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These Patients Had Sickle-Cell Disease. Experimental Therapies Might Have Cured Them.

Success against sickle-cell would be “the first genetic cure of a common genetic disease” and could free tens of thousands of Americans from agonizing pain.

Carmen Duncan, 20, of Charleston, S.C., had her spleen removed when she was 2, a result of complications from sickle-cell disease. She spent much of her childhood in and out of hospitals.

“Sometimes I would stay two weeks,” she said. Her arms and legs would ache from blocked blood vessels. “A simple touch really hurt.”

Monthly blood transfusions helped, she said, but they were onerous. Then she entered Bluebird’s gene therapy trial.

Today, doctors say, she no longer has signs of sickle-cell disease. She had longed to join the military but had been barred because of her condition. Now she plans to enlist.

Manny Johnson, 21, was the first patient in a trial at Boston Children’s Hospital in which researchers are attempting to restart production of fetal hemoglobin. It worked: Doctors say he no longer has the disease.

Partial-match transplants ease the grinding pain of sickle cell disease

Perfect matches are nearly impossible to find for sickle cell patients. But a parent is automatically a half-match, and thus eligible to donate bone marrow.

https://www.nbcnews.com/health/kids-health/less-perfect-still-good-partial-match-transplants-ease-pain-sickle-n958586

Virtual reality helps reduce pain among patients with sickle cell disease

https://www.healio.com/hematology-oncology/hematology/news/online/%7B5ab0e2a2-6198-4b7e-9420-8dcbff9d958b%7D/virtual-reality-helps-reduce-pain-among-patients-with-sickle-cell-disease

Breakthrough Therapy Designation Granted for Sickle Cell Disease Treatment

Officials with the FDA have granted Breakthrough Therapy designation to Novartis’ crizanlizumab (SEG101) for the prevention of vaso-occlusive crises (VOCs) in patients of all genotypes with sickle cell disease (SCD), according to a press release.
 
Patients with SCD face a high economic burden, with annual costs of more than $30,000 for adults with the disease, according to Novartis. SCD can lead to VOCs, which are painful complications caused by clusters of cells that block or reduce blood flow.  
 
“Painful sickle cell crises matter because they can disrupt patients’ lives, and often require hospital visits and medical attention,” Samit Hirawat, MD, head of Novartis Oncology Global Drug Development, said in a statement. “We look forward to working with the FDA over the coming months toward making crizanlizumab, a therapy that has the potential to prevent sickle cell pain crises, available in the US as soon as possible.”
 
Crizanlizumab, a monthly infusion, is a P-selectin inhibitor that reduces VOCs by binding to a molecule called P-selectin on the surface of platelets and endothelium in the blood vessels. It has been shown to inhibit interactions between endothelial cells, platelets, red blood cells, sickled red blood cells, and leukocytes.
 
The designation for crizanlizumab is based on data from the phase 3 SUSTAIN trial, which compared crizanlizumab with a placebo in patients with SCD. Patients in the trial were treated with either crizanlizumab 2.5 mg/kg or 5 mg/kg, or a placebo.
 
According to the data, crizanlizumab reduced the median annual rate of VOCs leading to health care visits by 45.3% compared with a placebo in patients with or without hydroxyurea therapy. The study also found that crizanlizumab significantly increased the percentage of patients who did not experience any VOCs versus a placebo during treatment.
 
Adverse events (AEs) that occurred in ≥10% of patients in either crizanlizumab treatment group and at a frequency that was at least twice as high as experienced in the placebo group included arthralgia, diarrhea, pruritus, vomiting, and chest pain. Patients who received crizanlizumab (5 mg/kg) experienced a similar incidence of AEs and serious AEs compared with a placebo. Patients receiving crizanlizumab experienced a low 3% incidence of discontinuations due to AEs. 
Novartis anticipates filing a New Drug Application for crizanlizumab in the first half of 2019.

Web Resource

 “Supporting the Student with Sickle Cell Disease” Free Handbook at https://www.chop.edu/health-resources/sickle-cell-school-outreach

We are excited to share tools developed by our team that support engagement between caregivers/students and their schools.  Our goal is to make necessary modifications if needed that will support individuals with sickle cell disease (SCD) optimally. So, we kindly ask for feedback through this link: https://redcap.chop.edu/surveys/?s=3YJDT3Y7E4

We have provided the handbook, templates and caregiver/student guides online under this link entitled “Sickle Cell School Outreach”.  

www.sc101.org update –
2018 was a fantastic year for Sickle Cell 101. Thank you for your partnership and support! Here is 2018 by the numbers:

We have over 30,000 followers in 103 countries on combined social media platforms and continue to consistently have the highest levels of engagement on social media!

Instagram: Most liked post received 1,816 likes Most commented post received 276 comments Facebook: Highest post reached 50,386 users with 4,090 reactions, comments & shares Twitter: Highest number of impressions 41,654 with 879 engagements
In a study, Sickle Cell 101 ranked 2nd most visited website by sickle cell patients.

