Characteristics and Outcome of Adults with Severe Autoimmune Hemolytic Anemia Admitted in Intensive Care Unit: Results from a Large French Observational Study

Abstract Introduction : Adult' autoimmune hemolytic anemia (AIHA) can be life-threatening with an overall mortality rate of 8-10% which can rise up to 30% for patients admitted in intensive care unit (ICU). The factors associated with the need of management in ICU are partially unknown as only few data are available in the literature. To better describe the baseline characteristics and outcome of severe adult'AIHA admitted in ICU and to identify some prognostic factors, an observational multicentre study was set up by the French reference center of adult' immune cytopenias. Patients and Methods : This was an observational retrospective multicentre study. Patients had to fulfill the following inclusion criteria : 1) Age ≥ 18 years at time of AIHA onset ; 2) Definite diagnosis of primary or secondary warm (wAIHA), cold (cAIHA) or mixed AIHA ; 3) At least one admission in ICU specifically for the management of AIHA. Patients with AIHA admitted in ICU for another reason than the severity of AIHA were excluded. Patients' baseline characteristics at time of admission in ICU were recorded by means of a standardized form including the Charlson comorbidity score, the Knaus score, the Sequential Organ Failure Assessment (SOFA) and the Simplified Acute Physiology Score (SAPS II). Categorical variables were expressed as number (percentage) and quantitative variable as median [interquartile range]. To identify factors associated with death in ICU or after 1 year of follow-up, patients' characteristics were compared using usual tests. In order to identify some parameters associated with the risk of admission in ICU, the main characteristics of the patients were compared to those of controls (1 to 2 ratio) diagnosed with AIHA and followed over the same period who were never admitted in ICU. Univariate logistic regressions analyses were performed followed by a multivariate logistic regression using a backward stepwise selection procedure. A p-value <0.05 was considered as statistically significant. Results : In total, 62 patients (42% of females) from 11 centers fulfilling the inclusion criteria were included for a total of 69 admissions in ICU (see table for baseline characteristics). Of note, 57/62 patients (92%) had a low (< 121) bone marrow reticulocytes index (BMRI) reflecting an impaired erythropoiesis. The mortality rate in ICU was 13%; 3 patients died from massive pulmonary embolism. Compared to the 54 survivors the 8 patients who died in ICU had: a higher CRP level (p value = 0.011); a higher need for transfusion (median number of packed red cells was 12 versus 4, p value = 0.008); higher SOFA and IGS scores (p value = 0.006); a higher number of organ failures on admission (p value < 0.001), thrombotic events (p value = 0.024) and sepsis during the stay in ICU (p value = 0.019). Among the survivors, 9/49 (5 lost of follow-up) eventually died within a year after the admission in ICU leading to an overall mortality rate of 30% at 1 year. For the management of AIHA in ICU, 56 patients (90%) were transfused (median number of packed red cells = 4 [2-7]); recombinant Epo was administered to 14 patients (22.5%) and 5 patients (8%) had plasma exchange. In ICU, 58 patients (95%) were treated with corticosteroids, 29 (46%) received at least one other treatment line including mostly : rituximab (n = 22), intravenous immunoglobulin (n = 10), iv cyclophosphamide (n = 5), cyclosporin (n = 3). Other treatment lines including chemotherapy-based regimen (n=8) were given afterwards. The characteristics of the 62 patients were compared to those of 138 controls with AIHA who were never admitted in ICU. In univariate analyses, younger age, Evans' syndrome, Hb level < 6 g/dl; reticulocytes count < 100 x 10 9/L, BMRI <121 and high bilirubin level were significantly associated with an admission in ICU. In multivariate analysis, a low Hb level and a high bilirubin level were the only parameters that were significantly associated with the risk of admission in ICU Conclusion : Based on this retrospective study, the mortality rate of adult patients admitted in ICU for AIHA was lower than expected (13%) but the 1 year mortality rate in this population of patients rose up to 30%. Patients with AIHA and a Hb level < 6g/dl, a high bilirubin level and/or an inadequate reticulocytes count must be treated promptly and monitored closely beyond the initial phase of the disease in order to reduce the mortality rate. The treatment of severe refractory cases is not consensual and should be harmonized. Figure 1 Figure 1. Disclosures Comont: Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Riviere: Octapharma: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Haioun: Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Miltenyi: Honoraria, Research Funding. Godeau: Amgen: Consultancy; Sobi: Consultancy; Novartis: Consultancy; Grifols: Consultancy. Michel: Amgen: Consultancy; Rigel: Honoraria; Alexion: Honoraria; UCB: Honoraria; Argenx: Honoraria; Novartis: Consultancy. OffLabel Disclosure: rituximab is commonly used off-label as a second line for adult' AIHA

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Use of Thymoglobulin for Graft Versus Host Disease Prophylaxis Does Not Increase the Incidence of Clostridium Difficile Infection in Recipients of Allogeneic Stem Cell Transplant Recipients

Blood ◽

10.1182/blood.v126.23.5447.5447 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5447-5447

Author(s):

Divaya Bhutani ◽

Paul Naylor ◽

Charles Jaiyeoba ◽

Joseph P. Uberti ◽

Voravit Ratanatharathorn ◽

...

