scholarly journals Progression of Central Nervous System Vasculopathy in Young Adults with Sickle Cell Anemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2290-2290
Author(s):  
Grace Champlin ◽  
Scott Hwang ◽  
Guolian Kang ◽  
Juan Ding ◽  
Jeremie H. Estepp ◽  
...  
Keyword(s):  
Young Adults ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Brain Mri ◽  
Brain Lesions ◽  
Advisory Committees ◽  
Cerebral Vessel ◽  
Vessel Stenosis ◽  
Disease Modifying

Introduction Silent cerebral infarcts (SCI) and cerebral vessel stenosis are common and progressive in sickle cell anemia (SCA). Most data regarding brain lesions in SCA are cross-sectional or derive from pediatric cohorts with short follow-up not spanning the transition into adulthood. While hydroxyurea and transfusions may reduce the incidence of SCI and abnormal transcranial Doppler (TCD) in children with SCA, data on the effectiveness of these therapies in young adults are lacking. We tested the hypothesis that SCI and cerebral vessel stenosis progressed in young adults with SCA, relative to their childhood years. In addition, we explored the relationship between progression of brain vasculopathy and exposure to disease-modifying therapy. Methods We obtained brain magnetic resonance imaging (MRI) and MR angiography (MRA) in adults with SCA (HbSS or HbSβ0-thalassemia) on chronic transfusions or hydroxyurea. Participants were recruited from the IRB-approved longitudinal cohort study, Sickle Cell Clinical Research and Intervention Program (Hankins et al., PBC 2018). Participants were ages 18.0 to 32.0 at adult imaging and had at least one prior MRI/MRA between 0 and 17.9 years. Pediatric MRI/MRAs were performed for clinical indications (e.g., neurologic concern). All pediatric and adult MRI/MRAs had similar imaging protocols and were centrally reviewed by a neuroradiologist. SCIs were defined as focal T2-weighted or FLAIR hyperintensity. MRIs were considered abnormal if SCI or overt strokes were present. MRI progression was defined as new SCI or new overt strokes. Vessel stenoses were graded using a validated vasculopathy scale from 0 to 6 (Helton et al., Blood 2014). Abnormal MRA was defined as a score ≥1 and progression as any increase in the vasculopathy grading. We retrospectively ascertained childhood TCDs, treatments, overt strokes, and transient ischemic attacks (TIA, <24 hours neurologic symptoms with no imaging change). The proportion of abnormal brain MRI/MRA was calculated for the participants' pediatric (0-11.9), adolescent (12.0-17.9), and young adult (18.0-32.0) years and compared using multivariate generalized linear mixed model. Multivariate logistic regression investigated the association of exposure to hydroxyurea or chronic transfusion with MRI/MRA progression from child to adulthood. Results Forty-one young adults with SCA, all African American, median age 19.0 years, (range 18.0-31.5) were included (Table 1). All received disease-modifying therapy prior to adult MRI/MRA; median duration of hydroxyurea was 10.4 years (range, 0.3 to 20.35) and chronic transfusion was 9.2 years (range, 2.5 to 14.6). Indications for chronic transfusion were: abnormal TCD (N=6), overt stroke (N=4), recurrent vaso-occlusive events (VOE) (N=1), and chronic kidney disease (N=1). Indications for hydroxyurea were: VOE (N=27), overt stroke (N=1), and abnormal TCD (N=1). The total follow-up time from pediatric to adult brain MRI/MRA was 804 person-years, during which 2 patients had new strokes and 5 had TIAs. Progression of MRI and MRA occurred in 12 (29%) and 8 (20%) young adults, respectively, in relation to their pediatric exams (p=0.04 and p=0.01), both among hydroxyurea (Figure 1a) and transfusion (Figure 1b) groups. Both MRI and MRA progression occurred more frequently among those with prior stroke or conditional or abnormal TCD velocities, p=0.015. Controlling for age at adult imaging, exposure to hydroxyurea was associated with decreased probability of MRI progression (OR=0.05, 95%CI: 0.01~0.52, p=0.01), but not MRA (OR=0.22, 95%CI: 0.02~2.34, p=0.2). When further adjusting for transfusions, exposure to hydroxyurea was still associated with decreased probability of MRI progression (OR=0.05, 95%CI: 0.4~0.64, p=0.021) but not transfusions (OR 0.94, 95%CI: 0.16~5.39, p=0.95). Conclusion Close to a quarter of young adults with SCA treated with disease-modifying therapies for approximately a decade, experienced progression of brain lesions despite treatment with disease-modifying therapies. Among patients exposed to hydroxyurea, less progression of SCIs occurred. Overt stroke or TCD elevation in childhood increased the risk of brain lesion progression. In children with SCA, the presence of SCI and vessel stenosis in childhood should prompt consideration of alternative treatments given the evidence that brain lesions progress as they emerge into adulthood. Disclosures Kang: MBIO: Other: St. Jude Children's Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Estepp:Forma Therapeutics: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Eli Lilly and Co: Research Funding; Pfizer: Research Funding; Esperion: Consultancy. Ataga:Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Modus Therapeutics: Honoraria; Emmaus Life Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. King:Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; Cell Works: Consultancy; Bioline: Consultancy; Celgene: Consultancy; Amphivena Therapeutics: Research Funding; Tioma Therapeutics (formerly Vasculox, Inc.):: Consultancy; RiverVest: Consultancy; WUGEN: Equity Ownership. Wang:Agios Pharmaceuticals: Consultancy; Novartis: Consultancy. Hankins:NHLBI: Honoraria; ASPHO: Honoraria; Novartis: Research Funding; LYNKS Foundation: Research Funding; Bluebird Bio: Consultancy; NHLBI: Research Funding; Global Blood Therapeutics: Research Funding; National Committee for Quality Assurance: Consultancy.

