ASH Annual Meeting
Highlights from the virtual American Society of Hematology Annual Meeting, December 2-11, 2020.
- Thrombotic events common in hospitalized COVID-19 patients
- Engagement with mobile health predicts sickle cell disease self-management in adolescents and young adults
- Higher mortality, hospitalization rate in Black SCD patients infected with COVID-19
- Cardiovascular disease is leading cause of mortality in thrombotic thrombocytopenic purpura survivors
- Gene therapy offers hope for one-time treatment in moderately severe and severe hemophilia B
- Mycophenolate-steroid combination effective for newly diagnosed immune thrombocytopenia
Thrombotic events common in hospitalized COVID-19 patients
Presenter: Stephanie Berg, DO
Thrombotic events occur in 7.2% of a racially diverse cohort of hospitalized patients infected with SARS-CoV-2, according to an analysis conducted across 3 university health systems in the Chicago metropolitan area.
The retrospective chart review included 2,189 patients hospitalized more than 24 hours with confirmed COVID-19 infection from March to May 2020 who had confirmed arterial or venous thrombosis and significant bleeding events.
The purpose of the analysis, presented by Stephanie Berg, DO, assistant professor of medicine, Loyola University, Chicago, was to define risk factors for thrombosis across 7 hospitals from 3 Chicago hospital systems, and to examine the importance of anticoagulation intensity for patients hospitalized with COVID-19.
Of the total cohort, 1,033 were hospitalized at Loyola University Health Systems (LUHS), 857 at Rush University System for Health (RUSH), and 299 at University of Illinois–Chicago (UIC). Overall, 56% were male, 47% were over age 60, 48% had a body mass index over 20 kg/m2, 62% had a cardiac comorbidity, and 41% had diabetes. Hispanics and African Americans represented 47% and 17% of LUHS patients, 32% and 42% of RUSH patients, and 36% and 51% of UIC patients, respectively.
Optimal anticoagulation intensities have yet to be established, but recent guidelines from the American Society of Hematology and the American College of Chest Physicians, recommend that prophylactic anticoagulation be used in COVID-19 hospitalized patients in the absence of contraindications, noted Dr. Berg.
Multiple institutions have used algorithms to escalate prophylaxis for certain patients who may be at risk for thrombosis due to uncontrolled coagulopathy, she said. The algorithm developed at LUHS, similar to one at RUSH, stratifies risk based on d-dimer levels and the sepsis-induced coagulopathy (SIC) score on admission, and then assigns a prophylaxis strategy based on the values. For example, in the LUHS cohort, 83% of patients on admission received prophylaxis for venous thrombosis, 65% of whom received prophylactic-dose anticoagulation, 25% of whom received intermediate anticoagulation, and 6% of whom received full-dose anticoagulation.
By health system, rates of documented thrombotic events were 5.0% (n = 56) at LUHS, 9.6% (n = 82) at RUSH, and 6% (n = 18) at UIC.
Across all 3 systems, risk factors for thrombosis were intensive care unit admission (P < .001), elevated white blood cell count (P < .001), d-dimer more than 5 times the upper limit of normal (P < .001), and the presence of diabetes (P = .029 at LUHS; P = .005 at RUSH; data not available at UIC) at presentation. The RUSH cohort also demonstrated a significant thrombosis risk with age older than 60 (P < .001) and obesity (P = .015). “Sex and ethnicity were not found to be associated with thrombosis across individual centers,” she said.
D-dimer levels were missing in about 40% of patients overall, and P values for this variable were calculated based on complete-case analysis.
The overall mortality rate was 15%. Death rates in patients with thrombosis varied by hospital system: 22% in the RUSH cohort and 21% at UIC vs 5% in the LUHS cohort.
“Based on these risk factors, identification of patients at most risk of thrombosis is needed to reduce the morbidity and mortality when diagnosed with COVID-19, and optimal anticoagulation strategies need to be determined,” said Dr. Berg. “We are particularly interested to see if different anticoagulation practices—using different anticoagulation intensities based on admission SIC score and d-dimer levels—could contribute to these findings.”
Dr. Berg has disclosed no relevant relationships.
Engagement with mobile health predicts sickle cell disease self-management in adolescents and young adults
Presenter: Anna M. Hood, PhD
Use of a mobile health app can help adolescents and young adults with sickle cell disease (SCD) manage their disease. In a single-site randomized controlled trial, however, engagement of the app was variable, resulting in differences in self-management and self-efficacy.