Keyword(s):

Research Funding ◽

P Value ◽

Transplant Recipients ◽

Graft Versus Host ◽

Gvhd Prophylaxis ◽

Group 3 ◽

Equity Ownership ◽

Baseline Characteristics ◽

Group 2

Abstract Introduction: Clostridium difficile (C.diff) colitis (CDI) continues to be a common complication in recipients of allogeneic stem cell transplantation (AlloSCT). Multiple risk factors were associated with CDI in this patient population including prior CDI, antibiotic prophylaxis and therapy, acute graft versus host disease (aGVHD), etc. Our aim in this study was to evaluate the effect of thymoglobulin used in GVHD prophylaxis on the incidence of CDI in patients undergoing AlloSCT. Methods: We studied 3 consecutive cohorts of AlloSCT recipients. Group1- related donor AlloSCT without thymoglobulin (N=100, transplanted 3/2010-12/2013); group 2 - unrelated donor AlloSCT with thymoglobulin (N=110, transplanted 4/2012-12/2013); and group 3 - unrelated AlloSCT without thymoglobulin (N=100, transplanted 12/2009-12/2011). Majority of patients except three in group 3 were diagnosed with CDI with a PCR based test. Results: All 3 groups were similar with respect to the baseline characteristics (Table 1). The median follow up for the 3 groups was 2 years. At a median follow up of 2 years the incidence of CDI in the three groups were 19%, 26%, 28% respectively, p=0.2 (table 2). The incidence of CDI prior to aGVHD was similar in three groups (18/100, 25/110 and 19/100 in groups 1, 2 and 3 respectively). The incidence of CDI after development of aGVHD was higher in group 3 (1/100, 4/110 and 9/100 p=0.06 in groups 1, 2 and 3 respectively). The incidence of Grade II-IV aGVHD was significantly higher in group 3 (63%) as compared to groups 1 and 2 (49 and 41%) p=0.006 (Table 2). Similarly the incidence of any grade GI GVHD was higher in group 3 (44% Vs 23% and 24%) p=0.0009. The median time to development of aGVHD was similar in all three groups (28 days in groups 1, 31 days in group 2 and 26 days in group 2). Multivariable analysis revealed that none of the factors examined (age, sex, diagnosis, intensity of conditioning, type of transplant, use of thymoglobulin, acute GVHD) was related to development of CDI. Development of GI GVHD tended to increase the risk of subsequent CDI (40% vs 27%, p=0.06). Development of CDI did not increase the risk of development of subsequent GI GVHD (30% vs. 26%). Use of thymoglobulin improved two year overall survival in patients undergoing unrelated transplant (p=0.006). Conclusion: Thymoglobulin use did not affect the overall incidence of CDI in recipients of Allo-SCT. There is a trend towards increased incidence of late onset CDI in patients undergoing unrelated Allo-SCT and not recieving thymoglobulin probably because of higher incidence of GVHD and steroid use. There was no difference in the incidence of CDI in related vs. unrelated transplant recipients. Use of thymoglobulin improved survival in recipients of unrelated Allo-SCT. Table 1. Baseline Characteristics: Related (N=100) unrelated with Thymo (N=110) Allo unrelated without Thymo (N=100) P-value Age Median 54 58 52 NS Gender F 42 47 51 NS M 58 63 49 Race Caucasian 83 99 91 NS Other 17 11 9 Conditioning regimen Myeloablative 76 59 63 NS RIC 24 51 37 Diagnosis Leukemia 47 61 56 NS Lymphoma 30 21 20 MDS 12 20 11 Other 11 8 13 Source of stem cells BM 9 6 10 NS PBSC 91 104 90 HLA match 10/10 94 71 71 NS* 9/10 2 26 21 8/10 13 8 Haploidentical 4 GVHD** Prophylaxis Tac/MMF 97 100 Tac/MMF/Thymo 101 Tac/Sirolimus/Thymo 9 *No difference in HLA match between the groups 2 and 3. **Tac (Tacrolimus); MMF (Mycophenolate Mofetil); THYMO (Thymoglobulin). Table 2. Results: Groups 1. Related 2. Unrelated with Thymo 3. unrelated without Thymo P value Incidence of aGVHD II-IV 48% 41% 63% p=0.006 Incidence of GI GVHD 23% 23.6% 44% p=0.0009 Use of systemic steroids 38% 32% 61% p=0.0001 Overall Incidence of CDI 19/100 (19%) 29/110 (26%) 28/100 (28%) p=0.20 Incidence of CDI prior to GVHD 18/100 (18%) 25/110 (22%) 19/100 (19%) NS Incidence of CDI after onset of GVHD 1/100 (1%) 4/110 (3.6)% 9/100 (9%) p=0.06 Median Overall survival at 2 year f/u 68% 52% 46% p=0.0057 Disclosures Deol: Bristol meyer squibb: Research Funding. Lum:Karyopharm Therapeutics Inc: Equity Ownership; Transtarget.Inc: Equity Ownership. Revankar:Actelion, Merck, Gilead, Astellas: Research Funding; Dara biosciences: Consultancy. Chandrasekar:Merck, Glaxo, Chimerix,: Research Funding.

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Simple compared to covariate-constrained randomization methods in balancing baseline characteristics: a case study of randomly allocating 72 hemodialysis centers in a cluster trial

10.21203/rs.3.rs-278523/v1 ◽

2021 ◽

Author(s):

Ahmed A Al-Jaishi ◽

Stephanie N Dixon ◽

Eric McArthur ◽

PJ Devereaux ◽

Lehana Thabane ◽

...