In our User Insight Survey with 124 participants (70% patients and ~19% caregivers) on the Likert scale Sickle Cell 101 scored: 92% Strongly agreed they found SC101’s content useful and/or engaging 93% Strongly agreed they would recommend SC101 to others
 
Sickle Cell Plus, a bulletin and calendar for the sickle cell community! Members of the sickle cell community will always be in the know regarding sickle cell related happenings. This digital bulletin board/calendar is open for anyone in the community to submit events, which will be reposted on the Sickle Cell Plus pages.  

The Sickle Cell Podcast, is another medium available to the sickle cell patient and caregiver population with engaging and essential sickle cell related material. This show covers a variety of topics and is hosted by patient and advocate Cassandra Trimnell and healthcare professional (PharmD, RPh) Dr. Stephen Boateng.  

Ask Dr. Q Facebook Live, our very own Dr. Keith Quirolo answers sickle cell related questions from patients and caregivers on Sickle Cell 101’s Facebook page. This highly utilized program has become a staple resource for the online sickle cell community. Users submit questions through our website or via email.

Community Education, provides sickle cell education and counseling on the ground through mini educational seminars and events. Community members will also receive supplemental literature.  

New Resources

NIH Hosts Rare Disease Day Event, Twitter Chat

Rare diseases affect an estimated 30 million people in the United States. On Feb. 28, 2019, NIH will host an event to raise awareness about these diseases, the people they affect, and current research collaborations.

Sponsored by the National Center for Advancing Translational Sciences (NCATS) and the NIH Clinical Center (CC), Rare Disease Day at NIH will take place from 8:30 a.m. to 4 p.m. ET in the Main Auditorium of the Natcher Conference Center in Building 45 on the NIH main campus in Bethesda, Maryland. The event will feature interactive panel discussions on collective research models for rare diseases, patient registries, rare cancer research initiatives, and “no disease left behind, no patient left behind.” New this year will be a presentation of the first ever Zebbie award for the NCATS Rare Diseases Are Not Rare! Challenge. Other highlights include posters and exhibits by rare disease groups and researchers as well as artwork, videos, networking opportunities and tours of the NIH Clinical Center.

Admission is complimentary and open to the public. In association with Global Genes®, participants are encouraged to wear their favorite pair of jeans. Be sure to follow the event on social media using #RDDNIH.

Prior to the event, on Feb. 22, 2019, NIH will host a Twitter chat on rare diseases from 1-2 p.m. ET. The chat will feature NIH Director Francis S. Collins, M.D., Ph.D., NCATS Director Christopher P. Austin, M.D., and CC CEO James K. Gilman, M.D., as well as representatives from the rare diseases advocacy community. Join in the conversation using #NIHchat and follow @ncats_nih_gov. Learn more at https://ncats.nih.gov/rdd and register at https://events-support.com/events/Rare_Disease_Day.