Real World Evidence of Prescription Patterns and Effect of Oxbryta (voxelotor) for Patients with Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 31-32
Author(s):  
Nirmish Shah ◽  
Ahmar Urooj Zaidi ◽  
Michael U. Callaghan ◽  
Darla Liles ◽  
Clarissa E. Johnson ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Real World ◽  
Research Funding ◽  
Cell Disease ◽  
Advisory Committees ◽  
Real World Evidence ◽  
Disease Modifying

Background: Sickle cell disease (SCD) is a chronic illness characterized by anemia, recurrent severe pain and recurrent organ damage, affecting approximately 100,000 persons in the United States. Prior to November 2019, FDA approved SCD disease-modifying treatments included only hydroxyurea (HU) and L-glutamine. However, voxelotor (Oxbryta®) was recently approved under an accelerated approval based on the HOPE study for the treatment of adult and pediatric patients with SCD 12 years of age and older. We aimed to provide real world evidence of the types of patients prescribed voxelotor and preliminary evidence of potential treatment effects. Methods: Patient records were reviewed from five medical centers with comprehensive sickle cell care. All patients prescribed voxelotor from Nov 25, 2019 to July 31, 2020 were included in our analysis. Data reviewed included: patient demographics, hydroxyurea use, as well as pre- and post- voxelotor changes on red cell transfusion number, vaso-occlusive crisis (VOC) and hemoglobin (Hb) values. In addition, voxelotor dosage changes, side effects, and patients perception on impact on their health were recorded. Descriptive and summary statistics were used to provide results. Results: We reviewed data from 60 patients (18 pediatric and 42 adult), across the five centers, who were prescribed voxelotor. Mean age was 33 (SD 13.8) years old with 63% female patients. All patients were African-American/Black and 96% were HbSS (2% Hb SC and 2% HbSOArab). Eighty (80)% were on hydroxyurea, 20% were on chronic transfusions, and 10% were on erythropoietin stimulating agents when prescribed voxelotor. Mean baseline hemoglobin during the 3 months prior to initiation was 7.38 g/dL (SD 1.46) with all patients started at the recommended dose of 1500mg. Annualized VOC events for the year prior to starting voxelotor was 0.62 (SD) or 7.44 VOCs per year. Across all sites, 31 patients were prescribed voxelotor but had either not initiated drug, not returned for follow up labs at time of analysis, or refused to take drug once approved (n=1). Nine patients had only 1 month of follow labs to review and an additional 18 patients with 3 months of follow up labs. These 27 patients were followed for an average of 6.0 months (SD 7.7) on treatment with 4 patients (15%) requiring dose adjustment to 1000mg. Dose adjustments were for side effects including abdominal pain, diarrhea, loose stools and nausea/vomiting. One patient had dosing changed from daily to three times a day. Average hemoglobin during steady state after 1 and 3 months of treatment were 8.6 g/dL (SD 1.8) and 8.0 g/dL (SD 1.8), respectively. In addition, 52% increased by 1g/dL at 1 month (n=21) and 44% increased by 1g/dL at 3 months (n=18). The mean maximum hemoglobin obtained during the 3-month period following initiation of voxelotor was 8.9 (SD 2.1) g/dL. During follow up visits, several patients reported 'more energy' and improvement in 'morning achiness' and 'quality of life', while a few patients noted no change in stamina or well-being. Three patients (5%) had drug discontinued due to becoming pregnant, unexplained elevation of liver enzymes, and due to excessive abdominal pain and nausea. Annualized VOC rates after voxelotor initiation were numerically decreased, although limited by short follow up. Conclusion: We present real world evidence of prescribing patterns and initial outcomes from the use of newly approved voxelotor. We found the majority of patients prescribed voxelotor were the HbSS genotype, on hydroxyurea, and with a mean baseline Hb &lt;7.5 g/dL, indicating an initial focus on more anemic patients. Interestingly, one-fifth of the prescribed patients where on chronic transfusions. Consistent with the HOPE trial, the average Hb levels was found to have increased at 1 month and 3-month follow up. Our preliminary results support an overall increase in hemoglobin in patients treated with voxelotor and we aim to continue following patients over a longer follow up period. This provides important real-world evidence for this newly approved disease-modifying therapy for SCD. Disclosures Shah: Alexion: Speakers Bureau; CSL Behring: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau; Bluebird Bio: Consultancy. Zaidi:Global Blood Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Emmaus Life Sciences: Consultancy, Honoraria; Imara: Consultancy, Honoraria; bluebird bio: Consultancy, Honoraria; Cyclerion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Callaghan:Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Research Funding; Sancillio: Other; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NovoNordisk: Other, Speakers Bureau; Biomarin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; Alnylum: Current equity holder in publicly-traded company; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Spark: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Hema Biologics: Honoraria, Membership on an entity's Board of Directors or advisory committees. De Castro:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; FORMA Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlycoMimetics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Transition Continuity Promotes Long-Term Retention in Adult Care Among Young Adults with Sickle Cell Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4676-4676
Author(s):  
Anjelica C. Saulsberry ◽  
Kristen Howell ◽  
Joacy Mathias ◽  
Jerlym S. Porter ◽  
Jason R. Hodges ◽  
...  
Keyword(s):  
Young Adults ◽  
Environmental Factors ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Transition Services ◽  
Location Model ◽  
Pediatric Care ◽  
Adult Care ◽  
Advisory Committees

Introduction: During transition from pediatric to adult care, young adults with sickle cell disease (SCD) experience increased acute healthcare utilization and mortality. Functional transitional programs maintain care quality; however, there is a dearth of program outcomes concerning adult care retention. The St. Jude Transition to Adult Care Program is embedded within a co-located medical home for SCD spanning the ages of 12-25 years. The co-location model bridges pediatric and adult care at three levels: (1) hematology provider (2) neuropsychologist and (3) transition nurse coordinator. Previous work demonstrated that young adults who receive care within a co-located transition model of care do not have the typical increase in acute care utilization during transition (Nolan, AJH 2017). Here, we tested the hypothesis that individuals who participated in the co-location model until age 25 years have greater retention in adult care 12- or 24- months after engaging in adult care, compared to those who only received pediatric co-location transition services (until age 18). Further, we explored adult environmental factors as predictors of retention in adult care at 12- and 24- months. Methods: With IRB approval, we analyzed the outcomes of participants of the longitudinal cohort study Sickle Cell Clinical Research and Intervention Program (SCCRIP, PBC 2018), who completed transfer from pediatric to adult care from January 2007 to December 2017. Participants were excluded if they did not have enough time in adult care for the 12- and 24-month retention analysis. Adult care retention was defined as continuation with the same provider for ≥12 or ≥24 months post-pediatric care and was compared among adults who transferred to adult care within the co-location model vs. those who did not. Chi-square tests were used to test associations between demographics and co-location model exposure. Logistic regression estimated the association between care abandonment (defined as voluntarily discontinuing pediatric care or dying before 12- or 24- months from initiating adult care) and co-location status at 12- and 24- months. Each model was tested for effect modification and confounding by the following variables: sex, genotype, year of last pediatric visit, and age at transfer. Fisher's Exact Test investigated predictors of adult care retention within the adult co-location model including employment status, education level, crowding, marital status, household income, and health insurance status during the first year of adult care. P-values <0.05 were significant. Results: Of the 364 patients who transferred to adult care, 211 (58.0%) participated in the transition co-location model. Fifty-three (14.5%) individuals were excluded from the 12-month analysis due to having <12 months of adult care opportunity (Figure 1A). Of the 311 participants included (51.5 % male; 63% HbSS/HbSβ0-thalassemia), the median age at last pediatric visit was 18 years (range 13 to 20). There was a significant difference in exposure to each transition model based on year of adult care transfer (Table 1). Those in the co-location model had a 47% significantly decreased odds of abandoning care within 12 months of transfer to adult care when compared to those in the non-co-location model when controlled for year of last pediatric visit (Figure 2; p=0.045). There were 91 (25%) individuals excluded from the 24-month analysis due to having <24 months of adult care opportunity (Figure 1B). Of the 273 participants included (52.01% male; 62.64% HbSS/HbSβ0-thalassemia), those within the co-location model until age 25 years had 52% significantly decreased odds of abandoning care within 24 months of transfer to adult care when compared to those in the co-location model in childhood only. (Figure 2; p=0.046). Exclusion of individuals who died yielded similar findings relative to the duration of co-location exposure and adult care retention. Within the adult co-location model, environmental factors were collected on 31 adults (median age 22 years, range 20-26). Participants who transfer earlier (17 vs. 18 years) was predictive of less attrition at 24 months (p= 0.014). No other environmental factors were significant. Conclusion: Continuity of providers from pediatric to adult care may increase long-term retention in adult care. Longitudinal monitoring of adult outcomes is critical to identifying the efficacy of transition services. Disclosures Ataga: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Emmaus Life Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Modus Therapeutics: Honoraria. Hankins:ASPHO: Honoraria; NHLBI: Honoraria; National Committee for Quality Assurance: Consultancy; Global Blood Therapeutics: Research Funding; NHLBI: Research Funding; LYNKS Foundation: Research Funding; Novartis: Research Funding; Bluebird Bio: Consultancy.