Keyword(s):

Principal Components ◽

Cluster Randomized Trial ◽

Median Number ◽

P Value ◽

Individual Level ◽

Level Data ◽

Parallel Group ◽

Baseline Characteristics ◽

Cluster Randomized

Abstract Background and aim: Some parallel-group cluster randomized trials use covariate-constrained rather than simple randomization. This is done to increase the chance of balancing the groups on cluster- and patient-level baseline characteristics. This study assessed how well two covariate-constrained randomization methods balanced baseline characteristics compared with simple randomization. Methods: We conducted a mock three-year cluster randomized trial, with no active intervention, that started April 1st, 2014, and ended March 31st, 2017. We included a total of 11,832 patients from 72 hemodialysis centers (clusters) in Ontario, Canada. We randomly allocated the 72 clusters into two groups in a 1:1 ratio on a single date using individual- and cluster-level data available up to April 1st, 2013. Initially, we generated 1,000 allocation schemes using simple randomization. Then, as an alternative, we performed covariate-constrained randomization based on historical data from these centers. In one analysis, we restricted on a set of 11 individual-level prognostic variables; in the other, we restricted on principal components generated using 29 baseline historical variables. We created 300,000 different allocations for the covariate-constrained randomizations, and we restricted our analysis to the 30,000 best allocations. We then randomly sampled 1,000 schemes from the 30,000 best allocations. We summarized our results with each randomization approach as the median (25th, 75th percentile) number of balanced baseline characteristics. There were 156 baseline characteristics, and a variable was balanced when the between-group standardized difference was ≤ 10%. Results: The three randomization techniques had at least 125 of 156 balanced baseline characteristics in 90% of sampled allocations. The median number of balanced baseline characteristics using simple randomization was 147 (142, 150). The corresponding value for covariate-constrained randomization using 11 prognostic characteristics was 149 (146, 151), while for principal components, the value was 150 (147, 151). The median number of balanced baseline characteristics using the two covariate-constrained randomizations were statistically different from simple randomization (p-value < 0.0001). Conclusion: In this setting with 72 clusters, constraining the randomization using historical information achieved better balance on baseline characteristics compared with simple randomization; however, the magnitude of benefit was modest.

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Autologous Stem Cell Transplant Outcome in Classic Hodgkin Lymphoma Patients in the Era of Post-Transplant Brentuximab Vedotin Consolidation

Blood ◽

10.1182/blood-2021-154492 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3935-3935

Author(s):

Shanee Chung ◽

Jennifer White ◽

Cynthia L. Toze ◽

Heather J. Sutherland ◽

David Sanford ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Median Number ◽

Salvage Chemotherapy ◽

Brentuximab Vedotin ◽

Relapse Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Classic Hodgkin Lymphoma

Abstract Introduction: Patients newly diagnosed with classic Hodgkin lymphoma (CHL) have over 80% chance of remission with first-line chemotherapy, such as ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) regime. However, 10-40% of patients relapse eventually and require salvage therapy. High-dose therapy with autologous stem cell transplantation (ASCT) remains the standard of care for patients with relapsed or refractory CHL, offering a cure rate of around 50%. This may be further improved to around 60% with post-transplant consolidation with brentuximab vedotin (BV). Post-SCT BV consolidation has been offered to all patients, regardless of the risk group, in British Columbia since late 2015. We set out to review the ASCT outcome in CHL patients in the recent decade at our institution. Methods: All adult patients who received ASCT for relapsed or refractory CHL between July 2011 and June 2020 were included in this retrospective analysis. Information pertaining to their demographics, disease characteristics, treatment history, transplant details, clinical outcomes and post-relapse therapy was obtained by review of electronic data. The data cut-off date was June 28, 2021. Survival outcomes were censored at the last known clinic visit for patients without relapse or death during follow up. Survival analysis was performed using Kaplan-Meier survival function and log-rank test. Pearson's chi-square test and ANOVA were used for comparison between cohorts. The statistical program used was Stata® version 16.1 (Texas, USA). Results: 114 patients underwent ASCT for relapsed/refractory CHL. Bulky disease and extranodal involvement were seen in 11% and 40% respectively at relapse. Looking at the 'high risk criteria' as defined in the AETHERA trial: 45/114 (40%) patients had primary refractory CHL, 21/114 (18%) had relapsed within 12 months of completing the front-line chemotherapy and 15/114 (13%) had relapsed beyond one year of completing initial treatment but with an extranodal disease. The most commonly used salvage chemotherapy regime was GDP (gemcitabine, dexamethasone, cisplatin; 111/114; 97%). 10/114 (9%) patients received BV after failing salvage chemotherapy pre-SCT. The median number of lines of therapy pre-SCT was two (range 2-5). 94/108 (98%) had a chemosensitive disease with 35/108 (32%) achieving complete remission. 6/108 (6%) patients had a progressive disease at the time of SCT. For the transplant, all patients had a peripheral blood stem cell source and the conditioning regime was either Carmustine/Etoposide/Cytarabine/Melphalan (76%) or Etoposide/Melphalan (24%). After median follow up of 62.2 months, 50/114 (44%) patients relapsed with median relapse-free survival of 20.2 months (range 0.9 - 113.5) and 16/114 (14%) died. The direct cause of death was lymphoma progression in all but three patients (PJP pneumonia, pulmonary fibrosis, traumatic subdural hematoma). Whereas only 4/51 (8%) patients (2 without relapse) received post-SCT BV consolidation via a compassionate access program between July 2011 and October 2015 (cohort 1), 45/63 (71%) patients (33 in remission) received routine BV consolidation between November 2015 and June 2020 (cohort 2). In cohort 2, 44% had primary refractory CHL compared to 33% in cohort 1 but the number of 'low risk' patients was similar at 29% (Table 1). The most common reason for no post-SCT BV consolidation in cohort 2 was patient refusal (7/18; 40%). Other causes included BV pre-SCT, early disease progression and patient comorbidities. Only 9/42 (21%) patients with available data in cohort 2 completed the planned 16 cycles of BV consolidation. The median number of cycles was 10.5 (range 1-16). The most common reasons for early termination of BV consolidation were peripheral neuropathy (22/33; 67%) and disease progression (9/33; 27%). There was no statistically significant difference in PFS or OS demonstrated between the two cohorts (Graphs 1, 2). Conclusion: After median follow up of 5 years, 86% of patients remain alive and 56% are alive in remission. In British Columbia, post-SCT BV consolidation has been widely adopted with over 70% of patients receiving at least one cycle since late 2015. Successful completion of post-SCT BV consolidation is, however, limited by a high rate of treatment-limiting peripheral neuropathy. Relapse-free survival benefit of routine post-SCT BV consolidation is not demonstrated in this single-centre cohort. Figure 1 Figure 1. Disclosures White: Novartis: Honoraria. Sutherland: Janssen: Consultancy, Research Funding; GSK: Research Funding; Karyopharm: Research Funding; Celgene: Consultancy; Amgen: Consultancy. Sanford: Abbvie: Membership on an entity's Board of Directors or advisory committees; Stellar: Membership on an entity's Board of Directors or advisory committees. Abou Mourad: Amgen: Consultancy; Paladin: Consultancy; Pfizer: Consultancy. Song: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Kite, a Gilead Company: Honoraria; Bristol Myers Squibb: Honoraria; Sanofi: Honoraria.