Articles in the medical literature

1. Mol Ther Methods Clin Dev. 2018 Dec 31;12:175-183. doi: 10.1016/j.omtm.2018.12.008. eCollection 2019 Mar 15. TALEN-Mediated Gene Editing of HBG in Human Hematopoietic Stem Cells Leads to Therapeutic Fetal Hemoglobin Induction. Lux CT1,2, Pattabhi S1, Berger M1, Nourigat C3, Flowers DA3, Negre O4, Humbert O3, Yang JG4, Lee C4, Jacoby K1, Bernstein I3, Kiem HP3,5,6, Scharenberg A1,2,7, Rawlings DJ1,2,7. Abstract Elements within the γ-hemoglobin promoters (HBG1 and HBG2) function to bind transcription complexes that mediate repression of fetal hemoglobin expression. Sickle cell disease (SCD) subjects with a 13-bp deletion in the HBG1 promoter exhibit a clinically favorable hereditary persistence of fetal hemoglobin (HPFH) phenotype. We developed TALENs targeting the homologous HBG promoters to de-repress fetal hemoglobin. Transfection of human CD34+ cells with TALEN mRNA resulted in indel generation in HBG1 (43%) and HBG2 (74%) including the 13-bp HPFH deletion (∼6%). Erythroid differentiation of edited cells revealed a 4.6-fold increase in γ-hemoglobin expression as detected by HPLC. Assessment of TALEN-edited CD34+ cells in vivo in a humanized mouse model demonstrated sustained presence of indels in hematopoietic cells up to 24 weeks. Indel rates remained unchanged following secondary transplantation consistent with editing of long-term repopulating stem cells (LT-HSCs). Human γ-hemoglobin expressing F cells were detected by flow cytometry approximately 50% more frequently in edited animals compared to mock. Together, these findings demonstrate that TALEN-mediated indel generation in the γ-hemoglobin promoter leads to high levels of fetal hemoglobin expression in vitro and in vivo, suggesting that this approach can provide therapeutic benefit in patients with SCD or β-thalassemia. PMCID: PMC6348980
PMID: 30705922
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2. Mol Diagn Ther. 2019 Jan 30. doi: 10.1007/s40291-019-00383-4. [Epub ahead of print] Gene Therapy for Beta-Hemoglobinopathies: Milestones, New Therapies and Challenges. Ghiaccio V1, Chappell M1, Rivella S1, Breda L2. . Abstract Inherited monogenic disorders such as beta-hemoglobinopathies (BH) are fitting candidates for treatment via gene therapy by gene transfer or gene editing. The reported safety and efficacy of lentiviral vectors in preclinical studies have led to the development of several clinical trials for the addition of a functional beta-globin gene. Across trials, dozens of transfusion-dependent patients with sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT) have been treated via gene therapy and have achieved reduced transfusion requirements. While overall results are encouraging, the outcomes appear to be strongly influenced by the level of lentiviral integration in transduced cells after engraftment, as well as the underlying genotype resulting in thalassemia. In addition, the method of procurement of hematopoietic stem cells can affect their quality and thus the outcome of gene therapy both in SCD and TDT. This suggests that new studies aimed at maximizing the number of corrected cells with long-term self-renewal potential are crucial to ensure successful treatment for every patient. Recent advancements in gene transfer and bone marrow transplantation have improved the success of this approach, and the results obtained by using these strategies demonstrated significant improvement of gene transfer outcome in patients. The advent of new gene-editing technologies has suggested additional therapeutic options. These are primarily focused on correcting the defective beta-globin gene or editing the expression of genes or genomic segments that regulate fetal hemoglobin synthesis. In this review, we aim to establish the potential benefits of gene therapy for BH, to summarize the status of the ongoing trials, and to discuss the possible improvement or direction for future treatments.
PMID: 30701409
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3. JAMA. 2019 Jan 29;321(4):334. doi: 10.1001/jama.2018.21119. Gene Therapy for Sickle Cell Disease Shows Promise. Rubin R.
PMID: 30694304
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4. Pediatr Blood Cancer. 2019 Jan 28:e27633. doi: 10.1002/pbc.27633. [Epub ahead of print] Use of the new pediatric PROMIS measures of pain and physical experiences for children with sickle cell disease. Singh A1, DasGupta M1, Simpson PM1, Panepinto JA1,2. Abstract BACKGROUND: There are new pediatric domains to measure patients’ pain and physical experiences in the Patient-Reported Outcomes Measurement Information System (PROMIS). The objective of this study was to establish the psychometric properties of these domains for children with sickle cell disease (SCD). PROCEDURE: We conducted a cross-sectional analysis of PROMIS assessments of children with SCD recruited from a pediatric tertiary care clinic. Validity of the new PROMIS domains was determined by comparing scores between known groups and describing their correlations with previously validated PROMIS measures. Cronbach’s alpha and item response theory (IRT) reliability were used to assess internal consistency reliability. Agreement between parent-proxy and child self-report was determined for all domains. RESULTS: Our study included 164 subjects, of whom 117 were eligible to self-report. The mean T-scores for physical stress experience, strength impact, pain behavior, and pain quality sensory scores were significantly different between children who used pain medications in the prior week and those who did not. There were also differences in T-scores across children reporting mild, moderate, and severe pain on the pain intensity scale. All measures had Cronbach’s alpha and IRT reliability > 0.80. The percentage of agreement between child and parent-proxy PROMIS domains ranged from 36% to 60% depending on the domain. CONCLUSIONS: The new PROMIS domains of physical stress experience, strength impact, pain behavior, and pain quality sensory domains are valid and reliable for children with SCD. The low-moderate agreement between parent-proxy and child self-report scores support the complementary information provided by the two perspectives. © 2019 Wiley Periodicals, Inc.