scholarly journals Clonal Tracking By Whole Genome Sequencing Permits Comprehensive Mapping of the Genomic Landscape in Pre- and Post-Gene Therapy Sickle Cell Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 559-559
Author(s):  
Alyssa H. Cull ◽  
Michael Spencer Chapman ◽  
Marioara Ciuculescu ◽  
Emily Mitchell ◽  
Myriam Armant ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Stem Cell ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Phylogenetic Trees ◽  
Insertion Site ◽  
Advisory Board ◽  
Advisory Committees ◽  
Genomic Landscape

Abstract Recent advances in clonal stem cell tracking strategies have enabled interrogation of unperturbed human hematopoiesis. Whole genome sequencing (WGS) can be used to map the clonal dynamics of hematopoietic stem and progenitor cells (HSPCs) by employing spontaneous somatic mutations as unique clonal tags (Lee-Six et al., Nature, 2018). These tags allow for retrospective analysis of individual stem cell clones and the construction of phylogenetic trees mapping out stem cell relatedness, with mutations being acquired in a near-linear fashion over the course of an individual's life. The unprecedented level of information obtained in these studies is particularly well-suited to understanding genomic changes in gene therapy trials aimed at curing diseases such as sickle cell disease (SCD). In addition to mapping relatedness between stem cells, sequencing data can be used to better define mutational signatures for HSPC clones that have been successfully gene-modified as well as those that lack an integrated copy of the therapeutic vector. Given this method's ability to identify low frequency mutations in individual HSPC clones, mutations with extremely low variant allele frequencies can be detected much more readily than through traditional bulk sequencing approaches, something that is particularly relevant given recent safety concerns in some SCD gene therapy trials. In this study, we have mapped the clonal dynamics of HSPCs obtained from pre- and post-gene therapy samples from 4 SCD patients who have undergone autologous gene therapy performed using a BCL11A shmiR lentivirus vector (NCT 03282656, 12-36 months follow-up). HSPCs from mobilized peripheral blood (pre-gene therapy), bone marrow aspirates (both pre- and post-gene therapy) or unmobilized peripheral blood (post-gene therapy) were expanded as single clones and 1508 individual colonies were then sequenced using WGS to an average sequencing depth of 12.3x. Initial results indicate that the mean mutation burden per cell in a pre-gene therapy sample is elevated for some patients compared to what would be expected based on patient age in similar studies. In pre-gene therapy samples, the structure of the phylogenetic trees appeared to be highly polyclonal, indicating that there were no significant clonal expansion events prior to gene therapy. In one patient where we undertook extensive profiling, approximately 15-20 excess mutations per HSPC were observed across the entire genome 24 months after transplantation, presumably acquired as a consequence of gene therapy and/or reconstitution post-transplantation, which is equivalent to approximately one year of normal ageing without a transplantation intervention. However, no clonal expansions or driver mutations were identified at this 24 month follow-up timepoint, suggesting that no strong selective advantage or pre-leukemic events were present prior to or following the gene therapy protocol. Extending this approach to a wider range and larger number of patients will allow for comprehensive mapping of the genomic landscape and clonal evolution of stem cells in sickle cell patients and will also set the stage for improved assessment of safety and potential leukemia-initiating events in the context of gene therapy. Disclosures Esrick: bluebird bio: Consultancy. Williams: bluebird bio: Membership on an entity's Board of Directors or advisory committees, Other: Insertion Site Analysis Advisory Board, Patents & Royalties: BCH licensed certain IP relevant to hemoglobinopathies to bluebird bio. The current license includes the potential for future royalty/milestone income. Bluebird has indicated they will not pursue this as a clinical program and BCH is negotiating return of, Research Funding; BioMarin: Membership on an entity's Board of Directors or advisory committees, Other: Insertion Site Advisory Board; Beam Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; Emerging Therapy Solutions: Membership on an entity's Board of Directors or advisory committees, Other: Chief Scientific Chair; Geneception: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; Alerion Biosciences: Other: Co-founder (now licensed to Avro Bio, potential for future milestones/royalties); Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee, Novartis ETB115E2201 (eltrombopag in aplastic anemia). Advisory fees donated to NAPAAC.; Orchard Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Membership on a safety advisory board (SAB): SAB position ended 05/20/2021. Co-founder , Patents & Royalties: Potential for future royalty/milestone income, X-SCID. Provided GMP vector for clinical trial, Research Funding. Campbell: Mu Genomics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Kent: STRM.bio: Research Funding.

scholarly journals Clinical and Biomarker Predictors for Avascular Necrosis in Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3091-3091
Author(s):  
Michael Rabaza ◽  
Maria Armila Ruiz ◽  
Liana Posch ◽  
Faiz Ahmed Hussain ◽  
Franklin Njoku ◽  
...  
Keyword(s):  
Risk Factors ◽  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Avascular Necrosis ◽  
Sickle Cell ◽  
Research Funding ◽  
Medical Attention ◽  
Cell Disease ◽  
Advisory Committees ◽  
Early Management