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Clinical Outcomes Following Treatment with Gilteritinib or Quizartinib in Patients with Relapsed/Refractory FLT3-ITD+ Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2020-136118 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 42-43

Author(s):

Alexander E. Perl ◽

Qiaoyang Lu ◽

Alan Fan ◽

Nahla Hasabou ◽

Erhan Berrak ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Myeloid Leukemia ◽

Research Funding ◽

Phase 3 ◽

Hematopoietic Stem ◽

Travel Costs ◽

Baseline Characteristics ◽

Acute Myeloid

Background: Gilteritinib is approved for patients (pts) with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML), based on findings from the phase 3 ADMIRAL trial (Perl AE, et al. N Engl J Med. 2019). A phase 3 trial, QuANTUM-R, demonstrated the benefit of quizartinib in pts with R/R AML with FLT3 internal tandem duplication (FLT3-ITD) mutations (Cortes JE, et al. Lancet Oncol. 2019). Although eligibility criteria across both studies were similar, QuANTUM-R was more stringent as to prior therapy intensity and remission duration, which potentially enriched for higher-risk pts. We sought to describe outcomes from ADMIRAL among pts who otherwise met eligibility for QuANTUM-R. Methods: In this post-hoc analysis, a subset of pts from ADMIRAL were matched with R/R FLT3-ITD+ AML pts from QuANTUM-R on the basis of baseline characteristics and prior treatment criteria. Matched pts were either refractory to initial anthracycline-based chemotherapy or had relapsed ≤6 mos after achieving composite complete remission (CRc) with an anthracycline-based regimen. Results: Overall, 218 pts with R/R FLT3-ITD+ AML in the ADMIRAL trial (gilteritinib, n=140; salvage chemotherapy [SC], n=78) were matched with the QuANTUM-R intention-to treat (ITT) population (N=367; quizartinib, n=245; SC, n=122). Proportions of pts preselected for high-intensity SC were 66% (n=143/218) in the matched ADMIRAL ITT population and 77% (n=281/367) in the QuANTUM-R ITT populations. Demographic and baseline characteristics of the matched ADMIRAL ITT population and QuANTUM-R ITT population were similar. Median durations of exposure to gilteritinib and quizartinib were 3.8 mos and 3.2 mos, respectively, and median number of treatment cycles received were five and four, respectively. Rates of hematopoietic stem cell transplantation (HSCT) were similar in pts treated with gilteritinib (35%; n=49/140) or quizartinib (32%; n=78/245), as were the proportions of pts who resumed gilteritinib (23%; n=32/140) or quizartinib (20%; n=48/245) therapy post-HSCT. Median overall survival (OS) in pts treated with gilteritinib or quizartinib was longer than that observed with SC. After a median follow-up of 17.4 mos, median OS was 10.2 mos with gilteritinib versus 5.6 mos with SC (hazard ratio [HR]=0.573 [95% CI: 0.403, 0.814]; one-sided nominal P=0.0008). After a median follow-up of 23.5 mos, median OS with quizartinib was 6.2 mos versus 4.7 mos with SC (HR=0.76 [95% CI: 0.58-0.98]; one-sided P=0.02). After censoring for HSCT, median OS was 9.3 mos with gilteritinib versus 5.5 mos with SC (HR=0.525 [95% CI: 0.356-0.775]; nominal one-sided P=0.0005), and 5.7 mos versus 4.6 mos with quizartinib versus SC, respectively (HR=0.79 [95% CI: 0.59, 1.05]; one-sided P=0.05). In both QuANTUM-R and matched ADMIRAL populations, the survival benefits of quizartinib and gilteritinib compared with SC were maintained across multiple subgroups, including high FLT3-ITD allelic ratio subsets. Compared with SC, high CRc rates were observed in pts treated with either gilteritinib (57%; n=80/140) or quizartinib (48%; n=118/245). The complete remission (CR) rate with gilteritinib was 23% (n=32/140), whereas the CR rate with quizartinib was 4% (n=10/245) (Table). Median time to achieve CRc was 1.8 mos with gilteritinib and 1.1 mos with quizartinib, median duration of CRc was 5.5 mos with gilteritinib and 2.8 mos with quizartinib. The safety profiles of gilteritinib and quizartinib were generally similar, though aspartate or alanine aminotransferase elevations (any grade) were more frequent with gilteritinib (41-44%) than quizartinib (≤13%), whereas neutropenia (14% vs 34%, respectively), fatigue (24% vs 39%, respectively), and prolonged QT intervals (9% vs 27%, respectively) were more frequent with quizartinib. Conclusions: In pts with R/R FLT3-ITD+ AML and similar baseline characteristics, both gilteritinib and quizartinib were generally well tolerated and associated with improved survival and treatment response compared with SC. Responses to gilteritinib and quizartinib, as measured by CRc, were similar; blood count recovery varied between the two FLT3 