Overview of Growth Development in Pediatric Patients Treated with Hydroxyurea (HU) in the Escort-HU Study

Abstract BACKGROUND HU (Hydroxycarbamide or Hydroxyurea) is a myelosuppressive drug marketed since 1968 for the treatment of hematological malignancies, and approved since 2007 in the European Union (EU) and 2017 in the Unites States of America (USA) for preventing vaso-occlusive crises (VOC) including acute chest syndromes (ACS) in adults, adolescents and children ≥2 years with sickle cell disease (SCD). One risk raised for using a cytotoxic drug such as HU in children would be a potential negative impact on growth. Hence, a continuous follow-up of the growth of children treated with HU is recommended. We hypothesized that as HU increased hemoglobin concentration and enhances quality of life it may have a positive impact on growth and even more significantly improve growth and nutritional status in SCD children, who are exposed by their disease to impaired growth due to higher metabolic rate, chronic anemia, and hypoxemia. Here, we present preliminary results on growth development of sickle cell (SC) children enrolled in the ESCORT-HU study (European Sickle Cell Disease COhoRT - HydroxyUrea), a multicentric, prospective, non-interventional European study whose objective is to evaluate the safety of HU in real life. METHOD Between January 2009 and June 2017, 1920 patients were enrolled from 63 centers in France, Germany, Greece and Italy. Of these 1920 patients, 849 (408 girls and 441 boys) were < 18 years of age. Patients' follow-up in ESCORT-HU is strictly observational and follows usual recommendations and local clinical practices. Patients are seen by their physician approximately every 3 to 6 months. Weights, heights and Body Mass Index (BMI) were thus collected all along the study. Patients previously treated with HU and HU-naïve before inclusion have been included in ESCORT-HU study which allowed comparison of these two groups of patients at inclusion in the study. The French population reference measurement scale (growth curve AFPA -CRESS/INSERM) was used for comparison of growth in children enrolled in ESCORT-HU as approximately 83% of children were included in France. RESULTS 547 children with reported height and/or weight were HU-naive at inclusion and 292 children were non-HU naive. Non-HU naïve patients had been treated for a median of 4.56 ± 3.29 years before inclusion in the ESCORT-HU cohort. Median duration of observation in the ESCORT-HU study was 2.60 ± 1.67 years Data on HU treatment and SC genotypes (90% SS) are displayed in table 1. Both heights and weights between HU-naive and non-HU naive girls and boys at enrolment were significantly different (p<0.001) (table 2 and 3). Non-HU naive girls and boys were taller and heavier compared to HU-naive patients, suggesting a positive impact of HU on growth. Mean heights and weights per age for girls were within the normal range all along the study with a mild decrease between 12 and 14 years old (Figure 1 and 2). For boys, weights and heights were within the normal range until the age of 11 and below the median normal range after 11 years (Figure 3 and 4). Mean BMIs stayed within the normal range for all age groups (Figure 5 and 6) during the course of treatment with HU. 12% of HU naive patients had a low BMI at enrolment but this percentage decreased constantly all along HU treatment (7.2% at year 2 and 3% at year 5). On the contrary, 6% of the patient were overweight (BMI above the normal range) and this percentage increased all along HU treatment (9.9% at year 2 and 15.8% at year 5). Among overweight patients, only seven were reported to have obesity and the percentage remained stable. CONCLUSION In the ESCORT-HU study children who were non HU-naive at enrolment were heavier and taller than HU-naive patients, but these differences faded during the course of HU treatment which confirmed the absence of negative impact of HU on growth. Heights and weights were within the normal range for girls whereas boys seemed to have a slower growth from 12 years of age. This difference may be due to pubertal delay in boys, but pubertal status was not collected in ESCORT-HU so this data could not be analysed. A minority of pediatric patients experienced overweight, suggesting to screen this possible complication. Disclosures Oevermann: Addmedica: Membership on an entity's Board of Directors or advisory committees. De Montalembert:Addmedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Brousse:Addmedica: Membership on an entity's Board of Directors or advisory committees. Pondarré:Blue Bird Bio: Honoraria; Novartis: Honoraria; Addmedica: Membership on an entity's Board of Directors or advisory committees.

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Sickle-Cell Disease Patients' Attitudes Towards Their Treatment with Hydroxycarbamide

Blood ◽

10.1182/blood-2019-125673 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1013-1013

Author(s):

Frédéric Galactéros ◽

Ersi Voskaridou ◽

Anoosha Habibi ◽

Giovanna Cannas ◽

Laure Joseph ◽

...