Abstract Introduction Sickle cell disease (SCD) affects 1 in 365 African Americans and approximately 25 million people world-wide. A common skeletal system complication is avascular necrosis (AVN), which can cause substantial pain and a reduced quality of life. While early management of AVN is focused on increasing range of motion with physical therapy and pain relief, there are no clear predictors for who is more likely to develop AVN and earlier institution of these preventive measure could help decrease disease progression. Vascular endothelial growth factor (VEGF) is a biomarker of endothelial injury and may indicate reduced vascular supply to the femoral or humeral head. Here we describe potential risk factors and biologic pathways for AVN in SCD, as understanding these may lead to improvements in future monitoring, early detection, and early intervention practices. Methods We investigated clinical and laboratory risk factors associated with AVN in a cohort of 435 SCD patients from our center. Blood samples, clinical, and laboratory data were collected at the time of enrollment during a clinic visit. Genotyping for alpha thalassemia was performed by PCR and the serum concentration of VEGF was measured by ELISA. AVN status was confirmed by review of the medical record and available imaging. We conducted a cross-sectional analysis comparing categorical and linear variables by AVN status using the chi-square and Kruskal-Wallis test, respectively. The independent association of the clinical and laboratory variables with AVN status was determined by logistic regression analysis. The initial model included variables with a P-value &lt; 0.1 on univariate analysis and the final model was ascertained by stepwise forward and backward selection. Median values and interquartile range (IQR) are provided. Results The median age of the cohort was 32 (IQR, 24 - 43) years, 57% (250/435) were female, and 46% (198/435) were on hydroxyurea. AVN was observed in 34% (149/435) of SCD patients. SCD patients with AVN were older, had more frequent vaso-occlusive crises requiring medical attention, and had a higher body mass index (Table I) (P ≤ 0.002). We measured VEGF in 241 of the SCD patients with serum samples available at the time of enrolment. Serum VEGF concentrations trended higher in SCD patients with versus without AVN (420 vs. 359 pg/mL, respectively; P = 0.078). In the multivariate analysis model, AVN was independently associated with increased number of vaso-occlusive crises (OR 1.1, 95% CI: 1.0 - 1.14; P = 0.02), AST concentration (natural log OR 0.5, 95% CI: 0.2 - 0.9; P = 0.03), VEGF concentration (natural log OR 1.4, 95% CI: 1.0 - 1.9; P = 0.047), and tobacco use (OR 1.9, 95% CI: 0.9 - 3.7; P = 0.078). Discussion In conclusion, we demonstrate a high prevalence of AVN in an adult cohort of SCD patients. The presence of AVN was independently associated with a greater frequency of vaso-occlusive pain episodes, which may demonstrate a shared pathophysiology between AVN and vaso-occlusion that merits further investigation. We demonstrate that serum VEGF concentrations are higher in SCD patients with AVN and may be a clinical tool to identify those at high-risk and for earlier intervention for this complication. Figure 1 Figure 1. Disclosures Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Predictors of Maternal Morbidity Among Participants Enrolled in the Sickle Cell Disease Implementation Consortium Registry

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-3
Author(s):  
Rita V Masese ◽  
Dominique Bulgin ◽  
Liliana Preiss ◽  
Mitchell Knisely ◽  
Eleanor Stevenson ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Transfusion Requirement ◽  
The United States ◽  
Acute Chest Syndrome ◽  
Maternal Outcomes ◽  
Maternal Complications ◽  
Advisory Committees ◽  
Increased Risk

Introduction Pregnancy in sickle cell disease (SCD) is associated with an exacerbation of SCD-related complications and an increased risk of maternal complications. The increased risk is partly due to physiologic adaptations in pregnancy, which include increased metabolic demands and a hypercoagulable state. The maternal death rate for SCD is 629 per 100,000 deliveries, compared to 12 per 100,000 deliveries in black women and 6 per 100,000 deliveries in the general population (Raider et al., 2016). Studies on maternal and perinatal outcomes of patients with SCD present inconsistent and conflicting results. Some studies have reported an increase in maternal complications such as pre-eclampsia, acute chest syndrome and thromboembolic events, while other studies have reported no significant risk in adverse maternal outcomes. The inconsistent findings reported in prior studies may be attributed to small sample sizes and single-centered sites. Our study aims to determine the prevalence and predictors of maternal morbidity among participants enrolled in the SCD Implementation Consortium (SCDIC) registry, which is the largest, most geographically diverse SCD participant sample in the United States. Methods This cross-sectional study included women enrolled in the SCDIC registry who had at least one pregnancy event. The SCDIC is composed of eight academic SCD centers across the United States and one data-coordinating center. Participants were enrolled in the SCDIC registry if they were 18 to 45 years of age and had a confirmed diagnosis of SCD. Enrolled participants completed a series of surveys that collected sociodemographic information, SCD and pregnancy history and data abstractions of participants' medical records was completed. Medical complications queried during pregnancy included: vaso-occlusive episodes, acute chest syndrome, blood transfusion requirement, preeclampsia, maternal diabetes and deep venous thrombosis. Descriptive analysis of sociodemographic, clinical and maternal characteristics was conducted. Bivariate analysis was performed using Chi-Square test, Mann-Whitney U test, t-test, and logistic regressions, as appropriate. A p-value of ≤ 0.05 was considered statistically significant for all analysis. Results The study sample included 743 women who had at least one pregnancy event, and a total of 1066 live births. Almost all women (96.3%) were African American, with a median age of 21 years (inter-quartile range of 19 to 23 years) at first birth. The majority had Hb SS SCD genotype (69.5%; 513 of the 738 with SCD genotype data). Of all reported pregnancies, participants did not use hydroxyurea during conception (78%), and pregnancy (84.5%). Only 2.7 % of the women reported using fertility drugs or assisted reproductive procedures. Seventy five percent of the pregnancies that ended in live births had maternal complications. The leading complications were vaso-occlusive episodes (61.2%), pregnancy requiring blood transfusion(s) (33.2%), preeclampsia (15.4%), deep venous thrombosis (5.6%) and acute chest syndrome (7.7%). When the pregnancies were stratified by SCD genotype, women with Hb SS had a higher occurrence of acute chest syndrome (63.4% vs. 26.7%), transfusion requirement (70.8% vs. 21%) and preeclampsia (66.7% vs 22.4%). In the univariate logistic regressions, multiparous women, with a history of adverse maternal outcomes in a previous pregnancy, had higher odds of vaso-occlusive episodes (OR: 3.42; 95% CI: 2.42-4.94) acute chest syndrome (OR:4.99; 95% CI:2.56- 9.48), transfusion requirement (OR:3.86; 95% CI:2.64- 5.69), and pre-eclampsia (OR:3.36; 95% CI:2.05-5.45). Conclusion In this large multicenter registry, we found pregnant women with SCD have significant maternal complications. Early antenatal care by healthcare providers knowledgeable about risk factors for adverse maternal outcomes in SCD is essential improve maternal and fetal outcomes and reduce the maternal death rate for SCD. Disclosures Hankins: Novartis: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria. Treadwell:Global Blood Therapeutics: Consultancy; UpToDate: Honoraria. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter:SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; Medscape: Honoraria; Guidepoint Global: Honoraria; bluebird bio, inc: Consultancy, Honoraria; Sanofi: Consultancy. Glassberg:Pfizer: Research Funding; Global Blood Therapeutics: Consultancy; Eli Lilly and Company: Research Funding. Shah:Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; CSL Behring: Consultancy; Bluebird Bio: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau.