inhibitors. Although cross-study comparisons have substantial limitations, the findings suggest that while remission is achieved faster with quizartinib, response may be more durable and survival potentially longer with gilteritinib. Disclosures Perl: Syndax: Consultancy, Honoraria; Leukemia & Lymphoma Society, Beat AML: Consultancy; Novartis: Honoraria, Other, Research Funding; Agios: Consultancy, Honoraria, Other; Jazz: Honoraria, Other; FORMA Therapeutics: Consultancy, Honoraria, Other; Daiichi Sankyo: Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding; FUJIFILM Pharmaceuticals USA, Inc: Research Funding; New Link Genetics: Honoraria, Other; Arog Pharmaceuticals Inc: Other: uncompensated consulting, travel costs for meetings; Actinium Pharmaceuticals Inc: Consultancy, Honoraria, Research Funding; Biomed Valley Discoveries: Research Funding; Astellas: Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding; Bayer HealthCare Pharmaceuticals: Research Funding; AbbVie Inc: Consultancy, Honoraria, Other, Research Funding; Takeda: Honoraria, Other: Travel costs for meeting; Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Consultancy, Honoraria, Other. Lu:Astellas: Current Employment. Fan:Astellas Pharma: Current Employment. Hasabou:Astellas Pharma: Current Employment. Berrak:Astellas: Current Employment. Tiu:Eli Lilly & Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Astellas Pharma Global Development: Current Employment.

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Role of ctDNA to predict risk of recurrence following potentially curative resection of biliary tract and pancreatic malignancies.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.336 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 336-336

Author(s):

Angela Lamarca ◽

Mairead Geraldine McNamara ◽

Richard Hubner ◽

Juan W. Valle

Keyword(s):

Relapse Rate ◽

Curative Resection ◽

Cox Regression ◽

Statistical Significance ◽

Molecular Profiling ◽

P Value ◽

Relapse Risk ◽

Baseline Characteristics

336 Background: The potential role of ctDNA to identify residual disease after potentially curative resection has been suggested in some malignancies; its role in resected pancreatico(P)-biliary(B) malignancies is unknown. Methods: Patients diagnosed with PB malignancies underwent molecular profiling (ctDNA) using FoundationMedicine Liquid (72 cancer-related genes) following potentially curative resection. Baseline patient characteristics and molecular profiling outcomes, including mutant allele frequency (MAF) for pathological alterations were extracted. Primary objective: prevalence of ctDNA identification and its correlation with recurrence (relapse-free survival (RFS) and relapse rate). Results: Total of 11 individuals had ctDNA analysed following potentially curative resection for PB malignancies: 8 B (4 extra-hepatic cholangiocarcinoma (eCCA), 2 ampulla, 1 intrahepatic cholangiocarcinoma (iCCA), 1 gallbladder cancer (GBC)) and 3 P. Baseline characteristics: 6 female (54.55%), median age 71.59 years (range 39.98-81.19). Most were pT2 (45.45%), pN0 (54.55%) and R0 (63.64%). Following surgery, 6 patients were started on adjuvant chemotherapy; at the end of follow-up (data cut-off 25/6/2020; median follow-up 11.15 months (range 5.45-13.52); 5 relapsed (45.45%) and 2 died (18.18%). Estimated median RFS was 11.43 months (95% CI 2.28-not reached); median overall survival was not reached. No sample failed ctDNA analysis; presence of ctDNA was identified in 3/11 (27.27%) of the samples; 2 and 1 samples had 2 and 1 pathological alterations identified, respectively: ALK fusion (1 sample; GBC), TP53 mutation (2 samples; eCCA and GBC), CHEK2 mutation (1 sample; pancreas), IDH2 mutation (1 sample; eCCA). Mean maximum MAF was 1.47 (2 in biliary; 0.43 in pancreas). Variants of unknown significance were identified in 72.73% of the samples (87.5% in B; 33.33% in P; p-value 0.152). None of the baseline characteristics explored correlated with presence of ctDNA. There was a trend towards increased relapse risk in the patients with ctDNA present following potentially curative surgery; Cox regression for RFS [HR 2.64 (95% CI 0.36-19.31); median RFS 11.44 months (95% CI 2.28-not reached) vs 10.87 (95% CI 2.21-not reached)]; relapse rate 37.5% (ctDNA absent) vs 66.67% (ctDNA present); statistical significance was not reached (p-value 0.340 and p-value 0.545, respectively). Conclusions: This pilot study demonstrates the feasibility of testing for ctDNA following potentially curative resection in PB malignancies. Presence of ctDNA may be associated with increased relapse risk; further studies are required to increase sample size and assess clinical implications.