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Fetal Hemoglobin ◽

Treatment Discontinuation ◽

Cell Disease ◽

Advisory Committees

Hydroxyurea (HU) is approved in the EU and USA for prevention of vaso-occlusive crises (VOC) including acute chest syndromes (ACS) in patients over 2 years with sickle-cell disease (SCD). The major benefits of HU in SCD are directly related to its abilities to increase HbF, decrease sickling of red blood cells and hemolysis, leading to reduction of vaso-occlusive episodes, need for blood transfusions and consequently reduction of morbidity and mortality. Adherence to the treatment is paramount for effectiveness, but in spite of proven benefits, barriers to adherence persist.[1] ESCORT-HU study (European Sickle Cell Disease COhoRT - HydroxyUrea), is a multicentric, prospective, non-interventional European study designed to evaluate the safety profile of HU in real life. Patients were enrolled from January 2009 to June 2017 with a follow-up of up to 10 years. All interruptions and resumptions of HU treatment exceeding 15 days were recorded in this study. We hereby present the analysis of the group of patients who self-discontinued HU at least once during the study before informing their caregiver, with a view to identify potential barriers to long-term adherence. In total, 1906 patients were enrolled in ESCORT-HU from 63 centers in France, Germany, Greece and Italy. Of these, 619 patients (32%) stopped HU for over 15 days at least once, and around a third (11% of all patients) were due to patient's will. The mean duration of HU treatment before the first discontinuation was 4.8 ± 5.1 years. Data are summarized in table 1. Compared to the rest of the cohort, the 'treatment discontinuation' group had similar distribution by gender and indication for HU prescription, but a higher proportion of adults stopped HU more than 15 days. It is notable that the proportion of patients with SC genotype was higher in the 'treatment discontinuation' group (4.5% vs 1.7%). The patients in the 'treatment discontinuation' group had more frequent SCD symptoms before enrolment in the study (table 2). Hematological and clinical improvement compared to the baseline was observed in both groups. However, average mean Corpuscular Volume (MCV) and Fetal Hemoglobin percentage (HbF%) were lower and mean percentages of patients with SCD symptoms were higher over the three years of follow-up in the 'treatment discontinuation' group, suggesting that HU daily dose was insufficient (table 2). Sixty patients have no treatment resumption date reported which suggest a permanent interruption of their treatment. Among them 32% preferred to switch to another HU medicinal product and 13% have safety issue (table 3). Understanding and managing self-discontinuation of HU before taking medical advice is challenging for the physician. It is tempting to speculate that it may be due, at least in part, to lack of effectiveness potentially due to an underdosage of the treatment. Resistance to the treatment may also be suggested based on past literature data revealing a great variability in the response (determined by HbF%) to HU therapy. There is evidence that genetic modifiers affect individual response to HU.[2],[3] Finally, weariness from long-term use may also explain the patient's wish to discontinue HU. But treatment at optimal effective should be the primary goal of caregivers. [1]Smaldone A., Manwani D., Green NS, Greater number of perceived barriers to hydroxyurea associated with poorer health-related quality of life in youth with sickle cell disease, Pediatr Blood Cancer. 2019 [2] Steinberg MH, Voskaridou E, Kutlar A, Loukopoulos D, Koshy M, et al. (2003). Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease. Am J Hematol 72: 121-126 [3] Ware RE, Despotovic JM, Mortier NA, Flanagan JM, He J, et al. (2011) Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia. Blood 118: 4985-4991 Disclosures Galactéros: Addmedica: Membership on an entity's Board of Directors or advisory committees. Voskaridou:Celgene Corporation: Consultancy, Research Funding; Protagonist: Research Funding; Genesis: Consultancy, Research Funding; Acceleron: Consultancy, Research Funding; Addmedica: Membership on an entity's Board of Directors or advisory committees. Cannas:Addmedica: Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽

10.1182/blood-2020-143434 ◽

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 <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.

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Real World Clinical Experience with Oxbryta Therapy in Individuals with Sickle Cell Disease

Blood ◽

10.1182/blood-2020-143219 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 15-16

Author(s):

Jaime Luis Betancourt ◽

Shuo You ◽

Sean Campbell ◽

Sabrina Pink ◽

Merin Thomas ◽

...