scholarly journals Sickle-Cell Disease in Greece: Patient Reported Outcomes Related to Clinical Complications, Treatment Choices and Attitudes, Beliefs and Trends Affecting Potential Participation in Clinical Trials - a Greek National Multicentric Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4838-4838
Author(s):  
Sophia Delicou ◽  
Michael D. Diamantidis ◽  
Konstantinos Manganas ◽  
Eftychios Eftychiadis ◽  
Despoina Pantelidou ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Educational Status ◽  
Current Treatment ◽  
Advisory Committees ◽  
Chi Square ◽  
Clinical Complications

Background: Sickle cell disease (SCD) is an autosomal recessive disorder caused by a point mutation in the β-globin chain of hemoglobin that forms hemoglobin S. It is clinically characterized by complicated episodes of veno-occlusive crises (VOC), emergency room (ER) visits and uncomplicated inpatient admissions. Aim: We investigated the clinical complications and treatment choices of a large cohort of Greek SCD patients, representative of the whole country. Most importantly, this study aimed to assess patients' attitudes and beliefs regarding their enrollment in clinical trials testing new drugs. We examined the factors influencing such a participation. Patients and Methods: A total of 254 patients from 10 Thalassemia and Sickle Cell Departments across Greece (110 men/144 women), aged 18 - over 65, 210 (82.7%) with β-thalassemia/sickle cell trait and 44 (17.3%) with homozygous SCD participated in the study. The participants had variable educational and socioeconomic background. They all answered an anonymous self-report questionnaire during their medical evaluations between November 2018 and May 2019, including their demographic and clinical characteristics, their current treatment and their opinion regarding a possible participation in a clinical trial for SCD. Descriptive statistical analysis using calculated scale variables and Chi-square test were performed. Results: All participants completed the survey. During the previous year, 64 patients (25.3%) had no admissions for VOC, 128 (50.6%) had 1-5, whereas 21 (8.3%) had 5-10 and 40 (15.8%) more than 10. Except for acute pain crises, the most frequent complications were chronic pain (59%), liver/spleen dysfunction (32.4%), infectious episodes (29.5%), iron overload (23.8%) and pulmonary hypertension (20.1%). In addition to hematological care, patients seeked medical attention from expert physicians for disease complications; 77.6% of the patients reported that they yearly visited a cardiologist, 42.4% an ophthalmologist, 31.9% an orthopedic, 28.4% a pneumonologist, 28.9% a hepatologist, 12.6% an urologist, 14% a nephrologist, 11.9% an infectious disease doctor, 10.1% a pain management specialist and 8.1% a neurologist. The therapeutic approaches included daily folic acid supplementation (86.1%), vaccines (68.3%), hydroxyurea (66.3%), antibiotics (57.1%), simple pain moderators (52.4%), opioids (48.8%) and iron chelators (30.2%). Previous experience in clinical trials was reported by only 17 patients (6.9%). Regarding the patients' attitudes towards a probable clinical trial, 41.3% were positive to try new therapies, 28.3% negative and 30.4% neutral. 67.2% were satisfied with their current treatment, without excluding a potential participation in clinical trials; such treatment satisfaction correlated significantly with older age, lower income and secondary hemochromatosis under chelation treatment (p<0.05). 40% reported that they had been waiting for years for a new treatment, but 43.2% strongly denied becoming an experimental mouse model, whereas 47.3% mentioned that they would trust their doctors' advice correlating positively with male gender and higher income (p<0.05). Lower educational status, prior intake of hydroxyurea and residence/origin in the capital in contrast to the countryside (chi-square, p<0.05) significantly correlated with a potential clinical trial participation. Internet and television information motivated patients to seek more details from their doctor. Concerning the factors rated as the most important for a potential participation in a clinical trial, 7 out of 10 patients of our cohort considered of utmost equal importance the effectiveness of a probable treatment and the relative toxicity. Conclusions: Most SCD patients have chronic complications and visit specialized physicians. Since the participation of larger number of patients in clinical trials is essential for the application of novel drugs, the most important factors of our cohort are the effectiveness of a probable treatment and the relative toxicity, along with the trust to the doctor. These factors are crucial, influencing patients' decision. Even though a proportion of our patients remain skeptical towards clinical trials, an increasing number is willing to participate, which correlates positively with residence in the capital, lower educational status and prior intake of hydroxyurea. Disclosures Kattamis: Apopharma: Honoraria; Vertex: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ionis: Membership on an entity's Board of Directors or advisory committees; ViFOR: Membership on an entity's Board of Directors or advisory committees; Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Symeonidis:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals The Grndad Registry: Contemporary Natural History Data and an Analysis of Real-World Patterns of Use and Limitations of Disease Modifying Therapy in Adults with SCD

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-36
Author(s):  
Alexandra Boye-Doe ◽  
Elizabeth Brown ◽  
Charu Puri-Sharma ◽  
Anjulika Chawla ◽  
Joshua J Field ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Clinical Characteristics ◽  
Reticulocyte Count ◽  
Principal Investigator ◽  
Advisory Committees ◽  
Disease Modifying Therapy ◽  
Disease Modifying ◽  
The Impact