SCD requires substantial self-management, including daily medications, monthly transfusions, immunizations, regular screenings, avoidance of triggers, and hydration. “Self-management has been cited as a critical concern for adolescents and young adults with SCD,” said Anna M Hood, PhD, from Great Ormond Street Institute of Child Health, University College London, UK.
Mobile technology has been proposed as a strategy to improve self-management in this population, who are “technology natives,” she said.
To this end, the iManage mobile app was co-designed by adolescents and young adults and their providers as a complement to group intervention (SCThrive). The technology is convenient, allows for momentary measurement throughout the day, promotes engagement in the healthcare system, supports goal-setting, and provides feedback.
Dr. Hood presented an assessment of 26 adults and young adolescents in the treatment arm of the study, who received the SCThrive intervention and used the mobile health app.
The sample included adolescents and young adults with SCD who were 13 to 21 years old (median, 16.7); 54% were female, 46% had the HbSS genotype, all were African American/Black), and all received 6-weekly group sessions (3 in person, 3 online). All SCThrive participants were provided with the iManage app on an iPad.
Participants logged on to the iManage app and viewed their pain diary on average once a week. “There was a lot of variability within that,” said Dr. Hood. “We had some individuals logging on almost every day, whereas others logged on much less frequently.” They viewed their self-management goals about once every 11 days, with a similar level of variability.
Some 88% saved a pain diary entry across the duration of the trial. All created at least one self-management goal, but only 54% completed at least one goal. Of the 149 self-management goals created, 25% were completed.
The most frequent self-management goals recorded were exercise (18% of total goals recorded, 12% completed), completing schoolwork (14% of total recorded, 14% completed), drinking more water (11% of total recorded, 23% completed), and changing the sleep schedule (11% of total recorded, 25% completed).
If an individual gave a rating of 7 or less to a goal (on scale of 1 to 10), completing the goal was unlikely. Completion of goals was much more likely when goals were given a rating 8 or more.
Completing more goals (r = .038), documenting pain symptoms (r = 0.54), and lower mood ratings (r = .054) were significantly correlated with logging onto the iManage app more frequently.
Controlling for baseline scores, logging onto the app was related to post-treatment self-management, with a similar nonsignificant relationship to post-treatment self-efficacy.
The number of logins to the iManage app (predicted self-efficacy P = .08, η2 = 0.13) on the Patient Activation Measure-13 (PAM-13) and self-management skills (P = .05, η2 = 0.17) on the Transition Readiness Assessment Questionnaire-5 (TRAQ-5). Completing more self-management goals on the app did not predict scores on the PAM-13, but, surprisingly, it predicted lower scores (less self-management) on the TRAQ-5 (P = .08, η2 = 0.14).
“It was challenging to maintain engagement in the mobile health app for adolescents and young adults with SCD, but those who did had better self-management, documented their pain more often, and had lower mood ratings,” said Dr. Hood.
Dr. Hood has disclosed no relevant relationships.
Higher mortality, hospitalization rate in Black SCD patients infected with COVID-19
Presenter: Lana Mucalo, MD
Black individuals with sickle cell disease (SCD) are 6.2 times more likely to die from COVID-19 infection compared with Blacks without SCD, according to data from an international SCD registry and public health data from the state of California. In addition, young adults and children with SCD are more likely to be hospitalized for COVID-19 than those in the general COVID-19 patient population.
Further, COVID-19 mortality rates are higher in Blacks with SCD than in the general Black population with COVID-19.
“Respiratory viral infections are a source of morbidity and mortality in persons with SCD,” said presenter Lana Mucalo, MD, from the Medical College of Wisconsin, Milwaukee. “Due to the current pandemic and potential future infectious disease epidemics, it is important to understand the impact that COVID-19 has on this medically vulnerable population.”
The international Surveillance Epidemiology of Coronavirus Under Research Exclusions (SECURE) SCD registry was established in March 2020 to collect data on pediatric and adult COVID-19 infection in people living with SCD. Only confirmed COVID-19 cases are reported by providers, with de-identified data that includes patient demographics; SCD medical history and comorbidities; COVID-19 severity, complications, and outcome; and management strategies and healthcare use.
For the study, data from the California Department of Public Health (CDPH) and the Coronavirus Disease 2019-Associated Hospitalization Surveillance Network (COVID-NET) were used to compare case-fatality rates and COVID-19 hospitalizations, respectively, with those reported in the SECURE registry.