Keyword(s):

Side Effects ◽

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Hemoglobin Concentration ◽

Cell Disease ◽

Advisory Committees ◽

Barriers To Access ◽

Dose Modifications

Background: Oxbryta is a recently approved drug for patients with Sickle Cell Disease (SCD), which decreases HbS polymerization, thus reducing red cell hemolysis and increasing hemoglobin concentration. It was first available for Expanded Access May 9, 2019 and received fast track approval for commercial use by the FDA on November 25, 2019. Objective: This analysis aims to gain insights to the real word experience for patients with SCD who are prescribed Oxbryta, identify barriers to its use, and measure health outcomes. Methods: Electronic medical records of 54 patients with SCD who were prescribed Oxbryta from January until June 2020 were reviewed and evaluated for data regarding demographics, initiation of treatment, hematological response, side effects, dosage modifications and terminal discontinuations. Results: A total of 54 patients were prescribed Oxbryta in the study period who were 96% (52/54) HbSS, and 4% HbSβ0 (2/54); 46% (25/54) male and 54% (29/54) female, and a mean age of 41 years (range 21-70). At time of initiation, 52% (28/54) of patients were taking hydroxyurea (HU). Indication for initiation of therapy was anemia and hemolysis. In this cohort, 65% of patients (35/54) were able to access drug with a mean time to obtain drug of 45 days (range 0-118 days). The most common barriers to obtaining drug were: requiring a prior authorization or appeal 9% (5/54), incomplete patient follow up 7% (4/54), missing documentation for application 6% (3/54) and high patient co-pay 6% (3/54). Of the 35 patients who started Oxbryta, 46% (16/35) experienced at least 1 side effect with 31% (11/35) reporting multiple side effects. The most common side effects reported were gastrointestinal distress (abdominal pain, nausea, vomiting and/or diarrhea) in 23% (8/35), dermatologic effects (itching and/or rash) in 17% (6/35), and experiencing an acute VOC or increase in daily pain in 11% (4/35). Twenty nine percent (10/35) of patients required a dose modification to address side effects (half who successfully continued the drug on a modified dosage), an additional 23% (8/35) of patients terminated usage of Oxbryta in response to side effects. After two to four weeks of taking Oxbryta 63% of patients had a hemoglobin increase of at least 1g/dl or greater. Conclusion: Oxbryta produces a substantial rise in hemoglobin for persons living with sickle cell and high baseline levels of hemolysis in about 60 % of patients, similarly to the results from the HOPE trial. However, there are significant barriers to access that require close follow up in the immediate period following prescription of the drug in order to minimize delays in access. Furthermore, in our cohort we observed a higher incidence of side effects than the 23% (900mg) -26% (1500mg) reported in the pivotal trial that led to its approval. While some individuals were able to be continue therapy after dose modifications, most discontinued therapy because of side effects. Figure Disclosures Minniti: CLS Behring: Consultancy; Roche: Consultancy; Emmaus: Consultancy; Forma: Consultancy; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Teutona: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Other; Sodium Nitrate for SCD leg ulcers: Patents & Royalties.

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Sustainability of Hematological and Clinical Benefits to HU Administration in the Prevention of Sickle-Cell Vaso-Occlusive Crises in Routine Practice

Blood ◽

10.1182/blood-2018-99-116040 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 855-855

Author(s):

Ersi Voskaridou ◽

Lena Oevermann ◽

Corinne Armari-Alla ◽

Uwe Kordes ◽

Frédéric Galactéros ◽

...

Keyword(s):

