subject Age

Eptacog Beta Efficacy in Children and Adolescents with Hemophilia A or B and Inhibitors: Subset Analysis Suggests Improved Caregiver Capacity to Assess Bleeding Episode Resolution with Subject Age

Prediction of Early Mortality with Non-Intensive Acute Myeloid Leukemia (AML) Therapies: Analysis of 1336 Patients from MRC/NCRI and SWOG

Prediction of Early Mortality with Non-Intensive Acute Myeloid Leukemia (AML) Therapies: Analysis of 1336 Patients from MRC/NCRI and SWOG

Outcome of Patients with T- Cell Histiocyte Rich B Cell Lymphoma: Single Institution Series

Outcome of Patients with T- Cell Histiocyte Rich B Cell Lymphoma: Single Institution Series