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Nephrology In-Reach Services Lead to Improvement in Mortality in Acute Kidney Injury – 3 (AKI-3)

10.21203/rs.3.rs-119034/v1 ◽

2020 ◽

Author(s):

E. Gkekas ◽

TYT. Tang ◽

M. Brazell ◽

M. Brennan ◽

H. Ayub ◽

...

Keyword(s):

Acute Kidney Injury ◽

Mortality Rate ◽

District Hospital ◽

Care Pathway ◽

Kidney Injury ◽

Evaluation Study ◽

Community Settings ◽

Inclusion Criteria ◽

Hospital Acquired ◽

Overall Mortality

Abstract Background: Acute Kidney Injury (AKI) is a sudden decline in kidney function. Early detection and prompt treatment of AKI is vital in improving the outcome of patients. We introduced in-reach nephrology services at South Tyneside District Hospital (STDH) as part of a reconfiguration of local NHS services. Aims: The principal aim of this study is to analyse patient outcomes relating to service developments and to explore prognostic characteristics among a cohort of AKI-3 patients Design: This was a single centre retrospective impact evaluation study.Methods: We studied all patients (n=246) who either presented with or developed AKI-3 during their admission at South Tyneside District Hospital from 2016 to 2018. The inclusion criteria included age 18-95 years and a diagnosis of AKI-3 as per KDIGO classification. Exclusion include those on established dialysis regime or on palliative care. Results: A total of 246 patients were admitted with AKI-3. There were 64 deaths from AKI-3 over the three-year period. Mortality decreased from 29.5% to 20.7% from 2016 to 2018. In patients with Community Acquired (CA-AKI3) the overall mortality rate was 24.2% (n=182), whereas the overall mortality rate of those with Hospital Acquired (HA-AKI3) was 31.3% (n=64). The pre-AKI use of ACEi, A2RB or diuretics increased from 39.7% in 2016 (n=78), to 59.3% in 2017 (n=86) and 64.6% in 2018 (n=82). Conversely, mortality associated with the use of these medications reduced each consecutive year (32.3%, 25.5%, 18.9%).Conclusion: Development of nephrology in-reach services, staff education measures and a primary care pathway could reduce AKI-3 mortality among patients in inpatient and community settings.

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Complications of Classical Tracheostomy and Management

Tropical Doctor ◽

10.1177/004947550303300309 ◽

2003 ◽

Vol 33 (3) ◽

pp. 148-150 ◽

Cited By ~ 2

Author(s):

P A Onakoya ◽

O G B Nwaorgu ◽

L A Adebusoye

Keyword(s):

Mortality Rate ◽

Home Care ◽

Retrospective Review ◽

Postoperative Management ◽

College Hospital ◽

Airway Diseases ◽

Complications And Mortality ◽

Overall Mortality

Tracheostomy can prevent many deaths in otherwise fatal airway diseases and problems but has numerous complications that are mostly avoidable if the procedure is carefully performed together with strict postoperative management. This is a retrospective review of tracheostomy complications over a 10 year period (1991–2002) in the Department of Otorhinolaryngology (ORL), University College Hospital, Ibadan. A total of 179 tracheostomies performed on 168 patients with 69 complications (38.6%) were documented. There was a significantly greater number of complications in the 43 emergency cases (54%) than in the 26 elective cases [(46%), P=0.0002]. The overall mortality rate was 2.2%. The most common complications of tracheostomy were infective in origin, representing 43% of all complications. This study highlights the complications and mortality and gives details of management that will prevent or minimize their occurrences. Those who require long-term tracheostomy must be on regular follow-up and taught home-care of the tracheostomy before discharge from the hospital.

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P1520Management and outcome of women with NSTEMI. Have there been any changes in recent years?

European Heart Journal ◽

10.1093/eurheartj/ehz748.0282 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

C Cacho ◽

T Gonzalez Ferrero ◽

A Torrelles Fortuny ◽

M Perez Dominguez ◽

C Abbou Johk ◽

...