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Routine Practice ◽

Red Cell ◽

Cell Disease ◽

Advisory Committees ◽

Clinical Benefits ◽

Adults And Children

Abstract Hydroxyurea (HU) is approved in EU and USA for preventing vaso-occlusive crises (VOC) including acute chest syndromes (ACS) in adults, adolescents and children ≥2 years with sickle-cell disease (SCD). Further to the double blinded, randomized controlled Multicenter Study of Hydroxyurea administration (MSH) which provided the first data on clinical efficacy of HU (Charache 1995), a few follow-up studies suggested that long-term use of HU resulted in significant clinical benefit on patient outcome. This was reflected by lower mortality rates in HU-treated patients compared to conventionally treated patients (Steinberg 2003 & 2010, Voskaridou 2010, Lê 2015). Sustained hematological and clinical response after several years of follow-up at maximal tolerated dose was further shown in subsequent studies, especially the LaSHS study (Voskaridou 2010). Based on these data, the ESCORT-HU (European Sickle Cell Disease COhoRT - HydroxyUrea) study was launched aiming in the establishment of the safety and the sustainability of hematological and clinical benefits to HU administration in the prevention of sickle-cell vaso-occlusive crises in routine practice. We hereby present preliminary results from a large cohort of patients enrolled in the study between January 2009 and June 2017. 1920 patients were enrolled from 63 centers in France, Germany, Greece and Italy, For 147 of the 600 HU-naive patients (never treated with HU before enrolment) and started on HU for VOC or ACS, there was documented clinical outcome (number of VOC >48h and ACS episodes per year) over a 4-year follow-up period. These patients were selected for analysis to evaluate sustainability of clinical and hematological HU response in routine practice. Demographic data and Hb genotypes are displayed in table 1. The children group was mainly composed of βS/βS patients, while adults were mainly βS/βS and βS/β-thal patients. As shown in figure 1 and 2, there was a dramatic reduction in the number of VOC >48h and ACS episodes (-79%) from year 1 in adults and children, with results comparable to previous randomised clinical trials in adults (Charache et al., 1995) and children (Jain et al, 2012). Overall, the reduction in number of VOC (>48h) and ACS was stable over the 4 years of follow-up. This reduction is inversely proportional to the increase in HbF. There were however a moderate rebound in children from year 2 while adults remained stable. Similarly, there was reduction in the proportion of adults and children requiring transfusion (figure 3). The clinical benefit of HU was higher in severe forms of SCD, as displayed by the markedly reduced number of patients with ≥ 3 VOC episodes (>48h)/year at year 1 (figure 4). Hematological response to HU was evidenced as soon as year 1 with a marked increase in HbF% (+6-10) and were maintained over subsequent years of treatment (figure 1 and 2) as the dose of HU was further increased. While there was no striking differences in HbF% variation between age groups and genotypes, the requirement for increase in HU dose over the 4 years of follow-up was markedly higher in children, probably reflecting the different severity between the two population at entry (figure 5). The red cell red cell mean corpuscular volume (MCV) could be used as a measurement of compliance, showing differences between age group (figure 5). There was, as expected, an apparent negative correlation between induction of HbF synthesis and number of VOC >48h and ACS episodes at year 1, attesting to reduced effectiveness of treatment in some patients (figure 6). Improvement in blood parameters was accompanied by mild reduction of absolute neutrophil and platelet count although not to the point of myelosuppression (defined as ANC < 2 x 109/L), showing that MTD was not targeted in routine practice. Treatment-emergent adverse reactions occurring in the 147 patients of the cohort over the 4 years of follow-up were consistent with the known safety profile of hydroxyurea. The commonest effects included neutropenia and thrombocytopenia (25 events in 13 patients) and were easily manageable with temporary discontinuation of treatment. No tumorigenesis was reported. In conclusion, preliminary results from ESCORT-HU in 147 patients treated with HU showed sustained hematological and clinical response while MTD was not targeted, with differences between adults and children which may be attributed in part to reduced compliance in the latter group. Disclosures Voskaridou: Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron: Membership on an entity's Board of Directors or advisory committees, Research Funding. Oevermann:Addmedica: Membership on an entity's Board of Directors or advisory committees. Thuret:Addmedica: Research Funding; bluebird bio: Research Funding; Novartis: Research Funding. Steschenko:Novartis: Membership on an entity's Board of Directors or advisory committees.

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First Year Comparison of Sickle Cell Pediatric Cohorts from Haiti and Miami (CSHSCD Multicenter Study): Baseline Data

Blood ◽

10.1182/blood-2021-148227 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2042-2042

Author(s):

Ofelia A. Alvarez ◽

Nora St Victor Dely ◽

Michele Paul-Hanna ◽

Alejandro Mantero ◽

Rony Saint Fleur ◽

...

Keyword(s):