At the time of this analysis, the registry included 366 cases of COVID-19 in Blacks (324 from the United States), of which 152 cases were in children age 18 or younger, and 122 were in adults over age 18. The predominant SCD genotype was HbSS/HbS-beta-0 (72.0% of adults, 71.7% of children). Hospitalization rates were 66.8% in adults and 46.1% in children, with mortality rates of 7.0% and 0.7%, respectively.
According to CDPH data, case-fatality rates for Blacks in the general population are less than 1% for all age groups, until age 49, when rates increase markedly. By comparison, the case-fatality rate in SCD patients in the SECURE-SCD registry increased from 0.8% in individuals 0 to 17 years, to 2.6% in those age 18 to 34, and to 11.9% in persons age 35 to 49. Mortality rates in SCD patients were highest in those age 50 to 64 (17.6%) and age 65 to 79 (20%), compared with a peak mortality rate of 34.3% in persons age 80 and older in the general CDPH Black population.
When comparing SCD patients with those in COVID-NET, children with SCD comprised 26.2% of the hospitalized population compared with less than 2% of the general population. The highest percentage of hospitalization among SCD patients occurred in persons age 18 to 49 (59.7%), compared with the highest hospitalization in individuals age 65 and older in the general population (37.4%).
Upon multivariable modeling, factors associated with hospitalization in children with SCD for COVID-19 included acute care for pain (odds ratio [OR] 4.641; 95% confidence interval [CI] 1.976–10.9; P = .006), SCD-related heart and lung comorbidities (OR, 4.173; 95% CI, 1.56-11.158; P = .004), and neurobehavioral disorders (OR 2.736; 95% CI, 1.099–6.813; P = .03). A more severe course of COVID-19 in children with SCD was associated with previous acute care for pain (OR, 3.964; 95% CI, 1.42–11.065; P = .03).
Neither the severity of COVID-19 infection nor hospitalization was affected by either SCD genotype (HbSS/HbS-beta-0 vs HbSC/HbS-beta+) (P = .68 and P = .41, respectively) or the use of hydroxyurea (P = .41 and P = .75).
Study limitations include a preponderance of patients with severe disease, underrepresentation of areas where testing is not available, comparisons of case-fatality rates with only cases in California, and a lack of information on testing dates.
Dr. Mucalo has disclosed research funding from NIH/NHLBI and NIH/NINDS.
Cardiovascular disease is leading cause of mortality in thrombotic thrombocytopenic purpura survivors
Presenter: Senthil Sukumar, MD
Patients who have survived thrombotic thrombocytopenic purpura (TTP) have a 2-fold higher mortality rate than the general population, with cardiovascular disease and TTP relapse being the leading causes of death, according to findings from a multicenter cohort study.
Prompt therapy of TTP, which includes plasma exchange and immunosuppression, has reduced the mortality rate from 90% to under 10% in the modern era, said lead investigator Senthil Sukumar, MD, from The Ohio State University, Columbus, OH.
“These TTP survivors were initially thought to return to their baseline levels of health after the acute event,” he said. “However, long-term follow-up has shown us that these patients exhibit high rates of adverse sequelae, including hypertension, obesity, stroke, cognitive impairment, mood disorders, and an overall poor quality of life. TTP survivors also have a higher all-cause mortality when compared with an age-, race-, and sex-matched population.”
Using data from The Ohio State University and Johns Hopkins Hospital Thrombotic Microangiopathy registries, researchers identified 213 patients with confirmed TTP with severely deficient ADAMTS13 (˂ 10%) either on initial presentation or during a relapse event.
Over a median follow-up of 5.2 years, 184 patients (72.8% female, 53.8% African American) were still alive, and 29 patients (55.3% female, 65.5% White) died. Significant differences were found between survivors and patients who died during follow-up in the total number of TTP episodes (1 vs 3 episodes, respectively; P ˂ .001), the rate of chronic kidney disease (19.0% vs 48.3%; P = .001), and average remission ADAMTS13 enzyme activity (63.2 vs 39.0; P = .010).
TTP survivors had a significantly higher mortality rate compared with a reference US population (2,228.3 vs 1,273.8 per 100,000 patient-years, respectively), and a significantly lower median age of death (49 vs 78.7 years). “These differences are persistent despite race or sex, though they are more pronounced in White patients as well as male patients,” noted Dr. Sukumar.
Relapsed TTP and cardiovascular disease were the most common causes of death, in 27.6% each, followed by cancer (20.7%), infectious causes (13.8%), and other or unknown causes (10.3%).