PMID: 30688017
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5. Mediterr J Hematol Infect Dis. 2019 Jan 1;11(1):e2019002. doi: 10.4084/MJHID.2019.002. eCollection 2019. New Therapeutic Options for the Treatment of Sickle Cell Disease. Matte A1, Zorzi F1, Mazzi F1, Federti E1, Olivieri O1, De Franceschi L1. . Abstract Sickle cell disease (SCD; ORPHA232; OMIM # 603903) is a chronic and invalidating disorder distributed worldwide, with high morbidity and mortality. Given the disease complexity and the multiplicity of pathophysiological targets, development of new therapeutic options is critical, despite the positive effects of hydroxyurea (HU), for many years the only approved drug for SCD. New therapeutic strategies might be divided into (1) pathophysiology-related novel therapies and (2) innovations in curative therapeutic options such as hematopoietic stem cell transplantation and gene therapy. The pathophysiology related novel therapies are: a) Agents which reduce sickling or prevent sickle red cell dehydration; b) Agents targeting SCD vasculopathy and sickle cell-endothelial adhesive events; c) Anti-oxidant agents. This review highlights new therapeutic strategies in SCD and discusses future developments, research implications, and possible innovative clinical trials. PMCID: PMC6328043 Free PMC Article
PMID: 30671208
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6. JAMA. 2019 Jan 22;321(3):266-276. doi: 10.1001/jama.2018.20059. Association of Matched Sibling Donor Hematopoietic Stem Cell Transplantation With Transcranial Doppler Velocities in Children With Sickle Cell Anemia. Bernaudin F1, Verlhac S2, Peffault de Latour R3, Dalle JH4, Brousse V5, Petras E6, Thuret I7, Paillard C8, Neven B9, Galambrun C7, Divialle-Doumdo L6, Pondarré C1,10, Guitton C11, Missud F4,12, Runel C13, Jubert C13, Elana G14, Ducros-Miralles E1, Drain E15, Taïeb O15, Arnaud C1, Kamdem A1, Malric A1, Elmaleh-Bergès M16, Vasile M2, Leveillé E1, Socié G3, Chevret S17; DREPAGREFFE Trial Investigators. Abstract Importance: In children with sickle cell anemia (SCA), high transcranial Doppler (TCD) velocities are associated with stroke risk, which is reduced by chronic transfusion. Whether matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) can reduce velocities in patients with SCA is unknown. Objective: To determine the association of MSD-HSCT with TCD velocities as a surrogate for the occurrence of ischemic stroke in children with SCA. Design, Setting, and Participants: Nonrandomized controlled intervention study conducted at 9 French centers. Patients with SCA were enrolled between December 2010 and June 2013, with 3-year follow-up ending in January 2017. Children with SCA were eligible if younger than 15 years, required chronic transfusions for persistently elevated TCD velocities, and had at least 1 sibling without SCA from the same 2 parents. Families agreed to HLA antigen typing and transplantation if a matched sibling donor was identified or to standard care in the absence of a matched sibling donor. Exposures: MSD-HSCT (n = 32), compared with standard care (n = 35) (transfusions for ≥1 year with potential switch to hydroxyurea thereafter), using propensity score matching. Main Outcomes and Measures: The primary outcome was the highest time-averaged mean of maximum velocities in 8 cerebral arteries, measured by TCD (TCD velocity) at 1 year. Twenty-five of 29 secondary outcomes were analyzed, including the highest TCD velocity at 3 years and normalization of velocities (<170 cm/s) and ferritin levels at 1 and 3 years. Results: Sixty-seven children with SCA (median age, 7.6 years; 35 girls [52%]) were enrolled (7 with stroke history). In the matched sample, highest TCD velocities at 1 year were significantly lower on average in the transplantation group (129.6 cm/s) vs the standard care group (170.4 cm/s; difference, -40.8 cm/s [95% CI, -62.9 to -18.6]; P < .001). Of the 25 analyzed secondary end points, 4 showed significant differences, including the highest TCD velocity at 3 years (112.4 cm/s in the transplantation group vs 156.7 cm/s in the standard care group; difference, -44.3 [95% CI, -71.9 to -21.1]; P = .001); normalization rate at 1 year (80.0% in the transplantation group vs 48.0% in the standard care group; difference, 32.0% [95% CI, 0.2% to 58.6%]; P = .045); and ferritin levels at 1 year (905 ng/mL in the transplantation group vs 2529 ng/mL in the standard care group; difference, -1624 [95% CI, -2370 to -879]; P < .001) and 3 years (382 ng/mL in the transplantation group vs 2170 ng/mL in the standard care group; difference, -1788 [95% CI, -2570 to -1006]; P < .001). Conclusions and Relevance: Among children with SCA requiring chronic transfusion because of persistently elevated TCD velocities, MSD-HSCT was significantly associated with lower TCD velocities at 1 year compared with standard care. Further research is warranted to assess the effects of MSD-HSCT on clinical outcomes and over longer follow-up. Trial Registration: ClinicalTrials.gov Identifier: NCT01340404.