African Americans ◽

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

First Year ◽

Cell Disease ◽

Advisory Committees ◽

Oral Tablet ◽

Hydroxyurea Treatment

Abstract Background: The NIH-sponsored observational study "Comparative Study of Haiti and Miami Cohorts of Sickle Cell Disease CSHSCD" (R01HL149121) coordinates the follow up of children with sickle cell disease (SCD) in Haiti and compares it to a Miami cohort of children of either Haitian or African American ethnicity for the purpose of assessing barriers through questionnaires and examining differences in the care received in their respective environments. Methods: Children less than 6 years of age with SCD are eligible for enrollment in five participating sites: University of Miami (UM, Miami, Florida), Hôpital Saint Damien (HSD, Tabarre, Haiti), Hôpital de l' Université d'Etat d'Haïti (HUEH, Port-au-Prince, Haiti), Hôpital Universitaire Justinien (HUJ, Cap Haitien, Haiti), and Hôpital Sacré Coeur (HSC, Milot, Haiti). Medians and interquartile ranges or percentages were compared at baseline regarding demographics, clinical and growth parameters, laboratory tests, and the children's hydroxyurea (HU) utilization during the first year of enrollment (May 25, 2020-May 24,2021). A Likert-scale barrier questionnaire was distributed at baseline to assess differences in healthcare access. A P value <0.05 was considered statistically significant to establish differences. Results: 130 children were enrolled during the reported period. Significant differences were observed in age, weight percentiles, hemoglobin levels, pain rates, HU treatment, and pneumococcal vaccination. Penicillin prophylaxis was always given by oral route in Miami, but only 39.8% times in Haiti, with 58% of children receiving prophylaxis by intramuscular injection every month and 2.2% (N=2 children) with either unknown or not receiving prophylaxis. Previous medication outsourcing accounted for the oral tablet form in Haiti. Parents in Haiti had more barriers regarding not able to afford treatment (21.5% compared to 8.1% in Miami) and had similar responses regarding not able to afford coming to clinic (21.5% vs. 18.9%). Parents in Miami expressed living far away from clinic (70.2% compared to 25.8% in Haiti), but had more help from other family members (78.4% vs. 33.3%). Interestingly, parents in Miami did not know sometimes what to do when the child was sick (40% respondents vs. 11% in Haiti). There were no major differences between the responses from the African Americans and Haitians living in Miami, except for not knowing sometimes what to do when child is sick (African-Americans having less doubts than Haitians; 25% vs. 52.6%). In short-term follow up, no enrolled children died, although two eligible children in Haiti died before enrollment. One child developed COVID-19 in Miami with only mild symptoms, which resolved. Conclusion: At entry children in Haiti are older, weigh less, are more anemic, have more pain episodes, and fewer receive hydroxyurea treatment. Under-vaccination with pneumococcal 13-valent conjugate (Prevnar-13) is notable in Haiti. There were significant differences detected on the barrier questionnaire among respondents in both countries. Acknowledgment: We acknowledge NHLBI for supporting this work. Figure 1 Figure 1. Disclosures Alvarez: GBT: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees.

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Nonmyeloablative Transplant for Sickle Cell Disease Does Not Lead to Kidney Dysfunction Post-HSCT

Blood ◽

10.1182/blood-2021-153230 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 984-984

Author(s):

Emily Limerick ◽

Santosh L. Saraf ◽

Neal Jeffries ◽

Farah O'Boyle ◽

Clarissa Diamantidis ◽

...

Keyword(s):

Renal Function ◽

Kidney Disease ◽

Board Of Directors ◽

Research Funding ◽

Cell Disease ◽

Normal Range ◽

Kidney Dysfunction ◽

Advisory Committees ◽

Matched Sibling

Abstract Hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for patients with sickle cell disease (SCD). Though HSCT can reverse the SCD phenotype, both acute kidney injury (AKI) and chronic kidney disease (CKD) have been associated with HSCT. SCD alters renal function thus the impact of HSCT on renal function in SCD patients is a critical area of exploration. Here, we report the effect of HSCT on renal function in people with SCD. This study analyzes data from 195 patients who received HLA-matched sibling or haploidentical HSCT for SCD at Imperial College London (ICL), National Institutes of Health (NIH), and University of Illinois Chicago (UIC). The former is a pediatric cohort and all sites employed a nonmyeloablative conditioning. Patients' renal function was assessed at baseline and annually thereafter for up to 3-years. We examined the prevalence of CKD before and after HSCT, estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR) trends after HSCT, and the incidence of AKI within 100 days of HSCT. We defined and staged AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria; we calculated eGFR with the CKD- epidemiology collaboration (CKD-EPI) equation for adults and Bedside Schwartz for children. The median eGFR declined annually but remained within the normal range throughout the follow-up period: the baseline median eGFR was 138 ml/min/1.73m 2 and declined by 7 in the first year of follow-up and by additional decreases of 5 and 3.6 ml/min/1.73m 2 in subsequent years (p-values of 0.07, 0.0002, and 0.0002 for years 1, 2, and 3 for comparison to baseline from regression model of eGFR). No differences in eGFR were seen for covariates in the model: haploidentical vs. matched sibling, engraftment status, gender, or site. The downward eGFR trend may represent an improvement in renal function toward normal as hyperfiltration (eGFR ≥150 ml/min/1.73m 2) was present in 28% of patients at baseline and steadily declined to 7% by 3 years post-HSCT. There was a corresponding increase in patients with normal eGFR (60-149 ml/min/1.73m 2) from 59% at baseline to 88% at 3 years post-HSCT. Among the ICL and NIH cohorts (UIC excluded due to use of a different AKI determination strategy), 58% of patients developed AKI in the early post-HSCT period. 67% of AKI cases were mild, stage 1; 25% were moderate, stage 2; and 8% were severe, stage 3 AKI. This study demonstrates that HSCT in patients with SCD is associated with a transient increase in UACR but not associated with a significant increase in CKD prevalence by 3-years post-HSCT. The stability of UACR compared to baseline by the 3-year time point suggests that even more mild renal damage may stabilize after HSCT. While there is a substantial decline in eGFR from baseline to each annual follow-up, the proportion of patients whose eGFR was in the normal range increased as the prevalence of hyperfiltration decreased. Finally, while AKI occurred in more than half the patients in our cohort, the preponderance developed only mild AKI. Therefore, our data indicate that nonmyeloablative HSCT for SCD does not lead to significant kidney dysfunction post-HSCT. Disclosures 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. Diamantidis: United Health Group: Consultancy.