Incremental improvement in care for children with sickle cell disease (SCD), arising from government-funded research over the last 4 decades, resulted in a dramatically reduced childhood mortality. However, the impact of iterative research and disease modifying therapy (DMT) on adults with SCD has not been as strong. Until now, there has been no coordinated, longitudinal, generalizable, natural history study of SCD that allowed for an assessment of the contemporary adult population. Here, we describe demographics at enrollment and cross-sectional clinical characteristics of 570 adults with SCD (SCA, homozygous HbSS or HbSb0 N=387, 68%, and compound heterozygous SCD variant, HbSC or HbSb+ N=183, 32%, Table I) on whom we have evaluable data. These data are from the multi-site REDCap-based prospective Globin Research Network for Data and Discovery (GRNDaD) registry, comprising 11 centers with over 1100 consented adults and children. The objective of this work was to evaluate the cohort at year of entry, including the use and clinical associations with DMT, and to explore indicators of disease progression as patients age. 16% of adults with SCA and 9.6% with variant disease stroke; 60.9% of adults with SCA and 41% with variant disease had a history of acute chest syndrome. Albuminuria was prevalent in both SCA (39.5%) and variant disease (19.4%). 185 adults (185/387, 47.8%) with SCA, previously referred for symptoms in clinic, had recorded tricuspid regurgitant jet velocity measurements, with a significantly abnormal result (&gt;2.7 m/s), in 92 (92/185, 49.7%). At enrollment, 45% of adults with SCA (175/387) and 14% of adults with variant disease (25/183) were on hydroxyurea (HU); 20.4% of adults with SCA were on chronic transfusions (79/387) compared with 7% of adults with variant disease (13/183). One third of all adults with SCA were not on or were not consistently on DMT, and had laboratory evidence for increased hemolysis (Table 1). Adults with SCA who were on HU had a higher MCV and higher HbF than other treatment states (Table 1). However, only 34% (60/175) of adults with SCA on HU were at maximally tolerated dose (MTD), per guideline-based recommendations, i.e. ANC ≤4.0 x109/L. On HU, those in the lowest quartile for ANC (&lt;3.2 x109/L) were older (mean age 35.9 years (95% Confidence Limit (CL) 32.5-39.3) vs. 31.2 (95% CL 28.2 to 34.4) years, P=0.04), had a lower mean reticulocyte count (119 x109/L (95% CL 76-162) vs. 203 (95% CL 129-278), P=0.05), and a higher mean MCV (104.4 fL (95% CL 100.2-108.7) vs. 92.5 (95% CL 87.2-97.8), P=0.0007), compared to those in the highest quartile for ANC (&gt;5.7 x109/L, N=34), but did not otherwise differ (including mean HbF, which was not measured in a standardized way). In older adults with SCD (Table 2), fewer people with SCA than with variant disease were &gt;54 years old, (26/387 HbSS, 7%, vs. 34/183, 19%, respectively). The older adult with SCA had a depressed reticulocyte count and a trend towards a higher creatinine. 45% of adults with SCA were on HU, and only a minority were at MTD, highlighting the challenges to optimal long-term therapy in chronic illness. Those patients not stably on DMT had laboratory evidence for worse anemia and hemolysis, without an evident increase in hospital admissions, perhaps due to a hyper hemolytic phenotype. Despite a more intensive regimen, SCA patients on transfusions had a higher Hgb but did not have hemolysis labs that differed from SCA patients on HU. Further, there was no difference in hospitalizations amongst treatments for SCA, although a decrease in hospitalizations was detectable in variant disease (Table 1). Successful use of DMTs in SCA was challenging even in academic centers, and there was evidence for ongoing hemolysis in treated and untreated patients. These real world data provide useful information about adults (&gt;17 years) with SCD. These data highlight opportunities to improve adherence to therapy (patient-centered) and to prescribing guidelines (provider-centered), and to consider less-burdensome alternatives. Importantly, we found that a large proportion of people with SCA were not on DMT, and with HU often not at MTD. In future, the GRNDaD registry will enable prospective longitudinal real-world analyses of the impact of DMTs and/or newer therapies on clinical outcomes, will enhance quality improvement, and will allow us to more fully explore clinical characteristics, of SCA and variant disease, in the aging adult. Disclosures Puri-Sharma: Bluebird Bio: Current Employment. Chawla:Bluebird Bio: Current Employment. Field:Shires: Research Funding; Ironwood: Research Funding. Neumayr:Emmaus: Consultancy; Bayer: Consultancy; CTD Holdings: Consultancy; Pfizer: Consultancy; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Micelle: Other: Site principal investigator; GBT: Other: Site principal investigator; PCORI: Other: site principal investigator; Novartis: Other: co-investigator; Bluebird Bio: Other: co-investigator; Sangamo Therapeutics: Other; Silarus: Other; Celgene: Other; La Jolla Pharmaceuticals: Other; Forma: Other; Imara: Other; National Heart, Lung, and Blood Institute: Other; Health Resources and Services Administration: Other; Centers for Disease Control and Prevention: Other; Seattle Children's Research: Other. Desai:Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; GBT, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ironwood Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Rockpointe Continuing Medical Education Company: Consultancy. Lanzkron:GBT: Research Funding; HRSA: Research Funding; Ironwood: Research Funding; NHLBI: Research Funding; PCORI: Research Funding; Pfizer: Research Funding; Pharmacy Times Continuing Education: Honoraria; Prolong: Research Funding. Little:Hemex Health, Inc.: Patents & Royalties: Microfluidic electropheresis (patent, no royalties); BioChip Labs: Patents & Royalties: SCD Biochip (patent, no royalties); GBT: Research Funding; GBT: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Research Funding; NHLBI: Research Funding.

scholarly journals T-MDS Is a Distinct Clinical and Pathological Entity Characterized By Better Survival Compared to t-AML

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3377-3377
Author(s):  
Mithun V. Shah ◽  
Rakchha Chhetri ◽  
Urshila Durani ◽  
Monika Kutyna ◽  
Hassan B. Alkhateeb ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
World Health ◽  
Advisory Committees ◽  
Disease Modifying Therapies ◽  
The World ◽  
Blast Count ◽  
Disease Modifying ◽  
Health Organization