PMID: 30667500
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7. Eur J Haematol. 2019 Jan 21. doi: 10.1111/ejh.13212. [Epub ahead of print] Insight into the complex pathophysiology of sickle cell anemia and possible treatment. Piccin A1,2,3,4, Murphy C4, Eakins E4, Rondinelli M5, Daves M3, Vecchiato C3, Wolf D2, Mc Mahon C1,6, Smith OP1,6. Abstract Sickle cell anaemia (SCA) is the consequence of abnormal haemoglobin production due to an inherited point mutation in the β -globin gene. The resulting haemoglobin tetramer is poorly soluble when deoxygenated, and when this is prolonged, intracellular gelation of sickle haemoglobin occurs, followed by haemoglobin polymerization. If many cycles of sickling and unsickling occur, the red cell membrane will be disrupted leading to haemolysis and vaso-occlusive events. Recent studies have also shown that leukocyte adhesion molecules and nitric oxide (NO) depletion are involved in endothelial damage. New insights in SCA pathophysiology and vascular biology have shown that cell derived microparticle (MP) generation is also involved in the vaso-occlusion. Endothelial damage is perpetuated by impaired production or increased consumption of protective modulators such as protein C, protein S and NO. New therapeutic interventions should address these aspects of SCA pathogenesis. To date, the only US-FDA approved therapies to prevent painful vaso-occulsive episodes is hydroxyurea that reduces haemoglobin polymerization in sickle cells by increasing the production of fetal haemoglobin and L-Glutamine. However, several new drugs have been tested in the last years in randomized clinical trials. We here report an update on the current status of knowledge on SCA. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
PMID: 30664257
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8. Blood. 2019 Jan 17;133(3):190-191. doi: 10.1182/blood-2018-11-886259. Resolving inflammation and pain of sickle cell. Fredman G1. PMCID: PMC6337876 Free PMC Article
PMID: 30655305
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9. Blood. 2019 Jan 17. pii: blood-2018-08-868893. doi: 10.1182/blood-2018-08-868893. [Epub ahead of print] A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease. Howard J1, Hemmaway CJ2, Telfer P3, Layton DM4, Porter J5, Awogbade M6, Mant T7, Gretler DD8, Dufu K9, Hutchaleelaha A9, Patel M9, Siu V9, Dixon S9, Landsman N9, Tonda M9, Lehrer-Graiwer J9. Abstract New treatments directly targeting polymerization of sickle hemoglobin (HbS), the proximate event in the pathophysiology of sickle cell disease (SCD), are needed to address the severe morbidity and early mortality associated with the disease. Voxelotor (GBT440) is a first-in-class, oral therapy specifically developed to treat SCD by modulating the affinity of hemoglobin for oxygen, thus inhibiting HbS polymerization and the downstream adverse effects of hemolytic anemia and vaso-occlusion. GBT440-001 was a phase 1/2 randomized, double-blind, placebo-controlled, single and multiple ascending dose study of voxelotor in adult healthy volunteers and patients with SCD which was followed by a single-arm, open-label extension study. This report describes results of voxelotor (500-1000 mg/day) in patients with sickle cell anemia (HbSS). The study evaluated the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of voxelotor and established proof-of-concept by improving clinical measures of anemia, hemolysis, and sickling. Thirty-eight patients with SCD received 28 days of voxelotor 500, 700, or 1000 mg/day, or placebo; 16 patients received 90 days of voxelotor 700 or 900 mg/day, or placebo. Four patients from the 90-day cohort were subsequently enrolled in an extension study and treated with voxelotor 900 mg/day for 6 months. All patients who received multiple doses of voxelotor for ≥28 days experienced hematologic improvements including increased hemoglobin and reduction in hemolysis and percent of sickled red cells, supporting the potential of voxelotor to serve as a disease-modifying therapy for SCD. Voxelotor was well tolerated with no treatment-related serious adverse events and no evidence of tissue hypoxia. ClinicalTrials.gov identification: #NCT02285088 and #NCT03041909. Copyright © 2019 American Society of Hematology.
PMID: 30655275
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10. J Pediatr Psychol. 2019 Jan 10. doi: 10.1093/jpepsy/jsy105. [Epub ahead of print] Investigating the Sleep-Pain Relationship in Youth with Sickle Cell Utilizing mHealth Technology. Valrie CR1,2, Kilpatrick RL3, Alston K4, Trout K5,6, Redding-Lallinger R7, Sisler I8, Fuh B9. Abstract Objectives: The current study utilized mHealth technologies that were objective (e.g., sleep actigraphy and pulse oximetry) and time-sensitive (e.g., ecological momentary assessments [EMAs]) to characterize sleep in youth with sickle cell disease (SCD) and investigate the relationships between sleep variables and pain. It also investigated the influence of age on sleep and the sleep-pain relationship. Methods: Eighty-eight youth with SCD (aged 8-17 years) were recruited from three regional pediatric SCD clinics. Youth completed twice daily EMAs for up to 4 weeks to assess nighttime subjective sleep quality and daily pain. They also wore a sleep actigraph for 2 weeks to assess sleep duration, sleep efficiency, and sleep latency, and a wrist-worn pulse oximeter for two nights to assess whether they had sleep apnea. Multilevel models were calculated predicting daily SCD pain using the sleep variables, age, and the interaction between age and the sleep variables. Results: None of the sleep variables were related to one another. Poor subjective sleep quality during the night was related to high pain severity the next day, and high pain was related to poor subjective sleep quality that night. Older age was associated with poorer subjective sleep quality, shorter duration of nighttime sleep, and high sleep latency. Also, findings indicated that as age increased, the strength of the relationship between poor continuous subjective sleep quality and high pain severity increased. Conclusions: Future research is needed to examine possible mechanisms connecting subjective sleep quality to high pain.