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Clinical and Biomarker Predictors for Avascular Necrosis in Sickle Cell Disease

Blood ◽

10.1182/blood-2021-147829 ◽

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 < 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.

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10-Year Mortality in Patients with Sickle Cell Disease from a Large Population-Based Cohort

Blood ◽

10.1182/blood-2020-141613 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 56-56

Author(s):

Kristina Lai ◽

Marianne McPherson Yee ◽

Beatrice Gee ◽

Maa-Ohui Quarmyne ◽

Ross M. Fasano ◽

...

Keyword(s):

Mortality Rate ◽

Board Of Directors ◽

Sickle Cell ◽

Bacterial Infections ◽

Mortality Rates ◽

Population Based ◽

Cell Disease ◽

Adult Care ◽

Advisory Committees ◽

Hb S

Background Mortality rates and causes of death in children with sickle cell disease (SCD) have changed significantly over the past several decades. With ongoing improvements in standards of care, modern mortality estimates must be updated. Children's Healthcare of Atlanta (CHOA) houses one of the largest pediatric SCD programs in the country. This analysis reviews mortality in children with SCD who were treated at CHOA between June 2010-June 2020. Methods We reviewed the CHOA's Sickle Cell Clinical Database (SCCD) for deceased patients. Demographics, SCD genotype, date and age at death, healthcare utilization, hydroxyurea (HU) use, chronic transfusion therapy (CTT), and bone marrow transplant (BMT) were obtained from the SCCD. Cause of death and history of significant comorbidities were abstracted from the medical record. Mortality rates were calculated using person-time for all CHOA SCD patients and population-based mortality was obtained from CDC WONDER Online Database. Results A total of 3,698 patients with SCD were seen at CHOA from June 2010-June 2020 and accounted for 19,998 person-years. Of the 46 patients who died during that time, all but 1 patient had been seen in the CHOA Sickle Cell Outpatient Clinic at least once. That patient received SCD care at a different institution, died from complications of a non-SCD related disease following transfer to CHOA, and was excluded from analysis. Of the 45 remaining patients (178 person-years), the majority were sickle cell anemia genotypes (n=37, 82%; Hb SS or Hb S β0 thalassemia), followed by Hb SC (n=5, 11.1%) and Hb S β+ thalassemia (n=3, 6.7%); 53% (n=24) were female. The average age at death was 12.8 years (1.0-22.8 years). Twenty-one (46.7%) patients had ever been treated with HU and 11 (24.4%) were currently on HU at the time of last contact (either death or last CHOA encounter). Eleven (24.4%) patients had ever been treated with CTT, and 3 (8.9%) were being treated with CTT at time of last contact. In comparison, during the same time period an average of 58% and 12% of the overall CHOA SCD population were being treated with HU and CTT, respectively. Forty-one patients had at least 1 SCD-related encounter at CHOA within 12 months prior to death. For the 4 patients who had not been seen at CHOA within 12 months, the average time since last contact was 1.72 years (1.03 - 2.7 years). Eighty percent (n=8) of the 10 patients who died at age >19 had either recently transitioned to adult care or had documentation of a transition plan. During this 10-year period, the crude death rate was 2.3 per 1,000 person-years. The majority of deaths (62%, n=28) were attributable SCD-related causes and corresponded to a cause-specific mortality rate of 1.40 per 1,000 person-years. The remaining 38% (n=17) of deaths were caused by complex non-SCD comorbidities or accidental trauma and corresponded to a non-SCD related mortality rate of 0.85 per 1,000 person-years. In comparison, the mortality rate for African American persons age <22 in Georgia from 2009-2018 was 0.9 per 1,000 person-years. Of the 28 patients who died due to an SCD-related cause: 12 (27%) experienced an acute illness related to SCD, 4 (9%) succumbed to acute bacterial infections, 3 (7%) died from complications of SCD treatment (1 procedure-related, 2 drug-induced hemolytic anemia), and 1 (2%) died from complications of BMT. Nine (20%) had either recently transitioned to adult care or were lost to follow-up and had no significant non-SCD comorbidities, therefore cause of death was unknown. Of the 17 non-SCD related deaths, 16 (36%) were due to complex non-SCD comorbidities (including cancers, autoimmune disorders, and congenital heart disease) and 1 (2%) from an accidental trauma. Conclusions To our knowledge, this is the largest and most recent study of mortality in patients with SCD from a single institution. Overall, the demographics of deceased patients were similar to those of the CHOA SCD population as a whole. This cohort indicates that trends in mortality of children with SCD have largely shifted away from bacterial infections to other complications of SCD, subsequent treatments, or comorbidities. Our data confirm that patients nearing transition to adult care are at high risk of mortality. This study is limited to deaths that are known to the CHOA system, so future analyses will expand this cohort to include data from death certificates and CDC's National Death Index. Disclosures Lane: FORMA Therapeutics: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees.