“Notably, our results are consistent with previously published data from the Oklahoma Registry. Importantly, cardiovascular disease appears to be a predominant cause of death in both of our cohorts,” he said.
After adjusting for the presence of hypertension, chronic kidney disease, and systemic lupus erythematosus, the following risk factors for early mortality in TTP survivors were identified: male sex (hazard ratio [HR] 4.39; 95% confidence interval [CI] 1.83–10.52; P = .001), age (HR, 1.03; 95% CI, 1.01–1.06; P = .0039), and the number of TTP episodes (HR 1.12; 95% CI 1.05–1.21; P = .001).
In a remission ADAMTS13 analysis in 97 patients for whom sufficient data were available, patients who died during follow-up were found to have significantly reduced ADAMTS13 activity compared with survivors (39.0% vs 63.2%, respectively; P = .01). Further, in patients with ADAMTS13 activity below 70%, median survival was 6.02 years vs 10.65 years in those with ADAMTS13 above 70%, which did not achieve significance (P = .068), “likely due to our small sample sizes,” said Dr. Sukumar.
“Reduced ADAMTS13 activity in remission is a possible targetable risk factor for early death,” he concluded. “Although the underlying mechanism is not clearly understood, reduced ADAMTS13 activity may be contributing to cardiovascular disease or more TTP relapses, as these were higher in the patients that died.”
Dr. Sukumar has disclosed no relevant relationships.
Gene therapy offers hope for one-time treatment in moderately severe and severe hemophilia B
Presenter: Steven W. Pipe, MD
Given as a single infusion, a gene therapy significantly increased factor IX production in adults with severe or moderate-severe hemophilia B, according to results from the phase 3 HOPE-B gene therapy trial.
“Treatments for hemophilia B, or factor IX deficiency, are limited to regular prophylactic intravenous infusions of factor IX concentrates,” said presenter Steven W. Pipe, MD, of the University of Michigan, Ann Arbor. “The goal of gene therapy for hemophilia B is to deliver a one-time procedure that establishes sustained factor IX activity in the mild-to-normal range that should be transformative for the patient, providing effective protection from spontaneous bleeding, eliminating the need for continuous prophylaxis, with accompanying improvements in quality of life.”
First results from HOPE-B suggest that in the future, this goal may be attainable.
Etranacogene dezaparvovec (AMT-061) was developed by combining the adeno-associated virus serotype 5 (AAV5) vector from AMT-060 with the naturally occurring Padua factor IX variant. It was studied in 54 adult men with a factor IX activity less than or equal to 2% of normal who had been on continuous prophylaxis for 2 months or longer; 81.5% had the severe phenotype (< 1% factor IX activity).
The exclusion of one characteristic, typically used in studies of such patients, was important, according to Dr. Pipe. “Notably, in contrast to all other AAV-mediated, liver-directed gene therapies for hemophilia to date, preexisting anti-AAV neutralizing antibodies were assessed but not used as an exclusion criterion,” he noted, emphasizing that 42.6% of patients had detectable neutralizing antibodies directed to the Ab5 capsid at baseline.
After a lead-in phase of 26 weeks, participants received AMT-061 (2 x 1013 genome copies/kg) as a single 1-hour infusion. Follow-up occurred weekly for 12 weeks, then monthly for the remaining first year, moving to biannual visits for the long-term, 5-year follow-up.
At month 6, mean factor IX activity was 37.2%, a change from baseline of 36.01% (P ˂ .0001). After 26 weeks, Dr. Pipe and colleagues observed similar factor IX expression. They found no correlation of pre-existing neutralizing antibodies with factor IX activity up to a titer of 678.2 (R2 = 0.078), confirming findings from phase 1/2 and phase 2 studies of AMT-160.
Compared with the lead-in period, total cumulative bleeds decreased by 83% (123 vs 21, respectively) within the first 26 weeks post-dosing, and the incidence of treated bleeding events decreased by 91% (107 vs 10). In addition, 72% of patients experienced no bleeds, compared with 30% of patients during the lead in.
In the per-protocol population, 98% of patients discontinued prophylaxis and remained prophylaxis-free, with reduced factor IX usage from 290,769 IU/yr/patient to 12,537 IU/yr/patient.
“The most common safety findings were transaminase elevations requiring steroid treatment and infusion-related reactions, supporting a safety profile that is consistent with early-phase studies,” said Dr. Pipe.
All 9 patients who required steroid treatment for transaminase elevations were able to discontinue steroid use before week 26, with a preservation of factor IX activity in the mild range (8%–39%). Despite infusion-related reactions in 7 patients, all but 1 successfully completed infusion.