Abstract Introduction: Therapy-related myeloid neoplasm (t-MN) includes acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) that occur as a complication of DNA-damaging therapies. The World Health Organization recommends considering t-MN as a single entity. Whether t-MDS and t-AML have distinct characteristics and outcomes is not known. The aim of this study was to compare clinicopathological characteristics and outcomes of t-MDS and t-AML. Methods: All patients diagnosed with t-MN based on the World Health Organization criteria were identified. Bone marrow biopsies, cytogenetic, and next-generation sequencing (NGS) were obtained at the treating physician's discretion. Pathogenic/likely pathogenic variants (PV) were called based on the standard criteria. Overall survival (OS) was calculated from the time of t-MN diagnosis until the last follow up using Kaplan-Meier analysis using Wilcoxon test. For survival analysis comparing chemotherapy to best supportive care (BSC) only, patients were censored at the time of allogeneic stem cell transplant (SCT). Multivariate analysis was performed using Cox proportional hazard method and corrected using false discovery rate (FDR). Statistical analysis was performed using JMP (v14.1, SAS Institute) and significance was defined as P&lt;0.05. Results: We identified 554 patients, of which 180 (32.4%), 365 (65.8%), and 9 (1.6%) presented as t-AML, t-MDS, and t-MDS/MPN respectively. t-MDS/MPN patients were excluded from further analysis due to a small number. Clinical and laboratory characteristics of the t-AML and t-MDS cohorts is shown in Table 1. t-AML patients were significantly more anemic and thrombocytopenic at presentation. As expected, t-AML had a higher peripheral blood and BM blast count. There was no difference in proportion of patients with chromosomal abnormalities, though a statistically significantly higher proportion of t-MDS patients had chromosome 5 abnormality, 5q deletion, monosomy 5, chromosome 7 abnormality, monosomy 7 compared to t-AML patients. On other hand, 11q23 (mixed lineage leukemia, MLL) rearrangement was more common in t-AML compared to t-MDS (9.3% vs. 2.8%, P=0.005). A higher proportion of t-MDS patients had PV detected by NGS compared to t-AML (92.9% vs. 85.6%, P=0.038). A higher proportion of t-MDS patients had PV in TP53 (37.6% vs. 21.4%, P=0.004) and ASXL1 (23% vs. 11.7%, P=0.016) genes; whereas a higher proportion of t-AML patients had PV in RAS (18.9% vs. 9.1%, P=0.013) and WT1 (8.1% vs. 2.9%, P=0.05) genes. One hundred twenty-eight (35%) of 365 t-MDS patients progressed to t-AML. The presence of any chromosomal abnormality at t-MDS diagnosis predicted a higher risk of transformation to t-AML (χ 2 3.9, P=0.03). t-AML patients had a significantly shorter OS compared to t-MDS (9.2 vs. 19.7 months, P&lt;0.0001, Figure A). This difference persisted when stratified by no disease modifying therapies (BSC only) 2 vs. 17 months (P&lt;0.0001, Figure B), as well as among those who received at least one line of chemotherapy (14 vs. 24.6 months, P&lt;0.001). Finally, a higher proportion of patients with t-AML underwent SCT and there was a trend towards improved survival for t-AML patients (vs. t-MDS 52.9 vs. 20.7 months, P=0.07) from the time of transplant. Multivariate analysis for OS performed to control for all the variables that were different at presentation (except for blast count), showed that t-MDS (as opposed to t-AML) phenotype at diagnosis, and undergoing SCT were independent predictors of improved survival (Table 2). Conclusion: t-MDS and t-AML have distinct clinical, cytogenetic, and genetic features at presentation. In the absence of disease modifying therapies, t-AML is a more aggressive phenotype, consistently associated with a shorter survival. Even after controlling adverse risk features, t-AML phenotype had a shorter survival compared to t-MDS. Figure 1 Figure 1. Disclosures Litzow: AbbVie: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Actinium: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Iron Unloading By Therapeutic Phlebotomy in Previously Transfused Children with Sickle Cell Anemia: The Twitch Experience

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1018-1018 ◽  
Author(s):  
Banu Aygun ◽  
Nicole Mortier ◽  
Zora R. Rogers ◽  
William Owen ◽  
Beng Fuh ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Research Funding ◽  
Chelation Therapy ◽  
Venous Access ◽  
Study Entry ◽  
Iron Loading ◽  
Advisory Committees

Abstract Background: TCD With Transfusions Changing to Hydroxyurea (TWiTCH, ClinicalTrials.gov NCT01425307), an NHLBI-sponsored Phase III multicenter trial, compared transfusions to hydroxyurea for maintaining TCD velocities in children with sickle cell anemia who previously received transfusions for abnormal TCD velocities. Iron overload was treated with serial phlebotomy in children randomized to hydroxyurea. At the first scheduled interim analysis, non-inferiority of hydroxyurea was demonstrated and the study was terminated prematurely. Methods: Participants randomized to hydroxyurea received decreasing volumes of monthly transfusions during hydroxyurea dose escalation to maximum tolerated dose (MTD), averaging 6-7 months. During this transfusion overlap period, no chelation therapy was given. After hydroxyurea MTD was reached, transfusions were discontinued and children started monthly phlebotomy if their entry liver iron concentration (LIC) by MRI-R2 (FerriScan®) was ≥2 mg Fe/g dry weight liver (DWL). The prescribed phlebotomy volume was 10 mL/kg (maximum 500 mL) with adjustments for anemia (5 mL/kg for Hb 8.0-8.5 g/dL and held if Hb <8.0 g/dL). Phlebotomy was performed over 30 minutes with immediate equal volume normal saline replacement, typically using peripheral venous access. LIC was assessed at study entry, midpoint (12 months), and exit (24 months/early closure). Ferritin was monitored monthly using a centralized laboratory. Iron loading calculations were based on actual transfusion and phlebotomy volumes. Results: Sixty children (mean age 9.7±3.2 years; range 5.2-19.0 years; 48% male) were randomized to the Hydroxyurea Treatment Arm. The average duration of previous transfusions was 4.5±2.8 years. Almost all (51/60, 85%) had previously received chelation, primarily deferasirox, and 48 (80%) were on chelation therapy at study enrollment. Hydroxyurea MTD was achieved in 57 children (95%), and 54 commenced phlebotomy (two had low iron burden with LIC <2 and one had Hb <8.0 g/dL). A total of 914 phlebotomy procedures were scheduled per protocol for these 54 children and 756 (83%) were fully completed. There were 77 procedures cancelled due to anemia and another 81 procedures cancelled due to planned anesthesia (16), provider preference (14), hydroxyurea-related cytopenia (13), intercurrent illness (11), inadequate iv access (9), family request (5) or other (13). In 94% of phlebotomy procedures that were initiated, the full volume was removed; for the remaining 6% (47 procedures), a reduced volume was removed due to loss of venous access (37), symptoms such as headache or lightheadedness (7), or other reasons (3). A total of 18 Adverse Events (17 Grade 2 and one Grade 3) occurred in 14 participants in association with phlebotomy (2.3% prevalence). The most common complication was light headedness/near-syncope (6) followed by anemia (4), hypotension (3), headache (3), and pain at the venous access site (1). One subject had a syncopal episode followed by transient weakness, which was centrally adjudicated as TIA. An average of 53.6±21.8 mL/kg blood was administered in the hydroxyurea-treated arm, which calculates to an average iron loading of 40.1±16.3 mg Fe/kg, while an average of 112 mL/kg of venous blood was removed by phlebotomy, which calculates to an average iron unloading of 36.1±15.7 mg Fe/kg. For the 54 children who received phlebotomy, the average LIC was 12.0± 9.7 mg/g at study entry, 13.4±10.3 at midpoint reflecting overlap transfusions without chelation, and 9.7±8.9 at study exit reflecting serial phlebotomy, for an average net LIC decrease of 2.3±4.1 mg/g. Average serum ferritin at study entry was 3105±741 ng/mL and 1392±1542 ng/mL at study exit. For 39 children who completed all 24 months of treatment before study closure, the overall average LIC decrease was 3.2±3.8 mg/gram DWL and 10 had final LIC measurements <3 mg Fe/g. Calculated net iron loading was not significantly associated with measured changes in LIC or ferritin. Conclusions: In the TWiTCH trial, phlebotomy was a feasible, safe, well-tolerated, and effective treatment for transfusional iron overload in children with sickle cell anemia. Although initial overlap transfusions without chelation limited the phlebotomy effects, in children who reached hydroxyurea MTD and discontinued chronic transfusions, monthly phlebotomy led to net iron unloading and lower LIC, and significantly reduced iron burden. Disclosures Rogers: Apopharma: Consultancy. Kalfa:Baxter/Baxalta/Shire: Research Funding. Kwiatkowski:Sideris Pharmaceuticals: Consultancy; Luitpold Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Apopharma: Research Funding; Ionis pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shire Pharmaceuticals: Consultancy. Wood:World Care Clinical: Consultancy; Biomed Informatics: Consultancy; Biomed Informatics: Consultancy; Celgene: Consultancy; Celgene: Consultancy; AMAG: Consultancy; Apopharma: Consultancy; Apopharma: Consultancy; AMAG: Consultancy; World Care Clinical: Consultancy; Vifor: Consultancy; Vifor: Consultancy; Ionis Pharmaceuticals: Consultancy; Ionis Pharmaceuticals: Consultancy. Ware:Global Blood Therapeutics: Consultancy; Biomedomics: Research Funding; Bayer Pharmaceuticals: Consultancy; Addmedica: Research Funding; Nova Laboratories: Consultancy; Bristol Myers Squibb: Research Funding.