Keyword(s):

P Value ◽

Evidence Based ◽

Short Term ◽

Killip Class ◽

Hospitalization Period ◽

Short Term Mortality ◽

Baseline Characteristics ◽

Long Term Mortality

Abstract Introduction Women have been less represented in every NSTEMI clinical trial. Moreover, it has been observed that this group of patients have usually received less revascularization and evidence based treatment, therefore presenting with a greater long and short-term mortality. Purpose The purpose of our study is to analyze the presence of differences in baseline characteristics, management and outcome of women with NSTEMI during the last decade. Methods and results Retrospective study including 861 women admitted for NSTEMI between 2003 and 2015 in our center. We divided 2 groups according to hospitalization period (2003–2008 and 2009–2015) with a medium follow up of 4.5±2.9 years. Baseline characteristics and treatment at discharge are described on table 1. We noticed a greater use of statins and ACEI/ARB on the second period as well as a greater percentage of patients receiving early revascularization. It is remarkable on women a non-significant reduction of heart failure hospitalization at follow up (6.8% vs 4.5%; p=0.091), neither differences on 30-day mortality (1.3% vs 0,4%) or 1-year mortality (7.1% vs 5.8%). However, long-term mortality for the second group is reduced (HR 0.69; CI 95% 0.52–0.89), even after performing a multivariate analysis (HR 0.64; CI 95% 0.48–0.85). Characteristic Population (n=861) 2003–2008 (n=395) 2009–2015 (n=466) p-value Age (years) 73±12 73±12 72±12 0.316 Hypertension 629 (73.1%) 285 (72.2%) 344 (73.8%) 0.318 Hypercholesterolemia 414 (48.1%) 190 (48.1%) 224 (48.1%) 0.523 Killip class 0.292 I 664 (77.1%) 299 (75.7%) 365 (78.3%) II 143 (16.6%) 74 (18.7%) 69 (14.8%) III 47 (5.5%) 20 (5.1%) 27 (5.8%) IV 4 (0.5%) 2 (0.5%) 2 (0.4) GRACE score 129±32 130±37 128±33 0.897 Early PCI 249 (29.3%) 76 (19.2%) 173 (38.0%) <0.005 Treatment at discharge AAS 698 (81.1%) 313 (79.2%) 385 (82.6%) 0.120 Clopidogrel 465 (54.0%) 221 (55.9%) 244 (52.4%) 0.162 ACEI/ARB 466 (54.1%) 191 (48.4%) 275 (59.0%) 0.001 Beta-blocker 509 (59.1%) 238 (60.3%) 271 (58.2%) 0.290 Statins 643 (74.7%) 275 (69.6%) 368 (79.0%) 0.001 Conclusions In recent years, early interventionist management and greater use of evidence-based therapies have been observed in women with NSTEMI. This has been associated with a lesser long-term mortality, although short-term events have remained the same.

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High Rate of Survival in Transformed Lymphoma after Autologous Stem Cell Transplant (ASCT): Pathologic Analysis and Comparison with De Novo DLBCL.

Blood ◽

10.1182/blood.v112.11.1137.1137 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1137-1137

Author(s):

Stephen S. Smith ◽

Brian Bolwell ◽

Anjali Advani ◽

Steven Andresen ◽

Josephine Chan ◽

...

Keyword(s):

De Novo ◽

Cleveland Clinic ◽

B Cell Lymphoma ◽

Rank Test ◽

P Value ◽

Cell Transplant ◽

Transformed Lymphoma ◽

Baseline Characteristics ◽

Pathologic Analysis

Abstract Introduction: Survival gains in follicular lymphoma (FL) have been variably attributed to improved first line and salvage therapies, and a decreasing frequency of histologic transformation (HT). Although ASCT is often used in patients (pts) with transformed lymphoma (TL), optimal pt selection and factors predictive of outcome are unclear. Although immunohistochemistry (IHC) has been applied to prognostication in de novo DLBCL, few studies have investigated IHC as a prognostic factor in TL. The purpose of this analysis was to review outcomes using ASCT for TL at the Cleveland Clinic Taussig Cancer Insitute (CCTCI) in light of modern IHC-based pathologic analysis. Methods: All pts undergoing ASCT for diffuse large B-cell lymphoma from 2003–2008 at CCTCI (n=130) were identified. IHC analysis for markers CD10, BCL2, BCL6, and MUM-1 was available for 56 pts, who were analyzed further. Pts with TL (n=25) were compared as a group to de novo cases (n=31). Baseline characteristics were compared using Fisher’s exact and Wilcoxon rank-sum tests. Relapse-free and overall survival (RFS and OS) were estimated with the Kaplan-Meier method and compared via log-rank test. Cox proportional hazards analysis was used to examine features predicting outcome after ASCT. Results: Median age was 57 years. Of 25 TL pts, 16 had prior FL, 1 each had small lymphocytic lymphoma and nodular LP Hodgkin lymphoma, and 7 presented with coexistent DLBCL and FL in the same biopsy specimen. Among 18 TL pts with metachronous presentation, HT occurred at a median of 26 months (range, 8–198 months). Pathologic characteristics (%) are: Group CD10 BCL6 MUM-1 BCL2 GCB phenotype* MedianKI67 index t(14;18) *Criteria from Hans et al, Blood2004;103(1):275–82 TL 84 95 38 84 92 70 8/10 de novo 61 88 43 63 71 80 1/8 P value .08 .62 1.0 .18 .09 .63 .02 Age and disease status at time of transplant were similar between groups. Three de novo pts and 2 TL patients underwent ASCT during first remission; all others underwent ASCT for relapsed/refractory disease. With a median follow-up of 25 months, 4 year RFS was 64% vs. 59% (p=.82) and OS 63% vs. 59% (p=.68) for TL and de novo pts, respectively (see Figures 1 and 2). No IHC feature predicted RFS or OS. Elevated LDH at time of ASCT predicted poor RFS (HR 4.6, p=.008) and OS (HR 6.3, p=.005) on multivariate analysis, and increasing number of prior regimens predicted poor RFS only (HR 1.4, p=.003). Conclusions: TL resembled de novo DLBCL in terms of IHC characteristics, but a higher proportion of TL cases bore the t(14;18) translocation. ASCT was effective in treating TL, with a 4-year RFS and OS exceeding 60%. This was indistinguishable from outcomes for de novo DLBCL pts treated with ASCT over the same period. Baseline characteristics were similar between TL and de novo pts. Survival in FL may be improving in part due to good outcomes using ASCT for TL. Confirmation of our observed RFS/OS among TL pts requires longer follow-up, given the ongoing risk of relapse of indolent disease. Outcome after ASCT cannot be predicted by IHC, and novel approaches are needed to improve pt selection and elucidate the biology of HT. Figure 1: RFS Figure 1:. RFS Figure 2: OS Figure 2:. OS