In all, 324 adverse events occurred in 53 patients, of whom 37 had 63 treatment-emergent adverse events. Most adverse events (76.2%) were mild, with influenza-like illness (13.0%), headache (13.0%), and increased alanine aminotransferase (13.0%) being the most common.
Final analysis of HOPE-B is planned in 1 year.
Disclosures: Dr. Pipe has disclosed consultancy for HEMA Biologics, Catalyst Biosciences, CSL Behring, ApcinteX, Takeda, uniQure, Siemens, Sangamo Therapeutics, Sanofi Genzyme, and Spark Therapeutics; and consultancy and contracted research for Bayer, BioMarin, Freeline Therapeutics, Novo Nordisk, Roche/Genentech.
Mycophenolate-steroid combination effective for newly diagnosed immune thrombocytopenia
Presenter: Charlotte Ann Bradbury, MD, MSc, PhD
Adding mycophenolate (MMF) to first-line corticosteroid treatment is effective and well-tolerated in select patients with newly diagnosed immune thrombocytopenia (ITP), and may reduce the risk of refractory or relapsed disease by as much as 50%, according to results from a trial known as FLIGHT.
Based on the results, “MMF may be considered first-line, alongside a short course of corticosteroids for patients with ITP,” said presenter Charlotte Ann Bradbury, MD, MSc, PhD, from the University of Bristol, City, UK. “MMF seems to approximately halve the risk of refractory or relapsed ITP.”
The currently recommended first-line treatment for ITP is high-dose corticosteroids, “but there are several downsides to this approach,” she said. Most patients suffer side effects, and about one-third discontinue treatment or need dose reductions due to these side effects.
The response to corticosteroids is heterogeneous, with up to 30% of patients refractory to treatment, 70% to 90% suffering relapse, and only 20% reaching long-term remission, she said.
FLIGHT is an open-label, multicenter, randomized study of first-line treatment pathways for newly diagnosed ITP, comparing the results of standard steroid treatment to combined treatment with steroids and MMF.
A total of 120 patients over age 16 with a platelet count less than 30 x 109/L and a need for first-line treatment were randomized to treatment with either corticosteroid alone (dexamethasone or prednisolone) or corticosteroid plus MMF. The mean age of patients was 54, 27.5% were over age 70, and 65% were men, and their mean platelet count at baseline was 7.2 x 109/L.
After a mean follow-up of 18 months, significantly fewer treatment failures were observed in patients treated with the corticosteroid-MMF combination compared with those treated with corticosteroids alone (22% vs 44%, respectively; adjusted hazard ratio 0.41; 95% confidence interval, 0.21–0.80; P = .0064). Likewise, significantly more complete or partial responses occurred in patients treated with the combination, and significantly fewer patients in the combination arm were refractory to treatment (6.8% vs. 24.6%; P = .011).
“Interestingly, at 2 weeks, the responses were very similar between the 2 groups, and this very much reflects the slower mechanism of action of MMF,” said Dr. Bradbury.
The incidence of side effects was also similar in patients treated with corticosteroids plus MMF and those treated with corticosteroids only, with the most common being corticosteroid-related effects, including weight gain (28.8% vs 34.4%, respectively; P = .56), difficulty sleeping (35.6% vs 27.9%; P = .43), and mood changes (30.5% vs 34.4%; P = .70).
The incidence of infection (23.7% vs. 23.0%; P = 1.0) and neutropenia (0% vs 6.6%; P = .12) was similar between the 2 groups, and no differences were found in the rate of gastrointestinal side effects (33.9% vs. 24.6%; P = .32).
No intracranial hemorrhages or fatal bleeds and no splenectomies occurred in either group.
In comparing patients treated with the corticosteroid-MMF combination and those treated with corticosteroids alone, bleeding events (22.0% vs 24.6%, respectively; P = .83) and rescue treatments including blood transfusion (5.1% vs 1.6%; P = .36), platelet transfusions (3.4% vs 0%; P = .24), tranexamic acid (8.5% vs 9.8%; P = 1.0), and intravenous immune globulin (13.6% vs 16.4%; P = .80) were all similar, in addition to the rate of hospital admissions (18.6% vs 14.8%; P = .63).
There were no significant differences in quality-of-life measures between the treatment groups.
At final follow-up, 56% of patients treated with corticosteroids alone did not require second-line treatment, running counter to findings from previous studies.