scholarly journals Germline and Acquired Genetic Variants in Myelodysplastic Syndromes in Young Adults without a Preexisting Disorder or Organ Dysfunction

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4339-4339
Author(s):  
Tzu Hua Chen-Liang ◽  
Ana M Hurtado López ◽  
Laura Palomo ◽  
Teresa Bernal Del Castillo ◽  
Mar Tormo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Young Adults ◽  
Family History ◽  
Board Of Directors ◽  
Research Funding ◽  
Bone Marrow Failure ◽  
Advisory Committees ◽  
Germline Variants ◽  
Very High ◽  
Congenital Syndrome

Abstract Background and Aim:It is increasingly recognized that patients with a de novomyelodysplastic syndrome (MDS) onset as young adults, lacking any other feature of a congenital disorder, may share a pathogenic overlap due to the presence of both germline and somatic variants. Identifying an inherited pathogenic variant has important therapeutic implications beyond family counselling: adapting the selection of sibling donor, the use of highly cytotoxic therapy and the monitoring for other cancer development. However, most studies have focused on patients with suspected inherited disorders based on the presence of physical abnormalities and/or family history. In addition, a mixture of pediatric and adult cases is usually reported. The aim of this study is to characterize the germline and tumor variants in a group of adult MDS patients without accompanying congenital physical anomalies and or family antecedent of bone marrow failure. Methods: We included 72 patients from 15 Spanish centers with a diagnosis of MDS between 18 and 60 years old (y.o). Patients with a previously diagnosed or suspected (one physical anomaly or family history) congenital syndrome were excluded. Diagnoses were made in accordance with the WHO 2016 classification. Whole-exome sequencing (WES) libraries were prepared using SureSelectXT Target Enrichment and sequenced on a HiSeq4000 platform (IlluminaInc.). Mean number of reads per sample was 138,726,017 with a Phred Quality Score >30 in 95.05% of bases. Read mapping sequence alignment and variant calling were performed using Biomedical Workbench (Qiagen). WES was performed on 72 tumor and 32 paired germinal DNA (buccal swab). To identify potential germline-causal mutations, a selection tool was implemented incorporating 239 genes associated with cause or predisposition to bone marrow failure or cancer. Variants with an ExAC, TOPMed and/or European 1000 Genomes minor allele frequency ≥0.01 were discarded. Results: The median age at diagnosis was 49 y.o. The cohort was categorised into two groups, less or equal 50 y.o. (62.5%) and between 50 and 60 y.o. (37.5%). In the first group, the frequency according to the WHO classification were 12% MDS with single lineage dyplasia (MDS-SLD), 8% MDS with ring sideroblasts (MDS-RS), 11% MDS with multilineage dyplasia (MDS-MLD), 24% MDS with excess blasts(MD-EB), 4% MDS with isolated del(5q)(MDS-del5q), 4% MDS unclassifiable and 4% chronic myelomonocytic leukemia (CMML). Meanwhile, in the group with age more than 50 y.o., the subtypes were 3.7% MDS-SLD, 7.4% MDS-RS, 29.6% MDS-MLD, 40.7% MD-EB, 3.7% MDS-del5q, and 14.8% CMML.Patients less or equal 50 y.o. were stratified based on IPSS-R as very low (4%), low (64%), intermediate (20%), high (12%) and very high (0%); and the group of more than 50 y.o. as very low (14.8%), low (33.3%), intermediate (29.6%), high (11.1%) and very high (11.1%).The mean number of somatic mutations was 0.68 in patients with less or equal 50 y.o. and 1.37 in those between 50 and 60 y.o., p=0.033 (U Mann-Whitney); and regarding germline variants, the first group mean number was 2.44 (p25-75, 1-3) and the second group showed a mean of 1.85 (QI 25-75, 1-3), p= 0,331.In the whole cohort, germline variants were found in 62 out of 72 patients, with the following frequencies: ATR(N=5, 6.9%), followed by BARD1(N=5, 6.9%), ERCC6L2(N=4, 5.6%), MSH6(N=4, 5.6%), TCIRG1(N=4, 5.6%), NBEAL2(N=4, 5.6%), ASXL1(N=3, 4.2%), ATM(N=3, 4.2%), MPL(N=3, 4.2%), NF1(N=3, 4.2%), RECQL4(N=3, 4.2%), SAMD9L(N=3, 4.2%), WRN(N=3, 4.2%).Among germline variants, those reported previously as pathogenic or likely pathogenic, or involving genes associated with familial MDS/AML included: ERCC6L2(N=4, 5.6%), SAMD9L(N=3, 4.2%), and one case mutated for DDX41, FANCC, JAK2, MSH6, SETBP1, MUTYH, BRCA1and RECQL4. In the whole cohort, somatic variants were found in 38 patients, with the following frequencies: TP53(N=7, 9.7%), ASXL1(N=7, 9.7%), SETBP1(N=5, 6.9%), NF1(N=5, 6.9%), SRSF2(N=4, 5.5%). Conclusion:In this subset of young adults with de novo MDS without congenital anomalies and/or familial history suggesting the presence of an undiagnosed congenital syndrome, 18% of the cohort harbored a likely causative germline variant. In addition, we noted a predominance of variants affecting genes with a cancer predisposition limited to the hematopoietic system, rather than classical telomere, DNA damage genes with an established mendelian link. Table. Table. Disclosures Díez-Campelo: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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