PMID: 30649539
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11. J Womens Health (Larchmt). 2019 Jan 16. doi: 10.1089/jwh.2018.7147. [Epub ahead of print] Acute Vaso-Occlusive Pain is Temporally Associated with the Onset of Menstruation in Women with Sickle Cell Disease. Sharma D1, Day ME1, Stimpson SJ1, Rodeghier M2, Ghafuri D1, Callaghan M3, Zaidi AU3, Hannan B3, Kassim A1, Zempsky W4, Wellons M5, James A6, Bruehl S7, DeBaun MR1. Abstract BACKGROUND: Acute vaso-occlusive pain episodes in sickle cell disease (SCD) are associated with increased rates of hospitalization and early mortality. Despite the observation that women have higher rates of acute vaso-occlusive pain episodes than men, sex-specific risk factors for acute vaso-occlusive pain have not been identified. We tested the hypothesis that acute vaso-occlusive pain is temporally associated with the onset of menstruation in women with SCD. METHODS: Initially, using a cross-sectional study design, we administered questionnaires, including validated measures of SCD pain frequency and severity within the last 30 days, as well as menstrual symptoms in a discovery group (n = 103). We then confirmed our findings by administering the same questionnaires online in a replication group (n = 118). A validated questionnaire was used to define dysmenorrhea. RESULTS: In the initial discovery group, 28% (29 of 103) reported acute vaso-occlusive pain episodes temporally associated with menstruation, and 72% (74 of 103) did not. Of the 29 reporting acute vaso-occlusive pain associated with menstruation, 90% (26) and 10% (3) did and did not meet criteria for dysmenorrhea, respectively. In the replication group, 36% (43 of 118) reported acute vaso-occlusive pain temporally associated with menstruation. Of the 43 reporting acute vaso-occlusive pain associated with menstruation, 60% (26) and 40% (17) did and did not meet criteria for dysmenorrhea, respectively. CONCLUSIONS: In both the discovery and replication groups, we demonstrate that acute vaso-occlusive pain is temporally associated with the onset of menstruation that women with SCD can distinguish from dysmenorrhea.
PMID: 30648915
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12. Biol Blood Marrow Transplant. 2019 Jan 10. pii: S1083-8791(19)30016-3. doi: 10.1016/j.bbmt.2019.01.008. [Epub ahead of print] Functional and Radiologic Assessment of the Brain after Reduced-Intensity Unrelated Donor Transplantation for Severe Sickle Cell Disease-Blood and Marrow Transplant Clinical Trials Network #0601. King AA1, McKinstry RC2, Wu J3, Eapen M4, Abel R2, Varughese T2, Kamani N5, Shenoy S2. Abstract Stroke and cognitive decline are hallmarks of sickle cell disease (SCD). The natural history predicts progressive loss of 1 intelligence quotient (IQ) point per year attributable to disease-related pathology. Hematopoietic cell transplantation (HCT) is curative by reverting to donor-derived erythropoiesis, but evidence that HCT can positively influence disease-induced cognitive decline is lacking. The Sickle Cell Unrelated Transplant Trial prospectively evaluated cognition and magnetic resonance imaging (MRI) of the brain 2 years following reduced-intensity conditioning followed by unrelated donor HCT. Thirteen study participants completed pre/post measurements of intelligence. Recipients’ mean age was 12.5 years (SD 3.3, range 6.7-17.4). Eleven of 13 recipients completed imaging studies at baseline and post-HCT. Seven had overt stroke pre-HCT; one had an elevated transcranial Doppler velocity with abnormal MRI. Average full-scale IQ was stable: 90.9 ± 13 at baseline and 91.2 ± 13 post. The average Performance IQ was 89.9 ± 13 versus 90.9 ± 13, and Verbal IQ was 93.4 ± 13 versus 93.2 ± 13 at baseline and post-HCT, respectively. Six recipients had stable MRI; two had resolution of all areas of infarction. Three had additional infarcts post-HCT noted at the 2-year timepoint. This is the first report describing stabilization of IQ and central nervous system outcomes after unrelated donor HCT despite prior central nervous system morbidity and post-HCT posterior reversible encephalopathy syndrome. These preliminary results post-HCT suggest that HCT may stabilize cognitive decline of SCD and should continue to be followed long-term. Copyright © 2019. Published by Elsevier Inc.
PMID: 30639825