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NT-Pro Brain Natriuretic Peptide Levels and the Risk of Stroke and Death in the Cooperative Study of Sickle Cell Disease.

Blood ◽

10.1182/blood.v114.22.1541.1541 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1541-1541 ◽

Cited By ~ 3

Author(s):

Roberto F Machado ◽

Mariana Hildescheim ◽

Laurel Mendelsohn ◽

Gregory J Kato ◽

Mark T Gladwin

Keyword(s):

High Risk ◽

Sickle Cell Disease ◽

Incidence Rate ◽

Sickle Cell ◽

Pediatric Patients ◽

Cooperative Study ◽

Cell Disease ◽

Risk Of Death ◽

History Of

Abstract Abstract 1541 Poster Board I-564 Background Elevations in NT-proBNP levels are associated with hemolysis-associated pulmonary hypertension and mortality in adults with sickle cell disease. The association of this vasculopathy with the risk of stroke has not been explored. The Cooperative Study of Sickle Cell Disease (CSSCD) is the largest cohort of adult and pediatric patients with sickle cell disease with the longest median follow-up. Using stored plasma samples from patients enrolled in the CSSCD, we tested the hypothesis that adult patients with high levels of NT-proBNP would be at a high risk of death and stroke and that pediatric patients with a high BNP might be at a high risk of stroke. Methods A threshold NT-pro-BNP value previously identified to predict mortality in adults with sickle cell disease was used to determine the association between the risk of stroke and mortality in a cohort of 758 participants (pediatric cohort, n=428 and adult cohort, n=330) in the CSSCD. Results The prevalence of an abnormal NT-proBNP level ≥ 160 pg/ml was 27.6 % in patients in the adult CSSCD cohort. The prevalence of a NT-proBNP level ≥ 160 pg/ml was 27.4 % in the pediatric cohort, which is at least in part explained by known higher normal NT-proBNP levels in children, especially during the first year of life. The incidence of the development of a high NT-proBNP level in subjects with a normal baseline level was 6 % over a mean follow-up time of 5.9 years (incidence rate per 100-person years of 1.03) in the pediatric cohort and 16.5 % over a mean follow-up time of 1.9 years in the adult cohort (incidence rate per 100-person years of 8.59). In subjects with normal baseline levels, multivariate logistic regression analysis of clinical and laboratory factors associated with the development of a high NT-proBNP level included increasing age (OR 3.43, 95% CI 1.6-7.2, P = 0.001), low hemoglobin (OR 0.47, 95% CI 0.3-0.7, P < 0.001), high white blood cell count (OR 1.69, 95% CI 1.05-2.7, P = 0.03), high creatinine (OR 2.22, 95% CI 1.1-4.3, P = 0.02), blood urea nitrogen (OR 1.64, 95% CI 1.2-2.3, P = 0.004), alanine aminotransferase (OR 1.26, 95% CI 1.01-1.6, P = 0.04) and uric acid levels (OR 2.32, 95% CI 1.4-3.8, P = 0.001), and history of leg ulcers (OR 7.46, 95% CI 2.0-28.5, P = 0.003). Elevated NT pro-BNP levels were associated with indices of hemolytic anemia (hemoglobin: OR 0.33, 95% CI 0.2-0.4, P < 0.001) and a history of stroke (OR 1.86, 95% CI 0.9-3.7, P = 0.02). An NT-pro-BNP level ≥160 pg/ml was a predictor of mortality (RR 6.24, 95% CI 2.9-13.3, P < 0.001) and stroke (RR 3.84, 95 % CI 1.0-14.3, P = 0.05) in this cohort. Conclusions A high NT-proBNP level is a major risk factor for death in patients with sickle cell disease. These findings provide further support for a mechanistic link between hemolytic anemia and the development of cardiovascular complications in this patient population. Finally, we have identified a novel widely available biomarker of the risk of death and stroke in sickle cell disease. Disclosures No relevant conflicts of interest to declare.