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Intracranial Hemorrhage in Patients with Hemophilia in the Prophylaxis Era.

Blood ◽

10.1182/blood.v112.11.3388.3388 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3388-3388

Author(s):

Char Witmer ◽

Rodney Pressley ◽

Roshni Kulkarni ◽

J. Michael Soucie ◽

Catherine Scott Manno

Keyword(s):

Mortality Rate ◽

Reference Group ◽

Univariate Analysis ◽

P Value ◽

Severe Hemophilia ◽

Clinical Factors ◽

Factors Associated ◽

Annual Visit ◽

Nested Case Control

Abstract Objective: With a mortality rate of 20%, intracranial hemorrhage (ICH) accounts for the highest number of deaths from bleeding in patients with hemophilia and is a common cause of long-term disability. We performed a nested case-control study within a cohort of males with hemophilia enrolled in the Centers for Disease Control and Prevention (CDC) Universal Data Collection (UDC) project. The study objective was to identify rates and risk factors associated with ICH in the modern era of prophylaxis. Patients and methods: Study participants were males with hemophilia A or B, enrolled in the CDC UDC project, 2 years or older, who had an initial visit, and at least one follow up event between May 1998 and March 2008. Patients were followed from the initial visit until their study termination event, defined as an ICH reported during a subsequent annual visit, death, or the latest annual visit held during the study period. Cases were patients who after UDC enrollment either had an ICH or whose cause of death was from an ICH. The following clinical factors were examined for an association with ICH: hemophilia type, severity level, prior ICH, presence of an inhibitor, treatment with prophylaxis, HIV status, chronic hepatitis B, hepatitis C, alcohol abuse, elevated prothrombin time, ethnicity and age. Data analysis was conducted using SAS 9.2 (SAS Institute, Cary, NC). Factors associated with ICH were identified using a nested case control design. Interaction effects were assessed using the Breslow-Day Test for homogeneity of the odds ratios. The independent association between prophylaxis and ICH was assessed using logistic regression. All hypothesis testing was two tailed with odds ratios and confidence intervals reported. Results: During the study period 10,262 patients were identified who met the inclusion criteria. Of these, 199 (1.9%) experienced an ICH. Based on patient follow up time (mean 4.9 +/−2.46 years) the incidence rate was 3.9 per thousand patient years. Thirty-nine of the 199 ICH cases died from the event, resulting in a mortality rate of 19.6%. In 148 (74%) of the ICH cases, the subjects had severe hemophilia. See table 1 for univariate analysis of all patients. Table 1: Clinical factors associated with ICH for all patients in the cohort, N=10,262 (univariate analysis) Clinical Factors Odds Ratio (95% CI) P-Value *Reference group White (non-Hispanic). **Reference group age 10–15 years. Prior ICH 3.62 (2.66–4.92) <0.001 Severe Hemophilia 3.25 (2.01–5.25) <0.001 High Titer Inhibitor 4.01 (2.40–6.71) <0.001 Hepatitis C 1.73 (1.30–2.29) <0.001 Black (non-Hispanic)* 2.07 (1.46–2.96) <0.001 Age 2-9 years** 1.85 (1.14–2.99) 0.01 Age >41 years** 2.17 (1.34–3.50) 0.001 For the entire cohort, prophylaxis use was not associated with a statistically significantly reduced risk of ICH (0.83 (0.61–1.15) p=0.26). However, further analysis (see table 2), restricted to patients with severe hemophilia, demonstrated a protective effect of prophylaxis use that was limited only to patients who did not have an inhibitor and who were not infected with HIV. Table 2: Clinical factors independently associated with ICH among 5,485 patients with severe hemophilia (multivariate analysis) Clinical Factors Odds Ratio (95% CI) P-Value **Reference group age 10–15 years. Prophylaxis no inhibitor 0.50 (0.32–0.77) 0.002 Prophylaxis no HIV 0.52 (0.34–0.81) 0.004 Prior ICH 3.24 (2.27–4.64) <0.0001 Chronic Hepatitis B 2.99 (1.03–8.63) 0.043 Age 2–9 years** 1.92 (1.05–3.51) 0.034 Conclusion: This study demonstrates that patients with severe hemophilia who use prophylaxis and are not HIV positive and do not have an inhibitor experience a 50% risk reduction for ICH. This study confirms the previously identified risk factors for ICH including severity of disease, prior ICH, young age and the presence of an inhibitor. The strongest predictor for ICH was a history of ICH before enrollment in the UDC. Unfortunately even in the age of widely available prophylactic therapy, the mortality rate from ICH remains quite high at 19.6%.

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