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13. Am J Hematol. 2019 Jan 13. doi: 10.1002/ajh.25401. [Epub ahead of print] Bone Marrow Transplantation for Adolescents and Young Adults with Sickle Cell Disease: Results of a Prospective Multicenter Pilot Study. Krishnamurti L1, Neuberg DS2, Sullivan KM3, Kamani NR4, Abraham A5, Campigotto F2, Zhang W2, Dahdoul T6, De Castro L7, Parikh S3, Bakshi N1, Haight A1, Hassell KL8, Loving R9, Rosenthal J10, Smith SL1, Smith W11, Spearman M12, Stevenson K2, Wu CJ2, Wiedl C11, Waller EK13, Walters MC14.   Abstract We conducted a multicenter pilot investigation of the safety and feasibility of bone marrow transplantation (BMT) in adults with severe sickle cell disease (SCD) (NCT 01565616) using a reduced toxicity preparative regimen of Busulfan (13.2 mg/kg), Fludarabine (175 mg/m2) and Thymoglobulin (6 mg/kg) and cyclosporine or tacrolimus and methotrexate for graft-versus-host disease (GVHD) prophylaxis. Twenty-two patients (median age 22 years; range 17-36) were enrolled at 8 centers. Seventeen patients received marrow from an HLA-identical sibling donor and 5 patients received marrow from an 8/8 HLA-allele matched unrelated donor. Before BMT, patients had stroke, acute chest syndrome, recurrent pain events, were receiving regular red blood cell transfusions, or had an elevated tricuspid regurgitant jet (TRJ) velocity, which fulfilled eligibility criteria. Four patients developed grade II-III acute GVHD (18%) and 6 developed chronic GVHD (27%) that was moderate in two and severe in one patient. One patient died of intracranial hemorrhage and one of GVHD. Nineteen patients had stable donor chimerism, 1-year post-transplant. One patient who developed secondary graft failure survives disease-free after a second BMT. The one-year overall survival and event-free survival (EFS) are 91% (95% CI 68-98%) and 86% (95% CI, 63-95%), respectively, and 3-year EFS is 82%. Statistically significant improvements in the pain interference and physical function domains of health-related quality of life were observed. The study satisfied the primary endpoint of 1-year EFS ≥70%. This regimen is being studied in a prospective clinical trial comparing HLA-matched donor BMT with standard of care in adults with severe SCD (NCT02766465). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
PMID: 30637784
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14. Pediatr Hematol Oncol. 2019 Jan 12:1-12. doi: 10.1080/08880018.2018.1505988. [Epub ahead of print] Healthcare utilization and hydroxyurea adherence in youth with sickle cell disease. Badawy SM1,2, Thompson AA1,2, Holl JL1,3, Penedo FJ4, Liem RI1,2. Abstract BACKGROUND: Sickle cell disease (SCD) complications lead to poor health-related quality of life (HRQOL) and increased healthcare utilization in this population, which could be mitigated with hydroxyurea therapy; however, adherence is suboptimal. We assessed the relationship of healthcare utilization to hydroxyurea adherence and HRQOL amongst youth with SCD. METHODS: Thirty-four patients with SCD (median age 14 years, IQR 12-18) on hydroxyurea participated in this cross-sectional study and completed Morisky Adherence Scale 8-items and Patient Reported Outcomes Measurement Information System (PROMIS®) HRQOL measures. A medical chart review was conducted to assess healthcare utilization. RESULTS: Participants with more frequent hospitalizations and emergency room (ER) visits and longer length of stay (LOS) had significantly lower fetal hemoglobin (rs=-0.44; rs=-0.45; rs=-0.46, p < 0.05) and mean corpuscular volume (rs=-0.47; rs=-0.42; rs=-0.48, p < 0.05), respectively. More frequent hospitalizations and ER visits and longer LOS correlated significantly with worse fatigue (rs=0.51; rs=0.41; rs=0.53, p < 0.05), pain (rs=0.41; rs=0.38; rs=0.47, p < 0.05), physical function mobility (rs=-0.67; rs=-0.59; rs=-0.67, p < 0.05), depression (rs=0.38; rs=0.31; rs=0.42, p < 0.05), and social isolation (rs=0.76; rs=0.76; rs=-0.84, p < 0.05), respectively. CONCLUSIONS: We conclude that increased healthcare utilization in youth with SCD is associated with low adherence to hydroxyurea and worse HRQOL domain scores. It is important emphasize the clinical benefits of high adherence to hydroxyurea, particularly among youth with SCD. Future longitudinal studies are warranted to assess the directionality of these relationships, and may reveal modifiable behavioral factors associated with early changes in hydroxyurea adherence levels.
PMID: 30636474
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15. N Engl J Med. 2019 Jan 10;380(2):187-189. doi: 10.1056/NEJMe1814706. Hydroxyurea – An Essential Medicine for Sickle Cell Disease in Africa. Luzzatto L1, Makani J1. Author information:
1. From the Department of Hematology and Sickle Cell Program, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania. Comment on Hydroxyurea for Children with Sickle Cell Anemia in Sub-Saharan Africa. [N Engl J Med. 2019]
PMID: 30625057 [Indexed for MEDLINE]
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16. Semin Hematol. 2018 Apr;55(2):68-75. doi: 10.1053/j.seminhematol.2018.04.007. Epub 2018 Apr 20. Novel Sickle Cell Disease Therapies: Targeting Pathways Downstream of Sickling. Morrone K1, Mitchell WB2, Manwani D3. Abstract Sickle cell disease is an inherited hemoglobinopathy characterized by hemolytic anemia, frequent painful episodes, poor quality of life, end organ damage and a shortened lifespan. Although the seminal event is the polymerization of the abnormal hemoglobin, the downstream pathophysiology of vaso-occlusion results from heterotypic interactions between the altered, adhesive sickle cell RBCs, neutrophils, endothelium, and platelets. Ischemia reperfusion injury, hemolysis and oxidant damage all contribute to heightened inflammation and activation of the hemostatic system. These downstream targets are the focus of emerging treatments with considerable potential to ameliorate disease manifestations. This review summarizes the progress on development of these agents. Copyright © 2018 Elsevier Inc. All rights reserved.
PMID: 30616808
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Association of Matched Sibling Donor Hematopoietic Stem Cell Transplantation With Transcranial Doppler Velocities in Children With Sickle Cell Anemia