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Comprehensive Structured Transition Program with Dedicated Transition Navigator Reduced Lost to Follow-up and Improved Medication Adherence in Sickle Cell Disease and Thalassemia Adolescents and Young Adults

Blood ◽

10.1182/blood.v128.22.317.317 ◽

2016 ◽

Vol 128 (22) ◽

pp. 317-317

Author(s):

Brooke Allemang ◽

Kate Allan ◽

Colleen Johnson ◽

Melina Cheong ◽

Patrina Cheung ◽

...

Keyword(s):

Medication Adherence ◽

Sickle Cell Disease ◽

Board Of Directors ◽

Transition Program ◽

Cell Disease ◽

Advisory Committees ◽

Appointment Attendance ◽

One Year ◽

Lost To Follow Up

Abstract Introduction: Adolescents and young adults (AYA) with sickle cell disease (SCD) and thalassemia transitioning from pediatric to adult health care experience a lack of engagement with adult care providers, are at high risk of loss to follow-up, emergence of psychosocial issues, morbidity and mortality. The shift from a pediatric to an adult setting can be challenging for AYA who are coping with multiple life transitions and are expected to acquire the necessary skills to manage their own care. Hypothesis: implementation of a comprehensive structured transition program with dedicated transition navigator (TN) in a pediatric and adult hemoglobinopathy comprehensive care center will reduce loss to follow-up and hospitalization, improve adherence to medication and attendance to appointments compared to an unstructured transfer from pediatric to adult program. Methods: A structured comprehensive transition program with a dedicated TN, based on a quality improvement framework with an iterative design to refine the intervention over time, was developed and deployed across a pediatric and adult hemoglobinopathy comprehensive care center (Hospital for Sick Children (HSC) and Toronto General Hospital (TGH) respectively) starting August 1, 2014. Prior to this, patients at age 18 were transferred without preparation. With the TN model, adolescents, from age 12 were followed at each visit by the TN and up to one year after transitioning. Prior to transition to the adult center, adolescents were seen jointly by pediatric and adult care providers and TN in a transition clinic. Patients were assessed for transition readiness and provided with tailored education at each appointment. This observational study compared all AYA with SCD or thalassemia who turned 18 years between August 1, 2013 and August 1, 2015. Patients in the cohort prior to the comprehensive transition program were compared to patients who transitioned through the formal program. Data from one year prior to last appointment at HSC and one year after the first appointment at TGH were collected. The effects of covariates on imaging/clinic/transfusion/subspecialist appointment attendance, medication adherence and hospitalizations were analyzed by multivariable regression. Results: 112 patients met the criteria for transfer/transition, of which 51 transferred prior to August 1, 2014 and 61 transitioned through the comprehensive transition program. No significant differences were observed in baseline demographics including age at transfer/transition, phenotype, distance from the center, medications, parental/guardian appointment attendance, immigration status, family structure, first language spoken or documented cognitive impairment. The youngest patient to undergo transition in the observation period was 16.6 years. The transition process significantly reduced the proportion of patients lost to follow-up from 29% (11/38) to 7% (4/57) (P = 0.0335, Figure 1). In patients who were on hydroxyurea or iron chelation, significant increase in the proportion of patients who maintained or improved their medication adherence to 4 or more days a week was observed in the transition cohort (P = 0.047, LR 4.668) and the presence of the transition program was independently associated with the improvement. A trend towards improvement or maintenance of ≥ 90% attendance to appointments was observed (P = 0.096, OR 2.254). Variations in appointment attendance can be explained by patient's age, distance from the comprehensive hemoglobinopathy center, and English as patient's first language. No independent predictor was found in frequency of hospitalization. No new overt strokes or deaths occurred in the year after moving to the adult center. Conclusions: Comprehensive structured transition program with dedicated transition navigator significantly reduced the number of AYA lost to follow-up, and significantly improved and maintained fair to good medication adherence. Further analysis of economic benefit and patient satisfaction will be conducted. A clustered randomized-controlled trial will be forthcoming to determine the effectiveness of this transition model of care on AYA patients with sickle cell disease on patient-important outcomes. Disclosures Allemang: Novartis: Other: Funding for the transition navigator program; ApoPharma: Other: Funding for the transition navigator program; Sickkids Foundation: Other: Funding for the transition navigator program. Kuo:Apotex: Other: Unrestricted education grant; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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