Francoise Bernaudin, MD; Suzanne Verlhac, MD; Regis Peffault de Latour,MD, PHD; Jean-Hugues Dalle,MD, PHD; Valentine Brousse, MD; Eleonore Petras, MD; Isabelle Thuret, MD; Catherine Paillard, MD, PHD; Benedicte Neven, MD, PHD; Claire Galambrun, MD; Lydia Divialle-Doumdo, MD; Corinne Pondarre,MD, PHD; Corinne Guitton, MD; Florence Missud, MD; Camille Runel, MD; Charlotte Jubert, MD; Gisele Elana, MD; Elisabeth Ducros-Miralles, PhD; Elise Drain, MD; Olivier Taieb,MD, PHD;

Cecile Arnaud, MD; Annie Kamdem, MD; Aurore Malric, MD; Monique Elmaleh-Berges, MD; Manuela Vasile, MD; Emmanuella Leveille, RN; Gerard Socie,MD, PHD; Sylvie Chevret, MD, PHD; for the DREPAGREFFE Trial Investigators

IMPORTANCE In children with sickle cell anemia (SCA), high transcranial Doppler (TCD) velocities are associated with stroke risk, which is reduced by chronic transfusion. Whether matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) can reduce velocities in patients with SCA is unknown.

OBJECTIVE To determine the association of MSD-HSCT with TCD velocities as a surrogate for the occurrence of ischemic stroke in children with SCA.

DESIGN, SETTING, AND PARTICIPANTS Nonrandomized controlled intervention study  conducted at 9 French centers. Patients with SCA were enrolled between December 2010 and June 2013, with 3-year follow-up ending in January 2017. Children with SCA were eligible if younger than 15 years, required chronic transfusions for persistently elevated TCD velocities, and had at least 1 sibling without SCA from the same 2 parents. Families agreed to HLA antigen typing and transplantation if a matched sibling donor was identified or to standard care in the absence of a matched sibling donor.

EXPOSURES MSD-HSCT (n = 32), compared with standard care (n = 35) (transfusions for  _1 year with potential switch to hydroxyurea thereafter), using propensity score matching.

MAIN OUTCOMES AND MEASURES The primary outcome was the highest time-averaged mean of maximum velocities in 8 cerebral arteries, measured by TCD (TCD velocity) at 1 year.  Twenty-five of 29 secondary outcomes were analyzed, including the highest TCD velocity  at 3 years and normalization of velocities (<170 cm/s) and ferritin levels at 1 and 3 years.

RESULTS Sixty-seven children with SCA (median age, 7.6 years; 35 girls [52%]) were enrolled (7 with stroke history). In the matched sample, highest TCD velocities at 1 year were significantly lower on average in the transplantation group (129.6 cm/s) vs the standard care group (170.4 cm/s; difference, −40.8 cm/s [95%CI, −62.9 to −18.6]; P < .001). Of the 25 analyzed secondary end points, 4 showed significant differences, including the highest TCD velocity at 3 years (112.4 cm/s in the transplantation group vs 156.7 cm/s in the standard care group; difference, −44.3 [95%CI, −71.9 to −21.1]; P = .001); normalization rate at 1 year (80.0%in the transplantation group vs 48.0%in the standard care group; difference, 32.0% [95%CI, 0.2%to 58.6%]; P = .045); and ferritin levels at 1 year (905 ng/mL in the transplantation group vs 2529 ng/mL in the standard care group; difference, −1624 [95%CI, −2370 to −879]; P < .001) and 3 years (382 ng/mL in the transplantation group vs 2170 ng/mL in the standard care group; difference, −1788 [95%CI, −2570 to −1006]; P < .001).

CONCLUSIONS AND RELEVANCE Among children with SCA requiring chronic transfusion because of persistently elevated TCD velocities, MSD-HSCT was significantly associated with lower TCD velocities at 1 year compared with standard care. Further research is warranted to assess the effects of MSD-HSCT on clinical outcomes and over longer follow-up.

TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01340404

JAMA. 2019;321(3):266-276. doi:10.1001/jama.2018.20059

Sickle Cell Conferences and Events

Hemoglobinopathy Counselor Training Course will be held on April 17-18, 2019.  The two-day course, presented by the Cincinnati Comprehensive Sickle Cell Center, will be held at Cincinnati Children’s Hospital Medical Center.  The  course registration fee is $250. The deadline to register is April 1, 2019 and registration space is limited.  For more information, including a course brochure, please email: SCDEvents@cchmc.org  Registration is also available online at  

www.regonline.com/2019SCDCounselorCourse

4th Global Congress on SCD will be taking place on March 30 to April 1, 2020, in Paris, France. website linkThe Foundation for Sickle Cell Disease Research will be hosting its 13th Annual Symposium June 7-9, 2019 in Fort Lauderdale, FL. Registration is now open.  

Sickle Cell Disease Association of America’s 47th National Convention will be held October 9-12, 2019 in Baltimore, MD.